University of Groningen Catalytic asymmetric …Table of contents Chapter 1 Catalytic Asymmetric Synthesis of Butenolides and γ-Butyrolactones 01 1.1 Introduction 02 1.2 Lactone-derived

University of Groningen

Catalytic asymmetric synthesis of butenolides and γ-butyrolactonesMao, Bin

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Catalytic Asymmetric Synthesis of Butenolides

and γ-Butyrolactones

Bin Mao

The work described in this thesis was executed at the Stratingh Institute for Chemistry,

University of Groningen, The Netherlands.

The authors of this thesis wish to thank the Netherlands Organisation for Scientific Research

(NWO) for funding and the China Scholarship Council (CSC) for a scholarship.

Cover design by Bin Mao and Nini Liu.

Printed by Ipskamp Drukkers BV, Enschede, The Netherlands.

RIJKSUNIVERSITEIT GRONINGEN

Catalytic Asymmetric Synthesis of Butenolides and γ-Butyrolactones

Proefschrift

ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen

op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op

vrijdag 18 october 2013 om 14.30 uur

door

Bin Mao

geboren op 19 september 1983

te Zhejiang

Promotor : Prof. dr. B. L. Feringa Copromotor : Dr. M. Fañanás-Mastral Beoordelingscommissie : Prof. dr. A. J. Minnaard Prof. dr. H. Hiemstra Prof. dr. A. Pfaltz

ISBN: 978-90-367-6561-9

Table of contents

Chapter 1 Catalytic Asymmetric Synthesis of Butenolides and γ-Butyrolactones 01

1.1 Introduction 02

1.2 Lactone-derived Enolates as Nucleophiles 04

1.2.1 Asymmetric aldol reaction 04

1.2.2 Asymmetric Mannich reaction 06

1.2.3 Asymmetric Michael reaction 07

1.2.4 Allylic substitution of MBH acetates 08

1.2.5 Enantioselective acylation 09

1.2.6 Enantioselective α-arylation 10

1.3 Furanone Derivatives as Electrophiles 11

1.3.1 Asymmetric conjugate addition 11

1.3.2 Enantioselective allylic alkylation 11

1.3.3 Enantioselective conjugate reduction 12

1.4 Core Structure Assembly through Single-step Reaction 13

1.4.1 Catalytic asymmetric Baeyer-Villiger oxidation 13

1.4.2 N-Heterocyclic carbene (NHC)-catalyzed umpolung reactions 13

1.4.3 Asymmetric cycloisomerization 14

1.4.4 Asymmetric hetero-Pauson-Khand reaction 14

1.4.5 Enantioselective halolactonization 15

1.5 Core Structure Assembly through Multi-step Reactions 16

1.6 Enantioselective Olefin Isomerization 18

1.7 Aim and Outline of this Thesis 19

1.8 References 20

Chapter 2 Catalytic Enantioselective Synthesis of Naturally Occurring

γ-Butenolides via Hetero-Allylic Asymmetric Alkylation and Ring Closing

Metathesis

24

2.1 Introduction 25

2.1.1 Ring-closing metathesis for the synthesis of γ-butenolides 25

2.1.2 Copper-catalyzed allylic asymmetric alkylation with Grignard Reagents 26

2.1.3 Combination of copper-catalyzed allylic asymmetric alkylation with RCM 28

2.2 Synthetic Strategy toward γ-Butenolides 29

2.3 h-AAA followed by RCM with 3-Bromopropenyl Esters 30

2.3.1 Initial investigations on the substrate reactivity and synthesis 30

2.3.2 h-AAA reactions of cinnamic substrate with various Grignard reagents 31

2.3.3 RCM of h-AAA reaction products 33

2.4 Total Synthesis of (–)-Whiskey lactone, (–)-Cognac lactone, (–)-Nephrosteranic

acid and (–)-Roccellaric acid 34

2.5 Conclusions 37

2.6 Experimental Section 38

2.7 References 46

Chapter 3 Diversity-Oriented Enantioselective Synthesis of Highly

Functionalized Cyclic and Bicyclic Esters 50

3.1 Introduction 51

3.1.1 Copper-catalyzed hetero-allylic asymmetric alkylation (h-AAA) 51

3.1.2 Copper-catalyzed AAA with functionalized Grignard reagents 53

3.1.3 Diversity oriented synthesis 55

3.2 Project Goal 55

3.3 Results and Discussion 57

3.3.1 Synthesis of cyclic benzoate esters via h-AAA and RCM 57

3.3.2 Cu-catalyzed h-AAA with Grignard reagents bearing an alkyne moiety 59

3.3.3 Synthesis of optically enriched 2,4-dienols 62

3.3.4 Domino enyne isomerization and Diels-Alder reaction 65

3.3.5 Intramolecular Diels-Alder reaction of optically enriched 2,4-dienol 66

3.3.6 Pauson-Khand (PK) reaction 67

3.4 Conclusions 70

3.5 Experimental Section 70

3.6 References 86

Chapter 4 Asymmetric Conjugate Addition of Grignard Reagents to Pyranones 92

4.1 Introduction 93

4.1.1 Enantioselective synthesis of 3,4-dihydropyran-2-ones 93

4.1.2 Copper-catalyzed asymmetric conjugate addition of cyclic enones and

cyclic esters with Grignard reagents 95

4.2 Project Goal 98

4.3 Results and Discussion 99

4.3.1 Screening of reaction parameters 99

4.3.2 Scope of Grignard reagents 101

4.3.3 Reactivity of chiral magnesium enolate 103

4.3.4 Stereoselective transformation of chiral 3,4-dihydro-pyran-2-ones 104

4.3.5 Copper-catalyzed ACA of Grignard reagents to 5,6-dihydro-2H-pyran-

2-one 106

4.4 Conclusions and Future Prospects 100 4.5 Experimental Section 102 4.6 References 111 Chapter 5 Copper-Catalyzed Asymmetric Conjugate Addition of Dialkylzinc Reagents to β-Phthalimino-α,β-unsaturated Ketones: towards the synthesis of β-Alkyl-β-amino acids

115

5.1 Introduction 116 5.1.1 Copper-catalyzed enantioselective conjugate addition of organozinc reagents

116

5.1.2 Enantioselective conjugate addition of organometallic reagents to β-heteroatom-substituted α,β-unsaturated substrates

118

5.2 Goal 120 5.3 Results and Discussion 121

5.3.1 Synthesis of starting materials 121 5.3.2 Optimization for ACA of Et2Zn to N-(3-oxo-3-phenyl-propenyl)- phthalimide

121

5.4 Conclusions 125 5.5 Experimental Section 125 5.6 References 128 Chapter 6 Highly Enantioselective Synthesis of 3-Substituted Furanones through Palladium-Catalyzed Kinetic Resolution of Allyl Acetates

130

6.1 Introduction 131 6.1.1 Kinetic resolution in the palladium-catalyzed allylic substitution 132 6.1.2 Selectivity factor of kinetic resolution 133 6.1.3 Palladium-catalyzed allylic asymmetric alkylation of silyl enol ethers 135 6.1.4 Iridium-catalyzed allylic asymmetric alkylation of silyl enol ethers 136

6.2 Project Goal 137 6.3 Results and Discussion 138

6.3.1 Optimization in the kinetic resolution of allylic substrates 138 6.3.2 Substrate scope and efficiency in the palladium catalyzed kinetic resolution 141 6.3.3 Determination of absolute configuration 144 6.3.4 Mechanistic investigation 145

6.4 Conclusions 149 6.5 Experimental Section 149 6.6 References 158

Chapter 7 Enantioselective Synthesis of 5-Substituted Furanones Through Palladium-catalyzed γ-Allylation of 2-Trimethylsilyloxyfuran

163

7.1 Introduction 164 7.1.1 Mechanism of the palladium-catalyzed allylic alkylation (Pd-AAA) with different types of nucleophiles

164

7.1.2 Phosphinooxazoline (PHOX) ligands in the palladium-catalyzed asymmetric allylic alkylation

165

7.1.3 Mechanistic investigations of palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of ketone enolates

168

7.1.4 Palladium-catalyzed γ-arylation of dienolates 169 7.2 Project Goal 171 7.3 Results and Discussion 172

7.3.1 Mechanistic studies 172 7.3.2 Screening of ligands and conditions 174 7.3.3 31P NMR studies 176 7.3.4 Proposed mechanism 177

7.4 Conclusions 179 7.5 Experimental Section 180 7.6 References 183 Summary 186 Nederlandse Samenvatting 191 Acknowledgements 196

Chapter 1

Catalytic Asymmetric Synthesis of Butenolides

and γ-Butyrolactones

A general overview for the catalytic enantioselective synthesis of γ-butenolides and γ-butyrolactones using metal-based catalysts or organocatalysts is presented in this chapter. Five main approaches were identified involving asymmetric synthesis and discussed briefly on the basis of the catalytic assembly of the butenolide or γ-butyrolactone core structure.

2

Chapter 1

1.1 Introduction

Five membered cyclic esters, known as butenolides and γ-butyrolactones (Figure 1),

constitute the structural core shared by many naturally occurring products.1 These

γ-lactones especially in enantiomerically pure form, often display an immense range of

biological activities which are important for the development of physiological and

therapeutic agents. Some representative members of this family are depicted in Figure 2.

For example, Strigol, featuring the presence of a chiral γ-butenolide ring in addition to

γ-butyrolactone, are known to trigger the germination of parasitic plant seeds and inhibit

plant shoot branching.2 Avenolide, a streptomyces hormone bearing a γ-butenolide core

has been shown to control antibiotic production in Streptomyces avermitilis.3 Paraconic

acids, bearing a carboxylic acid function at the position β to the carbonyl, represents an

important group of γ-butyrolactones that both display antitumor and antibiotic activities.4

Arglabin, a sesquiterpene α-methylene-γ-butyrolactone which is isolated from Artemisia

glabella, is assumed to prevent protein farnesylation without altering geranylgeranylation.5

Figure 1. Structure of butenolide and γ-butyrolactone.

Figure 2. Naturally occurring products contain chiral butenolide or γ-butyrolactone core.

3


Besides their widespread occurrence, enantioenriched γ-butenolides or γ-butyrolactones

also serve as useful chiral building blocks for the synthesis of diverse biological active

compounds and complex molecules. Numerous transformations could be performed to

access a range of versatile products due to the presence of several functional group on

these furanone structures.1 For example, the γ-enolizable butenolide offers the possibility

as an extended dienolate precursor to introduce δ-hydroxy-γ-butenolide through

enantioselective vinylogous aldol reaction. This transformation enables the stereospecific

construction of adjacent diol functionality and the resulted products can be further

elaborated as versatile surrogates for the construction of various important building blocks

through the highly selective substrate-controlled reactions of cyclic ester moiety or the

double bond.

Taking into account the interesting biological properties and synthetic potential associated

with the optically active γ-butenolide or γ-butyrolactone structure, much attention has

been paid towards the development of synthetic strategies for assembling such challenging

scaffolds. Among them, catalytic asymmetric synthesis has emerged as one of the most

rapid and efficient methods to prepare structurally diverse chiral butenolide and

γ-butyrolactone derivatives.

Scheme 1. Catalytic enantioselective approaches to γ-butenolides and γ-butyrolactone derivatives.

4

Chapter 1

This chapter will present an overview of the catalytic enantioselective synthesis of

γ-butenolides and γ-butyrolactones using metal catalysts or organocatalysts with emphasis

on representative examples from the recent literature. In this context, such methods will be

classified in five main sections based on the way of assembly of the butenolide or

γ-butyrolactone core structure (Scheme 1), in which single- or multi-step reaction methods

will be described separately. In addition, further use of the enantioenriched butenolide and

γ-butyrolactone derivatives in the synthesis of natural products or complex synthetic

intermediates will be briefly discussed.

1.2 Lactone-derived Enolates as Nucleophiles

1.2.1 Asymmetric aldol reaction

The catalytic asymmetric aldol reaction has been extensively investigated as one of the

most powerful methods for enantioselective C-C bond formation.6 This methodology

provides efficient access to functionalized β-hydroxy carbonyl compounds with up to two

new adjacent stereocenters. As a consequence of their common utility, the construction of

chiral γ-butenolides involving the vinylogous Mukaiyama aldol reaction (VMAR) of

silyloxyfurans has been well developed through this catalytic asymmetric approach.

Moreover, the simple alternative approach by using a direct vinylogous aldol reaction of

2(5H)-furanones was also explored with both chiral organic and metal catalyst.6e While the

asymmetric vinylogous aldol reaction has been identified as an effective strategy towards

the synthesis of γ-substituted butenolides and butyrolactones, reports on the

enantioselective synthesis of butenolides and butyrolactones with chiral substituents at the

α position are still relative rare.

In 1998, Figadère and co-workers reported the first catalytic, enantioselective VMAR of

2-(trimethylsilyloxy)furan (TMSOF) with achiral aldehydes, to form the desired

γ-butenolides with a high level of enantiomeric excess (Scheme 2).7a An auto-inductive

process involving the formation of a multicomponent titanium catalyst in the presence of

BINOL, Ti(OiPr)4 and the newly formed aldol product, was then shown to be effective in

allowing amplification of the enantioselectivity.7b This method has been also demonstrated

in a valuable route to access enantioenriched (+)-muricatacin and iso-cladospolide B.7c-d

5


Scheme 2. The vinylogous aldol reaction of 2-(trimethylsilyloxy)furan (TMSOF) catalyzed by chiral titanium-BINOL complex.

To overcome a distinct disadvantage of Mukaiyama aldol chemistry that is the amount of waste generated by employing silyl functionalized pronucleophiles, the use of furanone derivatives would provide an atom-economic entry towards the enantioselective synthesis of butenolides and butyrolactones. Due to the low reactivity of furanone derivatives as well as the insufficient regio- and stereocontrol, significant breakthroughs have been made only recently. Building upon the racemic synthesis of 5-substituted butenolides, Terada and coworkers reported the first asymmetric vinylogous aldol reaction of furanones to aldehydes, promoted by axially chiral guanidine base catalysts (Scheme 3).8 Halogenated or α-thio-substituted furanones instead of unsubstituted furanones were used as nucleophiles to avoid the competition for α-substitution and enhance the reactivity of furanones at the γ position. This method provides rapid access to the enantioenriched polyfunctionalized butenolides with moderate syn selectivity and excellent enantioselectivity for the syn isomers.

Scheme 3. The vinylogous aldol reaction of unactivated γ-butenolides to aldehydes catalyzed by chiral

guanidine base catalyst.

A chemoselective activation strategy developed by Shibasaki and co-workers, using a soft Lewis acid/amine binary catalytic system, has proved to be efficient for the direct asymmetric aldol reaction of α-sulfanyl lactones to aldehydes (Scheme 4).9 The authors

6

Chapter 1

proposed that the selective coordination between the chiral Lewis acid and α-sulfanyl moiety would activate the α position of the butyrolactone for the deprotonation and thereby generate the corresponding Ag enolate in a proper chiral environment. This catalytic reaction could be performed on a 19.1 gram scale, with respect to aldehyde, to afford the desired γ-butyrolactone 4 in 71% yield with high diastereomeric ratio (syn/anti = 13:1) and excellent ee (98%). Following reduction and selective protection of the resulting primary alcohols gave rise to compound 5 in 66% yield, which was subsequently used as a key building block to complete the stereoselective synthesis of viridiofungin A and NA 808.9

Scheme 4. Direct aldol reaction of α-sulfanyl lactones to aldehydes.

1.2.2 Asymmetric Mannich reaction

In 2006, Hoveyda and co-workers reported a highly diastereo- and enantioselective vinylogous Mannich reaction catalyzed by a silver phosphine complex, in which TMSOF reacted with aromatic aldimines to generate the γ-aminoalkyl-substituted γ-butenolides (Scheme 5).10a The process proved to be highly practical as this transformation could be carried out in air with undistilled THF as solvent in the presence of undistilled 2-propanol as additive. The reaction with various methyl-substituted 2-silyloxy furans were also examined to afford the desired butenolide adducts with excellent diastereo- and enantioselectivity.10b-c This protocol was amenable to achieve the unprotected chiral amine on a multigram scale after simple oxidative removal of the anisidyl group.

7


Scheme 5. Ag-catalyzed enantioselective vinylogous Mannich reaction of silyloxyl furans.

1.2.3 Asymmetric Michael reaction

The first enantioselective organocatalytic Mukaiyama-Michael reaction of silyloxy furans to α,β-unsaturated aldehydes was accomplished by MacMillan and co-workers in 2003 (Scheme 6).11 The use of iminium catalysis involving chiral imidazolidinone provided a novel strategy towards the synthesis of highly functionalized, enantiomerically enriched butenolide architectures. A demonstration of the utility of the chiral butenolide products is seen in the multiple-step synthesis of spiculisporic acid and 5-epi-spiculisporic acid.

3

2

212 2 2

1syn anti

2

2

2

2

Scheme 6. Enantioselective iminium based organocatalytic Mukaiyama-Michael reaction of silyloxy furans to α,β-unsaturated aldehydes.

In 2009, Trost and Hitce showed that a self-assembled dinuclear zinc complex 7 was able to facilitate the direct asymmetric Michael addition of 2(5H)-furanone to nitroalkenes (Scheme 7).12 This process, in the presence of preformed complex 7, gave rise to the corresponding Michael adducts in good yields and excellent stereocontrol (up to >20:1 dr and 96% ee). After simple transformation to the densely functionalized primary amine, bioactive lactam was obtained with complete diastereoselectivity. A bidentate bridging

8

Chapter 1

aromatic enolate A was postulated to be involved in the enantioselective C-C bond

forming event.

Scheme 7. Direct asymmetric Michael addition of 2(5H)-furanone to nitroalkenes.

1.2.4 Allylic substitution of MBH acetates

Shi and co-workers developed the asymmetric version of the allylic substitution of

acetates resulting from the Morita-Baylis-Hillman (MBH) reaction with TMSOF to

furnish γ-butenolides using a chiral phosphane organocatalyst 8a in toluene with water as

an effective additive (Scheme 8).13 Further studies revealed that the reaction could also

proceed smoothly by applying modified catalyst 8b in the presence of a protic solvent

(MeOH) or an aprotic solvent (CH3CN). A wide range of MBH acetates were explored to

generate the substituted products in good to excellent yields with high regio- and

diastereoselectivity. A mechanism involving endo-selective Diels-Alder cycloaddition of

silyloxyfuranate complex with subsequent Grob-type fragmentation was proposed by Shi

and co-authors.13 Computational investigation further supported that Diels-Alder-like

transition states could account for the origin of the diastereo- and enantioselectivity,

revealing that hydrogen bonding involving the proton of the amide moiety is the critical

factor for the catalyst to have high enantiofacial control.

9


1 2

12

1

2

1

2

2 2

Scheme 8. Asymmetric substitution of MBH acetates with 2-trimethylsilyloxy furan.

1.2.5 Enantioselective acylation

By using chiral arylpyrrolidine-based thiourea catalyst in combination with 4-pyrrolidinopyridine, Jacobsen and co-workers developed a highly enantioselective acylation of silyl ketene acetals to produce synthetic useful α,α-disubstituted butyrolactones (Scheme 9).14 This transformation was proposed to proceed through an anion-binding co-catalysts, involving the formation of a thiourea-bound acylpyridinium fluoride ion pair, followed by rate-determining desilylation and enantio-determing acylation via a thiourea-bond acylpyridinium enolate ion pair.

10

Chapter 1

31

2 2

1

o

3

3

t

2

2

31

1

2

2 Scheme 9. Enantioselective acylation of silyl ketene acetals.14

1.2.6 Enantioselective α-arylation

In 2002, Buchwald and Spielvogel disclosed that a Nickel-BINAP system could be used for the highly enantioselective α-arylation of α-substituted γ-butyrolactones with aryl chloride and bromides (Scheme 10).15 The addition of 15 mol% ZnBr2 as a THF solution is responsible for a dramatic increase in both the rate of the reaction and the isolated yield of the product. It seems reasonable that ZnBr2 acts as a Lewis acid that facilitates bromide abstraction from (BINAP)Ni(Ar)(Br) to form a cationic [(BINAP)Ni(Ar)]+ species that subsequently undergoes transmetalation more rapidly. A variety of electron-rich and electron-poor aryl halides with meta or para substituents could be successfully applied as electrophiles to generate the desired γ-butyrolactones with excellent enantioselectivities.

2

2 S

o

2

2

S

Scheme 10. Enantioselective α-arylation of α-substituted γ-butyrolactones.

11


1.3 Furanone Derivatives as Electrophiles

1.3.1 Asymmetric conjugate addition

The asymmetric conjugate addition (ACA) of diethylzinc to 2(5H)-furanone was achieved

by Chan and co-authors in 2004, using a copper complex based on a phosphite ligand.16

Soon after, Brown, Degrado and Hoveyda disclosed that the amino acid based phosphanes

could be employed to promote the catalytic ACA of dialkylzinc reagents to

2(5H)-furanone (Scheme 11).17 The reaction was carried out in the presence of an

aldehyde, preventing the ketene formation or intermolecular Michael addition. The

resulting aldol products could be further oxidized to afford the corresponding diketone in

high yields and in up to 97% ee.

Scheme 11. Asymmetric conjugate addition of diethylzinc to 2(5H)-furanone.

1.3.2 Enantioselective allylic alkylation

In 1999, Trost and Toste reported the highly enantioselective allylic substitution of

γ-acyloxybutenolides with phenol nucleophiles in the presence of a Pd(0) complex and the

Trost ligand 12 (Scheme 12).18a The use of a catalytic amount of Bu4NCl favors the

dynamic kinetic asymmetric transformation (DYKAT) process, delivering the

γ-aryloxybutenolides in high yield and up to 97% ee. The resulted products, utilized as

“chiral aldehyde” building blocks, allowed efficient synthesis of ()-aflatoxin B, BAY

36-7620 and (+)-bredeldin A in a highly concise and stereoselective manner.18

12

Chapter 1

Scheme 12. Highly enantioselective allylic substitution of γ-acyloxybutenolide with phenol nucleophiles.

1.3.3 Enantioselective conjugate reduction

In 2004, Buchwald and co-workers reported the first enantioselective 1,4-reduction of

β-substituted γ-butenolides,19 using an in situ generated chiral CuH species from

CuCl2·2H2O as copper source, NaOtBu as base, and p-tol-BINAP as chiral ligand (Scheme

13). The addition of alcoholic additives was crucial for higher yields of the desired

products. The rate-accelerating role of the alcohol was then inverstigated by Lipshutz and

co-authors.20 Three proton signals at the α- and β-sites of the product were detected, indicating

no exchange occurs between PMHS and tBuOD, revealing that the rate enhancement may well

be due to more rapid quenching of a copper enolate by the alcohol than by the silane.

Scheme 13. Enantioselective 1,4-reduction of β-substituted γ-butenolides.

13


1.4 Core Structure Assembly through Single-step Reaction

1.4.1 Catalytic asymmetric Baeyer-Villiger oxidation

In 2008, Ding et al. performed the catalytic asymmetric Baeyer-Villiger oxidation of

cyclobutanones using chiral Brønsted acids with 30% aqueous H2O2 as the oxidant to

afford the corresponding γ-butyrolactones in excellent yield and up to 93% ee (Scheme

14).21 Mechanistic studies suggested the chiral phosphoric acid play the role of a

bifunctional catalyst to activate both the reactants and the Criegee intermediate in a

synergistic manner.

Scheme 14. Organo-catalyzed asymmetric Baeyer-Villiger oxidation to afford the corresponding

γ-butyrolactones.

1.4.2 N-Heterocyclic carbene (NHC)-catalyzed umpolung reactions

Developed independently by Bode22 and Glorius23, N-heterocyclic carbene

(NHC)-catalyzed umpolung reactions of α,β-unsaturated aldehydes has enabled a powerful

method to access the γ-butyrolactone structure.24 A recent study from Ye et al. disclosed

the chiral N-heterocyclic carbene bearing a proximal hydroxy group derived from

L-pyroglutamic acid was an efficient catalyst for the [3+2] annulation of enals and isatin,

affording the corresponding spirocyclic oxindolo-γ-butyrolactones in good yields with

high diastereo- and enantioselectivities (Scheme 15).25 A possible transition state was

proposed, where H-bonding between the catalyst and isatin enhances the reactivity and

directs the nucleophilic addition of the resulting homoenolate.

14

Chapter 1

Scheme 15. N-Heterocyclic carbene (NHC)-catalyzed umpolung reaction to afford the corresponding

γ-butyrolactones.

1.4.3 Asymmetric cycloisomerization

Asymmetric cycloisomerization constitutes a powerful and efficient strategy for the

enantioselective synthesis of γ-butyrolactones with quantitative atom economy.26 Lu and

co-workers developed the asymmetric Pd(II)-catalyzed cycloisomerization of enyne esters

for the synthesis of γ-butyrolactones (Scheme 16).27 The use of chiral bidentate diamine

ligand 16 or 17 in the presence of catalytic palladium acetate renders the reaction

enantioselective providing a number of optically active γ-butyrolactones. The synthetic

utility of this asymmetric transformation was established by the convenient synthesis of

(3S)-(+)-A-factor.

Scheme 16. Pd(II)-catalyzed cycloisomerization of enyne esters.

1.4.4 Asymmetric hetero-Pauson-Khand reaction

A catalytic asymmetric hetero-Pauson-Khand reaction in the presence of a chiral

titanocene catalyst was reported by Crowe et al. where cyclocarbonylation of enals or

enones resulted in the formation of various optically active fused bicyclic γ-butyrolactones

(Scheme 17).28 The ansametallocene 18, (EBTHI)Ti(CO)2, exhibited higher reactivity

15


toward cyclocarbonylation than its unbridged counterpart, CpTi(CO)2. This air stable

chiral titanocene catalysts also allowed for operational simplicity of the procedure.

Scheme 17. Asymmetric hetero Pauson-Khand reaction for the synthesis of optically active fused bicyclic

γ-butyrolactones.

1.4.5 Enantioselective halolactonization

Taguchi and co-workers reported the first example on the catalytic desymmetrizing

enantioselective iodolactonization of malonate derivatives with iodine in the presence of

chiral titanium taddolate 19 to afford the corresponding fused γ-butyrolactone with

96-99% ee (Scheme 18). The absolute configuration of the products indicated that the

iodocarbocyclization proceed in a highly enantiofacial selective manner, in which the

strong coordination between the chiral titanium taddolate and malonate played a key

role.29 Other metal-catalyzed enantioselective halolactonizations promoted by chiral

salen-Co(II) complex30a and BINAP-Pd(II) complex30b were also investigated, allowing

facile synthesis of the γ-butyrolactones with good to excellent enantioselectivities.

2

22 2

22

2 22 2

Scheme 18. Chiral titanium taddol mediated enantioselective iodolactonization of malonate with I2.

16

Chapter 1

1.5 Core Structure Assembly through Multi-step Reactions

Relying on an organocatalytic cross-aldol reaction with subsequent reduction, Hajra and

co-workers developed a concise and efficient sequence for the synthesis of

4-(hydroxyalkyl)-γ-butyrolactones.31 With L-proline 20 as the catalyst, a series of

enantiomerically enriched γ-butyrolactone derivatives bearing two contiguous stereogenic

center were obtained in satisfactory yields with moderate to high stereoinduction. This

transformation served as an efficient key step in the asymmetric synthesis of

()-enterolactone and (7'R)-7'-hydroxyenterolactone.31

Scheme 19. Asymmetric synthesis of 4-(hydroxyalkyl)-γ-butyrolactones.

In 2010, List and co-workers reported the use of chiral phosphoric acid 21 as

organocatalyst for the kinetic resolution of homoaldols though an asymmetric

transacetalization reaction (Scheme 20).32 Excellent results were obtained with various

secondary and tertiary homoaldols in the presence of low catalyst loading, delivering the

cyclic acetals with high levels of stereoselectivity. A concise synthetic sequence, started

from the asymmetric transesterification and a subsequent Jones oxidation, was then

applied for the asymmetric synthesis of butenolide-containing natural products

(R)-(+)-boivinianin A and (S)-()-boivinianin A.

17


Scheme 20. Asymmetric synthesis of (R)-(+)-boivinianin A and (S)-()-boivinianin A.

Hall et al. have used the chiral Sn-diol complex as chiral Brønsted acid catalyst for the

catalytic enantioselective allylboration of various aldehydes with 2-bromoallylboronate

(Scheme 21).33 The resulting optically active alcohols were then converted into

exomethylene γ-butyrolactones with preservation of stereochemistry through a

nickel-promoted carbonylative cyclization. This two-step sequence provided an expedient

preparation of exomethylene γ-butyrolactones with high levels of enantiomeric excess.

Scheme 21. Enantioselective allylboration to aldehydes followed by cyclization.

1.6 Enantioselective Olefin Isomerization

In 2011, a highly enantioselective olefin isomerization through biomimetic proton transfer

catalysis with a chiral cinchona alkaloid catalyst was developed by Deng and co-workers

(Scheme 22).34 With low catalyst loading and simple conditions (see Scheme 22), this

reaction enabled the conversion of a broad range of mono- and disubstituted

β,γ-unsaturated butenolides into the corresponding chiral α,β-unsaturated butenolides in

high enantioselectivity and yield. Mechanistic studies have revealed the γ-protonation step

as the rate-determining step of the isomerization reaction. The author suggest that the

catalytic process was realized through prototropic rearrangement involving the

deprotonation of β,γ-unsaturated butenolide followed by γ-protonation, in which the

18

Chapter 1

protonated bifunctional catalyst served as the proton donor (Scheme 23). The driving force

of this reaction will be the generation of a conjugated system.

Scheme 22. Enantioselective olefin isomerization.

Scheme 23. Proposed mechanism.

1.7 Aim and Outline of Thesis

The major aim of this thesis is the development of catalytic asymmetric approach towards

the synthesis of optically active butenolides and γ-butyrolactones. Our group has been

involved in asymmetric synthesis of butenolides over the past twenty years.35 A simple and

inexpensive protocol to butenolides was developed based on the D-menthol derivatives of

5-hydroxy-2(5H) furanone.35a Furthermore, an atom economic route was developed by

using enantioselective acylation of 5-hydroxy-2(5H) furanone through lipase-catalyzed

dynamic kinetic resolution (DKR), which offered the complete conversion of racemic

furanone into a single enantiomer of γ-butyrolactone.35e A formal enantioselective

synthesis of ()-phaseolinic acid was also accomplished by using a cascade strategy

19


involving copper-catalyzed asymmetric 1,4-addition of Grignard nucleophiles to α,β-unsaturated thioester substrates with subsequent enolate trapping.35g This protocol provided the corresponding product in good yield with excellent control of relative and absolute stereochemistry across the three newly formed contiguous stereogenic centers.

Relying upon the methodology involving copper catalyzed hetero-allylic asymmetric alkylation (h-AAA) eastablished in our group,36 an efficient catalytic asymmetric synthesis of chiral γ-butenolides is reported in chapter 2 by applying such method as key step in combination with ring closing metathesis (RCM). The synthetic potential of the h-AAA-RCM protocol was illustrated with the facile synthesis of (−)-whiskey lactone, (−)-cognac lactone, (−)-nephrosteranic acid and (−)-roccellaric acid.

The attempted extention of copper catalyzed hetero-allylic asymmetric alkylation (h-AAA) by using functionalized Grignard reagents bearing an alkene or alkyne moiety is described in chapter 3. The corresponding alkylation products were further transformed to a variety of highly functionalized cyclic and bicyclic esters with excellent control of chemo-, regio- and stereoselectivity. This methodology provided a novel and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity.

In chapter 4, an efficient enantioselective synthesis of lactones is developed based on the catalytic asymmetric conjugate addition (ACA) of alkyl Grignard reagents to pyranones. The use of 2H-pyran-2-one for the first time in the ACA with Grignard reagents allows for a variety of further transformations to access highly versatile building blocks such as β-alkyl substituted aldehydes or β-bromo-γ-alkyl substituted alcohols with excellent regio- and stereoselectivity.

A novel catalytic asymmetric conjugate addition of organozinc reagents to β-phthalimino-α,β-unsaturated substrates is presented in Chapter 5. This process was realized by use of copper/phosphoramidite complex, producing optically active β-phthalimino-β-alkyl substituted carbonyl compounds in high yields albeit with only moderate enantioselectivities.

Chapter 6 described a near-perfect Pd-catalyzed kinetic resolution of 1,3-disubstituted unsymmetrical allylic acetates employing silyl enol ethers as nucleophiles to access the

20

Chapter 1

important 3-substituted-furanone scaffold. The reaction proceeds under mild conditions and provides the desired products with excellent chemo-, regio-, and enantioselectivity.

In the presence of enantiopure phosphinooxazoline (PHOX) ligand, palladium-catalyzed γ-allylation of 2-trimethylsilyloxyfuran (TMSOF) with allylic carbonate is described in chapter 7 as a novel method for the asymmetric synthesis of γ-substituted β,γ-unsaturated furanones. Further studies suggest the carbon-carbon bond formation might undergo an “inner sphere” reductive elimination instead of the alternative “outer sphere” SN2-substitution.

1.8 References 1 For reviews, see: a) H. M. R. Hoffmann, J. Rabe, Angew. Chem. Int. Ed. 1985, 24, 94-110; b) E.-I.

Negishi, M. Kotora, Tetrahedron 1997, 53, 6707-6738; c) R. Bruckner, Chem. Commun. 2001,

141-152; d) N. B. Carter, A. E. Nadany, J. B. Sweeney, J. Chem. Soc. Perkin Trans. 1 2002,

2324-2342; e) R. Bandichhor, B. Nosse, O. Reiser, Top. Curr. Chem. 2004, 243, 43-72; f) R. R. A.

Kitson, A. Millemaggi, R. J. K. Taylor, Angew. Chem. Int. Ed. 2009, 48, 9426-9451; g) S. Gil, M.

Parra, P. Rodriguez, J. Segura, Mini-Rev. Org. Chem. 2009, 6, 345-358; h) T. G. Elford, D. G. Hall,

Synthesis, 2010, 893-907; i) A. Kumar, V. Singh, S. Ghosh, Butenolide: A Novel Synthesis and

Biological Activities: A Research for Novel Drug Development, LAMBERT Academic Publishing,

Saarbrücken, 2012.

2 R. Matusova, K. Rani, F. W. A. Verstappen, M. C. R. Franssen, M. H. Beale, H. J. Bouwmeester,

Plant Physiol. 2005, 139, 920-934.

3 a) S. Kitani, K. T. Miyamoto, S. Takamatsu, E. Herawati, H. Iguchi, K. Nishitomi, M. Uchida, T.

Nagamitsu, S. Omura, H. Ikeda, T. Nihira, Proc. Natl. Acad. Sci. USA 2011, 108, 16410-16415; b)

M. Uchida, S. Takamatsu, S. Arima, K. T. Miyamoto, S. Kitani, T. Nihira, H. Ikeda, T. Nagamitsu, J.

Antibiot. 2011, 64, 781-787.

4 a) B. K. Park, M. Nakagawa, A. Hirota, M. Nakayama, J. Antibiot. 1988, 41, 751-758; b) S. Kumar

Kc, K. Müller, J. Nat. Prod. 1999, 62, 817-820.

5 a) S. M. Adekenov, M. N. Muchametzhanov, A. D. Kagarlitskii, A. N. Kuprianov, Khim. Prir.

Soedin. 1982, 655-656; b) R. Csuk, A. Heinold, B. Siewert, S. Schwarz, A. Barthel, R. Kluge, D.

Ströhl, Arch. Pharm. 2012, 345, 215-222.

6 a) M. Kalesse, Recent Advances in Vinylogous Aldol Reactions and Their Applications in the

Syntheses of Natural Products in Natural Products Synthesis II: Targets, Methods, Concepts, Vol.

21


244, (Ed.: J. Mulzer), Springer, Heidelberg, 2005, pp. 43-76; b) R. Mahrwald, Morden Aldol

Reactions, Wiley-VCH, Weinheim, 2004; c) T. D. Machajewski, C.-H. Wong, Angew. Chem. Int. Ed.

2000, 39, 1352-1375; d) B. M. Trost, C. S. Brindle, Chem. Soc. Rev. 2010, 39, 1600-1632; e) G.

Casiraghi, F. Zanardi, G. Appendino, G. Rassu, Chem. Rev. 2000, 100, 1929-1972; f) G. Rassu, F.

Zanardi, L. Battistini, G. Casiraghi, Chem. Soc. Rev. 2000, 29, 109-118; g) S. E. Denmark, J. R.

Heemstra, G. L. Beutner, Angew. Chem. Int. Ed. 2005, 44, 4682-4698; h) M. Kalesse, Top. Curr.

Chem. 2005, 244, 43-76; i) S. Hosokawa, K. Tatsuta, Mini-Rev. Org. Chem. 2008, 5, 1-18.

7 a) M. Szlosek, X. Franck, B. Figadère, A. Cavé, J. Org. Chem. 1998, 63, 5169-5172; b) M. Szlosek,

B. Figadère, Angew. Chem. Int. Ed. 2000, 39, 1799-1801; c) M. Szlosek, J.-C. Jullian, R.

Hocquemiller, B. Figadère, Heterocycles 2000, 52, 1005-1013; d) X. Franck, M. E. Vaz Araujo, J.-C.

Jullian, R. Hocquemiller, B. Figadère, Tetrahedron Lett. 2001, 42, 2801-2803.

8 H. Ube, N. Shimada, M. Terada, Angew. Chem. Int. Ed. 2010, 49, 1858-1861.

9 S. Takechi�, S. Yasuda, N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed. 2012, 51, 4218-4222.

10 a) E. L. Carswell, M. L. Snapper, A. H. Hoveyda, Angew. Chem. Int. Ed. 2006, 45, 7230-7233; b) H.

Mandai, K. Mandai, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130, 17961-17969; c)

L. C. Wieland, E. M. Vieira, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131, 570-576.

11 S. P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 1192-1194.

12 B. M. Trost, J. Hitce, J. Am. Chem. Soc. 2009, 131, 4572-4573.

13 Y.-Q. Jiang, Y.-L. Shi, M. Shi, J. Am. Chem. Soc. 2008, 130, 7202-7203.

14 A. Birrell, J. N. Desrosiers, E. N. Jacobsen, J. Am. Chem. Soc. 2011, 133, 13872-13875.

15 D. J. Spielvogel, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 3500-3501.

16 L. Liang, M. Yan, Y.-M. Li, A. S. C. Chan, Tetrahedron: Asymmetry 2004, 15, 2575-2578.

17 M. K. Brown, S. J. Degrado, A. H. Hoveyda, Angew. Chem. Int. Ed. 2005, 44, 5306-5310.

18 a) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121, 3543-3544; b) B. M. Trost, F. D. Toste, J.

Am. Chem. Soc. 2003, 125, 3090-3100; c) B. M. Trost, M. L. Crawley, Chem.-Eur. J. 2004, 10,

2237-2252.

19 G. Hughes, M. Kimura, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 11253-11258.

20 B. H. Lipshutz, B. A. Frieman, A. E. Tomaso, Angew. Chem. Int. Ed. 2006, 45, 1259-1264.

21 S. Xu, Z. Wang, X. Zhang, X. Zhang, K. Ding, Angew. Chem. Int. Ed. 2008, 47, 2840-2843.

22 C. Burstein, F. Glorius, Angew. Chem. Int. Ed. 2004, 43, 6205-6208.

23 S. S. Sohn, E. L. Rosen, J. W. Bode, J. Am. Chem. Soc. 2004, 126, 14370-14371.

22

Chapter 1

24 For reviews, see: a) K. Zeitler, Angew. Chem. Int. Ed. 2005, 44, 7506-7510; b) D. T. Cohen, K. A.

Scheidt, Chem. Sci. 2012, 3, 53-57; c) J. Izquierdo, G. E. Hutson, D. T. Cohen, K. A. Scheidt, Angew.

Chem. Int. Ed. 2012, 51, 11686-11698; d) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112,

6104-6155; e) H. U. Vora, P. Wheeler, T. Rovis, Adv. Synth. Catal. 2012, 354, 1617-1639; f) D. T.

Cohen, K. A. Scheidt, Chem. Sci. 2012, 3, 53-57.

25 L.-H. Sun, L.-T. Shen, S. Ye, Chem. Commun. 2011, 47, 10136-10138.

26 For reviews on the asymmetric cycloisomerization, see: a) I. J. S. Fairlamb, Angew. Chem. Int. Ed.

2004, 43, 1048-1052; b) I. Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127-2198; c) V.

Michelet, P. Y. Toullec, J.-P. Genêt, Angew. Chem. Int. Ed. 2008, 47, 4268-4315; d) I. D. G. Watson,

F. D. Toste, Chem. Sci. 2012, 3, 2899-2919; e) Y. Yamamoto, Chem. Rev. 2012, 112, 4736-4769.

27 Q. Zhang, X. Lu, J. Am. Chem. Soc. 2000, 122, 7604-7605.

28 S. K. Mandal, S. R. Amin, W. E. Crowe, J. Am. Chem. Soc. 2001, 123, 6457-6458.

29 T. Inoue, O. Kitagawa, O. Ochiai, M. Shiro, T. Taguchi, Tetrahedron Lett. 1995, 36, 9333-9336.

30 a) Z. Ning, R. Jin, J. Ding, L. Gao, Synlett 2009, 2291-2294; b) H. J. Lee, D. Y. Kim, Tetrahedron

Lett. 2012, 53, 6984-6986.

31 a) S. Hajra, A. K. Giri, J. Org. Chem. 2008, 73, 3935-3937; b) S. Hajra, A. K. Giri, S. Hazra, J. Org.

Chem. 2009, 74, 7978-7981; c) X. Li, X. Li, F. Peng, Z. Shao, Adv. Synth. Catal. 2012, 354,

2873-2885.

32 a) I. Čorić, S. Vellalath, B. List, J. Am. Chem. Soc. 2010, 132, 8536-8537; b) I. Čorić, S. Müller, B.

List, J. Am. Chem. Soc. 2010, 132, 17370-17373.

33 V. Rauniyar, D. G. Hall, J. Org. Chem. 2009, 74, 4236-4241.

34 Y. Wu, R. P. Singh, L. Deng, J. Am. Chem. Soc. 2011, 133, 12458-12461.

35 a) B. L. Feringa, B. De Lange, J. C. De Jong, J. Org. Chem. 1989, 54, 2471-2475; b) W. S. Faber, J.

Kok, B. de Lange, B. L. Feringa, Tetrahedron 1994, 50, 4775-4794; c) F. Toda, K. Tanaka, C. W.

Leung, A. Meetsma, B. L. Feringa, J. Chem. Soc., Chem. Commun. 1994, 2371-2372; d) A. van

Oeveren, J. F. G. A. Jansen, B. L. Feringa, J. Org. Chem. 1994, 59, 5999-6007; e) H. van der Deen,

A. D. Cuiper, R. P. Hof, A. van Oeveren, B. L. Feringa, R. M. Kellogg, J. Am. Chem. Soc. 1996, 118,

3801-3803; f) S. S. Kinderman, B. L. Feringa, Tetrahedron: Asymmetry 1998, 9, 1215-1222; g) G. P.

Howell, S. P. Fletcher, K. Geurts, B. ter Horst, B. L. Feringa, J. Am. Chem. Soc. 2006, 128,

14977-14985.

36 K. Geurts, S. P. Fletcher, B. L. Feringa, J. Am. Chem. Soc. 2006, 128, 15572-15573.

Chapter 2

Catalytic Enantioselective Synthesis of Naturally

Occurring γ-Butenolides via Hetero-Allylic

Asymmetric Alkylation and Ring Closing

Metathesis

An efficient catalytic asymmetric synthesis of chiral γ-butenolides was developed based on the hetero-allylic asymmetric alkylation (h-AAA) in combination with ring closing metathesis (RCM). The synthetic potential of the h-AAA-RCM protocol was illustrated with the facile synthesis of (−)-whiskey lactone, (−)-cognac lactone, (−)-nephrosteranic acid and (−)-roccellaric acid.

Part of this chapter has been published:

B. Mao, K. Geurts, M. Fañanás-Mastral, A. W. van Zijl, S. P. Fletcher, A. J. Minnaard, B. L. Feringa,

Org. Lett. 2011, 13, 948-951.

24

Chapter 2

2.1 Introduction In chapter 1 a general overview on the catalytic asymmetric synthesis of butenolide and γ-butyrolactone derivatives has been presented. The construction of such privileged scaffolds has been intensively investigated during the past decades, due to the interesting biological activities and important synthetic utilities often associated with chiral γ-butenolides1 bearing a stereogenic center in the γ-position (Figure 1).2,3

Figure 1. Representative catalytic asymmetric synthesis of γ-butenolide derivatives.

2.1.1 Ring-closing metathesis for the synthesis of γ-butenolides

Although a number of powerful methods have been described,3 there is still a major incentive to develop efficient catalytic asymmetric protocols toward γ-alkyl substituted butenolides. One approach that has been exploited is the use of ring-closing metathesis (RCM) as the key step to afford γ-butenolides from diolefinic precursors (Scheme 1).4,5

Various ruthenium complexes have proven to be efficient catalysts toward the formation of racemic butenolides in the presence of diolefinic acrylic esters.5

25

Catalytic Enantioselective Synthesis of Naturally Occurring γ-Butenolides

Scheme 1. Ring-closing metathesis in the synthesis of γ-butenolides.

Access to optically active γ-alkyl-γ-butenolides was also accomplished by employing Ru-based catalysts for the ring closure step.6 For example, Fujii et al. reported the enantioselective synthesis of γ-butenolides from commercially available racemic allylic alcohols through the combination of lipase-catalyzed transesterification and RCM (Scheme 2).6d The use of diolefinic acrylic ester moiety makes it possible to carry out the transformation of the substrate for RCM leading to the corresponding chiral γ-butenolides.

Scheme 2. Enantioselective synthesis of γ-butenolides through enzymatic transesterification with RCM.

2.1.2 Copper-catalyzed allylic asymmetric alkylation with Grignard Reagents

Copper-catalyzed allylic asymmetric alkylation (Cu-AAA) is one of the most powerful enantioselective C-C bond-forming transformations which allows the use of organometallic reagents for the direct introduction of alkyl groups into prochiral allylic substrates.7 In particular, the Cu-AAA with Grignard reagents has seen tremendous progress since the pioneering work reported by Bäckvall, Van Koten and co-workers in 1995.8 A brief overview of the copper-catalyzed allylic asymmetric alkylation with Grignard reagents in combination with various ligands is presented in Scheme 3.9, 10, 11

26

Chapter 2

Scheme 3. Overview of the copper-catalyzed asymmetric allylic alkylation with Grignard reagents.

Over the past decade, the catalyst developed by Feringa et al. has been shown as an efficient system to accomplish highly enantioselective Cu-catalyzed allylic alkylations

with Grignard reagents on a broad range of substrates.11 Novel prospects were offered by discovering that the transformation can also be performed with 3-bromopropenyl esters through hetero-allylic asymmetric alkylation (h-AAA) to yield the corresponding allylic esters with excellent enantiomeric control (Scheme 4).12 Cinnamyl derivatives presenting an α,β-unsaturated ester moiety were also well tolerated, providing allylic esters bearing a terminal olefin together with a cinnamate ester moiety in high yields with excellent regio- and enantioselectivities.

Scheme 4. Cu-catalyzed hetero-allylic asymmetric alkylation.

27


2.1.3 Combination of copper-catalyzed allylic asymmetric alkylation with RCM

The combination of Cu-AAA with ring-closing metathesis has been successfully applied in the synthesis of chiral carbo- or heterocycles.13,14 By employing ω-ethylenic allylic substrates as synthetic equivalent, Alexakis et al.13b described a new strategy to access highly enantioenriched cyclic systems in the copper-catalyzed enantioselective allylic alkylation of Grignard reagents followed by RCM (Scheme 5). The key feature of this reaction is the possibility to perform the reaction in a one-pot procedure as they have already demonstrated the compatibility between the metathesis catalyst with excess Grignard reagent, magnesium salts and the copper catalyst.9

Scheme 5. Synthesis of enantioenriched carbocyclic rings via Cu-AAA/RCM. TC = Thiophene-2-carboxylate.

Scheme 6. Enantioselective synthesis of N-heterocycles through Cu-AAA/RCM.12

Another illustration of combining the strategy of Cu-AAA with RCM to achieve the asymmetric synthesis of unsaturated nitrogen heterocycles was reported from our group (Scheme 6).14 Starting from allylic bromides containing protected amine, and terminal

28

Chapter 2

olefin moieties, copper-catalyzed allylic asymmetric alkylation with methylmagnesium bromide was carried out in the presence of chiral bidentate phosphine ligand L4. The resultant allylic products were obtained in high yield with excellent enantiomeric excess, which were subsequently transformed into the corresponding nitrogen heterocycles with no erosion of enantioselectivity through Ru-catalyzed ring-closing metathesis.

2.2 Synthetic Strategy toward γ-Butenolides

Scheme 7. Chiral γ-butenolides via h-AAA followed by RCM.

Inspired by previous successful AAA/RCM reactions,13, 14 we decided to develop a consecutive catalytic asymmetric protocol relying on h-AAA/RCM toward the synthesis of optically active γ-alkyl substituted butenolides. As shown in Scheme 7, the h-AAA of cinnamyl derived substrate 1 with alkyl Grignard reagent would give rise to enantiomerically enriched allylic ester 2 bearing a terminal olefin and a cinnamate ester moiety. These diolefinic substrates will directly lead to chiral γ-alkyl substituted butenolides through Ru-catalyzed RCM (Scheme 7).5, 6 Such a route could be a valuable alternative to current methods.3

2.3 h-AAA followed by RCM with 3-Bromopropenyl Esters 2.3.1 Initial investigations on the substrate reactivity and synthesis

During earlier studies in our group on the hetero-allylic asymmetric alkylation (h-AAA) with Grignard reagents and the following ring-closing metathesis, a series of 3-bromopropenyl esters have been designed to investigate the influence of electron density on the conjugated internal olefin (Scheme 8).15 Substrates 1a, 1b and 1c were synthesized according to the procedure of Trombini and Lombardo et al.16 Condensation of acrolein with acyl bromides, which were obtained through bromination with the corresponding acids by treating with PPh3/Br2 in CH2Cl2, gave rise to pure trans-products in moderate yield after crystallization from n-pentane at −15 oC or −50 oC.15

29


Scheme 8. Synthesis of 3-bromopropenyl esters.

Preliminary results have demonstrated that substrate 1c is the best substrate for the synthesis of chiral γ-butenolide precursors (Table 1), as the desired allylic ester 2c was achieved using 0.5 mol % CuBr·SMe2/L4 in high yield (80%) and excellent regioselectivity (γ/α >95:5).15 When substrate 1a was subjected to the optimized h-AAA conditions, compound 2a was obtained in moderate yield (66%) and good regioselectivity (γ/α = 95:5). However, substrate 1b bearing an electron donating group on the phenyl ring provided the allylic ester product 2b in moderate yield and excellent regioselectivity, albeit the rate of reaction was slightly lower (3d).

The electron delocalization of the α,β-unsaturated π-system into the aromatic ring leading toward an extended conjugated π-system may cause a diminished reactivity toward the RCM reaction.17 The use of the olefin of cinnamate esters as a metathesis partner has not been reported so far. The ring-closing metathesis (RCM) of the resulted allylic ester 2 was investigated employing Hoveyda-Grubbs 2nd generation catalyst in the previous study.12, 15 The formation of the desired products was observed in all cases, and γ-butenolide 3c was obtained in good yield with retention of enantiomeric excess after 2 days of heating at reflux in CH2Cl2. Full conversion of the allylic esters 2a and 2b to the corresponding γ-butenolides was also accomplished, although increased reaction time was required (Table 1, entries 1, 2).

30

Chapter 2

Table 1. h-AAA/RCM of 3-bromopropenyl esters15

entry 1 R3 2 time

(h) γ/αa

yieldb

(%) 3

Hoveyda-Grubbs 2nd

(mol %)

time

(d)

conversiond

(%)

eee

(%)

1 1a Et 2a 20 95:5 66 3a f 2 × 5 4 100 ndi

2 1b n-Bu 2b 72 >95:5 70 3bg 3 × 1 12 100 (41)b nd

3c 1c Et 2c 20 >95:5 80 3ch 10 2 100 (78)b 98

General conditions for h-AAA: 1.0 mol % of CuBr·SMe2, 1.0 mol % of L4, 2 equiv of R3MgBr in CH2Cl2 at −70 oC, unless noted otherwise. a Determined by 1H NMR spectroscopy. b Isolated yield. c 0.5 mol % of CuBr·SMe2, 0.5 mol % of L4. d Conversion was determined by 1H NMR spectroscopy. e Ee was determined by chiral HPLC analysis. f Reaction conditions for RCM: 5.0 mol % of Hoveyda-Grubbs 2nd, 50 mL CH2Cl2, reflux 24 h; concentrated to 5 mL, add 5 mol % of Hoveyda-Grubbs 2nd, reflux for 3 d. g Reaction conditions: 3 × 1 mol % Hoveyda-Grubbs 2nd, 10 mL CH2Cl2, rt for 9 d, reflux for 3 d. h 5.0 mM solution. i nd = not determined.

2.3.2 h-AAA reactions of cinnamic substrate with various Grignard reagents Considering the above results we envisioned that the cinnamyl substrate 1c might be a suitable substrate to afford a number of γ-butenolides via the h-AAA-RCM protocol. Therefore our initial approach focused on the copper-catalyzed h-AAA reaction of cinnamyl substrate 1c with a number of linear Grignard reagents in which alkyl moieties are present that will provide naturally occurring butenolides.(*) Under the optimized conditions,12 using 3.0 mol % CuBr·SMe2 and 3.6 mol % L4, the desired products 2d and 2e were obtained in high yields with excellent regioselectivity (>99:1) (Table 2, entries 1, 2). To avoid the precipitation of the Grignard reagents, the temperature was increased to −55 oC in those cases where Grignard reagents with long alkyl chains were introduced (entries 3, 4). As presented in Table 2, the regio- and enantioselectivities during the

(*) Ee values were determined after converting the resulting allylic esters to γ-butenolides.

31


formation of 2f and 2g were not affected by increasing the temperature. In addition, good yields were still obtained when the Grignard reagents bearing long alkyl chains (3 equiv) were added (entries 3, 4).

Table 2. h-AAA of cinnamyl substrate 1c.a,b

entry R 2 time

(h) γ/αc

yieldd

(%)

1 C4H9 2d

20 >99:1 91

2 C5H11 2e

20 >99:1 89

3e C11H23 2f

18 >99:1 84

4e C13H27 2g

18 >99:1 78

a General conditions for h-AAA: 3.0 mol % of CuBr·SMe2, 3.6 mol % of L4, 2 equiv of RMgBr in CH2Cl2 at −75 oC. b Ee was determined after converting compounds 2 to γ-butenolides 3. c Regioselectivity was determined by 1H NMR spectroscopy. d Isolated yield. e 3 equiv of RMgBr was employed at −55 oC.

2.3.3 RCM of h-AAA reaction products

With the isolated products 2 in hand, we turned our attention to the study of the ring closing metathesis (RCM) for these diolefinic esters.5, 6 The initial RCM reactions run on 2d showed the dependence of the reaction rate upon the concentration of the substrate. When a solution of 2d (0.005 M) was heated at reflux in CH2Cl2 with Hoveyda-Grubbs 2nd (6.0 mol %), the desired furanone 3d was obtained with 74% yield. However, a more concentrated solution of 2d (0.2 M) allowed to use a lower catalyst loading (3.0 mol %), and provided compound 3d in 83% yield with excellent enantiomeric excess (97% ee). Noteworthy, the reaction time was significantly reduced from 7 d to 24 h (Table 3, entry 1). It was known that low substrate concentration can indeed minimize the intermolecular formation of dimeric alkene products and may also imply a longer lifetime of the

32

Chapter 2

catalyst.18 On the other hand, more diluted system would decrease the rate of the reaction and require for high catalyst loading, thus leading to more side reactions.

Table 3. RCM of optically active allylic estersa

entry substrate 3 time (h)

yieldb (%)

eec (%)

1 2d 3d OO

C4H9

24

(7d)d 83

(74)d 97

2 2e 3e OO

C5H11

24 82 98

3 2f 3f

40 84 98

4 2g 3g OO

C13H27

40 82 97

a General conditions for RCM: 3.0 mol % of Hoveyda-Grubbs 2nd, 0.2 M solution of substrate. b Isolated

yield. c Determined by chiral HPLC analysis. d 6.0 mol % of Hoveyda-Grubbs 2nd, 0.005 M solution of

substrate.

The same procedure was followed for substrates 2e-2g (entries 2-4). It should be pointed out that good isolated yields (up to 84%) and excellent ee (up to 98%) were found in all cases under the optimized conditions. The yield of the RCM step was still good despite the fact that the reaction time was extended for 2f and 2g with a longer alkyl substituent at the γ-position (entries 3, 4).

2.4 Total Synthesis of (−)-Whiskey lactone, (−)-Cognac lactone, (−)-Nephrosteranic acid and (−)-Roccellaric acid

Whiskey and cognac lactones19 are well known perfume compounds with a distinct aroma, bearing the γ-butyrolactone ring as main structure. (−)-Nephrosteranic acid and (−)-roccellaric acid, belonging to naturally occurring γ-butyrolactones with a carboxylic acid group in the three position as their characteristic functionality, both of which exhibit interesting antifungal, antibiotic, antitumor, and antibacterial properties.20, 21 Despite extensive synthetic efforts towards their total synthesis either using chiral pool

33


compounds21a or chiral auxiliaries,21e there are limited reports on efficient catalytic enantioselective routes of these natural products. To further demonstrate the utility of the h-AAA/RCM protocol, the concise total synthesis of (−)-whiskey lactone, (−)-cognac lactone, (−)-nephrosteranic acid and (−)-roccellaric acid was proposed on the basis of the resulting chiral γ-butenolides.

Scheme 9. Retrosynthesis of (−)-whiskey lactone, (−)-cognac lactone, (−)-nephrosteranic acid and (−)-roccellaric acid.

As shown in the retrosynthetic route (Scheme 9), starting from the inexpensive commercial available cinnamic acid and acrolein,16 the allylic ester is readily obtained. The key intermediate γ-butenolides could be prepared through the h-AAA-RCM protocol. Thus the desired natural products (−)-nephrosteranic acid and (−)-roccellaric acid would be possible to obtain after the conjugate addition and subsequent enolate trapping to the corresponding γ-butenolides, followed by hydrolysis. The stereochemistry is anticipated to occur in an anti fashion due to the directing influence of the alkyl substituent at γ-position. Analogously, the appropriate γ-butenolides could be converted to (−)-whiskey lactone and (−)-cognac lactone by straightforward 1,4-addition.

34

Chapter 2

Scheme 10. Synthesis of (−)-whiskey and (−)-cognac lactones.

As shown in Scheme 10, chiral γ-butenolides 3d and 3e were used for the synthesis of (−)-whiskey and (−)-cognac lactone. The conjugate addition of dimethylcopper lithium (in situ formed from methyllithium and copper iodide in ether at −20 oC)19b to butenolide 3d provided 4d in 93% yield with complete diastereoselectivity. The homologous lactone 4e was prepared with 96% yield by performing the same reaction sequence. Their spectroscopic data and optical rotation were in agreement with those previously reported.19a-b

Scheme 11. Formation of trisubstituted γ-butyrolactone 5f. Conditions: a) HC(SMe)3, n-BuLi, THF, −78 oC, 2 h; b) MeI (10 equiv), HMPA (10 equiv), THF, −78 oC to −20 oC (46% overall yield).

Next we turned our attention to the formal synthesis of (−)-nephrosteranic acid and (−)-roccellaric acid. The first asymmetric synthesis of (+)-nephrosteranic acid was reported by the group of Momose19b via sequential Michael addition-enolate alkylation to γ-butenolide, in which the stereochemistry of the reaction was highly dependent on the nature of the substituent at γ-position of butenolide.22

To explore the possibility of preparing trisubstituted lactone as a key synthetic intermediate (Scheme 11), the reactivity of the chiral γ-lactone enolate resulting from [tris(methylthio)methyl]lithium addition towards methylation was investigated. Butenolide 3f was treated with lithiated tris(methylthio)methane at −78 oC,19b followed by quenching the resulting lithium enolate with methyl iodide (10 equiv) in the presence of hexamethylphosphoramide (HMPA). The trisubstituted product 5f was obtained in 46% yield and the intermediate lactone 4f was recovered in 42% yield. Unfortunately the use of

35


1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) instead of HMPA did not improve the double alkylation and a mixture of 4f and trisubstituted γ-butyrolactone 5f was obtained as well.

Scheme 12. Formation of trisubstituted γ-butyrolactone 5f and 5g. Conditions: a) HC(SMe)3, n-BuLi, THF, −78 oC, 2 h; b) NaHMDS (2 equiv), MeI (9 equiv), THF, −78 oC to −20 oC.

Taking this into account, we considered the possibility of completing the formation of 5f in two steps (Scheme 12). After the addition of lithiated tris(methy1thio)methane to 3f was completed, the reaction was quenched with saturated aqueous aqueous NH4Cl solution. Then the crude product was treated with NaHMDS23 and excess MeI at −78 oC. To our delight, the desired all trans product 5f was obtained with 86% yield over two steps in a fully diastereoselective manner. In an analogous way, trisubstituted γ-butyrolactone 5g was synthesized in 84% yield starting from the chiral butenolide 3g.

To complete the syntheses, the latter were finally engaged in the HgII- and Lewis acid-assisted hydrolysis24 to afford the desired natural products (−)-nephrosteranic acid 6f and (−)-roccellaric acid 6g in excellent yield (97% and 94%, respectively) (Scheme 13). Gratifyingly, the spectroscopic and physical data of 6f and 6g were consistent with the ones reported in the literature for (−)-nephrosteranic acid {[α]20

D = −27.2 (c 1.05, CHCl3), lit.: [α]

22D = −27.7 (c 0.90, CHCl3)}21f and (−)-roccellaric acid {[α]20

D = −24.3 (c 0.60, CHCl3), lit.: [α]

22D = −26.0 (c 0.50, CHCl3)}.21f

36

Chapter 2

Scheme 13. Synthesis of (−)-nephrosteranic acid and (−)-roccellaric acid.

2.5 Conclusions In summary, we have developed a novel method toward the synthesis of chiral γ-butenolides based on copper-catalyzed hetero-allylic alkylation (h-AAA) in combination with a ring-closing metathesis (RCM) strategy. The key step of this synthetic route is the enantioselective copper-catalyzed h-AAA of cinnamate-derived allylic bromides with various Grignard reagents using TaniaPhos as ligand, which provided the allylic ester products with diolefinic moieties in high yield and excellent regio- and enantioselectivity. The flexibility offered by those fuctionalized chiral allylic esters permits the facile construction of γ-alkyl substituted butenolides through the ring-closing metathesis facilitated by Hoveyda-Grubbs 2nd generation catalyst.

The synthetic potential of this h-AAA-RCM protocol is illustrated with the facile synthesis of (−)-whiskey and (−)-cognac lactone. Moreover, the biologically active γ-butyrolactones, (−)-nephrosteranic acid and (−)-roccellaric acid, were also prepared efficiently with this catalytic enantioselective synthetic route.

2.6 Experimental Section General remarks

All reactions were carried out under a nitrogen atmosphere using flame dried glassware. All the ligands and CuBr·SMe2 were purchased from Aldrich and used without further purification. Grignard reagents were prepared from the corresponding alkyl bromides and magnesium turnings in Et2O following standard procedures. Grignard reagents were titrated using sec-BuOH and catalytic amounts of 1,10-phenanthroline. Solvents were purified before use employing standard techniques.25

37


Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by staining with a solution of a mixture of KMnO4 (10 g) and K2CO3 (10 g) in H2O (500 mL). Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA) or by 1H-NMR spectroscopy. Mass spectra were recorded on a AEI-MS-902 mass spectrometer. All 1H NMR and 13C NMR/APT spectra were recorded on Varian Mercury Plus (400 MHz) spectrometer using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Melting points were determined on a Buchi B–545 melting point apparatus. Optical rotations were measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL). Enantiomeric excess were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector.

General procedure for copper-catalyzed hetero-allylic asymmetric alkylation:12

Starting material 1 was synthesized according to the procedure of Trombini and Lombardo et al.16 The corresponding Grignard reagent (2-3 equiv in Et2O) was added dropwise over 5 min to a homogeneous, stirred and cooled (۪−75 °C or −55 °C) solution of the allylic bromide 1 (303 mg, 1.12 mmol), CuBr·SMe2 (6.7 mg, 3 mol %) and (R,R)-(+)-TaniaPhos L4 (27.7 mg, 3.6 mol %) in CH2Cl2 (3.5 mL) under a nitrogen atmosphere. NMR or TLC analysis showed the reaction had reached completion (typically overnight) and the reaction was quenched with MeOH (5 mL). The reaction mixture was removed from the cooling bath and saturated aqueous NH4Cl (5 mL) was added. The mixture was partitioned between CH2Cl2 (5 mL) and water. The organic layer was dried (MgSO4), filtered and the solvent was evaporated in vacuo. Purification by flash chromatography over silica gel, using Et2O/n-Pentane 1% to 2% to afford the product 2 as colorless oils in good to excellent yield (78-91%).

38

Chapter 2

(+)-(S)-Hept-1-en-3-yl cinnamate (2d)

Colorless oil, 91% yield. [α]20D = +32.6 (c 0.2, CHCl3). 1H NMR

(400 MHz, CDCl3) δ 7.71 (d, J = 16.0 Hz, 1H), 7.52 (dd, J = 6.7, 3.0 Hz, 2H), 7.43-7.31 (m, 3H), 6.47 (d, J = 16.0 Hz, 1H), 5.86 (s, 1H),

5.39 (dd, J = 13.3, 6.2 Hz, 1H), 5.31 (dd, J = 9.9, 8.6 Hz, 1H), 5.19 (dd, J = 10.5, 1.1 Hz, 1H), 1.88-1.52 (m, 2H), 1.50-1.08 (m, 4H), 1.01-0.65 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 166.1, 144.7, 136.5, 134.3, 130.1, 128.8, 128.0, 118.3, 116.4, 74.8, 33.9, 27.2, 22.4, 13.9. HRMS (ESI, m/z): calcd for C16H20O2 [M]+: 244.1463; found: 244.1469. The configuration and enantioselectivity were determined after conversion to compound 3d.

(+)-(S)-Hept-1-en-3-yl cinnamate (2e)

Colorless oil, 89% yield. [α]20D = +31.1 (c 0.26, CHCl3). 1H NMR

(400 MHz, CDCl3) δ 7.70 (d, J = 16.0 Hz, 1H), 7.57-7.47 (m, 2H), 7.39 (dd, J = 4.9, 1.7 Hz, 3H), 6.46 (d, J = 16.0 Hz, 1H), 5.85 (ddd, J

= 16.9, 10.5, 6.3 Hz, 1H), 5.38 (dt, J = 12.4, 6.2 Hz, 1H), 5.29 (dt, J = 17.3, 1.3 Hz, 1H), 5.22-5.14 (m, 1H), 1.83-1.58 (m, 2H), 1.46-1.09 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 166.3, 144.7, 136.7, 134.5, 130.2, 128.8, 128.0, 118.4, 116.5, 74.9, 34.3, 31.6, 24.7, 22.5, 14.0. HRMS (ESI, m/z): calcd for C17H22O2 [M]+: 258.1620; found: 258.1606. The configuration and enantioselectivity were determined after conversion to compound 3e.

(+)-(S)-Tetradec-1-en-3-yl cinnamate (2f)

The reaction was performed at −55 oC with 3 equiv of Grignard reagent. Colorless oil, 84% yield. [α]20

D = +13.1 (c 1.7, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 16.0 Hz, 1H), 7.53 (dd, J =

6.5, 3.0 Hz, 2H), 7.38 (dd, J = 6.4, 3.5 Hz, 3H), 6.43 (dd, J = 43.9, 27.9 Hz, 1H), 5.85 (ddd, J = 17.2, 10.5, 6.3 Hz, 1H), 5.37 (q, J = 6.6 Hz, 1H), 5.29 (d, J = 17.2 Hz, 1H), 5.19 (d, J = 10.5 Hz, 1H), 1.78-1.61 (m, 2H), 1.44-1.04 (m, 18H), 0.88 (dd, J = 8.0, 5.6, 3H). 13C NMR (75 MHz, CDCl3) δ 166.5, 144.9, 136.9, 134.7, 130.4, 129.1, 128.3, 118.7, 116.7, 75.1, 34.5, 32.1, 29.9, 29.8, 29.7, 29.6, 29.6, 25.3, 22.9, 14.3. HRMS (ESI+, m/z): calcd for C23H34O2Na [M+Na]+: 365.2451; found: 365.2440. The configuration and enantioselectivity were determined after conversion to compound 3f.

39


(+)-(S)-Hexadec-1-en-3-yl cinnamate (2g)

The reaction was performed at −55 oC with 3 equiv of Grignard reagent. Colorless oil, 78% yield. [α]20

D = +12.9 (c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 16.0 Hz, 1H), 7.52 (dd, J =

6.5, 3.0 Hz, 2H), 7.43-7.32 (m, 3H), 6.47 (d, J = 16.0 Hz, 1H), 5.86 (ddd, J = 17.2, 10.5, 6.3 Hz, 1H), 5.40 (dd, J = 13.0, 6.6 Hz, 1H), 5.30 (d, J = 17.2 Hz, 1H), 5.19 (d, J = 10.5 Hz, 1H), 1.80-1.54 (m, 2H), 1.30 (m, 20H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 166.1, 144.5, 136.7, 134.4, 130.1, 128.7, 127.9, 118.3, 116.4, 74.8, 34.2, 31.9, 29.6, 29.6, 29.6, 29.5, 29.5, 29.3, 29.3, 25.0, 22.6, 14.0. HRMS (ESI, m/z): calcd for C25H38O2 [M]+: 370.2872; found: 370.2856. The configuration and enantioselectivity were determined after conversion to compound 3g.

Synthesis of Racemic γ-butenolides: 26

Typical procedure for the synthesis of racemic γ-butenolides: 2-trimethylsilyloxyfuran (1 mmol) and alkyl iodide (1.3 mmol) were added to a suspension of AgCO2CF3 (1.3 mmol) in dry CH2Cl2 (2.5 mL) with stirring under N2 at −78 oC. The temperature was slowly increased to 20 oC over 4h and the mixture was filtered through celite. Purification by flash chromatography gave the γ-butenolides.

General procedure for ring closing metathesis (RCM):

Enantiomerically enriched allylic ester 2 (0.7 mmol) was dissolved in the degassed CH2Cl2 (3.5 mL) under N2 atmosphere. Hoveyda-Grubbs 2nd generation catalyst (0.021 mmol) was tipped into the solution and then the stirred solution was heated at reflux for 24-40 h at 40 °C. After the mixture has cooled down to room temperature, solvent was removed under reduced pressure. Purification by flash chromatography (n-Pentane/Ether = 4/1) afforded the product.

40

Chapter 2

(+)-(S)-5-Butylfuran-2(5H)-one (3d)

Colorless oil, 83% yield. [α]25D = +103.5 (c 0.7, CHCl3). 97% ee was

determined by HPLC analysis (Chiral OJ-H column, heptane/i-PrOH 95:5, 0.5 mL/min, 210 nm). Retention time: tmajor = 17.40 and tminor = 18.34 min.

1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 5.7, 1.5 Hz, 1H), 6.11 (dd, J = 5.7, 2.0 Hz, 1H), 5.04 (ddt, J = 7.3, 5.4, 1.7 Hz, 1H), 1.82 -1.60 (m, 2H), 1.50-1.28 (m, 4H), 0.91 (dd, J = 14.4, 7.2 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.0 (s), 156.4 (d), 121.2 (d), 83.3 (d), 32.7 (t), 26.9 (t), 22.2 (t), 13.6 (q). HRMS (ESI, m/z): calcd for C8H12O2 [M]+: 140.0837; found: 140.0835. The absolute configuration was established by correlation with lit.6d [α]

22D = +100.4 (c 1.01, CHCl3).

(+)-(S)-5-Pentylfuran-2(5H)-one (3e)

Colorless oil, 82% yield. [α]25D = +97.0 (c 0.6, CHCl3). 98% ee was

determined by HPLC analysis (Chiral AS-H column, heptane/i-PrOH 95:5, 0.5 mL/min, 210 nm). Retention time: tmajor = 19.52 and tminor =

22.33 min. 1H NMR (400 MHz, CDCl3) δ 7.57-7.38 (m, 1H), 6.04 (dd, J = 5.7, 2.0 Hz, 1H), 4.99 (dd, J = 7.3, 5.5 Hz, 1H), 1.67 (m, 2H), 1.49-1.21 (m, 6H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.1, 156.4, 121.2, 83.3, 33.0, 31.3, 24.5, 22.3, 13.8. HRMS (ESI, m/z): calcd for C9H14O2 [M]+: 154.0994; found: 154.0987. The absolute configuration was established by correlation with lit.6d [α]25

D = +94 (c 1.05, CHCl3).

(+)-(S)-5-Undecylfuran-2(5H)-one (3f)

White wax, 84% yield. [α]20D = +47.5 (c 0.8, CHCl3). 98% ee determined

by HPLC analysis (Chiral OB-H column, heptane/i-PrOH 95:5, 0.5 mL/min, 210 nm). Retention time: tmajor = 12.17 and tminor = 13.15 min.

1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 5.7, 1.5 Hz, 1H), 6.09 (dd, J = 5.7, 1.9 Hz, 1H), 5.03 (ddd, J = 5.6, 3.5, 1.6 Hz, 1H), 1.83-1.58 (m, 2H), 1.51-1.09 (m, 18H), 0.87 (t, J = 6.3 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.1, 156.3, 121.4, 83.4, 33.2, 31.9, 29.5, 29.4, 29.3, 29.3, 29.3, 24.9, 22.6, 14.1. HRMS (ESI, m/z): calcd for C15H27O2 [M]+: 239.2006; found: 239.2003. The absolute configuration was established by correlation with lit.19b [α]

22D = −66.6 (c = 1.95, CHCl3).

41


(+)-(S)-5-Tridecylfuran-2(5H)-one (3g)

White wax, 82% yield. [α]20D = +53 (c 1.05, CHCl3). 97% ee determined

by HPLC analysis (Chiral OB-H column, heptane/i-PrOH 95:5, 0.5 mL/min, 210 nm). Retention time: tmajor = 10.71 and tminor = 11.77 min.

1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 5.7, 1.4 Hz, 1H), 6.07 (dd, J = 5.7, 2.0 Hz, 1H), 5.01 (ddd, J = 5.5, 3.4, 1.5 Hz, 1H), 1.81 -1.56 (m, 2H), 1.45-1.11 (m, 20H), 0.85 (t, J = 6.8 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.1, 156.3, 121.4, 83.4, 33.1, 31.8, 29.6, 29.6, 29.5, 29.4, 29.3, 29.3, 29.2, 24.9, 22.6, 14.0. HRMS (ESI, m/z): calcd for C17H31O2 [M]+: 267.2319; found: 267.2318. The absolute configuration was established by correlation with lit.19b [α]25

D = −56.6 (c = 2.285, CHCl3).

General procedure for synthesis of (−)-whiskey lactone and (−)-cognac lactone:19a-b

A solution of methyllithium (1.6 M) in ether (1.25 mL) was slowly added to a suspension of CuI (190.4 mg, 1 mmol) in Et2O (2.5 mL) at −20oC. The resulting mixture was cooled to −60 ºC before a solution of substrate (0.2 mmol) in ether (2 mL) was added dropwise. After stirring at −60 ºC over 2h, the reaction mixture was quenched with aq. HCl (1.0 M, 3 mL) and filtered over Celite. The organic layer was separated and the aqueous layer was extracted with Et2O (3×5 mL). The combined organic layer were washed with saturated aqueous NaHCO3 and dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (n-Pentane/Ether = 4/1).

(−)-(4R,5S)-5-Butyl-4-methyldihydrofuran-2(3H)-one (4d)

Colorless oil, 93% yield. [α]20D = −83.3 (c 0.17, CHCl3). 1H NMR (400

MHz, CDCl3) δ 4.00 (td, J = 8.1, 3.8 Hz, 1H), 2.73-2.56 (m, 1H), 2.30-2.07 (m, 2H), 1.75-1.27 (m, 6H), 1.13 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz,

3H). 13C NMR (100.6 MHz, CDCl3) δ 176.6, 87.4, 37.1, 36.1, 33.7, 27.8, 22.5, 17.5, 13.9. HRMS (ESI+, m/z): calcd for C9H17O2 [M+H]+: 157.1223; found: 157.1210. The absolute configuration was established by correlation with lit.19a [α]25

D = +84.5 (c = 2.13, MeOH).

42

Chapter 2

(−)-(4R,5S)-4-Methyl-5-pentyldihydrofuran-2(3H)-one (4e)


MHz, CDCl3) δ 4.00 (td, J = 7.8, 4.0 Hz, 1H), 2.75-2.54 (m, 1H), 2.32-2.06 (m, 2H), 1.75-1.21 (m, 9H), 1.13 (d, J = 6.4 Hz, 3H), 0.89 (t, J

= 7.0 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 176.6, 87.4, 37.1, 36.0, 33.9, 31.5, 25.4, 22.5, 17.4, 14.0. HRMS (ESI+, m/z): calcd for C10H18O2Na [M+Na]+: 193.1199; found: 193.1185. The absolute configuration was established by correlation to lit.19a [α]25

D = +82.2 (c = 0.71, MeOH).

General procedure for the synthesis of (−)-nephrosteranic acid and (−)-roccellaric acid19b

To a stirred solution of HC(SMe)3 (58.5 μL, 0.44 mmol) in THF (1.5 mL) was added n-BuLi (1.7 M, 275 μL, 0.44 mmol) in hexane at −78 °C. After being stirred for 1h, a solution of butenolide (0.4 mmol) in 1 mL THF was slowly added to the mixture at −78 °C over 15 min. The mixture was stirred for 3h, then the reaction was quenched by saturated aqueous NH4Cl. The reaction mixture was extracted by EtOAc (3×5 mL) and dried over Na2SO4 and concentrated. A solution of NaHMDS (1 M, 0.88 mL, 0.88 mmol) in THF was dropwise added to the crude mixture dissolved in THF (4 mL) at −78 oC. After stirring for 1 h at −78 oC, MeI (249 μL, 4 mmol) was added slowly to the reaction mixture. The reaction mixture was stirred for 3 h before increasing the temperature from −78 oC to rt. Then the reaction was quenched by adding saturated aqueous NH4Cl and EtOAc. The organic phase was separated, and the aqueous phase was extracted with EtOAc (3×5 mL). The combined phases were dried over MgSO4 and concentrated. Flash chromatography (n-Pentane/Ether = 5/1) gave the product 5f-5g.

(−)-(3R,4R,5S)-3-Methyl-4-(tris(methylthio)methyl)-5-undecyldihydrofuran-2(3H)-one (5f)


MHz, CDCl3) δ 4.75-4.57 (m, 1H), 3.12-2.98 (m, 1H), 2.29 (td, J = 3.7, 1.9 Hz, 1H), 2.22-2.13 (m, 9H), 1.70-1.46 (m, 2H), 1.41 (dd, J = 7.7, 1.9

43


Hz, 3H), 1.25 (m, 18H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 179.3, 80.6, 73.1, 57.5, 39.1, 38.3, 31.9, 29.6, 29.6, 29.5, 29.4, 29.3, 29.1, 25.7, 22.7, 19.1, 14.1, 13.8. HRMS (ESI+, m/z): calcd for C20H38O2S3Na [M+Na]+: 429.1926; found: 429.1921.

(−)-(3R,4R,5S)-3-Methyl-4-(tris(methylthio)methyl)-5-undecyldihydrofuran-2(3H)-one (5g)


MHz, CDCl3) δ 4.73-4.54 (m, 1H), 3.06 (qd, J = 7.7, 3.8 Hz, 1H), 2.29 (t, J = 3.5 Hz, 1H), 2.18 (s, 9H), 1.70-1.46 (m, 2H), 1.41 (d, J = 7.7 Hz, 3H),

1.25 (s, 22H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 179.3, 80.6, 73.1, 57.6, 39.2, 38.3, 31.9, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.1, 25.7, 22.7, 19.1, 14.1, 13.8. HRMS (ESI+, m/z): calcd for C22H42O2S3Na [M+Na]+: 457.2239; found: 457.2206.

BF3·OEt2 (140 μL, 1.11 mmol) was added dropwise to a suspension of trisubstituted lactone (0.074 mmol) and HgO (80 mg, 0.368 mmol) in THF/H2O (4:1, 1 mL). After stirring at room temperature for 23 h, H2O (2 mL) and EtOAc (2 mL) were then added. After the organic solvent was separated, the aqueous solution was extracted with EtOAc (5 mL) for three times. The combined organic phases were washed with brine and dried over MgSO4, and the solvent was removed by rotary evaporation. Flash chromatography (n-Pentane/Ether 1/1 to 1/4) gave the product 6f-6g.

(−)-(2S,3R,4R)-4-Methyl-5-oxo-2-undecyltetrahydrofuran-3-carboxylic acid (6f)

Colorless solid, 97% yield. [α]20D = −27.2 (c 1.05, CHCl3), lit.:21f [α]

22D =

−27.7 (c 0.90, CHCl3). m.p. 106-107 oC. 1H NMR (400 MHz, CDCl3) δ 4.47 (tt, J = 10.5, 5.3 Hz, 1H), 2.98 (dd, J = 11.4, 7.1 Hz, 1H), 2.70 (dd, J

= 11.3, 9.5 Hz, 1H), 1.95-1.62 (m, 2H), 1.38 (dt, J = 21.7, 9.7 Hz, 3H), 1.32-1.16 (m, 18H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 176.6, 176.0, 79.3, 53.9, 39.8, 34.9, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 25.3, 22.7, 14.5, 14.1. HRMS (ESI+, m/z): calcd for C17H30O4Na [M+Na]+: 321.2036; found: 321.2029.

44

Chapter 2

(−)-(2S,3R,4R)-4-Methyl-5-oxo-2-tridecyltetrahydrofuran-3-carboxylic acid (6g)

Colorless crystals, 94% yield. [α]20D = −24.3 (c 0.60, CHCl3), lit.:21f [α]

22D

= −26.0 (c 0.5, CHCl3). m.p. 108-110 oC. 1H NMR (400 MHz, CDCl3) δ 4.48 (dd, J = 9.2, 4.0 Hz, 1H), 2.98 (dq, J = 11.3, 7.1 Hz, 1H), 2.70 (dd, J

= 11.4, 9.4 Hz, 1H), 1.92-1.60 (m, 2H), 1.47-1.17 (m, 25H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 176.7, 175.1, 79.3, 53.8, 39.8, 34.9, 31.9, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 25.3, 22.7, 14.5, 14.1. HRMS (ESI-, m/z): calcd for C19H33O4 [M-H]-: 325.2373; found: 325.2379.

2.7 References 1 A. Kumar, V. Singh, S. Ghosh, Butenolide: A Novel Synthesis and Biological Activities: A Research

for Novel Drug Development, LAMBERT Academic Publishing, Saarbrücken, 2012.

2 For reviews on synthetic approaches to butenolides, see: a) Y. S. Rao, Chem. Rev. 1976, 76,

625-694; b) H. M. R. Hoffmann, J. Rabe, Angew. Chem. Int. Ed. 1985, 24, 94-110; c) N. B. Carter,

A. E. Nadany, J. B. Sweeney, J. Chem. Soc. Perkin Trans. 1 2002, 2324-2342; d) R. R. A. Kitson, A.

Millemaggi, R. J. K. Taylor, Angew. Chem. Int. Ed. 2009, 48, 9426-9451; e) S. Gil, M. Parra, P.

Rodriguez, J. Segura, Mini-Rev. Org. Chem. 2009, 6, 345-358.

3 For representative examples of the catalytic asymmetric synthesis of γ-butenolides, see: a) S. P.

Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 1192-1194; b) B. M.

Trost, J. Hitce, J. Am. Chem. Soc. 2009, 131, 4572-4573; c) H. Ube, N. Shimada, M. Terada, Angew.

Chem. Int. Ed. 2010, 49, 1858-1861; d) E. L. Carswell, M. L. Snapper, A. H. Hoveyda, Angew.

Chem. Int. Ed. 2006, 45, 7230-7233; e) Y.-Q. Jiang, Y.-L. Shi, M. Shi, J. Am. Chem. Soc. 2008, 130,

7202-7203; f) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121, 3543-3544; g) B. Zhang, Z.

Jiang, X. Zhou, S. Lu, J. Li, Y. Liu, C. Li, Angew. Chem. Int. Ed. 2012, 51, 13159-13162; f) Y. Wu,

R. P. Singh, L. Deng, J. Am. Chem. Soc. 2011, 133, 12458-12461.

4 For seletected reviews on the ring-closing metathesis, see: a) R. H. Grubbs, S. Chang, Tetrahedron

1998, 54, 4413-4450; b) A. Fürstner, Angew. Chem. Int. Ed. 2000, 39, 3012-3 043; c) T. M. Trnka,

R. H. Grubbs, Acc. Chem. Res. 2000, 34, 18-29; d) S. K. Chattopadhyay, S. Karmakar, T. Biswas, K.

C. Majumdar, H. Rahaman, B. Roy, Tetrahedron 2007, 63, 3919-3952; e) A. H. Hoveyda, A. R.

Zhugralin, Nature 2007, 450, 243-251; f) C. Samojlowicz, M. Bieniek, K. Grela, Chem. Rev. 2009,

109, 3708-3742; g) G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev. 2010, 110, 1746-1787.

5 For selected examples of the synthesis of racemic γ-butenolides via RCM, see: a) A. Fürstner, O. R.

Thiel, L. Ackermann, H.-J. Schanz, S. P. Nolan, J. Org. Chem. 2000, 65, 2204-2207; b) G. Hughes,

45


M. Kimura, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 11253-11258; c) M. Bassetti, A.

D'Annibale, A. Fanfoni, F. Minissi, Org. Lett. 2005, 7, 1805-1808; d) A. Michrowska, R. Bujok, S.

Harutyunyan, V. Sashuk, G. Dolgonos, K. Grela, J. Am. Chem. Soc. 2004, 126, 9318-9325.

6 For selected examples of the synthesis of optically active γ-butenolides through RCM, see: a) A. K.

Ghosh, J. Cappiello, D. Shin, Tetrahedron Lett. 1998, 39, 4651-4654; b) M. Carda, S. Rodríguez, F.

González, E. Castillo, A. Villanueva, J. A. Marco, Eur. J. Org. Chem. 2002, 2649-2655; c) K. J.

Quinn, A. K. Isaacs, R. A. Arvary, Org. Lett. 2004, 6, 4143-4145; d) M. Fujii, M. Fukumura, Y. Hori,

Y. Hirai, H. Akita, K. Nakamura, K. Toriizuka, Y. Ida, Tetrahedron: Asymmetry 2006, 17,

2292-2298.

7 For reviews on Cu-catalyzed allylic asymmetric alkylation, see: a) N. Krause, Modern

Organocopper Chemistry, WILEY-VCH, Weinheim, 2002; b) H. Yorimitsu, K. Oshima, Angew.

Chem. Int. Ed. 2005, 44, 4435-4439; c) C. A. Falciola, A. Alexakis, Eur. J. Org. Chem. 2008,

3765-3780; d) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem.

Rev. 2008, 108, 2824-2852; e) A. Alexakis, J. E. Bäckvall, N. Krause, O. Pàmies, M. Diéguez,

Chem. Rev. 2008, 108, 2796-2823; f) Z. Lu, S. M. Ma, Angew. Chem. Int. Ed. 2008, 47, 258-297; g)

J. F. Teichert, B. L. Feringa, Angew. Chem. Int. Ed. 2010, 49, 2486-2528.

8 M. van Klaveren, E. S. M. Persson, A. del Villar, D. M. Grove, J.-E. Bäckvall, G. van Koten,

Tetrahedron Lett. 1995, 36, 3059-3062.

9 K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem. Int. Ed. 2004, 43, 2426-2428.

10 S. Tominaga, Y. Oi, T. Kato, D. K. An, S. Okamoto, Tetrahedron Lett. 2004, 45, 5585-5588.

11 a) F. López, A. W. van Zijl, A. J. Minnaard, B. L. Feringa, Chem. Commun. 2006, 409-411; b) A. W.

van Zijl, F. López, A. J. Minnaard, B. L. Feringa, J. Org. Chem. 2007, 72, 2558-2563; c) T. den

Hartog, B. Maciá, A. J. Minnaard, B. L. Feringa, Adv. Synth. Catal. 2010, 352, 999-1013; d) M.

Fañanás-Mastral, B. ter Horst, A. J. Minnaard, B. L. Feringa, Chem. Commun. 2011, 47, 5843-5845;

e) V. Hornillos, A. W. van Zijl, B. L. Feringa, Chem. Commun. 2012, 48, 3712-3714.

12 K. Geurts, S. P. Fletcher, B. L. Feringa, J. Am. Chem. Soc. 2006, 128, 15572-15573.

13 a) A. Alexakis, K. Croset, Org. Lett. 2002, 4, 4147-4149; b) F. Giacomina, D. Riat, A. Alexakis, Org.

Lett. 2010, 12, 1156-1159.

14 J. F. Teichert, S. Zhang, A. W. van Zijl, J. W. Slaa, A. J. Minnaard, B. L. Feringa, Org. Lett. 2010,

12, 4658-4660.

15 K. Geurts, Ph.D. thesis, University of Groningen (The Netherlands), 2008.

16 a) M. Lombardo, S. Morganti, C. Trombini, J. Org. Chem. 2003, 68, 997-1006; b) M. Lombardo, R.

Girotti, S. Morganti, C. Trombini, Chem. Commun. 2001, 2310-2311.

46

Chapter 2

17 a) A. Fürstner, K. Langemann, J. Am. Chem. Soc. 1997, 119, 9130-9136; b) A. K. Chatterjee, J. P.

Morgan, M. Scholl, R. H. Grubbs, J. Am. Chem. Soc. 2000, 122, 3783-3784;

18 a) T. A. Kirkland, R. H. Grubbs, J. Org. Chem. 1997, 62, 7310-7318; b) M. Ulman, R. H. Grubbs, J.

Org. Chem. 1999, 64, 7202-7207.

19 a) H. Takahata, Y. Uchida, T. Momose, Tetrahedron Lett. 1994, 35, 4123-4124; b) H. Takahata, Y.

Uchida, T. Momose, J. Org. Chem. 1995, 60, 5628-5633; c) K. Ito, M. Yoshitake, T. Katsuki,

Tetrahedron 1996, 52, 3905-3920; d) H. Nishikori, K. Ito, T. Katsuki, Tetrahedron: Asymmetry

1998, 9, 1165-1170; e) S. Tsuboi, J.-I. Sakamoto, H. Yamashita, T. Sakai, M. Utaka, J. Org. Chem.

1998, 63, 1102-1108.

20 a) R. Bandichhor, B. Nosse, O. Reiser, Top. Curr. Chem. 2004, 243, 43-72; b) b) M. S. Maier, D. I.

G. Marimon, C. A. Stortz, M. T. Adler, J. Nat. Prod. 1999, 62, 1565-1567; c) B. K. Park, M.

Nakagawa, A. Hirota, M. Nakayama, J. Antibiot. 1988, 41, 751-758.

21 For selected examples of syntheses of (−)-nephrosteranic acid and (−)-roccellaric acid, see: a) J.

Mulzer, N. Salimi, H. Hartl, Tetrahedron: Asymmetry 1993, 4, 457-471; b) M. Bella, R. Margarita,

C. Orlando, M. Orsini, L. Parlanti, G. Piancatelli, Tetrahedron Lett. 2000, 41, 561-565; c) C. Böhm,

O. Reiser, Org. Lett. 2001, 3, 1315-1318; d) M. P. Sibi, P. Liu, J. Ji, S. Hajra, J.-X. Chen, J. Org.

Chem. 2002, 67, 1738-1745; e) M. T. Barros, C. D. Maycock, M. R. Ventura, Org. Lett. 2003, 5,

4097-4099; f) R. B. Chhor, B. Nosse, S. Sörgel, C. Böhm, M. Seitz, O. Reiser, Chem.-Eur. J. 2003,

9, 260-270; g) S. Braukmüller, R. Brückner, Eur. J. Org. Chem. 2006, 2110-2118; h) J. Fournier, O.

Lozano, C. Menozzi, S. Arseniyadis, J. Cossy, Angew. Chem. Int. Ed. 2013, 52, 1257-1261.

22 M. Ibrahim-Ouali, J.-L. Parrain, M. Santelli, Org. Prep. Proced. Int. 1999, 31, 467-505.

23 a) F. Schleth, A. Studer, Angew. Chem. Int. Ed. 2004, 43, 313-315; b) F. Schleth, T. Vogler, K.

Harms, A. Studer, Chem.-Eur. J. 2004, 10, 4171-4185.

24 E. Vedejs, P. L. Fuchs, J. Org. Chem. 1971, 36, 366-367.

25 D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., Pergamon Press,

Oxford, 1988.

26 C. W. Jefford, A. W. Sledeski, J. Boukouvalas, J. Chem. Soc., Chem. Commun. 1988, 364-365

.

Chapter 3

Diversity-Oriented Enantioselective Synthesis of

Highly Functionalized Cyclic and Bicyclic Esters

Copper-catalyzed hetero-allylic asymmetric alkylation (h-AAA) with functionalized Grignard reagents bearing an alkene or alkyne moiety has been achieved with excellent regio- and enantioselectivity. The corresponding alkylation products were further transformed to a variety of highly functionalized cyclic and bicyclic esters with excellent control of chemo-, regio- and stereoselectivity.


B. Mao, M. Fañanás-Mastral, M. Lutz, B. L. Feringa, Chem.-Eur. J. 2013, 19, 761-770.

48

Chapter 3

3.1 Introduction Cyclic and bicyclic alcohols as the common structural elements are present in a large number of natural products and pharmaceuticals (Figure 1).1 For example, Oseltamivir phosphate (Tamiflu), bearing a cyclic alcohol moiety, has recently attracted considerable attention because it was approved as the only orally available drug for both prophylaxis and treatment of human influenza2 and H5N1 avian flu.3 Bicyclic alcohols are also found in the family of sesquiterpenoids possessing important biological activities such as antitumor and antimicrobial properties.4 Moreover, (+)-dihydrocompactin was often recognized as hypo-cholesterolemic agents because of its low toxicity and extremely potent competitive inhibition of 3-hydroxy-3-methylglutaryl co-enzymeA (HMG-CoA) reductase.5

Figure 1. Bioactive compounds with various cyclic and bicyclic alcohols.

The rapid construction of highly functionalized ring-structures and control over the regio- and stereochemistry of single or fused ring systems continue to offer important synthetic challenges. Methodologies for the asymmetric synthesis of cyclic and bicyclic alcohols including the use of chiral synthons, chiral auxiliaries, kinetic resolution or asymmetric CBS reduction have been intensively described. However, the formation of enantiopure bicyclic alcohols in a concise and efficient way is still highly challenging.6 The development of fully catalytic and highly stereoselective synthetic protocols towards cyclic and bicyclic alcohols via short routes is of particular interest in the context of diversity-oriented synthesis7 of stereochemically complex structures.

3.1.1 Copper-catalyzed hetero-allylic asymmetric alkylation (h-AAA)

Copper-catalyzed allylic asymmetric alkylation (AAA) represents a very powerful tool for the enantioselective construction of optically active molecules (Figure 2).8 As described in chapter 2, a highly regio- and enantioselective synthesis of optically active allylic esters

49

Diversity-Oriented Enantioselective Synthesis of Cyclic and Bicyclic Esters

via Cu-catalyzed hetero-allylic asymmetric alkylation (h-AAA) with Grignard reagents was introduced by our group.9 One of the major features of this methodology is that it provides access to protected chiral allyl alcohols in combination with other functional groups that allow for further transformations giving rise to a variety of important structures.9, 10

Figure 2. Copper-catalyzed AAA vs h-AAA. LG = leaving group; PG = protecting group; X = heteroatom.

In 2007, Hoveyda and coworkers disclosed an efficient method for enantioselective synthesis of a range of allylsilanes by Cu-catalyzed hetero-asymmetric allylic alkylation (h-AAA) of Si-substituted unsaturated phosphates with dialkyl- and diarylzinc reagents (Scheme 1).11 Transformations are promoted by 1-2.5 mol % of chiral N-heterocyclic carbene based (NHC based) catalyst L1, affording enantiomerically enriched allylsilanes in up to 98% ee with over 70% yield.

Scheme 1. h-AAA of Si-substituted unsaturated phosphates with organozinc reagents.

Soon after, Hall and Carosi developed the first copper-catalyzed asymmetric substitution of 3-halopropenylboronates with various alkyl magnesium bromides, affording enantioenriched α-substituted allylboronates in high regioselectivity and excellent enantioselectivity (Scheme 2).12 It was further demonstrated that the resultant chiral

50

Chapter 3

reagents could add with very high diastereoselectivity to aldehydes in a convenient one-pot fashion, providing an efficient route to reactive allylic trifluoroborate salts.

2 2o

N N

Scheme 2. h-AAA of 3-halopropenylboronate with ethylmagnesium bromide.

All the reactions mentioned above demonstrated that copper-catalyzed allylic alkylation has the advantage of being broadly tolerant of various functionalized substrates, which allows the formation of products bearing a stereocenter bonded to a heteroatom.

3.1.2 Copper-catalyzed AAA with functionalized Grignard reagents

Copper-catalyzed allylic asymmetric alkylation provides an opportunity to use organometallic-base nucleophiles such as Grignard reagents, furnishing the branched enantiomerically pure products with a terminal double bond. Moreover, the functionality group embedded in the substrate together with the terminal olefin could be transformed into a wide range of synthetic valuable building blocks through simple cyclization or cycloaddition. On the other hand, the introduction of functionalized Grignard reagents has also been successfully applied under the condition of Cu-AAA reaction, in which the functional groups didn’t interfere with catalysis by displaying their labilities or through complexation with the catalyst. The corresponding chiral allylic product was recognized as ideal starting material to afford diversified compounds (Scheme 3).13

Scheme 3. Further transformation of Cu-AAA products. FG = functional group; LG = leaving group.

51


By using chiral TADDOL- or BINOL derived catalyst in combination with CuTC (copper thiophene 2-carboxylate), Alexakis and co-workers reported the highly enantioselective allylic alkylation with Grignard reagents bearing a terminal alkene group.14 When aryl-substituted (cinnamyl-type) allylic chlorides were employed as substrates, the regio- and enantioselectivity were usually better with the TADDOL-derived ligand L3. In the case of β-methylcinnamyl chloride, an optimal catalyst system of CuTC/L4 resulted in high selectivities in favor of the γ product with up to 97% ee. Ring-closing metathesis (RCM) of the resulted allylic products yielded five- or six-membered carbocylcles containing di- or tri-substituted double bond without compromising the enantiomeric excess (Scheme 4).

Scheme 4. Further transformation of Cu-AAA products.

3.1.3 Diversity oriented synthesis

Diversity-oriented synthesis (DOS) provide a systematic and general process for obtaining a dense matrix of stereochemically and skeletally diverse products in a small number of synthetic transformations.7 Schreiber et al. have described a strategy which has been commonly applied in the context of DOS (Scheme 5).7b This “build/couple/pair” strategy involves firstly “building” the required chiral starting units. Next, a densely functionalized molecule is synthesized by coupling these starter units, ideally using multicomponent coupling reactions. Finally, pairing different parts of the densely functionalized molecule, in functional group specific reactions, generates different molecular skeletons.7b-c Despite of the extensive developments of diversity-oriented synthesis, it is still relatively under exploration for the application of enantioselective catalysis which could give rise to the starting compounds with high level of stereoselectivity.15

52

Chapter 3

Scheme 5. Generation of stereochemical diversity with the build/couple/pair strategy.

3.2 Project Goal The aim of this research was to employ the functionalized Grignard reagents containing alkene or alkyne moieties in the Cu-catalyzed h-AAA in combination with several stereoselective cyclization and cycloaddition16 reactions. This approach would give easy access to highly functionalized cyclic or bicyclic protected alcohols in a concise and enantioselective manner. Although alkyl Grignard reagents bearing alkene moieties have been applied in Cu-catalyzed AAA/RCM reactions,9a, 14 to the best of our knowledge, there is no example of the use of alkyl Grignard reagent bearing an alkyne moiety17 in this transformation.

Due to the high affinity of copper for triple bonds,18 the presence of alkyne moiety could represent a problem in the regio- or stereocontrol of the Cu-catalyzed AAA. However, a successful Cu-catalyzed h-AAA with these particular Grignard reagents would give rise to various enynes bearing a protected chiral alcohol motif which could be further transformed to a wide range of highly functionalized ring systems.

Starting from vinyl ester 1, an efficient Cu-catalyzed h-AAA with alkene-containing Grignard reagents followed by ring-closing olefin metathesis19 would provide cyclic benzoate esters20 including the formation of 5-, 6- and 7-membered ring structures (Scheme 6). Relying on the Cu-catalyzed h-AAA with alkyne-containing Grignard reagents, the resulted enynes could be transformed into optically active 2,4-dienol esters21

53


with different ring sizes via enyne metathesis.22 In addition, highly stereoselective synthesis of different ring-fused functionalized carbobicycles from the corresponding 2,4-dienol esters or internal enyne esters are feasible through Diels-Alder23 or Pauson-Khand24 reactions. The distinctive feature of this convergent strategy is the highly regio- and enantioselective synthesis of allylic esters and the potential stereocontrol in subsequent transformations to reach a variety of different cyclic and bicyclic alcohols.

Scheme 6. Proposed routes to cyclic and bicyclic esters with h-AAA of functionalized Grignard reagents as key step.

3.3 Results and Discussion 3.3.1 Synthesis of cyclic benzoate esters via h-AAA and RCM

Our initial studies were focused on the copper-catalyzed h-AAA reaction of substrates 1 with Grignard reagents bearing a terminal alkene moiety. Under the optimized conditions for the addition of simple alkyl Grignard reagent,9 employing CuBr·SMe2 and (R,R)-(+)-Taniaphos (L5) as the catalytic system, the desired alkylation products 3 were obtained in high yields (up to 96%) with excellent regio- (>99:1) and enantioselectivities (96-97% ee; Table 1). Various functionalized Grignard reagents with different spacer

54

Chapter 3

length proceeded equally well, where the yield decreased slightly with the increasing chain length of Grignard reagents.

Table 1. h-AAA of 3-bromopropenyl ester with unsaturated Grignard reagent bearing an alkene moiety.a

entry n 3 γ/αb Yieldc (%) eed (%)

1 0 3a

>99:1 96 97

2 1 3b

>99:1 95 97

3 2 3c

>99:1 83 96

4 3 3d

>99:1 80 n.d.e

a General conditions for h-AAA: 5.0 mol % of CuBr·SMe2, 5.5 mol % of (R,R)-(+)-Taniaphos L5, 2 equiv of Grignard reagent 2 in dry CH2Cl2 at -70 ºC. b Regioselectivity was determined by 1H NMR spectroscopy of the crude mixture. c Isolated yield. d Ee was determined by chiral HPLC analysis. e n.d. = Not determined.

With the isolated products 3 in hand, we attempted the synthesis of cyclic benzoate esters20 by applying ring-closing metathesis (RCM). When 3a was treated with Grubbs 2nd generation catalyst (5 mol %), 5-membered carbocycle (S)-4a was obtained in 85% yield and excellent enantioselectivity (97% ee).9a The use of longer alkyl chains at the Grignard reagent did not affect the outcome of the reaction and allowed us to access the optically active six- and seven-membered ring structures 4b and 4c in 85-89% yield and excellent enantioselectivities (95% ee; Table 2). It should be emphasized that high yields and excellent enantioselectivity were found in all cases under the optimized conditions. No significant loss of enantioselectivity takes place during the ring-closure step.

55


Table 2. Synthesis of various cyclic benzoate esters via RCM.a

entry n 4 yieldb (%) eec (%)

1d 0 4a

85 97

2 1 4b

89 95

3 2 4c

85 95

4e 3 4d

- -

a General conditions for RCM: Allylic ester 3 (0.05 M) and Grubbs 2nd generation catalyst (5.0 mol %) was dissolved in degassed CH2Cl2 (12 mL) at 40 oC for 18 h. b Isolated yield. c Ee was determined by chiral HPLC analysis. d The absolute configuration was assigned by comparison of optical rotation with known compounds. e No conversion was observed.

Unfortunately, efforts to cyclize 1,8-diene ester to make the corresponding eight-membered carbocycle were not successful with Grubbs second generation catalyst, leading to the recovery of starting material. It’s known in literature that the synthesis of eight-membered ring through the ring-closing metathesis was extremely challenging, where the kinetics of ring closure, the strain inherent in eight-membered ring, and the competing metathesis-based polymerization of reactants and/or products are among the factors contributing to the problem.25

3.3.2 Cu-catalyzed h-AAA with Grignard reagents bearing an alkyne moiety

We next turned our attention to the challenging Grignard reagents bearing an alkyne functional group for the Cu-catalyzed hetero-allylic asymmetric alkylation (h-AAA)

56

Chapter 3

(Table 3). To prevent the competitive coordination between terminal alkyne and copper (I) species,18 trimethylsilyl-protected alkynes were employed. Under the same conditions for Cu-catalyzed h-AAA with alkene-containing Grignard reagents, product 6b was obtained with only modest enantioselectivity (36% ee; Table 3, entry 1).

Table 3. Screening of reaction condition for Cu-catalyzed h-AAA with Grignard reagents bearing an alkyne moiety.a

entry 1a/5b addition time [h] γ/αb ee of 6bc (%)

1 1:2 0.1 >99:1 36

2 1:2 0.5 >99:1 88

3 1:2 2 >99:1 92

4 1:1.5 2 >99:1 94

5 1:1.5 4 >99:1 97

a Reactions performed on a 0.32 mmol scale. 5b (1.5 M in ether) was diluted with dry CH2Cl2 and added dropwise. Full conversion was achieved in all cases. b Regioselectivity was determined by 1H NMR spectroscopy of the crude mixture. c Ee was determined by chiral HPLC analysis.

Screening of different reaction parameters indicated that lower amount (1.5 equiv) and slower addition (4 h) of Grignard reagent is essential for obtaining 6b in a total SN2’ enantioselective manner. The effect on the enantioselectivity of the reaction could be attributed to a possible intermolecular coordination of the alkyne present in the Grignard reagent to the copper complex. A faster addition would provide a higher amount of the alkyne in the reaction solution which would facilitate the intermolecular coordination. On the other hand, the slow addition avoids the accumulation of alkyne-bearing Grignard reagent as it is consumed by the catalytic reaction.

57


It was particularly rewarding to find that treatment of 3-bromopropenyl ester 1a with Grignard reagent 5a in the presence of optimized conditions (Table 3, entry 5), also provided the desired SN2’ product 6a with excellent regio- (>99:1) and enantioselectivities (98% ee; Scheme 7). Grignard reagent 5b in combination with cinnamyl ester 1b, readily provided alkylation products 6c again in good yield with excellent regio- and enantioselectivity (>99:1, 96% ee; Scheme 7).

2 2o

n2

Scheme 7. Substrate scope of h-AAA with Grignard reagents bearing an alkyne moiety.

Next we focused on the h-AAA reaction of β-substituted substrate 1c. As ferrocenyl ligand L1 was not the proper ligand for such reaction,9a we turned our attention to phosphoramidites8h as the potential chiral ligands. When the reaction was carried out with ligand L5, which was described as an optimal ligand for related transformations,9a, 14b product 6d was obtained with high enantiocontrol (94% ee) but poor regioselectivity (γ/α = 1:2; Scheme 8). However, ligand L6 afforded the desired product 6d with better regioselectivity (γ/α = 6:1) while a similar enantiomeric excess was observed (92% ee; Scheme 8).

58

Chapter 3

Scheme 8. Cu-catalyzed h-AAA of β-substitued substrate with Grignard reagent 5b.

3.3.3 Synthesis of optically enriched 2,4-dienols

Optically enriched 2,4-dienols are key structural motifs in a variety of natural products.21 Despite the importance and versatility of these compounds, the enantioselective synthetic approaches so far are limited to the lipase catalyzed kinetic resolution of racemic dienols.21b-d In order to obtain the chiral dienol derivatives, TMS (trimethylsilyl) protected allylic ester 6a was subjected to enyne metathesis22 using Grubbs first generation catalyst. No reaction was observed during this process presumably due to the steric effects of the trimethylsilyl group.22a Since it is known that enyne metathesis proceeds better with terminal alkynes,22a allylic products 6 were transformed to the corresponding terminal enyne products 7 without compromising the stereochemical integrity by treating them with 2 equiv of tetra-n-butylammonium fluoride (TBAF) solution in THF.

We then investigated the ring-closing metathesis of enynes 7 in the presence of catalytic amount of Grubbs first generation catalyst under an ethylene atmosphere (Table 4). The influence of ethylene was found to be essential for accelerating the reaction to access diene ester 8.26 Reaction with enyne 7a to form five-membered cyclic 2,4-dienol ester 8a proceeds smoothly and again no erosion of the enantioselectivity was observed during this transformation.27 The homologous six-membered dienol ester 8b was prepared in 87% yield with 96% ee by performing the reaction under the same conditions (Table 4). Although enyne 7c bearing a cinnamyl ester moiety showed a slightly lower reactivity resulting in a longer reaction time, the desired diene product 8c was obtained with 85% yield and 96% ee. These results indicate that the strategy combining hetero-allylic

59


asymmetric alkylation with ring-closing enyne metathesis is a highly versatile method for the enantioselective synthesis of cyclic 2,4-dienol esters.

Table 4. Deprotection of TMS group followed by Enyne metathesis.a,b

a Isolated yield. b Determined by chiral HPLC analysis. c The absolute configuration was assigned by comparison of optical rotation with known compound.21b

Unfortunately, when enyne 7d, obtained after the removal of TMS group on 6d, was exposed to the same conditions discussed above, the enyne metathesis proceeded to the linear product 9 in an intermolecular fashion with ethylene instead of intramolecularly with the terminal olefin (Table 5). The reaction could not be improved further by alternating the reaction conditions (solvent, temperature and atmosphere). Other ruthenium complexes including Grubbs 2nd and Hoveyda-Grubbs 2nd were also tested but the formation of the desired product 8d was not observed (Table 5, entries 2-4). Less bulky NHC containing ruthenium complex (Hoveyda-Grubbs analog), which is more reactive towards hindered C–C double bonds,22d failed to promote the intramolecular enyne metathesis of 7d (Table 5, entries 5). As discussed in earlier literature,28 an intramolecular reaction is observed in the formation of trisubstituted dienes through metathesis of gem-disubstituted olefins, although only at high dilution. Initiation occurs through the less

60

Chapter 3

substituted olefin and the new alkylidene undergoes the intramolecular reaction providing the desired product. When no monosubstituted olefin is present on the RCM substrate, however, the reaction is not observed.28 Herein, the low reactivity of 7d with gem-disubstituted olefins indicates that formation of tetrasubstituted cyclic olefin 8d through cross metathesis is not feasible using such Ru-alkylidene catalysts.

Table 5. Further transformation of enyne 6d.

entry Ru-based catalyst solvent atm. temp. (oC) yield of 9a,b (%)

1 Grubbs 1st CH2Cl2 ethylene 40 66

2 Grubbs 2nd Toluene ethylene 80 n.d.c

3 Grubbs 2nd Toluene Argon 80 n.d.

4 Hoveyda-Grubbs 2nd Toluene ethylene 80 n.d.

5 Hoveyda-Grubbs analog Toluene ethylene 80 n.d.

a Isolated yield. b The formation of product 8d was observed in less than 5% yield. c n.d. = Not determined.

3.3.4 Domino enyne isomerization and Diels-Alder reaction

Dienols 8 are suitable substrates for Diels-Alder reaction which could give rise to the important bicyclic scaffolds 10 via a cycloaddition reaction in a diastereoselective

61


fashion.29 An one-pot consecutive enyne metathesis/Diels-Alder reaction in the presence of diethyl acetylenedicarboxylate was depicted in Scheme 5. Optical enriched terminal enynes 7a and 7b were subjected to enyne metathesis conditions described above. The dienophile was then subsequently added after the complete formation of diene ester 8. To our delight, chiral intermediate 8 underwent cycloaddition with dienophile at 160 oC to yield in each case a single diastereomer of the corresponding cycloadduct 10 (Scheme 9). Considering the complexity of this multistep transformation, yields on the order of 54% and 68% for each product are satisfactory.

Scheme 9. One-pot consecutive sequence of enyne metathesis and Diels-Alder reaction.

The relative configuration was assigned on the basis of 1H-NMR and NOESY spectrum of products 10a and 10b (Figure 3). The vicinal proton coupling constant measured between Ha-Hb of product 10a is Ja-b = 9.0 Hz, and the analogous coupling constant for 10b is J a-b = 10.5 Hz. Important NOE correlations were observed between Ha-Hc and Hb-Hd in each case, whereas no cross-peak between Ha and Hb was detected. All these results indicated an anti stereochemical relationship for Ha-Hb. The exclusive stereochemical outcome is attributed to the stereogenic center established in the Cu-catalyzed h-AAA reaction and the face selectivity of Diels-Alder reaction.30 In both cases, cycloaddition occurred preferentially from the diene face anti to the chiral allylic ester substituent. It should be pointed out that the enantiomeric excess of the cycloaddition product was also not compromised during the reactions. This sequential stereoselective approach offers rapid access to enantiomerically pure complex bicyclic molecules.

62

Chapter 3

Figure 3. Relevant NOESY correlations of products 10a and 10b.

3.3.5 Intramolecular Diels-Alder reaction of optically enriched 2,4-dienol

The dienol system and related derivatives have proven to be valuable building blocks in the synthesis of natural products via intramolecular cycloaddition.31 In 2004, Kita et al. presented an efficient lipase-catalyzed dynamic kinetic resolution (DKR) utilizing the ruthenium catalysts (L7 or L8) to accelerate the racemization of racemic alcohols (Scheme 10).21b Subsequent intramolecular Diels–Alder reaction of the resultant dienol ester intermediates afforded the cycloadducts bearing multi-ring-fused structure in good to high yields with excellent enantiomeric excess (up to 97% ee). Those products are useful chiral intermediates for the synthesis of compactin32 and forskolin.33

Scheme 10. Domino DKR/intramolecular Diels-Alder reaction.

As an extension of our studies on synthetic applications of dienol esters, a facile intermolecular cycloaddition of unactivated cinnamic ester was investigated. When a solution of 8c in toluene was heated at reflux or exposured to microwave radiation, the only product observed was the starting compound (Scheme 11). In retrospect, this result is not unduly surprising. Given previous discussion of intramolecular Diels-Alder reactions in which the diene and dienophile are tethered by an ester functionality, one might surmise

63


that compound 8c would be resistant to cyclization due to the intrinsic low reactivity and

unfavorable geometry of the double bond on the cinnamic ester.34

Scheme 11. Domino DKR/intramolecular Diels-Alder reaction. S.M. = starting material.

3.3.6 Pauson-Khand (PK) reaction

To establish the synthetic compatibility of allylic ester 6 for the purpose of

diversity-oriented synthesis, the intramolecular Pauson-Khand (PK) reaction of 1,5-enyne

6a and 1,6-enyne 6b have been explored to achieve functionalized

bicyclo[3.3.0]pentanones in a stereoselective manner (Scheme 12). A solution of the

corresponding enyne in CH2Cl2 was treated with a slight excess of [Co2(CO)8] at room

temperature until disappearance (by TLC) of the starting material, and the resulting

hexacarbonyldicobalt complex was then treated under thermal condition (CH3CN, 80 oC).

This transformation gave rise to the substituted cyclopentenone 10 in 55-64% yield with

total selectivity as a single diastereoisomer. HPLC analysis of the products 11a and 11b

showed the complete conservation of enantiomeric excess (Scheme 12).

Scheme 12. Domino DKR/intramolecular Diels-Alder reaction.

The relative stereochemistry of the two adjacent stereogenic centers in 11a and 11b was

determined by 1H NMR and NOESY spectroscopy. The observation of NOE correlation

between Ha-Hc, Ha-He, Hb-Hd, Hb-Hf in each case indicated an anti stereochemical

64

Chapter 3

relationship for Ha-Hb. X-ray crystal structure determination of 11a confirmed the relative configuration (Figure 5). The absolute stereochemistry was unequivocally established by using the Flack parameters (see experimental section).

Figure 5. Molecular structure of 11a in the crystal.35

The observed exo configuration in the formation of bicyclic alcohol 11a could be rationalized through the accepted mechanism of the PK reaction proposed by Carretero and co-workers (Scheme 13).36 The stereochemically decisive step would be the formation of the putative cis-cobaltacycle after insertion of the C-Co bond of the hexacarbonyldicobalt complex into the C=C double bond. Two plausible diastereomeric cis-cobaltacycles C and D were envisioned, in which the steric interaction between the OR and TMS groups might cause the lability problem for the intermediate C. Such interaction would not appear in the intermediate D, involved in the formation of the exo adduct, in which the OR and TMS groups are located on opposite sides of the bicyclic structure. This kind of steric effect would reinforce the exo stereoselectivity.

Scheme 13. Rationalization of the observed exo stereoselectivity.

Enantiomerically enriched bicyclic compounds 11 possess a high degree of functionalization including an ester group and an α,β-unsaturated ketone with

65


α-substitution by a TMS group (Scheme 14). Starting from those densely functionalized bicyclic compounds, versatile transformations are envisaged to access a variety of chiral building blocks.

Scheme 14. Envisaged transformations of bicyclic compounds 11.

The synthetic diversity of this strategy was illustrated by the facile installation of an all-carbon quaternary stereogenic center37 at the bridgehead carbon (Scheme 15). Bicyclic pentanone 11a was treated with lithium dimethylcuprate in diethyl ether at −20 oC. After removal of the TMS group, the final product 12 was obtained as a single isomer in 62% yield. The relative configuration of the product was established on the basis of the 1H-NMR and NOESY spectrum analysis. The stereochemical outcome suggested that the attack of the incoming nucleophile to unsaturated conjugated system occurred from the side with less steric hindrance.

Scheme 15. Synthesis of all-carbon quaternary stereogenic center at the bridgehead carbon in 11a.

3.4 Conclusions In summary, we have developed a highly regio- (>99:1) and enantioselective (up to 98% ee) Cu-catalyzed hetero-allylic asymmetric alkylation (h-AAA) with functionalized Grignard reagent bearing alkene or alkyne moieties for the first time. A novel strategy based on h-AAA in combination with ring-closing metathesis (RCM) of diene and enyne has been applied towards the catalytic enantioselective synthesis of cyclic allylic esters.

66

Chapter 3

In addition, compounds 6 showed high potential for further functonalization in the content of diversity-oriented synthesis (DOS). We have completed the stereoselective synthesis of four different ring-fused carbon [5,6], [6,6], [5,5], [6,5] bicyclic structures through Diels-Alder reactions on 2,4-dienol esters or Pauson-Khand reactions on enyne substrates. The synthetic versatility of this methodology was illustrated by stereocontrolled installation of an all-carbon quaternary center on the bridgehead carbon of a carbon [5,5] bicyclic structure. The resulting compounds are suitable synthons for multiscaffold library synthesis.


All experiments were carried out in flame-dried or oven-dried glassware, under an atmosphere of nitrogen (unless otherwise specified) by standard Schlenk techniques. Schlenk reaction tubes with screw caps, equipped with a Teflon-coated magnetic stirrer bar were oven dried under vacuum and allowed to return to room temperature prior to being charged with reactants. A manifold permitting alternation between nitrogen atmosphere and vacuum was used to control the atmosphere in the reaction vessel. Column chromatography was performed on silica gel Merk type 9385 230-400 mesh. TLC was performed on Merck TLC silica gel 60 Kieselguhr F254. Components were visualized by UV and staining with a solution of a mixture of KMnO4 (10 g) and K2CO3 (10 g) in H2O (500 mL). Mass spectra were recorded on a LTQ Orbitrap XL mass spectrometer (ESI+/APCI+/APPI+) or a Xevo® G2 QTof mass spectrometer with DART ionization. 1H and 13C NMR spectra were recorded on a Varian AMX400 (400 and 100.6 MHz, respectively) or a Varian Unity Plus Varian-500 (500 and 125 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Optical rotations were measured in CHCl3 on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL). Conversion of the reaction were determined by GC (GC, HP6890: MS HP5973) with an HP5 column (Agilent Technologies, Palo Alto, CA). The regioselectivity of the resulted product was determined by 1H NMR spectroscopy of the crude mixture. Enantiomeric excess were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector.

67


All solvents were reagent grade and were dried and distilled prior to use, if necessary. Tetrahydrofuran and diethylether were distilled over Na/benzophenone. Toluene and dichloromethane were distilled over calcium hydride. All the ligands and CuBr·SMe2 were purchased from Aldrich and used without further purification. Alkyl bromides except 4-bromo-1-trimethylsilyl-1-butyne38 and 5-bromo-1-trimethylsilyl-1-pentyne38 were purchased from Aldrich. All other commercially available reagents were used as received compounds. 1a, 1b and 1c were synthesized according to the procedure described by Trombini and Lombardo et al.39 Grignard reagents were prepared from the corresponding alkyl bromides and magnesium turnings in Et2O following standard procedures. Grignard reagents were titrated using sec-BuOH and catalytic amounts of 1,10-phenanthroline. Products 3a and 4a were reported elsewhere.9a

General procedure for copper catalyzed hetero-allylic asymmetric alkylation9a with Grignard reagent bearing terminal alkene group:

Grignard reagent 2 (0.64 mmol, 2 equiv) in Et2O was added dropwise over 5 min to a homogeneous, stirred and cooled (–70 °C) solution of the allylic bromide (0.32 mmol), CuBr·SMe2 (5.0 mol %) and L5 (5.5 mol %) in CH2Cl2 (3.5 mL) under a nitrogen atmosphere. The reaction mixture was stirred at the temperature indicated (typically overnight) until completion and then quenched with MeOH (5 mL). The reaction mixture was allowed to warm to room temperature and a saturated aqueous NH4Cl solution (5 mL) was added. The mixture was partitioned between CH2Cl2 (5 mL) and water. The organic layer was dried (MgSO4), filtered and the solvent was evaporated in vacuo. Purification by flash chromatography over silica gel, using Et2O/n-Pentane (1% to 2%) afforded the pure product 3 as a colorless oil.

68

Chapter 3

(+)-(S)-Octa-1,7-dien-3-yl benzoate (3b)

Synthesized according to the general procedure. Compound 3b was obtained as a colorless oil (95% yield, 97% ee). [α]20

D = +33.2 (c 3.6 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 2H), 7.56 (t, J = 6.9 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.99 – 5.68 (m, 2H), 5.62 – 5.44 (m,

1H), 5.33 (d, J = 17.2 Hz, 1H), 5.21 (d, J = 10.5 Hz, 1H), 5.04 (s, 1H), 5.00 – 4.88 (m, 1H), 2.11 (q, J = 7.0 Hz, 2H), 1.90 – 1.67 (m, 2H), 1.52 (dd, J = 15.2, 7.6 Hz, 2H). 13C NMR (100.6 MHz, CDCl3) δ 166.1, 138.5, 136.7, 133.1, 130.0, 129.8 (2×C), 128.6 (2×C), 116.9, 115.1, 75.4, 34.0, 33.7, 24.6. HRMS (ESI+, m/z): calcd for C15H18O2Na [M+Na]+: 253.11990, found 253.12015. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (Heptane/i-Propanol = 99/1, 0.5 mL/min, 224 nm, column temperature 40 °C), retention times: tR (major) 9.94 min, tR (minor) 11.54 min.

(+)-(S)-Nona-1,8-dien-3-yl benzoate (3c)

Compound 3c was obtained as a colorless oil (83% yield, 96% ee). [α]20D

= +21.4 (c 3.4 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.10 – 8.00 (m, 2H), 7.61 – 7.51 (m, 1H), 7.45 (m, 2H), 5.89 (ddd, J = 14.4, 10.3, 5.1 Hz, 1H), 5.84 – 5.69 (m, 1H), 5.49 (ddd, J = 12.2, 6.1, 1.1 Hz, 1H), 5.38 – 5.28 (m, 1H), 5.20 (dt, J = 10.5, 1.2 Hz, 1H), 5.07 – 4.87 (m, 2H),

2.10 – 2.03 (m, 2H), 1.88 – 1.66 (m, 2H), 1.52 – 1.34 (m, 4H). 13C NMR (100.6 MHz, CDCl3) δ 166.1, 138.9, 136.8, 133.1, 130.8, 129.8, 128.6, 116.9, 114.7, 75.5, 34.4, 33.8, 28.9, 24.8. HRMS (ESI+, m/z): calcd for C16H20O2Na [M+Na]+: 267.13555, found 267.13507. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (Heptane/i-Propanol = 98/2, 0.5 mL/min, 226 nm, column temperature 40°C), retention times: tR (major) 8.68 min, tR (minor) 10.00 min.

(+)-(S)-Deca-1,9-dien-3-yl benzoate (3d)

Compound 3c was obtained as a colorless oil (80% yield). [α]20D = +26 (c

0.6 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.00 (m, 2H), 7.58 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 5.89 (ddd, J = 14.1, 10.2, 4.9 Hz, 1H), 5.84 – 5.73 (m, 1H), 5.50 (dd, J = 13.1, 6.2 Hz, 1H), 5.32 (d, J = 17.2 Hz, 1H), 5.20 (d, J = 10.5 Hz, 1H), 5.05 – 4.89 (m, 2H), 2.04 (dd, J = 13.2,

6.4 Hz, 2H), 1.92 – 1.64 (m, 2H), 1.51 – 1.32 (m, 6H). 13C NMR (100.6 MHz, CDCl3) δ 165.8, 138.9, 136.6, 132.8, 130.6, 129.6, 128.3, 116.6, 114.3, 75.3, 34.3, 33.6, 28.9, 28.7,

OPh

O

OPh

O

OPh

O

69


24.9. HRMS (ESI+, m/z): calcd for C17H22O2Na [M+Na]+: 281.15120, found 281.15155. Enantiomeric excess of product was not successfully determined by chiral GC or HPLC.

General procedure for Ru-catalyzed ring-closing metathesis (RCM):9

Allylic ester 3 (0.6 mmol) was dissolved in degassed CH2Cl2 (12 mL) under a N2 atmosphere. Grubbs second generation catalyst (0.03 mmol) was tipped into the solution and then the mixture was heated at reflux for 18 h (40 °C). The mixture was cooled to room temperature and the solvents were removed under reduced pressure. Purification by flash chromatography (Ether/n-Pentane 1% to 2%) afforded the desired product 4.

(–)-(S)-Cyclohex-2-en-1-yl benzoate (4b)


D = –187.3 (c 3.7 in CHCl3). [lit.,40 (S isomer, 90% ee): [α]20

D = –164 (c 0.96 in CHCl3)]. 1H NMR (400 MHz, CDCl3) δ 8.31 – 7.83 (m, 2H), 7.61 – 7.50 (m, 1H), 7.48 – 7.34 (m, 2H), 6.11

– 5.94 (m, 1H), 5.90 – 5.80 (m, 1H), 5.51 (dd, J = 3.4, 1.6 Hz, 1H), 2.15 – 2.04 (m, 2H), 2.03 – 1.94 (m, 1H), 1.93 – 1.77 (m, 2H), 1.77 – 1.65 (m, 1H). 13C NMR (100.6 MHz, CDCl3) δ 166.4, 133.1, 133.0, 131.0, 129.8, 128.5, 125.9, 68.8, 28.6, 25.2, 19.2. HRMS (ESI+, m/z): calcd for C13H14O2Na [M+Na]+: 225.08860, found 225.04333. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (Heptane/i-Propanol = 99.9/0.1, 0.5 mL/min, 226 nm, column temperature 40 °C), retention times: tR (major) 19.55 min, tR (minor) 18.66 min.

(–)-(S)-Cyclohept-2-en-1-yl benzoate (4c)

Synthesized according to the general procedure. Compound 4c was obtained as a colorless oil (85% yield, 95% ee). [α]20

D = –37.4 (c 2.3 in CHCl3). [lit.,40 (S isomer, 97% ee): [α]20

D = –52 (c 0.85 in CHCl3)]. 1H NMR (400 MHz, CDCl3) δ 8.15 – 8.00 (m, 2H), 7.64 – 7.51 (m, 1H), 7.49 – 7.35 (m, 2H), 5.95

– 5.85 (m, 1H), 5.83 – 5.76 (m, 1H), 5.71 – 5.63 (m, 1H), 2.33 – 2.21 (m, 1H), 2.20 – 2.09 (m, 1H), 2.07 – 1.93 (m, 2H), 1.90 – 1.66 (m, 3H), 1.53 – 1.45 (m, 1H). 13C NMR (100.6

O

O

Ph

O

O

Ph

70

Chapter 3

MHz, CDCl3) δ 166.1, 133.7, 133.0, 132.2, 130.9, 129.8, 128.5, 74.9, 33.1, 28.8, 26.9, 26.8. HRMS (ESI+, m/z): calcd for C14H16O2Na [M+Na]+: 337.12304, found 337.12205. Enantiomeric excess was determined by chiral HPLC, Chiralpak AS-H (Heptane/i-Propanol = 99.9/0.1, 0.5 mL/min, 226 nm, column temperature 40 °C), retention times: tR (major) 11.60 min, tR (minor) 10.50 min.

General procedure for the preparation of alkyl bromide containing alkyne functional group:

To a stirred solution of PPh3 (33 mmol, 1.1 equiv) and the particular alcohol (30 mmol) in CH2Cl2 (30 mL) at room temperature was added N-bromosuccinimide (32 mmol, 1.07 equiv) and stirring was continued at room temperature for 5 h. The resulting phosphine oxides were precipitated by washing with the mixture of pentane/diethyl ether (1:1) and then filtered. The combined organic solution was dried over MgSO4, filtered and the solvent was removed in vacuum. The crude residue was then purified by Kugelrohr distillation to yield the corresponding alkyl bromide. The analytical data were identical in all respects to those previously reported.39

Procedure for the copper catalyzed hetero-allylic asymmetric alkylation with Grignard reagents bearing an alkyne moiety:

Method A: A solution of the appropriate Grignard reagent 5 (0.48 mmol, 1.5 equiv) in Et2O (1.5 M and 1.6 M for 5a and 5b, respectively) was diluted with CH2Cl2 (combined volume of 1 mL) and added dropwise for 4 h to a homogeneous, stirred and cooled (–80 °C) solution of the allylic bromide (0.32 mmol), CuBr·SMe2 (5.0 mol %) and L5 (5.5 mol %) in CH2Cl2 (3.2 mL) under a nitrogen atmosphere. The reaction mixture was stirred at that temperature (typically overnight) until completion and quenched with MeOH (5 mL). The mixture was removed from the cooling bath and a saturated aqueous NH4Cl

71


solution (5 mL) was added. The mixture was partitioned between CH2Cl2 and water. The organic layer was dried over MgSO4, filtered and the solvent was evaporated in vacuo. Purification by flash chromatography over silica gel, using Et2O/n-Pentane 1% to 2%, afforded the products 6a-c as colorless oils.

Method B: A solution of the appropriate Grignard reagent 5b (0.38 mmol, 1.2 equiv) in Et2O (1.6 M) was diluted with CH2Cl2 (combined volume of 1 mL) and added dropwise during 4 h to a homogeneous, stirred and cooled (–80 °C) solution of the allylic bromide 1c (0.32 mmol), copper(I) thiophenecarboxylate (CuTC, 3.0 mol %) and L4/L5 (3.3 mol %) in CH2Cl2 (3.2 mL) under a nitrogen atmosphere. The following steps are the same as described by method A.

(+)-(S)-7-(Trimethylsilyl)hept-1-en-6-yn-3-yl benzoate (6a)

Synthesized according to the general procedure Method A. Compound 6a was obtained as a colorless oil (74% yield, 98% ee). [α]20

D = +14.2 (c 1.3 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 9.8, 1.6 Hz, 1H), 7.61 – 7.51 (m, 1H), 7.44 (t, J = 6.8 Hz, 1H), 5.98 – 5.79 (m, 1H), 5.57 (dd, J = 12.4, 6.6 Hz, 1H), 5.35 (d, J = 16.0 Hz, 1H), 5.24 (d, J = 10.6 Hz,

1H), 2.36 (t, J = 7.5 Hz, 1H), 2.14 – 1.87 (m, 1H), 0.13 (s, 4H). 13C NMR (100.6 MHz, CDCl3) δ 165.6, 135.7, 132.9, 130.3, 129.6, 129.6, 128.3, 117.2, 105.9, 85.3, 74.1, 33.3, 16.0, 0.0. HRMS (ESI+, m/z): calcd for C17H22O2SiNa [M+Na]+: 309.12813, found 309.12846. Enantiomeric excess was determined by chiral HPLC, Chiralpak AS-H (Heptane/i-Propanol = 99.9/0.1, 0.5 mL/min, 226 nm, column temperature 40°C), retention times: tR (major) 11.60 min, tR (minor) 10.50 min.

(+)-(S)-8-(Trimethylsilyl)oct-1-en-7-yn-3-yl benzoate (6b)

Synthesized according to the general procedure Method A. Compound 6b was obtained as a colorless oil (84% yield, 97% ee). [α]20

D = +10.1 (c 5.7 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.20 – 7.91 (m, 2H), 7.63 – 7.51 (m, 1H), 7.50 – 7.32 (m, 2H), 6.11 –

Ph O

O

TMS

Ph O

O

TMS

72

Chapter 3

5.77 (m, 1H), 5.53 (dd, J = 12.7, 6.3 Hz, 1H), 5.34 (d, J = 17.2 Hz, 1H), 5.22 (d, J = 10.6 Hz, 1H), 2.28 (t, J = 7.1 Hz, 2H), 2.01 – 1.81 (m, 2H), 1.75 – 1.54 (m, 2H), 0.14 (s, 9H). 13C NMR (100.6 MHz, CDCl3) δ 165.8, 136.3, 132.9, 130.4, 129.6, 128.3, 116.8, 106.7, 85.0, 74.7, 33.3, 24.2, 19.7, 0.1. HRMS (ESI+, m/z): calcd for C18H24O2SiNa [M+Na]+: 323.14378, found 323.14404. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (Heptane/i-Propanol = 99.9/0.1, 0.5 mL/min, 226 nm, column temperature 40 °C), retention times: tR (major) 13.80 min, tR (minor) 12.98 min.

(+)-(S)-8-(Trimethylsilyl)oct-1-en-7-yn-3-yl cinnamate (6c)

Synthesized according to the general procedure Method A. Compound 6c was obtained as a colorless oil (75% yield, 96% ee). [α]20

D = +16.0 (c 0.4 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 16.0 Hz, 1H), 7.60 – 7.47 (m, 2H), 7.44 – 7.29 (m, 3H), 6.46 (d, J = 16.0 Hz, 1H), 5.90 – 5.78 (m, 1H),

5.41 (d, J = 5.9 Hz, 1H), 5.31 (d, J = 15.9 Hz, 1H), 5.21 (d, J = 10.5 Hz, 1H), 2.30 – 2.24 (m, 2H), 1.80 (t, J = 6.6 Hz, 2H), 1.68 – 1.52 (m, 2H), 0.13 (s, 9H). 13C NMR (100.6 MHz, CDCl3) δ 166.8, 144.8, 136.3, 134.4, 130.3, 128.9, 128.1, 118.3, 116.8, 106.7, 85.0, 74.3, 33.3, 24.2, 19.6, 0.1. HRMS (ESI+, m/z): calcd for C20H26O2SiNa [M+Na]+: 349.15943, found 349.15943. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (Heptane/i-Propanol = 99/1, 0.5 mL/min, 270 nm, column temperature 40 °C), retention times: tR (major) 14.48 min, tR (minor) 12.64 min.

(+)-(S)-2-Methyl-8-(trimethylsilyl)oct-1-en-7-yn-3-yl benzoate (6d)

Synthesized according to the general procedure Method B. Compound 6d was obtained as a colorless oil (72% yield, 92% ee). [α]20

D = +13.0 (c 1.9 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 8.1, 1.0 Hz, 2H), 7.64 – 7.52 (m, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.44 (t, J = 6.5 Hz, 1H), 5.05 (s, 1H), 4.94 (s, 1H), 2.28 (t, J =

6.9 Hz, 2H), 1.91 (dt, J = 14.4, 4.7 Hz, 2H), 1.81 (s, 3H), 1.70 – 1.52 (m, 2H), 0.14 (s, 9H). 13C NMR (100.6 MHz, CDCl3) 165.71, 142.9, 132.9, 130.5, 129.6, 128.3, 112.8, 106.7, 85.1, 77.3, 31.7, 24.3, 19.6, 18.2, 0.1. HRMS (APCI+, m/z): calcd for C19H27O2Si [M+H]+: 315.17748, found 315.17749. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (Heptane/i-Propanol = 99.9/0.1, 0.5 mL/min, 226 nm, column temperature 40 °C), retention times: tR (major) 14.62 min, tR (minor) 12.83 min.

O

O

Ph

TMS

Ph O

O

TMS

73


General procedure for deprotection of trimethylsilyl (TMS) alkynes:

In a roundbottom flask, a solution of tetra-n-butylammonium fluoride (TBAF) (1.0M in THF) (2.0 equiv) was added dropwise to a solution of allylic ester 6 (1.0 equiv) in dry THF (0.05 M) at 0 oC. The mixture was allowed to warm to rt over 1 h. The reaction was quenched with water and the mixture was extracted with diethyl ether (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography over silica gel (Et2O/n-Pentane 1% to 2%) to yield the desired product 7.

(+)-(S)-Hept-1-en-6-yn-3-yl benzoate (7a)

Synthesized according to the general procedure. Compound 7a was obtained as colorless oil (74%, 98% ee). [α]20

D = +15.6 (c 0.8 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.16 – 7.99 (m, 2H), 7.59 – 7.54 (m, 1H), 7.46 – 7.43 (m, 2H), 6.01 – 5.80 (m, 1H), 5.61 (dd, J = 12.9, 6.3 Hz, 1H),

5.37 (d, J = 17.2 Hz, 1H), 5.25 (d, J = 10.6 Hz, 1H), 2.33 (td, J = 7.3, 2.6 Hz, 2H), 2.19 – 1.85 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 165.7, 135.6, 133.0, 130.3, 129.6, 128.4, 117.3, 83.1, 73.9, 69.0, 33.1, 14.6. HRMS (ESI+, m/z): calcd for C14H14O2Na [M+Na]+: 237.08860, found 237.08813. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (Heptane/i-Propanol = 99/1, 0.5 mL/min, 226 nm, column temperature 40°C), retention times: tR (major) 17.15 min, tR (minor) 14.71 min.

(+)-(S)-Oct-1-en-7-yn-3-yl benzoate (7b)


D = +18.7 (c 3.7 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.15 – 7.97 (m, 2H), 7.63 – 7.51 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 5.90 (ddd, J = 16.9, 10.5, 6.2 Hz, 1H),

5.55 (d, J = 6.2 Hz, 1H), 5.34 (d, J = 17.2 Hz, 1H), 5.22 (d, J = 10.5 Hz, 1H), 2.25 (m, 2H), 1.97 (s, 1H), 1.89 (m, 2H), 1.78 – 1.52 (m, 2H). 13C NMR (100.6 MHz, CDCl3) δ 165.7, 136.2, 132.9, 130.4, 129.6, 128.3, 116.9, 83.8, 74.7, 68.8, 33.3, 24.0, 18.2. HRMS (ESI+,

Ph O

O

Ph O

O

74

Chapter 3

m/z): calcd for C15H16O2Na [M+Na]+: 251.10425, found 251.10459. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (Heptane/i-Propanol = 98/2, 0.5 mL/min, 226 nm, column temperature 40 °C), retention times: tR (major) 13.95 min, tR (minor) 16.48 min.

(+)-(S)-Oct-1-en-7-yn-3-yl cinnamate (7c)


D = +33.0 (c 1.1 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 16.0 Hz, 1H), 7.60 – 7.48 (m, 2H), 7.45 – 7.36 (m, 3H), 6.46 (d, J = 16.0 Hz, 1H),

5.85 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H), 5.41 (dd, J = 13.0, 6.2 Hz, 1H), 5.31 (dt, J = 17.2, 1.3 Hz, 1H), 5.21 (dt, J = 10.5, 1.2 Hz, 1H), 2.25 (td, J = 7.0, 2.6 Hz, 2H), 1.97 (s, 1H), 1.88 – 1.78 (m, 2H), 1.70 – 1.57 (m, 2H). 13C NMR (100.6 MHz, CDCl3) δ 166.2, 144.9, 136.3, 134.4, 130.3, 128.9, 128.1, 118.2, 116.9, 83.9, 74.3, 68.7, 33.2, 24.0, 18.2. HRMS (ESI+, m/z): calcd for C17H18O2Na [M+Na]+: 277.11990, found 277.12027. Enantiomeric excess was determined by chiral HPLC, Chiralpak OJ-H (Heptane/i-Propanol = 99/1, 0.5 mL/min, 270 nm, column temperature 40 °C), retention times: tR (major) 31.19 min, tR (minor) 35.12 min.

General procedure for the Ru-catalyzed ene-yne metathesis:

The corresponding substrate 7 was dissolved in degassed CH2Cl2 (0.05 M) and Grubbs 1st generation catalyst (10.0 mol %) was added to the solution in two portions. The mixture was heated at reflux under an ethylene atmosphere (1 atm, balloon) until full conversion was achieved (24-48 h), as indicated by GC-MS. The mixture was concentrated after filtration through a pad of silica and purified by column chromatography over silica gel (Et2O/n-Pentane 1% to 2%) to yield the desired products 8 as a colourless oil.

O

O

Ph

75


(−)-(S)-3-Vinylcyclopent-2-en-1-yl benzoate (8a)

Synthesized according to the general procedure. Compound 8a was obtained as a colorless oil (43% yield, 98% ee). [α]20

D = −145.4 (c 3.2 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.06 – 7.95 (m, 2H), 7.53 (dd, J = 10.5, 4.3 Hz, 1H), 7.39-7.46 (m, 2H), 6.62 (dd, J = 17.5, 10.6 Hz, 1H), 6.04 – 5.93 (m, 1H),

5.88 (s, 1H), 5.29 (d, J = 17.5 Hz, 1H), 5.25 (d, J = 10.7 Hz, 1H), 2.76 – 2.65 (m, 1H), 2.41-2.55 (m, 2H), 2.07 (ddd, J = 8.7, 6.4, 3.6 Hz, 1H). 13C NMR (100.6 MHz, CDCl3) δ 166.4, 148.2, 132.8, 132.7, 130.7, 129.6, 128.2, 127.8, 117.5, 81.0, 30.1, 29.2. TOF-MS (DART, m/z): calcd for C14H14O2 [M+H]+: 215.1028, found 215.0989. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (Heptane/i-Propanol = 99/1, 0.5 mL/min, 226 nm, column temperature 40 °C), retention times: tR (major) 17.73 min, tR (minor) 11.67 min.

(−)-(S)-3-Vinylcyclohex-2-en-1-yl benzoate (8b)


D = −204 (c 5.5 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.08 – 8.02 (m, 2H), 7.64 – 7.50 (m, 1H), 7.49 – 7.28 (m, 2H), 6.38 (dd, J = 17.5, 10.7 Hz, 1H), 5.86 (d, J = 3.5 Hz, 1H), 5.62

(d, J = 4.3 Hz, 1H), 5.27 (d, J = 17.5 Hz, 1H), 5.09 (d, J = 10.8 Hz, 1H), 2.30 (dt, J = 17.3, 5.7 Hz, 1H), 2.23 – 2.09 (m, 1H), 2.06 – 1.83 (m, 3H), 1.83 – 1.70 (m, 2H). 13C NMR (100.6 MHz, CDCl3) δ 166.2, 140.7, 139.0, 132.8, 130.7, 130.5, 129.6, 128.3, 126.4, 113.5, 69.5, 28.4, 23.6, 19.1. HRMS (ESI+, m/z): calcd for C15H16O2Na [M+Na]+: 251.10425, found 251.10461. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (Heptane/i-Propanol = 99/1, 0.5 mL/min, 226 nm, column temperature 40 °C), retention times: tR (major) 15.08 min, tR (minor) 10.45 min.

(−)-(S)-3-Vinylcyclohex-2-en-1-yl benzoate (8c)


D = −197 (c 3.1 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 16.0 Hz, 1H), 7.55 (dd, J = 6.7, 2.8 Hz, 2H), 7.44 – 7.37 (m, 3H), 6.47 (d, J = 16.0 Hz, 1H), 6.41

(dd, J = 17.5, 10.8 Hz, 1H), 5.83 (d, J = 3.3 Hz, 1H), 5.54 (d, J = 4.0 Hz, 1H), 5.29 (d, J = 17.4 Hz, 1H), 5.12 (d, J = 10.8 Hz, 1H), 2.31 (dt, J = 17.2, 5.6 Hz, 1H), 2.23 – 2.14 (m, 1H), 2.03 – 1.70 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 169.3, 147.3, 143.4, 141.7, 137.2, 132.9, 131.6, 130.7, 129.1, 121.2, 116.2, 71.6, 31.2, 26.4, 21.5. HRMS (ESI+, m/z):

O Ph

O

O Ph

O

O

O

Ph

76

Chapter 3

calcd for C17H18O2Na [M+Na]+: 277.11990, found 277.12029. Enantiomeric excess was determined by chiral HPLC, Chiralpak AS-H (Heptane/i-Propanol = 99/1, 0.5 mL/min, 221 nm, column temperature 40°C), retention times: tR (major) 10.54 min, tR (minor) 14.00 min.

(+)-(S)-2-Methyl-7-methylenenona-1,8-dien-3-yl benzoate (9)

In a roundbottom flask, a solution of tetra-n-butylammonium fluoride (TBAF) (1.0 M in THF) (2.0 equiv) was added dropwise to a solution of allylic ester 6d (1.0 equiv) in dry THF (0.05 M) at 0 oC. The mixture was allowed to warm to rt over 1h. The reaction was quenched with water and the mixture was extracted with ether (3×10 mL). The

combined organic extracts were dried over MgSO4, filtered, and concentrated. The corresponding intermediate 7d was then dissolved in degassed CH2Cl2 (0.05 M) and Grubbs 1st generation catalyst (10 mol %) was added to the solution in two portions. The mixture was heated at reflux under an ethylene atmosphere (1 atm, balloon) until full conversion was achieved (20 h), as indicated by GC-MS. The mixture was concentrated after filtration through a pad of silica and purified by column chromatography over silica gel (Et2O/n-Pentane 1% to 2%) to yield the desired product 9 as a colourless oil in 66% yield. [α]20

D = +11 (c 1.0 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.59 – 7.88 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 5.68 (d, J = 2.9 Hz, 1H), 5.42 (d, J = 6.5 Hz, 1H), 5.39 (d, J = 3.0 Hz, 1H), 5.03 (s, 1H), 4.92 (s, 1H), 4.83 (s, 1H), 4.81 (s, 1H), 2.24 (t, J = 7.4 Hz, 2H), 1.79 (s, 3H), 1.77 – 1.66 (m, 2H), 1.57 – 1.40 (m, 2H). 13C NMR (100.6 MHz, CDCl3) δ 165.8, 152.9, 151.2, 143.2, 132.8, 130.6, 129.6, 128.3, 125.3, 112.7, 111.5, 77.8, 35.2, 32.3, 23.6, 18.2. HRMS (APCI+, m/z): calcd for C18H23O2 [M+H]+: 271.16926, found 271.16884.

General procedure for one-pot consecutive enyne metathesis /Diels−Alder reaction:

Substrate 7 was dissolved in dry toluene (0.05 M) and Grubbs first generation catalyst (10.0 mol %) was added to the solution in two portions (5.0 mol % at the beginning and 5.0 mol % after 6 h). The mixture was heated in toluene (80 oC) under an ethylene atmosphere (1 atm, balloon) until full conversion to dienol ester 8 was achieved, as

Ph O

O

77


indicated by TLC. Then diethyl acetylenedicarboxylate (10 equiv) was added dropwise and the resulting solution was heated at 160 oC in a sealed tube until TLC analysis indicated complete consumption of diene 8. The reaction mixture was filtered through a plug of silica and concentrated in vacuo. The residue was subjected to flash chromatography over silica gel (EtOAc/n-Pentane 10% to 20%) to yield the desired product 10. The stereochemical outcome was determined by 1H-NMR and NOESY analysis.

(+)-(3S,3aR)-Diethyl-3-(benzoyloxy)-2,3,3a,6-tetrahydro-1H-indene-4,5-dicarboxylate (10a)

Synthesized according to the general procedure. Compound 10a was obtained as a colorless oil (54% yield, 97% ee). [α]20

D = +70.2 (c 0.7 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.4 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 5.62 (s, 1H), 5.22 (dt, J = 9.0,

7.5 Hz, 1H), 4.19 – 4.24 (m, 4H), 3.96 – 4.01 (m, 1H), 3.83 – 3.89 (m, 1H), 3.62 (ddd, J = 10.5, 9.0, 1.2 Hz, 1H), 3.19 (dt, J = 22.5, 6.0 Hz, 1H), 2.99 (dd, J = 22.5, 11.9 Hz, 1H), 2.58 (d, J = 11.8 Hz, 1H), 2.39 – 2.48 (m, 2H), 1.85 – 1.74 (m, 1H), 1.29 (t, J = 7.3 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 171.4, 168.5, 168.4, 141.8, 138.1, 135.8, 132.6, 132.3, 131.1, 130.5, 119.1, 64.0, 63.8, 48.9, 32.4, 32.3, 30.6, 29.5, 16.7, 16.3. HRMS (ESI+, m/z): calcd for C22H25O6 [M+H]+: 385.16456, found 385.16560. Enantiomeric excess was determined by chiral HPLC, Chiralpak OJ-H (Heptane/i-Propanol = 97/3, 0.5 mL/min, 232 nm, column temperature 40 °C), retention times: tR (major) 10.54 min, tR (minor) 14.00 min.

(+)-(8S,8aR)-Diethyl-8-(benzoyloxy)-3,5,6,7,8,8a-hexahydronaphthalene-1,2 dicarboxylate (10b)


D = +87.0 (c 2.4 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J = 8.2, 1.2 Hz, 2H),

7.57 (dd, J = 10.6, 4.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 5.58 (s, 1H), 4.90 (td, J = 10.5, 4.4 Hz, 1H), 4.20 (dq, J = 10.9, 7.1 Hz, 1H), 4.11 (dq, J = 10.9, 7.1 Hz, 1H), 3.80 (dq, J = 10.7, 7.2 Hz, 1H), 3.64 (dt, J = 10.5, 6.5 Hz, 1H), 3.45 (dq, J = 10.7, 7.2 Hz, 1H), 3.18 (dd, J = 23.2, 7.3 Hz, 1H), 2.85 (dddd, J = 23.2, 6.1, 3.9, 2.3 Hz, 1H), 2.34 (d, J = 13.0 Hz, 1H), 2.27 (dd, J = 12.5, 3.4 Hz, 1H), 2.02 (t, J = 13.0 Hz, 1H), 1.91 (d, J = 13.1 Hz, 1H), 1.71 – 1.59 (m, 1H), 1.54 – 1.42 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H).

BzO CO2EtCO2Et

H

BzO CO2EtCO2Et

H

78

Chapter 3

13C-NMR (125 MHz, CDCl3) δ 169.4, 167.3, 165.5, 135.0, 134.6, 133.2, 131.7, 130.2, 129.9, 128.4, 117.5, 77.1, 61.3, 61.2, 45.0, 34.7, 32.9, 28.0, 25.1, 14.2, 13.2. HRMS (ESI+, m/z): calcd for C23H29O6Na [M+Na]+: 421.16216, found 421.16245. Enantiomeric excess was determined by chiral HPLC, Chiralpak OJ-H (Heptane/i-Propanol = 99/1, 0.5 mL/min, 233 nm, column temperature 40 °C), retention times: tR (major) 32.440 min, tR (minor) 28.68 min.

General procedure for the Pauson-Khand reaction:

A solution of enyne 6 (1.0 equiv) in dry CH2Cl2 (0.05 M) was added to a flask containing Co2(CO)8 (1.1 equiv) under a N2 atmosphere. The resulting solution was stirred at room temperature for 2 h until TLC analysis showed that formation of the cobalt complex was complete, and the solvent was then removed in vacuo. The residue was diluted with CH3CN (0.025 M) and the resulting solution was heated to 80 oC until disappearance of the cobalt complex (purple). The reaction mixture was filtered through a plug of silica and washed by diethyl ether. The combined organic solvents were evaporated and the residue was purified by chromatography over silica gel (EtOAc/n-Pentane 5% to 20%) to yield the desired products 11.

(−)-(1S,6aS)-5-Oxo-4-(trimethylsilyl)-1,2,3,5,6,6a-hexahydropentalen-1-yl benzoate (11a)

Synthesized according to the general procedure. Compound 11a was obtained as colorless crystals (64% yield, 98% ee). M.p. 85 – 91 oC. [α]20

D = −19.0 (c 0.8 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 4.99 (dd, J = 12.5,

8.5 Hz, 1H), 3.32 – 3.18 (m, 1H), 2.94 (ddd, J = 18.4, 11.7, 2.5 Hz, 1H), 2.82 – 2.71 (m, 1H), 2.67 (dd, J = 17.9, 6.6 Hz, 1H), 2.64 – 2.57 (m, 1H), 2.42 (dd, J = 17.8, 3.9 Hz, 1H), 2.21 (tt, J = 12.7, 8.4 Hz, 1H), 0.24 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 215.9, 193.9, 169.1, 141.2, 135.8, 132.6, 132.3, 131.1, 55.3, 44.7, 34.3, 29.3, 1.5. HRMS (ESI+, m/z): calcd for C18H22O3SiNa [M+Na]+: 337.12304, found 337.12205. Enantiomeric excess was determined by chiral HPLC, Chiralpak AS-H (Heptane/i-Propanol = 99/1, 0.5 mL/min,

BzO H

TMS

O

79


229 nm, column temperature 40 °C), retention times: tR (major) 12.56 min, tR (minor) 11.75 min.

(+)-(7S,7aS)-2-Oxo-3-(trimethylsilyl)-2,4,5,6,7,7a-hexahydro-1H-inden-7-yl benzoate (11b)

Synthesized according to the general procedure. Compound 11b was obtained as colorless crystals (55% yield, 97% ee). M.p. 79 – 82 oC. [α]20

D = +166.2 (c 1.0 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 8.06 (dd, J = 8.0, 0.9 Hz, 2H), 7.60 (dd, J = 10.5, 4.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 4.78

(td, J = 10.9, 4.3 Hz, 1H), 3.06 (d, J = 13.8 Hz, 1H), 3.02 – 2.93 (m, 1H), 2.54 (dd, J = 18.7, 6.9 Hz, 1H), 2.37 – 2.30 (m, 1H), 2.30 – 2.17 (m, 1H), 2.16 – 2.07 (m, 1H), 1.85 – 1.64 (m, 1H), 1.65 – 1.47 (m, 1H), 0.34 – 0.02 (m, 9H). 13C NMR (125 MHz, CDCl3) δ 211.7, 185.5, 165.9, 139.5, 133.1, 130.2, 129.6, 128.4, 78.5, 49.0, 40.1, 31.2, 30.3, 23.8, –0.4. HRMS (ESI+, m/z): calcd for C19H24O3SiNa [M+Na]+: 351.13869, found 351.13911. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (Heptane/i-Propanol = 95/5, 0.5 mL/min, 228 nm, column temperature 40 °C), retention times: tR (major) 14.14 min, tR (minor) 11.34 min.

The synthesis of an all-carbon quaternary stereogenic center:

A solution of methyllithium (1.6 M) in dry diethyl ether (0.62 mL, 1 mmol) was added slowly to a suspension of CuI (95.2 mg, 0.5 mmol) in diethyl ether (1 mL) at 0 oC under a N2 atmosphere. The mixture obtained was cooled to −20 ºC before a solution of substrate 11a (15.7 mg, 0.05 mmol) in diethyl ether (1 mL) was added dropwise. After stirring at −20 ºC over 4 h, the reaction mixture was quenched with a saturated aqueous NH4Cl solution (4 mL) and extracted with diethyl ether (3×5 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated in vacuo. The crude mixture was dissolved in dry THF and tetra-n-butylammonium fluoride (TBAF) in THF (1 M in THF, 0.1 mL, 0.1 mmol) was added dropwise to the solution at 0 ºC. The mixture was allowed to warm to room temperature over 1 h. The organic solvent was removed in vacuo. The crude product was purified by column chromatography over silica gel (Et2O/n-Pentane 10% to 20%) to produce the desired product 12 as a colorless oil in 62% yield.

BzOH

TMS

O

80

Chapter 3

(+)-(1S,3aR,6aS)-3a-Methyl-5-oxooctahydropentalen-1-yl benzoate (12)

[α]20D = +23.8 (c 0.7 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J =

7.9 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 5.19 (dt, J = 6.2, 3.1 Hz, 1H), 2.75 (ddd, J = 11.4, 10.4, 1.6 Hz, 1H), 2.56 – 2.46 (m, 1H), 2.42 – 2.21 (m, 4H), 2.13 – 2.03 (m, 1H), 1.97 (dt, J = 13.3, 8.0 Hz, 1H),

1.80 (ddd, J = 13.5, 8.0, 5.7 Hz, 1H), 1.39 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 220.9, 168.8, 135.5, 133.0, 132.0, 131.0, 85.6, 55.8, 54.8, 48.7, 45.2, 40.9, 34.1, 31.1. HRMS (APPI+, m/z): calcd for C16H18O3 [M+H]+: 259.13287, found 259.13288.

Crystal structure determination of 11a

Crystal data. C18H22O3Si, Fw = 314.45, colourless plate, 0.52 x 0.44 x 0.04 mm3, orthorhombic, P212121 (no. 19), a = 8.6212(3), b = 12.3575(3), c = 15.7882(4) Å, V = 1682.01(8) Å3, Z = 4, Dx = 1.242 g/cm3, μ = 0.15 mm-1. 31746 Reflections were measured on a Bruker Kappa ApexII diffractometer with sealed tube and Triumph monochromator (λ = 0.71073 Å) up to a resolution of (sin θ/λ)max = 0.65 Å-1 at a temperature of 150(2) K. Intensity data were integrated with the Eval15 software.41 Absorption correction and scaling was performed based on multiple measured reflections with SADABS (0.53 − 0.75 correction range).42 3867 Reflections were unique (Rint = 0.028), of which 3660 were observed [I > 2σ(I)]. The structure was solved with Direct Methods using the program SHELXS-97 and refined with SHELXL-9743 against F2 of all reflections. All non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were located in difference Fourier maps and refined with a riding model. 203 Parameters were refined with no restraints. R1/wR2 [I > 2σ(I)]: 0.0253 / 0.0665. R1/wR2 [all refl.]: 0.0280 / 0.0677. S = 1.063. Flack parameter44 x = 0.01(8). Residual electron density between −0.22 and 0.25 e/Å3. Geometry calculations and checking for higher symmetry was performed with the PLATON program.45

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19 For selected reviews on ring-closing olefin metathesis, see: a) M. Schuster, S. Blechert, Angew.

Chem. Int. Ed. 1997, 36, 2036-2056; b) R. H. Grubbs, S. Chang, Tetrahedron 1998, 54, 4413-4450;

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20 For the selected examples on the enantioselective synthesis of cyclic benzoate esters, see: a) M. B.

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J. Org. Chem. 2010, 75, 7917-7919; g) M. Gärtner, D. Kossler, D. Pflästerer, G. Helmchen, J. Org.

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Sato, M. Mori, Adv. Synth. Catal. 2002, 344, 678-693.

27 The moderate isolated yield (43%) of product 8a is possibly attributed to volatility problems.

28 T. A. Kirkland, R. H. Grubbs, J. Org. Chem. 1997, 62, 7310-7318.

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32 K. Takatori, K. Hasegawa, S. Narai, M. Kajiwara, Heterocycles 1996, 42, 525-528.

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35 CCDC-889474 (11a) contains the supplementary crystallographic data for this paper. These data

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36 a) J. Adrio, M. Rodríguez Rivero, J. C. Carretero, Angew. Chem. Int. Ed. 2000, 39, 2906-2909; b) J.

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85


center on the bridgehead carbon, see: b) L. A. Paquette, P. G. Meister, D. Friedrich, D. R. Sauer, J.

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38 Y. Nishimoto, M. Kajioka, T. Saito, M. Yasuda, A. Baba, Chem. Commun. 2008, 6396-6398.

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Chapter 4

Asymmetric Conjugate Addition of Grignard

Reagents to Pyranones

An efficient enantioselective synthesis of lactones was developed based on the catalytic asymmetric conjugate addition (ACA) of alkyl Grignard reagents to pyranones. The use of 2H-pyran-2-one for the first time in the ACA with Grignard reagents allows for a variety of further transformations to access highly versatile building blocks such as β-alkyl substituted aldehydes or β-bromo-γ-alkyl substituted alcohols with excellent regio- and stereoselectivity.


B. Mao, M. Fañanás-Mastral, B. L. Feringa, Org. Lett. 2013, 15, 286-289.

87

Chapter 4

4.1 Introduction In previous chapter, the catalytic asymmetric synthesis of butenolides and butyrolactones has been developed by using copper-catalyzed allylic asymmetric alkylation and ring-closing metathesis as key steps. Other important oxygen containing heterocyclic compounds are six-membered lactones. Pyranones, in particular dihydropyran-2-ones and their derivatives, have attracted major attention due to the interesting biological activities1 and the synthetic perspective2 associated with these privileged structures (Figure 1). For instance, the densely functionalized secologanin glucoside has been shown to be the common biosynthetic precursor of several structurally diverse classes of natural products.3

Figure 1. Bioactive compounds with the pyranone core structure.

4.1.1 Enantioselective synthesis of 3,4-dihydropyran-2-ones

Several synthetic approaches have been reported towards the preparation of enantiomerically pure 3,4-dihydropyran-2-ones.4, 5 In 2006, Bode and co-workers reported the enantioselective NHC-catalyzed Diels–Alder reaction of racemic α-chloro aldehydes4a with enones to provide 3,4,6-trisubstituted dihydropyran-2-ones (Scheme 1).4b This reaction was amenable to aromatic and aliphatic α-chloro aldehydes and electron-withdrawing aromatic and aliphatic enones. The reaction proceeded with 0.5 mol % catalyst loadings of NHC precursor C1 through the formation of a Breslow intermediate and provided the dihydropyran-2-ones in 70–95% yield, 86–99% ee and 3:1 to > 20:1 dr (Scheme 1). The cis-diastereoselectivity was attributed to the formation of the

88

Asymmetric Conjugate Addition of Grignard Reagents to Pyranones

(Z)-enolate in the NHC-redox reaction with the α-chloro aldehyde and a high preference

for the (Z)-enolate to react in an endo cycloaddition with the enone. Moreover, Bode and

co-workers also described that α-chloroaldehyde bisulfite adducts react with unsaturated

carbonyls under biphasic reaction conditions, affording dihydropyran-2-ones in high

yields and enantioselectivities.4c It should be noted that all the above reactions gave rise to

the substituted enol ester (R1 H) and hence putting some limitations to the resultant enol

functionality.

Scheme 1. Enantioselective synthesis of trisubstituted dihydropyran-2-ones through NHC-catalyzed

hetero-Diels–Alder reaction.4b-c Mes = mesityl.

Mukaiyama and coworkers has reported an enantioselective one-pot synthesis of

3,4-dihydropyran-2-ones by asymmetric domino Michael addition and lactonization

between α,β-unsaturated ketones and various ketene silyl acetals derived from phenyl

carboxylates in the presence of catalytic amount of cinchona-alkaloid-derived quaternary

ammonium phenoxide C2 (Scheme 2).5 The organocatalyst C2 was easily prepared from

commercially available cinchona alkaloids and afforded 3,4-dihydropyran-2-ones in high

yields and enantioselectivities within only one hour. In this reaction, the phenoxy group on

the silyl enolate behaved as an effective leaving group to facilitate intramolecular

cyclization of the in situ generated Michael adduct, and the liberated phenoxide ion acted

also as a Lewis base catalyst to activate silyl enolate. It’s important to note that for this

transformation, only substituted enol esters were obtained (R1 H) and the R2 group was

limited to aromatic substituents in most cases.

89

Chapter 4

Scheme 2. Synthesis of 3,4-dihydropyran-2-ones catalyzed by quaternary ammonium phenoxide.

4.1.2 Copper-catalyzed asymmetric conjugate addition of cyclic enones and cyclic esters with Grignard reagents

The copper-catalyzed asymmetric conjugate addition (ACA) of organometallic reagents to α,β-unsaturated carbonyl compounds is one of the most versatile synthetic methods for the enantioselective construction of C–C bonds.6 Over the past decade, extensive efforts have been made to develop efficient catalysts for the copper-catalyzed asymmetric conjugate addition (ACA) of Grignard reagents to the large variety of acceptors including acyclic α,β-unsaturated enones,7 esters and thioesters.8 The copper-catalyzed ACA reaction of Grignard reagents to cyclic enones has also been successfully achieved with good to excellent enantioselectivities by applying various catalytic systems.9

Tomioka and co-authors developed a chiral amidophosphine catalyst to promote the highly enantioselective conjugate addition of Grignard reagents to cyclic enones.9d-e In addition to expand the substrate scope for this catalytic system, an unsaturated cyclic ester was also examined to provide the corresponding 1,4-addition products in moderate yields with promising levels of enantiomeric excess (76-90% ee, Scheme 3).9f However, the requirement of high catalyst loading (32.0 mol %) imposed some limitations on the further application for this catalytic system.

90


Scheme 3. Cu-catalyzed ACA of Grignard reagents to 5,6-dihydro-2H-pyran-2-one with a chiral

amidophosphine catalyst.

In 2004, our group reported the copper-catalyzed asymmetric conjugate addition of

Grignard reagents to cyclic enones with enantioselectivities up to 96% (Scheme 4a).9g This

excellent level of stereocontrol is achieved by using CuCl or CuBr·SMe2 as metal source,

simple alkylmagnesium bromides as nucleophiles, and commercially available ferrocenyl

diphosphines as chiral ligands. However, this method still present limitations using less

reactive unsaturated esters such as simple 5,6-dihydro-2H-pyran-2-one, providing the

corresponding addition product with modest enantioselectivities up to 82% ee (Scheme

4b).

•

n n

R,St

•

R,R

Scheme 4. ACA of Grignard reagents to cyclohexenone and 5,6-dihydro-2H-pyran- 2-one.

Schmalz and co-workers developed a strategy based on the use of bidentate

Taddol-derived phophine-phosphite ligands in combination with CuBr·SMe2 to explore the

copper-catalyzed ACA of various Grignard reagents to cyclic α,β-unsaturated systems.9j-k

It is noteworthy that this was the first Cu-based catalyst system described which allowed

91

Chapter 4

to transfer alkenyl and aryl Grignard reagents to cyclohexenone substrate with high enantioselectivity. However, when using 5,6-dihydro-2H-pyran-2-one under the optimized conditions for ACA of cyclohexenone, the desired 1,4-addition product was obtained in high conversion with only 71% ee (Scheme 5).9k For these α,β-unsaturated lactones, further improvements in the enantioselectivity of the reaction as well as reducing the catalyst loading still remain a challenge.

Scheme 5. Conjugate addition of ethylmagnesium bromide to 5,6-dihydro-2H-pyran-2-one with a chiral phophine-phosphite ligand.

A recent study from our group disclosed the chiral bidentate phosphine ligand L6 as an efficient ligand for the Cu-catalyzed asymmetric conjugate addition of Grignard reagents to coumarins, affording the desired products in good yields with high enantioselectivities (Scheme 6).10 Various coumarin derivatives and functionalized Grignard reagents were shown to be tolerated in this reaction. In addition, the corresponding enolate has been demonstrated as a highly versatile starting point for the synthesis of a variety of chiral products such as esters and amides, which was previously unavailable via a direct conjugate addition protocol.

Scheme 6. Cu-catalyzed conjugate addition of Grignard reagents to coumarins.

92


4.2 Project Goal As mentioned, protocols that allow the introduction of alkyl groups at the newly formed stereogenic center have been slower to develop in the asymmetric synthesis of structurally diverse 3,4-dihydropyran-2-ones. While addressing this challenge, we envisioned the possibility of applying 2H-pyran-2-one11 as substrate in the Cu-catalyzed asymmetric conjugate addition (ACA) of Grignard reagents, to access optically active dihydropyran-2-ones (Scheme 7).10

Scheme 7. Catalytic asymmetric 1,4-addition of Grignard reagents to 2H-pyran-2-one.

2H-Pyran-2-ones, featuring an electron deficient diene moiety, are common precursors for [4+2] and [2+2] cycloadditions to construct bicyclic building blocks.12 However, the increased electron delocalization, compared with acyclic α,β-unsaturated esters, results in a lower reactivity towards ACA reactions. There is also considerably more difficulty in controlling the regioselectivity of the addition to these extended conjugate systems, due to the presence of different electrophilic sites, as well as the stereoselectivity.13 To the best of our knowledge, asymmetric 1,4-additions of Grignard reagents to 2H-pyran-2-ones still remain elusive. Such a reaction could provide an efficient, direct and versatile method towards the synthesis of chiral 4-alkyl-3,4-dihydropyran-2-ones. In addition, the resulting chiral intermediates would allow for a variety of further transformations in particular by addition to the enol ester moiety to access densely functionalized intermediates with excellent regio- and stereochemical control (Scheme 8).

3

Scheme 8. Proposed routes to intermediates by transformation of chiral dihydropyran-2-ones.

93

Chapter 4

4.3 Results and Discussion 4.3.1 Screening of reaction parameters

We began our studies by examining the conjugate addition of ethylmagnesium bromide to 2H-pyran-2-one with (RFe,R)-TaniaPhos L1 as ligand, which has been successfully employed in the conjugate addition of Grignard reagents to cyclic enones,9g 2a was obtained only as a racemic 1,4-addition product (Table 1, entry 1). Although potential competing pathways for pyran-2-one include 1,6-conjugate addition13,14 and 1,2-addition, exclusive formation of 1,4-addition product with moderate enantioselectivity was observed when we applied to (RFe,S)-JosiPhos L3 in the presence of a catalytic amount of CuBr·SMe2. Additionally, ligand L78d ((S)-Tol-Binap) also provided 2a with low level of enantioselectivity (10% ee). In contrast, a promising enantiomeric excess (72% ee) was obtained with full conversion using commercially available reverse-JosiPhos ligand L6 (Table 1, entry 3).15 Moreover, a more diluted reaction system (0.05 M) led to slightly high level of enantiocontrol (Table 1, entry 5).

Encouraged by the initial screening, general experimental parameters including solvent and temperature were examined with respect to yield, regio- and enantioselectivity. The use of Et2O resulted in a low enantiomeric excess as well as the formation of 1,2-addition product. It is important to note that employing t-BuOMe as solvent is essential to yield the product in a highly enantioselective fashion, albeit this improvement of enantiomeric excess was accompanied by a decrease in yield (38%, Table 1, entry 7).

94


Table 1. Catalyst screening and optimizationa

entry ligand solvent temperature

(oC)

yieldb

(%) eec (%)

1d L1 CH2Cl2 −80 36 0

2d L3 CH2Cl2 −80 54 38

3d L6 CH2Cl2 −80 63 72

4d L7 CH2Cl2 −80 40 10

5 L6 CH2Cl2 −80 65 76

6f L6 Et2O −80 n.d.e 42

7 L6 t-BuOMe −80 38g 84

8 L6 t-BuOMe −72 67 90

9h L6 t-BuOMe −72 42 91

*Formation of 1,6- or 1,2-addition product was not observed unless otherwise noted. a General conditions for ACA: 0.35 mmol of 1, 5.0 mol % of CuBr·SMe2, 6.0 mol % of Ligand, 2 equiv of EtMgBr in 7 mL solvent, after a reaction time of 18 h. b Isolated yield. c Enantiomeric excesses of products were determined by chiral HPLC analysis. d 2.5 mL CH2Cl2 (0.14 M). e n.d. = Not determined. f 1,2-addition product was obtained. g Full conversion was not achieved after 48 h. h 1.5 equiv of EtMgBr.

A slight increase in temperature (−72 oC) led to full conversion and an enhancement of enantiomeric excess to 90% was observed (Table 1, entry 8). Decreasing the amount of

95

Chapter 4

ethylmagnesium bromide from 2.0 to 1.5 equivalents gave a similar enantiomeric excess,

although lower yield was obtained due to incomplete conversion (42%).

Different copper(I) salts in combination with ligand L6 were also investigated. It turned

out that the use of copper halide was essential in terms of conversion. In the case of CuCl,

full conversion was obtained and the enantiomeric excess slightly decreased to 80% (Table

2, entry 2). Both CuTC (Copper(I)-thiophene-2-carboxylate) and (CuOTf)2·C6H6 complex

are less effective, providing the desired product with less than 10% conversion. As

reflected by this screening, CuBr·SMe2 was still the most effective copper(I) complex for

further studies (Table 2, entry 1).

Table 2. Influence of copper complexes in the optimization process a

entry [Cu] time (h) conversionb (%) eec

1 CuBr·SMe2 18 100 90

2 CuCl 18 100 80

3 CuTC 36 <10 n.d.d

4 (CuOTf)2·C6H6 36 <10 n.d.d

a General conditions for ACA: 0.35 mmol of 1, 5.0 mol % of CuBr·SMe2, 6.0 mol % of L6, 2 equiv of

EtMgBr in 7 mL t-BuOMe at 72 oC. b Conversion was determined by 1H NMR spectroscopy of the

crude mixture. c Enantiomeric excesses of products were determined by chiral HPLC analysis. d n.d. =

Not determined.

4.3.2 Scope of Grignard reagents

With the optimized reaction conditions established, we directed our efforts towards

expanding the scope of Grignard reagents. By employing linear hexylmagnesium reagent

as nucleophile, product 2b was obtained in 82% yield with 88% ee (Table 3, entry 2).

96


Table 3. Screening of Grignard reagentsa

entry R product yieldb (%)

eec,d

1 2a O

O

67 90

2 2b O

O

5

82 88

3 2c

85 90

4e 2d

O

O

47 70

5 2e

O

O

55 88

6f Me 2f

O

O

traces -

7f Ph 2g

O

O

Ph

traces -

a General conditions for ACA: 0.35 mmol of 1, 5.0 mol % of CuBr·SMe2, 6.0 mol % of L6, 2 equiv of RMgBr in 7 mL t-BuOMe at −72 oC, after a reaction time of 18 h. b Isolated yield. c Enantiomeric excesses of products 2 were determined by chiral HPLC analysis. d The absolute configuration of the product is unknown. e 85% conversion after 48h, determined by GC-MS. f The reaction was performed at −72 oC, and then the temperature was slowly increased to 0 oC.

97

Chapter 4

In addition, the reaction could be carried out at 3.0 mmol scale to afford the similar result.

Functionalized Grignard reagent bearing a terminal alkene moiety also worked well to

afford the product 2c in 85% yield and 90% ee (Table 3, entry 3). In contrast,

butenyl-substituted product 2e was only accessible with low yield (47%) and moderate

enantioselectivity (70% ee). The lower reactivity of but-3-en-1-ylmagnesium bromide led

to 85% conversion after 48 h, which might cause inferior effect in terms of

enantioselectivity (Table 3, entry 4). The addition of branched Grignard reagent (R = i-Bu)

provided the desired product with good enantioselectivity (88% ee) (Table 3, entry 5). A

decrease in yield was attributed to the volatility of product. To further demonstrate the

potential of this method, we attempted to employ methylmagnesium bromide and

phenylethylmagnesium bromide under the optimized conditions. Only trace amount of the

desired products were obtained, even though the temperature was increased from 72 oC

to 0 oC.

4.3.3 Reactivity of chiral magnesium enolate

Enantioselective copper-catalyzed 1,4-addition of Grignard reagents produce reactive

chiral magnesium enolates, which can be further protonated to afford β-substituted

carbonyl compounds or trapped with other electrophiles.16 During the study on the ACA

reaction of Grignard reagents to coumarins, it was observed that the chiral intermediate

could be functionalized through protonation with ethanol to trap the magnesium enolate

and subsequent ring opening reaction invoked by in situ generated methoxide reagent as a

nucleophile.10 The resulting ester product was obtained in high yield without

compromising the enantioselectivity.

With an effective method for Cu-catalyzed conjugate addition to 2H-pyran-2-one in hand,

we then turned our attention to explore the reactivity of the chiral magnesium enolate 3

which could be further converted to more advanced chiral building blocks such as

functionalized β-substituted aldehydes (Scheme 9).

Scheme 9. Proposed synthesis of chiral β-substituted aldehydes.

98


2H-Pyran-2-one 1 was treated with hexylmagnesium bromide under the optimized conditions, followed by quenching the resulting enolate 3 with MeOH (5 equiv) at −72 oC. After warming up to room temperature, β-substituted aldehyde 6, bearing an ester group, was isolated in 66% yield and 88% ee (Scheme 10). The formation of product 6 is presumably due to protonation of intermediate 3 followed by transesterification, since the plausible methoxide magnesium bromide generated from deprotonation of methanol serve as a nucleophile to facilitate the ring opening of the lactone.

Scheme 10. Proposed synthesis of β-substituted aldehydes

It should be noted that it is highly challenging to obtain β-substituted aldehydes by performing the direct asymmetric conjugate addition with organometallic reagents to substrates such as α,β-unsaturated aldehydes or β,γ-unsaturated-α-ketoesters.17 The present transformation reveals a valuable alternative upon which to design the stereoselective synthesis of highly functionalized β-substituted aldehydes in a concise manner.

4.3.4 Stereoselective transformation of chiral 3,4-dihydro-pyran-2-ones

Although strategies have been introduced for the asymmetric α-bromination of aldehydes based upon organocatalysis,18 to date, there is no example for the synthesis of optically active α-bromoaldehyde through a cascade protocol involving organometallic reagents.

Here we envisioned that the resulted 4-alkyl-3,4-dihydro-pyran-2-ones 2 are potential synthons to produce chiral α,β-substituted aldehydes through diastereoselective bromination. Enantioenriched product 2b was first treated with N-bromosuccinimide (NBS) for bromination catalyzed by NH4OAc19 in MeOH to afford α-bromoaldehyde 7 in a completely diastereoselective fashion (Scheme 11). Due to instability problems,18c the

99

Chapter 4

intermediate 7 was then treated with NaBH4 (3 equiv) at 0 oC to provide the corresponding alcohol 8 in 71% yield and high enantiomeric excess (86% ee). The relative configuration of product 8 was assigned on the basis of 1H-NMR and NOESY analysis.

Scheme 11. α-Bromination of 2b followed by reduction.

With respect to the stereochemistry of the product, it’s most likely that exposure of 3,4-dihydro-pyran-2-one 2b to N-bromosuccinimide (NBS) at low temperatures delivered the bromonium intermediate as a single dominant trans diastereomer. The bromonium ion was then opened through a plausible SN2 reaction pathway with methanol acting as a nucleophile. A sequential ring opening reaction followed by hydrolysis of the resulting hemiacetal enable the formation of the α-bromoaldehyde 7 in a diastereocontrolled manner (Scheme 12). The stereochemical outcome is attributed to the stereoinduction of new stereogenic carbon center formed in the copper-catalyzed ACA reaction.

533

Scheme 12. Tentative mechanism for the tandem bromination/ring opening process.

4.3.5 Copper-catalyzed ACA of Grignard reagents to 5,6-dihydro-2H-pyran- 2-one

The application of our catalytic protocol to the copper catalyzed ACA of Grignard reagents to 5,6-dihydro-2H-pyran-2-one 9 was also examined. Although examples of this conjugate addition have been reported, 9e,9g,9k,20 high loading of chiral ligands9e or reduced enantioselectivity9g,9k frequently imposed limitations on these procedures. To our delight, the present catalytic system of reversed-JosiPhos L6/CuBr·SMe2 is highly versatile in the

100


ACA reaction of Grignard reagents to yield products 10 with excellent enantioselectivity

(up to >98% ee, Table 4).

Representive results with various Grignard reagents are summarized in Table 4. When

substrate 9 was subjected to ACA conditions using EtMgBr identical to those used for

reactions of 2H-pyran-2-one 1, the desired 1,4-addition product 10a was obtained with

high yield (81%) and excellent enantiomeric excess (90% ee). Noteworthy, the relative

amount of Grignard reagents could be reduced from 2.0 to 1.5 equiv possibly due to the

higher reactivity of lactone 9. Transformations with Grignard reagent bearing longer alkyl

chains afforded the optically active esters 10b in 88% yield with 88% ee (Table 4, entry 2).

Unlike reaction with 2H-pyran-2-one (Table 3), the 1,4-addition between the

functionalized Grignard reagent bearing a terminal alkene moiety and

5,6-dihydro-2H-pyran-2-one provided the desired product 10c with a high enantiomeric

excess (86% ee). Remarkably, in the case of the branched Grignard reagent (R = i-Bu), the

desired product 10d is obtained as a single enantiomer (>98% ee). The copper-catalyzed

ACA of less reactive methylmagnesium bromide proceeded also, although this

transformation suffers from lower enantioselectivity (50% ee, Table 4, entry 5). In general,

this system shows improved enantioselectivities in the conjugate addition of Grignard

reagents to 5,6-dihydro-2H-pyran- 2-one compared to the similar reaction employing

2H-pyran-2-one as a Michael acceptor.

4.4 Conclusions and Future Prospects

In summary, we have developed a highly efficient enantioselective synthesis of

structurally diverse lactones based on the asymmetric conjugate addition of Grignard

reagents to 2H-pyran-2-one and 5,6-dihydro-2H-pyran-2-one. The present method

significantly enhances the general utility of Cu-catalyzed ACA of alkyl Grignard reagents

to less reactive unsaturated lactones. The synthetic applicability of the products from this

catalytic C-C bond formation was demonstrated in the stereoselective synthesis of an

optically active β-alkyl substituted aldehyde and a β-bromo-γ-alkyl substituted alcohol,

which are valuable chiral multifunctional synthons.

101

Chapter 4

Table 4. Copper-catalyzed ACA of Grignard reagents to 5,6-dihydro-2H-pyran-2-one a

entry R product yieldb (%)

eec

1 10a O

O

81 90

2 10b O

O

5

88 88

3 10c

O

O

85 94

4 10d

O

O

84 >98

5 Me 10e

O

O

68 50

a General conditions for ACA: 0.35 mmol of 1, 5.0 mol % of CuBr·SMe2, 6.0 mol % of L6, 1.5 equiv of RMgBr in 7 mL t-BuOMe at −72 oC. b Isolated yield. c Enantiomeric excesses of products were determined by chiral GC analysis.

This catalytic asymmetric transformation offers immense possibilities for further study. For instance, the resulted enantiomerically enriched 3,4-dihydro-pyran-2-ones would be suitable starting point towards the diastereoselective dihydroxylation or epoxidation followed by ring contraction to afford versatile building blocks (Scheme 13).

102


Scheme 13. Possible transformation of enantiomerically enriched 3,4-dihydro-pyran-2-ones

As discussed before, the chiral magnesium enolate was disclosed as a reactive species which could be further converted into highly functionalized products. Another potential interest would be to perform the enolate trapping with simple aliphatic or aromatic aldehydes (Scheme 14).

Scheme 14. Further elaboration of chiral magnesium enolate to access densely functionalized pyran-2-one products.

This consective conjugate addition/enolate trapping strategy might give access to the corresponding aldol product with three contiguous stereogenic centers. Finally, densely functionalized pyran-2-one products bearing up to five stereogenic center might be achieved with further stereoselective elaboration on the double bond.21


Column chromatography was performed on silica gel (Silica-P flash silica gel from Silicycle, size 40-63 μm). TLC was performed on silica gel 60/Kieselguhr F254. Components were visualized by UV and staining with a solution of a mixture of KMnO4 (10 g) and K2CO3 (10 g) in H2O (500 mL). Mass spectra were recorded on a AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.6 MHz, respectively) or a Varian Unity Plus Varian-500 (500 and 125 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s =

103

Chapter 4

singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants

(Hz), and integration.

Optical rotations were measured in CHCl3 on a Schmidt + Haensch polarimeter

(Polartronic MH8) with a 10 cm cell (c given in g/100 mL). Conversion of the reaction

was determined by GC (GC, HP6890: MS HP5973) with an HP5 column (Agilent

Technologies, Palo Alto, CA). Enantioselectivities were determined by HPLC analysis

using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode

array detector.

All reactions were carried out under a nitrogen atmosphere using oven dried glassware and

using standard Schlenk techniques. All solvents were reagent grade and were dried and

distilled prior to use, if necessary. Tetrahydrofuran (THF), tert-butyl methyl ether

(t-BuOMe) and diethylether (Et2O) were distilled over Na/benzophenone. Toluene and

dichloromethane (CH2Cl2) were distilled over calcium hydride. All the ligands, copper

salts and pyranones were purchased from Aldrich and used as received. Grignard reagents

RMgBr (R = Me, Et, n-Hexyl, i-Bu) were purchased from Aldrich.

Hept-6-en-1-ylmagnesium bromide and but-3-en-1-ylmagnesium bromide were prepared

from the corresponding alkyl bromides and magnesium turnings in Et2O following

standard procedures. Grignard reagents were titrated using sec-BuOH and catalytic

amounts of 1,10-phenanthroline.

General procedure for the synthesis of racemic product of the copper catalyzed

1,4-addition of Grignard reagents to 2H-pyran-2-one:

CuBr·SMe2 (0.0175 mmol, 3.6 mg) and PPh3 (0.042 mmol, 11.0 mg) were dissolved in

dry t-BuOMe (5.0 mL) and the mixture was stirred at room temperature for 15 min. The

mixture was cooled to 72 oC and subsequently 2.0 equiv of the appropriate Grignard

reagent was added dropwise. The mixture was stirred at 72 °C for another 15 min. Then a

solution of 2H-pyran-2-one (0.35 mmol, 37.0 mg) in 2 mL t-BuOMe was added slowly

over 1h by a syringe pump. The reaction mixture was stirred until TLC (Et2O/n-pentane

1/3) showed full conversion and quenched by saturated aqueous NH4Cl solution (2 mL).

104


The organic layer was separated and the water layer was extracted by diethyl ether (3×5 mL). After drying over MgSO4 and filtering, the solvent was evaporated under vacuo (Note: in some cases products are very volatile). Purification by flash chromatography over silica gel, using diethyl ether/n-pentane 1/9 afforded the pure racemic product as colorless oil.

General procedure for the enantioselective copper catalyzed 1,4-addition of Grignard reagents to 2-pyrone:

CuBr·SMe2 (0.0175 mmol, 3.6 mg) and L6 (R,S)-Rev-Josiphos (0.021 mmol, 12.5 mg) were dissolved in dry t-BuOMe (5.0 mL) and the mixture was stirred at room temperature for 15 min. The mixture was cooled to −72 oC and subsequently the corresponding Grignard reagent solution (2.0 equiv) was added dropwise. The mixture was stirred at −72 °C for another 15 min. Then a solution of 2H-pyran-2-one 1 (0.35 mmol, 37.0 mg) in t-BuOMe (2.0 mL) was added slowly over 1h using a syringe pump. The mixture was stirred until TLC (diethyl ether/n-pentane 25%) showed full conversion and the reaction was quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was separated and the water layer was extracted with diethyl ether (3×5 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated under vacuo (Note: in some cases products are very volatile). Purification by flash chromatography over silica gel, using diethyl ether/n-pentane 1/9 afforded the pure product 2 as colorless oil.

(−)-(R)-4-Ethyl-3,4-dihydro-2H-pyran-2-one (2a)

Colorless oil, obtained after column chromatography (SiO2, diethyl ether/n-pentane 1/9), [67% yield, 90% ee]. [α]20

D = −1.0 (c 1.7, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.48 (dd, J = 6.0, 1.5 Hz, 1H), 5.35 – 5.12 (m, 1H),

2.81 – 2.61 (m, 1H), 2.51 – 2.39 (m, 1H), 1.55 – 1.39 (m, 2H), 1.37 – 1.24 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 168.6, 140.6, 110.1, 34.6, 32.0, 27.5, 10.7. HRMS (ESI+, m/z): calcd for C7H11O2 [M+H]+: 127.07536, found 127.07546. Enantiomeric excess was determined by chiral HPLC, Chiralpak AS-H

O

O

105

Chapter 4

(Heptane/i-Propanol = 99/1, 0.5 mL/min, 211 nm, column temperature 40 °C), retention

times: tR (major) 18.23 min, tR (minor) 20.62 min.

()-(R)-4-Hexyl-3,4-dihydro-2H-pyran-2-one (2b)

Colorless oil, obtained after column chromatography (SiO2, diethyl

ether/n-pentane 1/9), [82% yield, 88% ee]. [α]20D = 4.1 (c 0.8, CHCl3).

1H NMR (400 MHz, CDCl3) δ 6.47 (dd, J = 6.0, 1.5 Hz, 1H), 5.25 (dd,

J = 5.9, 4.0 Hz, 1H), 2.70 (dd, J = 15.3, 6.0 Hz, 1H), 2.55 – 2.47 (m, 1H), 2.40 (dd, J =

15.3, 8.1 Hz, 1H), 1.35 – 1.20 (m, 10H), 0.92 – 0.83 (m, 3H). 13C NMR (100.6 MHz,

CDCl3) δ 168.7, 140.5, 110.5, 35.0, 34.7, 31.6, 30.5, 29.1, 26.3, 22.5, 14.0. HRMS (ESI+,

m/z): calcd for C11H19O2 [M+H]+: 183.13796, found 183.13813. Enantiomeric excess was

determined by chiral HPLC, Chiralpak AD-H (Heptane/i-Propanol = 99.5/0.5, 0.5 mL/min,

213 nm, column temperature 40 °C), retention times: tR (major) 21.16 min, tR (minor)

19.50 min.

()-(R)-4-(Hept-6-en-1-yl)-3,4-dihydro-2H-pyran-2-one (2c)


ether/n-pentane 1/9), [85% yield, 90% ee]. [α]20D = 7.8 (c 0.9,

CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.46 (dd, J = 6.0, 1.4 Hz,

1H), 5.78 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.24 (dd, J = 5.8, 4.1 Hz, 1H), 4.98 (dd, J =

17.1, 1.6 Hz, 1H), 4.93 (d, J = 9.5 Hz, 1H), 2.70 (dd, J = 15.3, 6.0 Hz, 1H), 2.56 – 2.45 (m,

1H), 2.40 (dd, J = 15.4, 8.0 Hz, 1H), 2.03 (dd, J = 14.1, 6.9 Hz, 2H), 1.50 – 1.27 (m, 8H).

13C NMR (100.6 MHz, CDCl3) δ 168.5, 140.6, 138.8, 114.4, 110.4, 35.0, 34.6, 33.6, 30.4,

28.9, 28.7, 26.2. HRMS (ESI+, m/z): calcd for C12H19O2 [M+H]+: 195.13796, found

195.13802. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H

(Heptane/i-Propanol = 99.5/0.5, 0.5 mL/min, 223 nm, column temperature 40 °C),

retention times: tR (major) 33.64 min, tR (minor) 28.83 min.

()-(R)-4-(But-3-en-1-yl)-3,4-dihydro-2H-pyran-2-one (2d)

Colorless oil, obtained after column chromatography (SiO2, diethyl ether/n-pentane 1/9),

[47% yield, 70% ee]. [α]20D = 8.1 (c 1.1, CHCl3).

1H NMR (400 MHz,

CDCl3) δ = 6.49 (dd, J = 6.0, 1.0, 1H), 5.77 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H),

5.26 (dd, J = 5.6, 4.3 Hz, 1H), 5.08 – 4.97 (m, 2H), 2.73 (dd, J = 15.5, 6.2 Hz,

1H), 2.60 – 2.50 (m, 1H), 2.43 (dd, J = 15.5, 7.8 Hz, 1H), 2.16 2.07 (m, 2H), 1.59 – 1.49 (m,

2H). HRMS (APCI+, m/z): calcd for C9H15O2 [M+H]+: 153.09101, found 153.09106.

O

O

O

O

O

O

106


Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H



()-(R)-4-Isobutyl-3,4-dihydro-2H-pyran-2-one (2e)


ether/n-pentane 1/9), [55% yield, 88% ee]. [α]20D = 6.5 (c 1.2, CHCl3).

1H

NMR (400 MHz, CDCl3) δ 6.44 (dd, J = 6.0, 1.5 Hz, 1H), 5.23 (dd, J = 5.9,

4.0 Hz, 1H), 2.72 – 2.61 (m, 1H), 2.60 – 2.51 (m, 1H), 2.35 (dd, J = 15.4, 7.8 Hz, 1H),

1.66 (dt, J = 13.8, 6.7 Hz, 1H), 1.36 – 1.26 (m, 1H), 1.25 – 1.17 (m, 1H), 0.88 (dd, J = 6.6,

4.3 Hz, 6H). 13C NMR (100.6 MHz, CDCl3) δ 168.6, 140.5, 110.6, 43.9, 35.2, 28.3, 25.0,

22.5, 22.3. HRMS (ESI+, m/z): calcd for C9H15O2 [M+H]+: 155.1067, found 155.1064.

Enantiomeric excess was determined by chiral GC analysis, CP-Chiralsil-Dex-CB (25 m x

0.25 mm), initial temp. 50 oC (hold for 20 min), then 10 oC/min to 180 oC for 5 min, then

10 oC/min to 50 oC (final temp), retention times (min.): 28.16 (major) and 28.24 (minor).

General procedure for the synthesis of (R)-Methyl 3-(2-oxoethyl)nonanoate:

CuBr·SMe2 (0.0175 mmol, 3.6 mg) and L6 (R,S)-Rev-JosiPhos (0.042 mmol, 11.0 mg)

were dissolved in dry t-BuOMe (5.0 mL) and the mixture was stirred at room temperature

for 15 min. The mixture was cooled to 72 oC and subsequently the hexylmagnesium

bromide solution (c = 2.0 M in Et2O, 0.7 mmol, 0.35 mL) was added dropwise. The

reaction mixture was then stirred at 72 °C for another 15 min. Then a solution of

2-pyrone 1 (0.35 mmol, 37.0 mg) in 2 mL t-BuOMe was added slowly over 1h using a

syringe pump. The reaction mixture was stirred until TLC (diethyl ether/n-pentane 1/3)

showed full conversion and then MeOH (1.75 mmol, 71 μL) was added in one portion.

The reaction mixture was warmed to room temperature and stirred at that temperature for

12h. Then the reaction was quenched by the addition of saturated aqueous NH4Cl solution

(2 mL). The mixture was separated and the water layer was extracted by diethyl ether (3×5

mL). The combined organic layers were dried over MgSO4, filtered and the solvent was

evaporated under vacuo (Note: in some cases products are very volatile). Purification by

O

O

107

Chapter 4

flash chromatography over silica gel, using diethyl ether/n-pentane 1/9 afforded the pure product 6 as colorless oil.

(−)-(R)-Methyl 3-(2-oxoethyl)nonanoate (6)

Colorless oil, obtained after column chromatography (SiO2, diethyl ether/n-pentane 1/9), [66% yield, 88% ee]. [α]20

D = −25.4 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 3.68 – 3.62 (m,

2H), 3.50 – 3.42 (m, 1H), 2.49 – 2.40 (m, 2H), 1.40 – 1.18 (m, 10H), 0.93 – 0.78 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 201.8, 172.9, 65.8, 51.5, 48.2, 38.4, 34.1, 31.7, 30.0, 29.2, 22.3, 14.0. HRMS (APCI, m/z): calcd for C12H23O3 [M+H]+: 215.16417; found: 215.16422. Enantiomeric excess was determined by chiral GC analysis, Chiraldex G-TA (30 m x 0.25 mm), initial temp. 40 oC (hold for 15 min), then 10 oC/min to 150 oC (hold for 10 min), then 10 oC/min to 40 oC (final temp), retention times (min.): 32.9 (major) and 33.2 (minor).

General procedure for synthesis of (−)-(R)-methyl 3-((S)-1-bromo-2-hydroxyethyl) nonanoate

(R)-4-Hexyl-3,4-dihydro-2H-pyran-2-one 2b (0.4 mmol, 72.8 mg) was dissolved in 4 mL of MeOH at rt. Ammonium acetate (0.1 mmol, 7.7 mg) was added as a catalyst. The solution was cooled to −78 °C, and N-bromosuccinimide (0.48 mmol, 85.4 mg) was added in one portion. The yellow mixture was allowed to warm to 0 °C over 4 h. Sodium borohydride (1.2 mmol, 45.3 mg) was then added. The resulting solution was warmed up to room temperature and then quenched with saturated aqueous NH4Cl solution (2 mL) until GC-MS analysis showed full conversion. The mixture was separated and the water layer was extracted by diethyl ether (3×5 mL). The combine organic layers were dried over MgSO4, filtered and the solvent was evaporated under vacuo. Purification by flash chromatography over silica gel, using diethyl ether/n-pentane 1/9 afforded the pure product 8 as colorless oil.

OCH3OHC

O5

108


()-(R)-Methyl-3-((S)-1-bromo-2-hydroxyethyl)nonanoate (8)


ether/n-pentane 1/9), [71% yield, 86% ee]. [α]20D = 3.0 (c 1.6,

CHCl3). 1H NMR (400 MHz, CDCl3)

δ 5.37 (bs, 2H), 4.23 (bs, 1H),

3.58 (s, 3H), 2.61 (d, J = 14.9 Hz, 1H), 2.46 – 2.35 (m, 2H), 1.36 – 1.21 (m, 10H), 0.95 –

0.83 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 168.4, 104.4, 57.1, 51.2, 33.2, 33.2, 31.7,

31.6, 29.0, 25.7, 22.5, 14.0. HRMS (APCI+, m/z): calcd for C12H22BrO3 [M+H]+:

293.07468; found: 293.07290. Enantiomeric excess was determined by chiral GC analysis,

CP-Chiralsil-Dex-CB (25 m x 0.25 mm), initial temp. 50 oC (hold for 20 min), then 10 oC/min to 180 oC for 5 min, then 10 oC/min to 50 oC (final temp), retention times (min.):

34.3 (major) and 34.6 (minor).

General procedure for the synthesis of racemic product of the copper catalyzed

1,4-addition of Grignard reagents to 5,6-dihydro-2H-pyran-2-one:

A solution of the appropriate Grignard reagent in ether (1.2 equiv) was slowly added to a

suspension of CuI (57.0 mg, 0.3 mmol) in Et2O (5 mL) at 0 oC. After stirring for 15 min at

0 oC, 5,6-dihydro-2H-pyran-2-one 9 (0.3 mmol) was added dropwise. The reaction

mixture was stirred for 2h and quenched by saturated aqueous NH4Cl solution (2 mL). The

mixture was warmed up to room temperature and partitioned between ether and water. The

organic layer was dried over MgSO4, filtered and the solvent was evaporated under vacuo.

Purification by flash chromatography over silica gel, using Et2O/n-pentane 1/1 afforded

the pure racemic product 10 as pale yellow oil.

General procedure for the copper catalyzed ACA of Grignard reagents to

5,6-dihydro-2H-pyran-2-one:

OCH3

O

Br

HO

5

109

Chapter 4

CuBr·SMe2 (0.0175 mmol, 3.6 mg) and L6 (R,S)-Rev-JosiPhos (0.021 mmol, 12.5 mg)

were dissolved in dry t-BuOMe (5.0 mL) and stirred at room temperature for 15 min. The

mixture was cooled to 72 oC and subsequently the appropriate Grignard reagent (1.5

equiv) was added dropwise. The reaction mixture was stirred at 72 °C for another 15 min.

Then a solution of 5,6-dihydro-2H-pyran-2-one 9 (0.35 mmol, 34 mg) in 2 mL t-BuOMe

was added slowly over 1h by a syringe pump. The reaction mixture was stirred until TLC

(Et2O/n-Pentane 1/1) showed full conversion and quenched with saturated aqueous NH4Cl

solution (2 mL). The mixture was warmed up to room temperature and partitioned

between ether and water. The organic layer was dried over MgSO4, filtered and the solvent

was evaporated under vacuo. Purification by flash chromatography over silica gel, using

Et2O/n-pentane 1/1 afforded the pure product 10 as colorless oil.

()-(S)-4-Ethyl-tetrahydro-2H-pyran-2-one (10a)

Pale yellow oil was obtained after column chromatography (SiO2,

Et2O/n-pentane 1/1), [81% yield, 90% ee]. The physical data were identical in

all respects to those previously reported.20c [α]20D = 14.8 (c 0.50, CHCl3),

[lit.20c (R isomer, 99:1 er): [α]20D = +21.9 (c 0.51, CHCl3)]. Enantiomeric excess was

determined by chiral GC analysis, Chiraldex G-TA (30 m x 0.25 mm), initial temp. 50 oC,

then 10 oC/min to 90 oC, then 0.3 oC/min to 105 oC (hold for 5 min), then 10 oC/min to

50oC (final temp), retention times (min.): 107.2 (major) and 109.6 (minor).

()-(S)-4-Hexyl-tetrahydro-2H-pyran-2-one (10b)

Pale yellow oil obtained after column chromatography (SiO2,

Et2O/n-pentane 1/1), [88% yield, 88% ee]. [α]20D = 8.8 (c 1.0, CHCl3).

1H NMR (400 MHz, CDCl3) δ 4.39 (dt, J = 11.3, 4.3 Hz, 1H), 4.23 (td,

J = 10.9, 3.5 Hz, 1H), 2.67 (ddd, J = 17.3, 6.8, 1.3 Hz, 1H), 2.12 (dd, J = 17.3, 9.7 Hz, 1H),

2.00 – 1.87 (m, 2H), 1.55 – 1.44 (m, 1H), 1.38 – 1.18 (m, 10H), 0.87 (t, J = 6.6 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 171.5, 68.5, 36.6, 36.2, 31.7, 31.4, 29.2, 28.9, 26.3, 22.5,

14.0. HRMS (APCI+, m/z): calcd for C11H21O2 [M+H]+: 185.15361; found: 185.15425.


0.25 mm), initial temp. 40 oC, then 10 oC/min to 85 oC, then 0.5 oC/min to 160 oC, then 10 oC/min to 40 oC (final temp), retention times (min.): 85.5 (major) and 86.2 (minor).

O

O

O

O

110


()-(S)-4-(But-3-en-1-yl)-tetrahydro-2H-pyran-2-one (10c)


Et2O/n-pentane 1/1), [85% yield, 94% ee]. [α]20D = 15.0 (c 1.0, CHCl3).

1H NMR (400 MHz, CDCl3) δ 5.75 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.05

– 4.92 (m, 2H), 4.39 (dt, J = 11.3, 4.4 Hz, 1H), 4.23 (td, J = 11.2, 3.6 Hz, 1H), 2.67 (ddd, J

= 17.2, 5.7, 1.5 Hz, 1H), 2.16 – 2.05 (m, 3H), 2.02 – 1.89 (m, 2H), 1.57 – 1.37 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 171.2, 137.6, 115.3, 68.4, 36.4, 35.2, 30.8, 30.5, 28.8.

HRMS (APCI+, m/z): calcd for C9H15O2 [M+H]+: 155.10666; found: 155.10684.


0.25 mm), initial temp. 40 oC, then 10 oC/min to 85 oC, then 0.5 oC/min to 160 oC, then 10 oC/min to 40 oC (final temp), retention times (min.): 54.9 (major) and 56.1 (minor).

()-(S)-4-Isobutyl-tetrahydro-2H-pyran-2-one (10d)


Et2O/n-pentane 1/1), [84% yield, >98% ee]. [α]20D = 25.4 (c 1.0, CHCl3).

1H NMR (400 MHz, CDCl3) δ 4.38 (dt, J = 11.3, 4.5 Hz, 1H), 4.23 (td, J =

10.9, 3.7 Hz, 1H), 2.64 (ddd, J = 16.6, 5.1, 1.2 Hz, 1H), 2.11 – 1.96 (m, 2H), 1.94 – 1.85

(m, 1H), 1.69 – 1.54 (m, 1H), 1.52 – 1.41 (m, 1H), 1.26 – 1.10 (m, 2H), 0.87 (d, J = 6.6

Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 171.4, 68.5, 45.5, 36.7, 29.1, 29.1, 24.6, 22.5,

22.5. HRMS (ESI+, m/z): calcd for C9H17O2 [M+H]+: 157.1250; found: 157.1228.

Enantiomeric excess was determined by chiral GC analysis, Chiraldex G-TA (30 m x 0.25

mm), initial temp. 50 oC, then 10 oC/min to 110 oC, then 0.3 oC/min to 140 oC (hold for 5

min), then 10 oC/min to 50 oC (final temp), retention times (min.): 74.9 (minor) and 76.0

(major).

()-(S)-4-Methyltetrahydro-2H-pyran-2-one (10e)

Pale yellow oil obtained after column chromatography (SiO2, Et2O/n-pentane

1/1), [68% yield, 50% ee]. [α]20D = 11.7 (c 1.0, CHCl3). [lit.

2b (S isomer, 98%

ee): [α]20D = 22.6 (c 1.0, CHCl3)]. The physical data were identical in all

respects to those previously reported. 1H NMR (400 MHz, CDCl3) δ 4.35 (dt, J = 11.4, 4.4

Hz, 1H), 4.21 (td, J = 11.0, 3.8 Hz, 1H), 2.61 (q, J = 10.0 Hz, 1H), 2.20 – 1.96 (m, 2H),

1.86 (dd, J = 13.6, 3.9 Hz, 1H), 1.58 – 1.37 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H). 13C NMR

(101 MHz, CDCl3) 171.1, 68.4, 38.1, 30.5, 26.4, 21.3. Enantiomeric excess was

determined by chiral GC analysis, Chiraldex G-TA (30 m x 0.25 mm), initial temp. 60 oC

O

O

O

O

O

O

111

Chapter 4

(hold for 15 min), then 5 oC/min to 150 oC (hold for 25 min), then 10 oC/min to 40 oC (final temp), retention times (min.): 34.8 (major) and 35.0 (minor).

4.6 References 1 For representative biological activities of dihydropyran-2-ones and their derivatives, see: a) S. E.

Hagen, J. V. N. Vara Prasad, F. E. Boyer, J. M. Domagala, E. L. Ellsworth, C. Gajda, H. W.

Hamilton, L. J. Markoski, B. A. Steinbaugh, B. D. Tait, E. A. Lunney, P. J. Tummino, D. Ferguson,

D. Hupe, C. Nouhan, S. J. Gracheck, J. M. Saunders, S. VanderRoest, Med. Chem. 1997, 40,

3707-3711; b) C. J. Douglas, H. M. Sklenicka, H. C. Shen, D. S. Mathias, S. J. Degen, G. M.

Golding, C. D. Morgan, R. A. Shih, K. L. Mueller, L. M. Scurer, E. W. Johnson, R. P. Hsung,

Tetrahedron 1999, 55, 13683-13696; d) A. Evidente, A. Cabras, L. Maddau, S. Serra, A. Andolfi, A.

Motta, J. Agri. Biol. Chem. 2003, 51, 6957-6960.

2 For selected examples of the synthetic application, see: a) M. Willot, L. Radtke, D. Könning, R.

Fröhlich, V. H. Gessner, C. Strohmann, M. Christmann, Angew. Chem. Int. Ed. 2009, 48, 9105-9108;

b) K. Lehr, R. Mariz, L. Leseurre, B. Gabor, A. Fürstner, Angew. Chem. Int. Ed. 2011, 50,

11373-11377.

3 a) J. Stöckigt, M. H. Zenk, J. Chem. Soc., Chem. Commun. 1977, 646-648; b) T. M. Kutchan,

Phytochemistry 1993, 32, 493-506.

4 For review on the N-heterocyclic carbene-catalyzed reactions of α-reducible aldehydes to provide

dihydropyran-2-ones, see: a) H. U. Vora, P. Wheeler, T. Rovis, Adv. Synth. Catal. 2012, 354,

1617-1639; For representative examples, see: b) M. He, G. J. Uc, J. W. Bode, J. Am. Chem. Soc.

2006, 128, 15088-15089; c) M. He, B. J. Beahm, J. W. Bode, Org. Lett. 2008, 10, 3817-3820; d) J.

Kaeobamrung, M. C. Kozlowski, J. W. Bode, Proc. Natl. Acad. Sci. USA 2010, 107, 20661-20665;

e) X. Fang, X. Chen, R. Y. Chi, Org. Lett. 2011, 13, 4708-4711.

5 a) T. Tozawa, Y. Yamane, T. Mukaiyama, Chem. Lett. 2006, 35, 56-57; b) T. Tozawa, H. Nagao, Y.

Yamane, T. Mukaiyama, Chem. Asian J. 2007, 2, 123-134.

6 For reviews on the copper-catalyzed asymmetric conjugate addition, see: a) B. L. Feringa, Acc.

Chem. Res. 2000, 33, 346-353; b) F. López, A. J. Minnaard, B. L. Feringa, Acc. Chem. Res. 2007,

40, 179-188; c) F. López and B. L. Feringa, in Asymmetric Synthesis—The Essentials, (Ed. M.

Christmann and S. Bräse), Wiley-VCH, Weinheim, 2007, pp. 78-82; d) S. R. Harutyunyan, T. den

Hartog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008, 108, 2824-2852; e) A. Alexakis,

J. E. Ba�ckvall, N. Krause, O. Pàmies, M. Diéguez, Chem. Rev. 2008, 108, 2796-2823; f) T.

Jerphagnon, M. G. Pizzuti, A. J. Minnaard, B. L. Feringa, Chem. Soc. Rev. 2009, 38, 1039-1075; g)

112


T. Thaler, P. Knochel, Angew. Chem. Int. Ed. 2009, 48, 645-648; h) S.-Y. Wang, T.-P. Loh, Chem.

Commun. 2010, 46, 8694-8703; i) J. F. Teichert, B. L. Feringa, Angew. Chem. Int. Ed. 2010, 49,

2486-2528; j) C. Hawner, A. Alexakis, Chem. Commun. 2010, 46, 7295-7306.

7 For selected examples of copper-catalyzed ACA reaction of Grignard reagents to acyclic enones,

see: a) F. Lambert, D. M. Knotter, M. D. Janssen, M. van Klaveren, J. Boersma, G. van Koten,

Tetrahedron: Asymmetry 1991, 2, 1097-1100; b) M. van Klaveren, F. Lambert, D. J. F. M.

Eijkelkamp, D. M. Grove, G. van Koten, Tetrahedron Lett. 1994, 35, 6135-6138; c) F. López, S. R.

Harutyunyan, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2004, 126, 12784-12785; d) B.

Maciá, M. Á. Fernández-Ibáñez, N. Mršić, A. J. Minnaard, B. L. Feringa, Tetrahedron Lett. 2008,

49, 1877-1880.

8 For selected examples of copper-catalyzed ACA reaction of Grignard reagents to acyclic esters and

thioesters, see: a) F. López, S. R. Harutyunyan, A. Meetsma, A. J. Minnaard, B. L. Feringa, Angew.

Chem. Int. Ed. 2005, 44, 2752-2756; b) S. R. Harutyunyan, F. López, W. R. Browne, A. Correa, D.

Peña, R. Badorrey, A. Meetsma, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2006, 128,

9103-9118; c) R. Des Mazery, M. Pullez, F. López, S. R. Harutyunyan, A. J. Minnaard, B. L.

Feringa, J. Am. Chem.Soc. 2005, 127, 9966-9967; d) S.-Y. Wang, S.-J. Ji, T.-P. Loh, J. Am. Chem.

Soc. 2007, 129, 276-277; e) B. Maciá Ruiz, K. Geurts, M. Á. Fernández-Ibáñez, B. ter Horst, A. J.

Minnaard, B. L. Feringa, Org. Lett. 2007, 9, 5123-5126; f) B. ter Horst, B. L. Feringa, A. J.

Minnaard, Chem. Comm. 2007, 489-491; g) S.-Y. Wang, T.-K. Lum, S.-J. Ji, T.-P. Loh, Adv. Synth.

Catal. 2008, 350, 673-677.

9 For selected examples of copper-catalyzed ACA reaction of Grignard reagents to cyclic enones, see:

a) G. M. Villacorta, C. Pulla Rao, S. J. Lippard, J. Am. Chem. Soc. 1988, 110, 3175-3182; b) M.

Spescha, G. Rihs, Helv. Chim. Acta 1993, 76, 1219-1230; c) Q.-L. Zhou, A. Pfaltz, Tetrahedron Lett.

1993, 34, 7725-7728; d) M. Kanai, K. Tomioka, Tetrahedron Lett. 1995, 36, 4273-4274; e) M.

Kanai, K. Tomioka, Tetrahedron Lett. 1995, 36, 4275-4278; f) M. Kanai, Y. Nakagawa, K. Tomioka,

Tetrahedron 1999, 55, 3843-3854; g) B. L. Feringa, R. Badorrey, D. Peña, S. R. Harutyunyan, A. J.

Minnaard, Proc. Natl. Acad. Sci. USA 2004, 101, 5834-5838; h) D. Martin, S. Kehrli, M. d'Augustin,

H. Clavier, M. Mauduit, A. Alexakis, J. Am. Chem. Soc. 2006, 128, 8416-8417; i) Y. Matsumoto,

K.-i. Yamada, K. Tomioka, J. Org. Chem. 2008, 73, 4578-4581; j) T. Robert, J. Velder, H.-G.

Schmalz, Angew. Chem. Int. Ed. 2008, 47, 7718-7721; k) Q. Naeemi, T. Robert, D. P. Kranz, J.

Velder, H.-G. Schmalz, Tetrahedron: Asymmetry 2011, 22, 887-892.

10 J. F. Teichert, B. L. Feringa, Chem. Commun. 2011, 47, 2679-2681.

11 For reviews on 2H-pyran-2-ones, see: a) K. Afarinkia, V. Vinader, T. D. Nelson, G. H. Posner,

Tetrahedron 1992, 48, 9111-9171; b) G. P. McGlacken, I. J. S. Fairlamb, Nat. Prod. Rep. 2005, 22,

113

Chapter 4

369-385.

12 For selected synthetic applications of [4+2] cycloaddition of 2H-pyran-2-ones, see: a) K. C.

Nicolaou, J. J. Liu, C. K. Hwang, W. M. Dai, R. K. Guy, J. Chem. Soc., Chem. Commun. 1992,

1118-1120; b) K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F.

Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan, E. J. Sorensen, Nature 1994, 367, 630-634;

c) H. Okamura, H. Shimizu, Y. Nakamura, T. Iwagawa, M. Nakatani, Tetrahedron Lett. 2000, 41,

4147-4150; d) H. Shimizu, H. Okamura, T. Iwagawa, M. Nakatani, Tetrahedron 2001, 57,

1903-1908; e) Y. Wang, H. Li, Y.-Q. Wang, Y. Liu, B. M. Foxman, L. Deng, J. Am. Chem. Soc. 2007,

129, 6364-6365; f) H. M. Nelson, K. Murakami, S. C. Virgil, B. M. Stoltz, Angew. Chem. Int. Ed.

2011, 50, 3688-3691. For selected [2+2] cycloaddition of 2H-pyran-2-ones, see: g) E. J. Corey, J.

Streith, J. Am. Chem. Soc. 1964, 86, 950-951; h) B. R. Arnold, C. E. Brown, J. Lusztyk, J. Am.

Chem. Soc. 1993, 115, 1576-1577.

13 For review on the conjugate addition reactions to electron-deficient dienes, see: A. G. Csaky, G. de

la Herran, M. C. Murcia, Chem. Soc. Rev. 2010, 39, 4080-4102.

14 For selected examples of asymmetric copper-catalyzed 1,6-conjugate addition, see: a) T. den Hartog,

S. R. Harutyunyan, D. Font, A. J. Minnaard, B. L. Feringa, Angew. Chem. Int. Ed. 2008, 47,

398-401; b) H. Hénon, M. Mauduit, A. Alexakis, Angew. Chem. Int. Ed. 2008, 47, 9122-9124.

15 The opposite enantiomer of ligand L4 is also commercially available.

16 Z. Galeštoková, R. Šebesta, Eur. J. Org. Chem. 2012, 2012, 6688-6695.

17 a) M. Fañanás-Mastral,; B. L. Feringa, J. Am. Chem. Soc. 2010, 132, 13152-13153; b) L. Palais, L.

Babel, A. Quintard, S. Belot, A. Alexakis, Org. Lett. 2010, 12, 1988-1991; c) L. Gremaud, A.

Alexakis, Angew. Chem. Int. Ed. 2012, 51, 794-797.

18 For reviews on the enantioselective α-bromination, see: a) M. Marigo, K. A. Jorgensen, Chem.

Commun. 2006, 2001-2011; b) M. Ueda, T. Kano, K. Maruoka, Org. Biomol. Chem. 2009, 7,

2005-2012. For representative examples, see: c) S. Bertelsen, N. Halland, S. Bachmann, M. Marigo,

A. Braunton, K. A. Jorgensen, Chem. Commun. 2005, 4821-4823; d) T. Kano, F. Shirozu, K.

Maruoka, Chem. Commun. 2010, 46, 7590-7592.

19 K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi, T. Horaguchi, Chem. Commun. 2004,

470-471.

20 For the copper catalyzed ACA reaction of other organometallic reagents to

5,6-dihydro-2H-pyran-2-one, see: a) M. Yan, Z.-Y. Zhou, A. S. C. Chan, Chem. Commun. 2000,

115-116; b) M. T. Reetz, A. Gosberg, D. Moulin, Tetrahedron Lett. 2002, 43, 1189-1191; c) M. K.

Brown, S. J. Degrado, A. H. Hoveyda, Angew. Chem. Int. Ed. 2005, 44, 5306-5310; d) M. K. Brown,

114


A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130, 12904-12906.

21 Preliminary studies based on X-ray analysis disclosed the hydrogen bonding interaction between the

hydroxyl group and the oxygen on the carbonyl group helps to prevent the hydrolysis and thus

stabilize the final product.

Chapter 5

Copper-Catalyzed Asymmetric Conjugate

Addition of Dialkylzinc Reagents to

β-Phthalimino-α,β-unsaturated Ketones: towards

the synthesis of β-Alkyl-β-amino acids

β-Phthalimino-α,β-unsaturated ketones have been investigated as new substrates for copper-catalyzed asymmetric conjugate additions of organozinc reagents. Although the enantioselectivities achieved so far are only moderate, the results provide a good basis for further studies on this potentially highly valuable transformation which can lead to chiral β-alkyl substituted β-aminoacids.

116

Chapter 5

5.1 Introduction 5.1.1 Copper-catalyzed enantioselective conjugate addition of organozinc reagents

Copper-catalyzed 1,4-addition of organometallic reagents to α,β-unsaturated substrates has become highly versatile synthetic methodogy in contemporary organic chemistry.1 In particular, the exploitation of dialkylzinc reagents with various chiral ligands has been extremely successful in the development of highly enantioselective catalytic 1,4-additions in recent years.2 Among these, phosphoramidite ligands3 constitute the most representative group of chiral ligands used in the copper-catalyzed enantioselective conjugate addition. Their modular structure allows the rapid synthesis of ligand libraries and the easy fine-tuning for a specific catalytic reaction.3 Futhermore, phosphoramidites frequently exhibit exceptional selectivity and versatility, and their monodentate nature is essential in combinatorial catalysis.3

The first application for the copper-catalyzed asymmetric 1,4-additions of dialkylzinc reagents to cyclic and acyclic enones, using phosphoramidite ligands L1 or L2 derived from 2,2’-binaphthol, was successfully achieved by our group in 1996 (Scheme 1).4 Cycohexenone and chalcone were tested as the substrates for the conjugate addition of Et2Zn in the presence of CuI and monophos ligand L1, affording the corresponding products with 35% and 47% ee, respectively. While applying Cu(OTf)2 together with L2 as chiral catalyst, the enantioselectivity of the conjugate addition was enhanced to 63% and 90% ee, respectively.

Scheme 1. Conjugate addition of diethylzinc to cyclohexenone and chalcone in the presence of chiral phosphoramidite ligands. Tf = trifluoromethane sulfonate.

A remarkable increase in the enantioselectivity of the copper-catalyzed conjugate addition of Et2Zn to cyclic enones (Scheme 2) was observed when an amine moiety bearing

117

Enantioselective Synthesis of 3-Substituted Furanones via Pd-AAA

additional chiral structural units was incorporated in the phosphoramidite ligand.5 Excellent yields (up to 95%) and enantiomeric excesses (up to 98% ee) were achieved for the first time in the addition of various alkylzinc reagents to different cyclic enones in the presence of the bis(1-phenylethyl)amino derived ligand L3.5 When ligand L3 was further tested for the copper-catalyzed conjugate addition of Et2Zn to a broad range of 5-substituted cyclohexenones, a highly efficient kinetic resolution process was then developed to produce the disubstituted cyclohexenones in high enantioselectivities.6

Scheme 2. Enantioselective 1,4-additions of Et2Zn to cyclohexenones catalyzed by Cu(OTf)2 /L3.

By utilizing a combination of racemic or dynamic biphenyl moieties with chiral amines, a further modification on the ligand structure was introduced by Alexakis et al. to perform the enantioselective 1,4-addition of Et2Zn to various linear enones (Scheme 3).7 High enantioselectivity values were also obtained for the conjugate addition of Et2Zn to nitroalkenes.7

Scheme 3. Enantioselective 1,4-additions of Et2Zn to cyclic or linear enones catalyzed by CuTC /L4.

Besides phosphoramidite ligands, other ligands such as phosphines bearing amino acid moieties,8 phosphines,9 phosphites,10 NHC compounds11 as well as ligands with mixed

118

Chapter 5

functionalities12 were also intensively investigated in the conjugated addition of alkylzinc reagents to α,β-unsaturated compounds.

An important feature for the copper-catalyzed 1,4-addition of Et2Zn to α,β-unsaturated substrates is the functional group tolerance (e.g. esters, nitriles). One representative example demonstrating the privileged synthetic utility of functionalized organozinc reagents was the total synthesis of prostaglandin E1 methyl ester.13 The conjugate addition of dialkylzinc reagent 3 bearing an ester moiety to α,β-unsaturated cyclopentenone 1 in the presence of Cu(OTf)2/L3, and subsequent enolate trapping with aldehyde 2, resulted in the formation of product 4 in high enantiomeric excess with three contiguous stereogenic centers (Scheme 4). The final product was obtained with an overall yield of 7% in seven steps.

Scheme 4. Catalytic enantioselective synthesis of (−)-Prostaglandin E1 methyl ester via a tandem 1,4-addition/aldol reaction using functionalized organozinc reagents.

5.1.2 Enantioselective conjugate addition of organometallic reagents to β-heteroatom-substituted α,β-unsaturated substrates

The use of bicycle[2,2,2]-octadiene ligands is associated mainly with Hayashi et al. who synthesized a library of distinct ligands that were used in the conjugate addition of arylboronic reagents to various unsaturated compounds (Scheme 5).14 In this regard, chiral 1,4-diene ligand L10 has proven to be a good ligand for the enantioselective addition of the arylboronic acids to β-silyl α,β-unsaturated carbonyl compounds in the presence of

119


RhCl[(C2H4)2]2. The catalytic addition of various arylboronic acids to β-silyl enones

proceeds with excellent yields and enantioselectivities.15

Scheme 5. Enantioselective addition of arylboronic acids to β-silyl-α,β-unsaturated carbonyl compounds

in the presence of RhCl[(C2H4)2]2/L10.

Similar results were also obtained in the asymmetric 1,4-addition of arylboronic acids to

β-phthaliminoacrylate esters, yielding the β-aryl-β-N-phthaloylamino acid ester in high

yields with excellent enantioselectivities (Scheme 6).16 Although KOH is often used for

the in situ generated hydroxorhodium catalysts from rhodium chloride complexes, it was

observed that the addition of KOH decreases the catalytic activity of the rhodium/diene

catalyst in this case. It should be noted that the use of more bulky ester such as

2,6-dimethylphenyl ester lead to a significant increase in the ee value up to 98%. Finally,

chiral β-aryl-β-N-phthaloylamino acid esters were readily converted into the

corresponding β-amino acid derivatives without loss of enantiomeric excess.

S,S

L11S,S

t

Scheme 6. Rodium-catalyzed asymmetric conjugate addition (ACA) of arylboronic acid to

β-phthaliminoacrylate esters.

Rh-catalyzed ACA has been shown to be limited to the use of arylboronic acids as

nucleophiles. The use of organozinc reagents under copper catalysis is attractive to the

synthesis of the corresponding addition products with both alkyl- or aryl- substitutes.

Hoveyda and co-workers reported the first asymmetric conjugate reaction of dialkyl- and

120

Chapter 5

diarylzinc reagents to β-silyl-α,β-unsaturated ketones, promoted by a simple valine-based

chiral phosphine ligand (Scheme 7).17 Asymmetric addition of diarylzincs proceeded in

dimethoxyethane (DME) to achieve similar results (up to 94% ee) as were obtained from

the addition of dialkylzincs in toluene (up to 96% ee).

Scheme 7. Cu-catalyzed ACA of dialkyl- and diarylzinc reagents to acyclic β-silyl-α,β-unsaturated

ketones.

5.2 Goal

The aim of this research project is to develop a catalytic asymmetric method for the

conjugate addition of organometallic reagents to β-phthalimino-α,β-unsaturated substrates.

As previous mentioned, rhodium catalyzed conjugate addition of boronic acids suffers a

limitation on the nucleophile scope. Thus, an effective catalytic enantioselective approach

for the copper-catalyzed ACA of readily available dialkyl zinc reagents to

β-phthalimino-α,β-unsaturated substrates would be of value. The introduction of

dialkylzincs would result in the formation of optically active β-phthalimino-β-alkyl

substituted carbonyl compounds, providing further opportunities to access the important

structure of β-alkyl-β-amino acids through subsequent Baeyer–Villiger oxidation,

deprotection and hydrolysis. Such a protocol would provide an alternative and efficient

route towards the formation of chiral β-amino acids (Scheme 8).

Scheme 8. Retrosynthesis of β-alkyl substituted β-amino acids.

121


5.3 Results and Discussion 5.3.1 Synthesis of starting materials

The synthetic approach to install the enamine moiety was based upon literature precedents.16, 18 In a typical procedure, N-phthalimide underwent a smooth reaction with activated alkynes at room temperature, promoted by a catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO). The reaction appeared to be general with a number of alkynes affording conjugate addition products in moderate yields with excellent stereoselectivity (Scheme 9). Only the E-isomer was formed in all the reactions.

Scheme 9. Synthesis of β-phthalimino-α,β-unsaturated substrates.

5.3.2 Optimization for ACA of Et2Zn to N-(3-oxo-3-phenyl-propenyl)-phthalimide

We began our studies* by examining the conjugate addition of diethylzinc to substrate 8b in the presence of a catalytic amount of Cu(OTf)2 and ligand L3. Full conversion was reached after 2 h when the reaction was carried out in toluene at 0 oC, affording the corresponding product 10b in high yield with moderate enantioselectivity (32% ee; Table 1, entry 1). Product from nucleophilic attack of Et2Zn to carbonyl group was not isolated. Decreasing the temperature from 0 oC to −40 oC led to a slight increase in the enantiomeric excess (40% ee; Table 1, entry 2), albeit incomplete conversion (85%) was achieved after 20 h. By adding the solution of Et2Zn over 1 h at −40 oC in toluene, a similar result was obtained. Reducing the amount of catalyst loading to 5 mol % did not have any effect on the reactivity while the ee value was maintained (34%; Table 1, entry 4).

* Initial attempts with Grignard reagents were not successful due to the formation of 1,2-addition products

122

Chapter 5

Table 1. Optimization for ACA of diethylzinc to 8ba

entry Cu(OTf)2

(mol %)

time for addition of

Et2Zn (min)

temperature

(oC)

reaction

time (h)

conversionb

(%)

ee of 10bc

(%)

1 5 5 0 2 100

(95)d 32

2 5 5 −40 20 85 40

3 5 60 −40 20 87 40

4 2.5 5 0 2 100 34

*Formation of 1,2-addition product was not observed unless otherwise noted. a General conditions for ACA: 5.0 mol % of Cu(OTf)2, 10 mol % of L3, 3 equiv of Et2Zn in 2 mL toluene. b Conversion was determined by GC analysis. c Enantiomeric excess was determined by chiral HPLC analysis. d Isolated yield.

Under these conditions (Table 1, entry 4), several different ligands were tested and the results achieved are summarized in Table 2. The use of phosphoramidites bearing a bis(tetrahydronaphthalene) moiety (L13), Taddol framework (L14) or racemic biphenyl backbone (L15) in enantioselective addition did not show any high asymmetric induction. The same reaction was also studied in the presence of o-methoxy-substituted phosphoramidites L16 and L17, in both cases, only low asymmetric induction was observed (Table 2, entries 6-7). Phosphoramidite (R,R,R)-L18 gave no enantiomeric excess which is significant different when compared to (S,R,R)-L3, representing a strong mismatch behavior of these ligands. The screening of more than 15 different phosphoramidite ligands concluded with ligands (R,S)-L21 and (S,S)-L22 being the most suitable in terms of enantioselectivity (42% and 43% ee, respectively; Table 2 entries 10-11).

123


Table 2. Catalyst screening for ACA of diethylzinc to 8ba

entry ligand reaction

time (h)

conv.b

(%)

ee c

(%) entry ligand

reaction

time (h)

conv.b

(%)

ee c

(%)

1 L3 2 100 34 2 L13 2 100 20

3 L14 16 80 17 4 L15 2 100 3

5 L16 4 100 23 6 L17 4 100 4

7 L18 4 100 0 8 L19 4 100 6

9 L20 4 100 14 10 L21 2 100 42

11 L22 2 100 43 12 L23 4 83 7

13 L24 4 86 10

*Formation of 1,2-addition product was not observed unless otherwise noted. a General conditions for ACA: 2.5 mol % of Cu(OTf)2, 5 mol % of ligand, 3 equiv of Et2Zn in 2 mL toluene. b Conversion was determined by GC analysis. c Enantiomeric excess was determined by chiral HPLC analysis.

124

Chapter 5

S,R,R R,R R - S,R,R

(S,S,S) (R,R,R (S,R)-

(R,S)- (S,S)- (S,R)- (R,S)-

(R)-

Table 3. ACA of diethylzinc to various β-phthalimino-α,β-unsaturated substratesa

o2

2

(R,S)-

entry substrate reaction

time (h)

conversionb

(%) product

ee c

(%)

1e 8a (R = OEt) 24 n.d.d 10a -

2 8b (R = Me) 2 100 10b 42

3 8c (R = Ph) 2 100 10c 14

a General conditions for ACA: 2.5 mol % of Cu(OTf)2, 5 mol % of (R,S)-L21, 3 equiv of Et2Zn in 2 mL toluene at 0 oC. b Conversion was determined by GC analysis. c Enantiomeric excess was determined by chiral HPLC analysis. d n.d. = Not determined. e The reaction was carried out at 0 oC for 4 h, then the temperature was slowly increased to 25 oC.

125


The synthetic applicability of this procedure was also examined using a set of β-phthalimino-α,β-unsaturated substrates under optimized conditions (Table 3). Conjugate addition with ester 8a did not provide the desired product. In fact, only starting material was recovered even when the reaction temperature was increased to 25 oC. Reaction of phenyl ketone 8c which would provide a better substrate for the Bayer-Villiger oxidation resulted in lower enantiomeric excess for the corresponding product 10c (Table 3, entry 3).

5.4 Conclusions In summary, we have developed a novel catalytic asymmetric conjugate addition of organozinc reagents to β-phthalimino-α,β-unsaturated substrates, which was realized by use of copper/phosphoramidite complex, producing optically active β-phthalimino-β-alkyl substituted carbonyl compounds in high yields although with only moderate enantioselectivities so far.


Column chromatography was performed on silica gel (Silica-P flash silica gel from Silicycle, size 40-63 μm). TLC was performed on silica gel 60/Kieselguhr F254. Components were visualized by UV and staining with a solution of a mixture of KMnO4 (10 g) and K2CO3 (10 g) in H2O (500 mL). Mass spectra were recorded on a AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.6 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration.

Conversion of the reaction was determined by GC (GC, HP6890: MS HP5973) with an HP5 column (Agilent Technologies, Palo Alto, CA). Enantiomeric excess was determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector.

All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. All solvents were reagent grade and were dried and

126

Chapter 5

distilled prior to use, if necessary. Toluene was distilled over calcium hydride. Cu(OTf)2, Et2Zn (1 M in toluene) were purchased from Aldrich and used as received. Phosphoramidite ligands L3, L13-L24 were prepared as reported in the literature.20, 21 Substrate 8a was prepared following the literature procedures.18, 19 Racemic 1,4-addition products were synthesized by reaction of the β-phthalimino-α,β-unsaturated ketones 8b-c with diethylzinc reagent (3 equiv) at 0 oC in toluene in the presence of PPh3 (10 mol %) and Cu(OTf)2 (5 mol %).

General procedure for the synthesis of β-phthalimino-α,β-unsaturated ketones (8b-c):

Phthalimide 6 (18.3 mmol, 2.69 g), 1,4-diazabicyclo[2.2.2]octane (DABCO) (3.6 mmol, 404 mg), and alkyne 7 (18.3 mmol) were stirred in CH2Cl2 (30 mL) at 0 oC for 2 h and at room temperature for another 2 h. The reaction mixture was concentrated under vacuuo. The residue was passed through a short column of silica gel with hexane/ethyl acetate (1/1). After the evaporation of the solvent, the crude product was purified by recrystallization from CH2Cl2/hexane to give the final product 8b or 8c as colorless crystals.

N-(3-oxo-3-methyl-propenyl)-phthalimide (8b)

Colorless crystals, 82% yield. 1H NMR (400 MHz, CDCl3) δ = 8.00 – 7.90 (m, 2H), 7.88 – 7.75 (m, 3H), 7.30 (d, J = 14.8 Hz, 1H), 2.35 (s, 3H). 13C NMR (100.6 MHz, CDCl3) δ = 198.0, 165.5, 135.2, 131.4, 130.0, 124.3, 116.5, 28.5. HRMS (ESI+, m/z): calcd for C7H11O2

[M+Na]+: 238.04746, found 238.04726.

N-(3-oxo-3-phenyl-propenyl)-phthalimide (8c)

Colorless crystals, 69% yield. 1H NMR (400 MHz, CDCl3) δ 8.19 – 8.06 (m, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.99 – 7.93 (m, 2H), 7.88 – 7.78 (m, 2H), 7.61 – 7.57 (m, 1H), 7.54 – 7.47 (m, 2H). 13C NMR (100.6 MHz, CDCl3) δ 190.2, 165.7, 137.9, 135.2, 133.0, 131.5, 131.2,

N Me

OO

O

N Ph

OO

O

127


128.6, 128.5, 124.3, 111.7. HRMS (ESI+, m/z): calcd for C11H19O2 [M+H]+: 278.08117, found 278.08104.

General procedure for the copper-catalyzed asymmetric conjugate addition of diethylzinc to β-phthalimino-α,β-unsaturated ketones:

o2

2

(R,S)-

Cu(OTf)2 (0.00625 mmol, 2.3 mg) and L21 (0.0125 mmol, 6.6 mg) were dissolved in dry toluene (2.0 mL) and the mixture was stirred at room temperature for 15 min. Then a solution of β-phthalimino-α,β-unsaturated ketone 8 (0.25 mmol) in toluene (1.0 mL) was added to the mixture at room temperature. The reaction was cooled to 0 oC and subsequently the diethylzinc solution (1 M in toluene, 0.75 mmol, 0.75 mL) was added dropwise over 5 min. The reaction mixture was stirred at 0 oC until TLC (ethyl acetate/n-pentane 50%) showed full conversion and subsequently quenched with saturated aqueous NH4Cl solution (2 mL). The mixture was separated and the water layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated under vacuo (Note: in some cases products are very volatile). Purification by flash chromatography over silica gel, using ethyl acetate /n-pentane 1/2 afforded the pure product 10 as a white waxy solid.

N-(3-oxo-3-methyl-propenyl)-phthalimide (10b)

White waxy solid, 95% yield, 42% ee. 1H NMR (400 MHz, CDCl3) 7.78 (dd, J = 5.3, 3.0 Hz, 2H), 7.67 (dd, J = 5.4, 2.9 Hz, 2H), 4.69 – 4.48 (m, 1H), 3.30 (dd, J = 17.6, 8.7 Hz, 1H), 2.94 (dd, J = 17.6, 5.7

Hz, 1H), 2.10 (s, 3H), 2.01 – 1.84 (m, 1H), 1.78 – 1.62 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ = 205.6, 168.4, 133.9, 131.7, 123.1, 48.4, 45.4, 30.1, 25.7, 10.8. HRMS (ESI+, m/z): calcd for C7H11O2 [M+H]+: 246.11247, found 246.11234. Enantiomeric excess was determined by chiral HPLC, Chiralpak OD-H (Heptane/i-Propanol = 95/5, 0.5 mL/min, 216 nm, column temperature 40 °C), retention times: tR (major) 22.91 min, tR (minor) 20.33 min.

N Me

OO

O

Et

128

Chapter 5

N-(3-oxo-3-phenyl-propenyl)-phthalimide (10c)

White waxy solid, 69% yield, 14% ee. 1H NMR (400 MHz, CDCl3)

7.99 – 7.90 (m, 2H), 7.80 (dd, J = 5.4, 3.1 Hz, 2H), 7.68 (dd, J = 5.5,

3.0 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 4.83 (tt,

J = 10.3, 5.4 Hz, 1H), 3.93 (dd, J = 17.6, 8.6 Hz, 1H), 3.45 (dd, J = 17.6, 5.4 Hz, 1H), 2.16

– 2.02 (m, 1H), 1.93 – 1.78 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz,

CDCl3) δ 197.5, 168.5, 136.6, 133.8, 133.2, 131.8, 128.6, 128.0, 123.2, 48.9, 40.6, 25.8,

10.9. HRMS (ESI+, m/z): calcd for C11H19O2 [M+H]+: 308.12812, found 308.12819.

Enantiomeric excess was determined by chiral HPLC, Chiralpak OD-H



5.6 References

1 For reviews, see: a) P. Perlmutter in Tetrahedron Organic Chemistry Series, Vol. 9, Pergamon Press,

Oxford, 1992; b) K. Tomioka, Y. Nagaoka in Comprehensive Asymmetric Catalysis, Vol. 3 (Eds.: E.

N. Jacobsen, A. Pfaltz, H. Yamamoto) Springer, Berlin, 1999, pp. 1105-1120; c) M. Kanai, M.

Shibasaki in Catalytic Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley, New York, 2000, pp.

569-592; d) A. Alexakis and C. Benhaim, Eur. J. Org. Chem., 2002, 3221-3236; e) S. Woodward,

Angew. Chem. Int. Ed. 2005, 44, 5560-5562; f) F. Lopez, A. J. Minnaard, B. L. Feringa, Acc. Chem.

Res. 2007, 40, 179-188; g) F. Lopez, B. L. Feringa in Asymmetric Synthesis—The Essentials (Eds.:

M. Christmann, S. Bräse), Wiley-VCH, Weinheim, 2007, pp. 78-82; h) A. Alexakis, J. E. Bäckvall,

N. Krause, O. Pàmies, M. Diéguez, Chem. Rev. 2008, 108, 2796-2823; i) S. R. Harutyunyan, T. den

Hartog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008, 108, 2824-2852; j) T.

Jerphagnon, M. G. Pizzuti, A. J. Minnaard, B. L. Feringa, Chem. Soc. Rev. 2009, 38, 1039-1075; k)

T. Thaler, P. Knochel, Angew. Chem. Int. Ed. 2009, 48, 645-648.

2 a) B. L. Feringa, Acc. Chem. Res. 2000, 33, 346-353; b) B. L. Feringa, R. Naasz, R. Imbos and L. A.

Arnold in Modern Organocopper Chemistry, (Ed.: N. Krause), Wiley-VCH, Weinheim, 2002, pp.

224-258; c) M. Kotora, R. Betík, in Catalytic Asymmetric Conjugate Reactions, Chapter 2 (Ed.: A.

Córdova), Wiley-VCH, 2010. pp. 71-144.

3 J. F. Teichert, B. L. Feringa, Angew. Chem. Int. Ed. 2010, 49, 2486-2528.

4 A. H. M. de Vries, A. Meetsma, B. L. Feringa, Angew. Chem. Int. Ed. 1996, 35, 2374-2376.

5 B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M. de Vries, Angew. Chem. Int. Ed. 1997,

36, 2620-2623.

N Ph

OO

O

Et

129


6 R. Naasz, L. A. Arnold, A. J. Minnaard, B. L. Feringa, Angew. Chem. Int. Ed. 2001, 40, 927-930.

7 A. Alexakis, D. Polet, S. Rosset, S. March, J. Org. Chem. 2004, 69, 5660-5667.

8 S. J. Degrado, H. Mizutani, A. H. Hoveyda, J. Am. Chem. Soc., 2001, 123, 755-756.

9 L.-T. Liu, M.-C. Wang, W.-X. Hao, Y.-L. Zhou, X.-D. Wang, Tetrahedron: Asymmetry, 2006, 17,

136-141.

10 M. Yan, L.-W. Yang, K.-Y. Wong, A. S. C. Chan, Chem. Commun., 1999, 11-12.

11 F. Guillen, C. L. Winn, A. Alexakis, Tetrahedron: Asymmetry, 2001, 12, 2083-2086.

12 X. Hu, H. Chen, X. Zhang, Angew. Chem., Int. Ed., 1999, 38, 3518-3521.

13 L. A. Arnold, R. Naasz, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2001, 123, 5841-5842.

14 T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829-2844.

15 R. Shintani, K. Okamoto, T. Hayashi, Org. Lett. 2005, 7, 4757-4759.

16 T. Nishimura, J. Wang, M. Nagaosa, K. Okamoto, R. Shintani, F.-Y. Kwong, W.-Y. Yu, A. S. C.

Chan, T. Hayashi, J. Am. Chem. Soc. 2009, 132, 464-465.

17 M. A. Kacprzynski, S. A. Kazane, T. L. May, A. H. Hoveyda, Org. Lett. 2007, 9, 3187-3190.

18 M.-J. Fan, G.-Q. Li, Y.-M. Liang, Tetrahedron 2006, 62, 6782-6791.

19 K. Nozaki, N. Sato, K. Ikeda, H. Takaya, J. Org. Chem. 1996, 61, 4516-4519.

20 L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. de Vries, R. Naasz, B. L. Feringa, Tetrahedron 2000,

56, 2865-2878.

21 M. G. Pizzuti, A. J. Minnaard, B. L. Feringa, J. Org. Chem. 2008, 73, 940-947.

Chapter 6

Highly Enantioselective Synthesis of

3-Substituted Furanones through

Palladium-Catalyzed Kinetic Resolution of Allyl

Acetates

A near-perfect Pd-catalyzed kinetic resolution of 1,3-disubstituted allylic acetates which uses silyl enol ethers as nucleophiles to access the important 3-substituted-furanone scaffold is described. The reaction proceeds under mild conditions and provides the desired products with excellent chemo-, regio-, and enantioselectivity.


B. Mao, Y. Ji, M. Fañanás-Mastral, G. Caroli, A. Meetsma, B. L. Feringa, Angew. Chem. Int. Ed.

2012, 51, 3168-3173.

131

Chapter 6

6.1 Introduction Palladium-catalyzed allylic asymmetric alkylation (Pd-AAA) with carbon nucleophiles holds a prominent position among the most versatile methods for carbon-carbon bond formation widely applied in the natural product synthesis.1 This transformation typically features broad functional group tolerance and excellent regio- and enantioselectivities.2 The general catalytic cycle of the Pd-AAA reaction, involves olefin complexation, subsequent ionization of the leaving group, and then nucleophilic addition and decomplexation (Scheme 1).1c Except for decomplexation of the olefin from the palladium-ligand system, where the chirality has already been set, each of these steps provides an opportunity for enantioselection.1c For instance, in the olefin complexation step, if one complex leads to ionization at a rate significantly faster than the other, and nucleophilic capture of that diastereomer is fast relative to π-σ-π equilibration, then enantiotopic olefin face complexation becomes the enantiodetermining step.1c When the initial olefin coordination is rapid and reversible, two diastereomeric palladium complexes can form. These complexes can equilibrate through a π-σ-π equilibration step, where either the more abundant or the more reactive diastereomeric complex leads to product.1c This type of selection usually constitutes a dynamic kinetic asymmetric transformation.3

Scheme 1. Catalytic cycle in the Pd-catalyzed asymmetric allylic alkylation.

132


6.1.1 Kinetic resolution in the palladium-catalyzed allylic substitution

Although the nature of the transition state of the nucleophilic attack and its role in determining the enantioselectivity of the overall process have been intensively investigated, the studies on the activation of the allylic substrate by a Pd(0) complex involving a kinetic resolution step has only received attention in the recent year.4 In most cases, the rapid equilibration of the enantiomers of Pd-substrate complex takes place and obscures the kinetic resolution process. A chiral ferrocenylphosphine–palladium catalyst effects highly selective kinetic resolution of racemic allyl acetates such as 1-[(E)-styryl]-2-methylpropyl acetate in asymmetric allylic alkylation was observed by Hayashi and co-workers in 1986.5 Osborn and co-authors soon revealed the kinetic resolution of cyclohexenyl acetate and dimethylpropenyl acetate which occur in the presence of (R,R)-duxantphospholane ligands and proposed a mechanism that involves a favored rotational isomer.6 In the same year, Gais and co-workers described the observation of high selectivities in both kinetic resolution and enantioselective substitution in the reaction of 1,3-diphenylpropenyl carbonate with lithium tert-butylsulfinate by using the chiral phosphinooxazoline ligand L1 (Scheme 2a).7a Soon afterwards, the same group disclosed the highly selective kinetic resolution of cyclic and acyclic symmetrical carbonates in reactions with sufinate anions and thiols by using chiral phosphinooxazoline ligand L1 or bisphosphinoamide ligand L2 (Scheme 2b).7b-c The Pd-catalyzed kinetic resolution of cyclohexenyl acetate with the hydrogen carbonate ion in water was reported by Gais et al.7d Moreover, several other groups also encountered the kinetic resolution during the studies in the Pd-AAA reaction.8

2 2 t

2t2

S i

2 2 t

2 2 2 422t

R,R

2 2

2

2 3 3

2 3 3

Scheme 2. Selective kinetic resolution through palladium-catalyzed allylic alkylation.

The use of unsymmetrical allylic substrates as electrophiles represents a major problem to achieve regio- and enantioselective palladium-catalyzed allylic alkylation with various

133

Chapter 6

nucleophiles. Examples for Pd-catalyzed kinetic resolution of unsymmetrical allylic racemic substrates in high yield and enantioselectivity are still scarce.5,9 Upon treatment of unsymmetrical allylic acetate in the presence of chiral catalyst Pd(0)/L2 and water, Gais and co-workers revealed an example of highly selective kinetic resolution through Pd-AAA reaction (Scheme 3).9a Furthermore, it was of interest to see that the reaction employing more reactive unsymmetrical allylic carbonates as substrates resulted in a dynamic kinetic asymmetric transformation, providing the chiral alcohols with high enantio- and regioselectivities.

Scheme 3. Kinetic resolution of unsymmetric acetate via Pd-AAA.

6.1.2 Selectivity factor of kinetic resolution

In the simplest cases of KR, both the substrate enantiomers interact with a chiral catalyst to generate two diastereomeric transition states. The free energies of these competing transition states define the rate constants for conversion of the fast-reacting and slow-reacting enantiomers, and the ratio kfast/kslow (typically expressed as krel or the selectivity factor s) controls the product distribution (Eq. 1).4e

( )1./ EqKKKS slowfastret ==

When studying a kinetic resolution using enantiopure catalyst which follows the simplest form of Michaelis-Menten kinetics, preequilibrium binding of the R and S enantiomers to an enantiopure catalyst followed by an irreversible product formation step (Scheme 4) make it clear that the selectivity factor s in the kinetic resolution highly depends on the equilibrium binding (KS vs KR) and the rate constants (K’S vs K’R).10

134


Scheme 4. Kinetic resolution displaying simple Michaelis-Menten kinetics.11

( )( )[ ]( )( )[ ] ( )2.

1111

EqeeCIneeCIn

Kss

srel +−

−−==

( )( )[ ]( )( )[ ] ( )3.

1111

EqeeCIneeCIn

Ksp

prel −−

+−==

Figure 1. Plot of ee vs conversion as a function of Krel for (a) recovered substrate and (b) product. Curves were calculated using Eq. 2 and 3.12

Upon simple first-order kinetics for the substrate and the absence of nonlinear effects associated to the catalyst,4e the selectivity factor s could be calculated using Equation 2 in which C (0 ≤ C ≤ 1) represents conversion of substrate and ees (0 ≤ ees ≤ 1) stands for the enantiomeric excess of the starting material (Figure 1a).12 As is evident from Figure 1a, the enantiomeric purtity of the starting material obtained in the kinetic resolution changes as a function of conversion.4c In such case, kinetic resolutions have the ability to provide substrates with high enantioenrichment for even modestly selective processes at higher levels of conversion. By contrast, a high selectivity factor is necessary in order to obtain the product with high ee value in the kinetic resolution (Equation 3).4c For cases in which the product is also chiral, equation 3 can be used to check for accuracy of conversion (C)

135

Chapter 6

whereas the precise determination of C is relatively difficult.4e As reflected by the plot in Figure 1b, the enantiomeric excess of product (eep) decreases as the reaction proceeds to achieve higher conversion.

6.1.3 Palladium-catalyzed allylic asymmetric alkylation of silyl enol ethers

Despite the impressive progress made in the palladium-catalyzed allylic asymmetric alkylation, this transformation suffers from a significant drawback: the limitation in the type of carbon nucleophile.13 Stabilized carbon nucleophiles are generally used for this type of reaction, typical examples being the anions of malonic esters, β-keto esters, α-imino esters, and sulfones.13a Although nonstabilized preformed enolates such as silyl enol ethers and silyl ketene acetals were developed about simultaneously and turned out to be exceptionally useful in the context of aldol reactions, they were hardly applied as nucleophiles in the palladium-catalyzed allylic substitutions.

The use of silyl enol ether for the palladium-catalyzed allylic alkylation with moderate control of the regioselectivity was reported by Trost and Keinan for the first time.14 Later, Tsuji and co-workers observed that a formal dehydrogenation to the α,β-unsaturated carbonyl compound rather than allylic alkylation occurred in the reaction of enol silanes and ketene acetals with allyl carbonate in acetonitrile.15 Allylic alkylation between the silylketene acetal and unsymmetrical allylic acetates was reported by the group of Musco in 1991, delivering the corresponding products with moderate regioselectivity.16

In 2004, Stoltz and co-authors reported the enantioselective intermolecular Tsuji allylation1g of silyl enol ethers using a diallyl carbonate as a coupling partner (Scheme 5).17 Although Tsuji et al. reported the allylation of silyl enol ethers without an exogenous activator,18 it was found that the addition of fluoride donor tetrabutylammonium difluorotriphenylsilicate (TBAT) was necessary for the enantioselective reaction at 25 oC. Employing the same catalytic system, enantioselective Pd-catalyzed allylation of fluorinated silyl enol ethers was reported by Paquín and co-workers in 2007.19 This reaction provides an efficient, stereoselective approach to allylated tertiary α-fluoroketones from achiral fluorinated precursors.

136


Scheme 5. Enantioenriched cycloalkanones produced from silyl enol ethers.

Based on their previous finding (see Scheme 4), Stoltz and co-workers developed the palladium-catalyzed asymmetric alkylation of simple dioxanone derivatived triethylsilyl enol ethers in the presence of catalytic amount of Pd(dmdba)2 (dmdba=bis(3,5-dimethoxybenzylidene)acetone) with one equivalent of TBAT.20 This asymmetric alkylation tolerates diverse α-substituted silyl enol ethers in combination with various allyl carbonates, affording the products in high yields and high entantiomeric excess (Scheme 6). The synthetic utility of the catalytic system has been proved by the formal synthesis of (−)-quinic acid.

Scheme 6. Pd-catalyzed enantioselective allylation of dioxanone derived triethylsilyl enol ethers.

6.1.4 Iridium-catalyzed allylic asymmetric alkylation of silyl enol ethers

Although Pd-catalyzed AAA using silyl enol ethers have been limited to the use of simple allyl carbonates, regio- and enantioselective γ-allylation of silyl enol ether derived from acetophenone with monosubstituted allylic carbonates to form the branched products in the presence of metallacyclic iridium catalysts was reported by Graening and Hartwig in 2005 (Scheme 7).21 Iridium complexes derived from simple phosphoramidite ligands were shown to catalyze this reaction with excellent selectivities. In addition, the presence of fluoride ions was indispensable for any conversion, and no reaction occurred with the silyl enol ether alone. The optimal activation was found to be a combination of cesium fluoride

137

Chapter 6

and zinc fluoride, although it is still uncertain whether a cesium, a zinc, or a hypervalent silicon enolate is the reactive nucleophile in this procedure.

Scheme 7. Iridium-catalyzed allylation of silyl enol ethers.

6.2 Project Goal Although excellent results of allylic alkylation have been reported with preformed or in situ- generated enolates,22 to the best of our knowledge, Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) of unsymmetrically substituted secondary allylic substrates with a silyl enol ether as nucleophile remains a challenge (Scheme 8). The undesired side reactions as well as insufficient control of regioselectivity and diastereoselectivity has kept the Pd-AAA reaction of silyl enol ethers with unsymmetrically allylic substrates from having been developed further.

1

32

34 5

13

5

4

2

6

13

4

5

2

substitution -substitution

Scheme 8. Pd-catalyzed AAA of unsymmetrical substrates with silyl enol ethers as nucleophiles.

During the last decades, 2-trimethylsilyloxyfuran23 has emerged as a keystone for the assembly of a wide variety of butenolides and their derivatives.24 As electrophilic attack usually takes place exclusively at C-5, products arising by C-3 attack are rarely observed.25 Consequently, this electron-rich furan is considered as a stable, readily accessible synthon for the γ-anion of 2(5H)-furanones (Figure 2).

138


Figure 2. 2-Trimethylsilyloxyfuran as synthon for γ-anion of 2(5H)-furanones.

As part of our program to develop catalytic enantioselective methodologies to access optically active γ-butenolides and lactones, we envisioned the possibility of using 2-trimethylsilyloxyfuran (TMSOF) as nucleophile in a palladium-catalyzed AAA reaction. Although TMSOF has served as an extended dienolate precursor to introduce the chiral γ-butenolide structure through various enantioselective reaction including aldol reaction, Mannich reaction or conjugate addition,24 application of this nucleophile for the Pd-catalyzed allylic substitution reaction has never been reported in the literature.

The aim of this research was to develop an efficient, stereocontrolled approach towards the synthesis of γ-butenolides through the Pd-AAA with TMSOF. The ability to facilitate a stereospecific allylic alkylation with TMSOF would circumvent the problems associated with regiochemical infidelity of unsymmetrical substrates as well as the current repertoire of unstabilized nucleophiles. This process would provide an opportunity to investigate in detail the mechanism involved in the Pd-AAA reaction using silyl enol ethers as nucleophiles.

6.3 Results and Discussion 6.3.1 Optimization in the kinetic resolution of allylic substrates

For our initial investigation, we examined the allylic substitution of methyl carbonate 1a in the presence of the chiral palladium catalyst based on Trost Ligand L1, using 2-trimethylsilyloxyfuran as nucleophile (Scheme 8). Both the 3-substituted furanone product 3 and 5-substituted furanone product 4 were obtained in a 2:1 ratio and 36% ee for product 3. To our surprise, the major product 3 came from the attack of the C-3 of TMSOF to the allylic carbonate 1a. This result was quite unexpected, as already mentioned before, products arising by C-3 attack of TMSOF are rarely observed in the literature.24 Moreover, the exclusive formation of α-substitution product implied that the reaction proceeded with complete control of the regioselectivity towards the less steric position on the unsymmetrical allylic substrate.

139

Chapter 6

Scheme 9. Preliminary study on the Pd-catalyzed AAA of unsymmetrical substrates with silyl enol ether as nucleophile.

Temperature as well as the nature of leaving group of the substrates were then investigated. The obtained results are listed in Table 1. Using a lower temperature (0 oC), the enantiomeric excess of product 3 was slightly increased (49% ee, Table 1, entry 2). With tert-butyl carbonate as leaving group, the regioselectivity shifted in favour of the formation of the 5-substituted furanone product (3/4 = 1/2, entry 3). When allylic acetate 1c was used, 80% conversion was reached at room temperature and both the regio- and enantioselectivity toward the formation of product 3a were significantly enhanced (3/4 = 5/1, 78% ee, entry 4). Remarkably, the recovered acetate 1 had an S:R enantiomer ratio of 98:2 (96% ee (S), entry 4), indicating that the kinetic resolution might occur in the substrate-activation step.

140


Table 1. Selection of reaction parameters in the Pd-AAA of TMSOF.

entry 1 T(oC) Time

(h)

Conv

(%)c

ee (%)d of

recovered 1 3/4c

ee (%)d of

product 3

1a 1a rt 21 100 - 2/1 36

2a 1a 0 25 100 - 2/1 49

3a 1b rt 22 100 - 1/2 60

4a 1c rt 24 80 96(S)e 5/1 78

5a 1c 0 7 53 99(S)e >99/1 99

6b 1c 0 7 52 99(S)e >99/1 99

a 2 equiv of 2a was used. b 1 equiv of 2a was used. c The conversion and ratio of regioisomers were determined by GC analysis using n-dodecane as internal standard. d Determined via chiral HPLC analysis. e The absolute configuration was assigned by comparison of sign of optical rotation with published values.26

Encouraged by these results, the reaction of allyl acetate 1c was carried out at 0 oC instead of room temperature. In this case, the reaction ceased at 53% conversion providing enantiomerically pure recovered acetate (S)-1c through kinetic resolution of the substrate. Furthermore, product 3c was obtained as the only reaction product showing near-perfect chemo-, regio- (3/4 >99:1) and enantio- (99% ee) selectivity. The reaction could also be carried out using one equiv of 2a instead of 2 equiv to afford the same results (Table1, entry 6). Notably, when ligand (S,S)-L1 was used, the recovered acetate and product were obtained with opposite configuration with similar conversion and ee.

141

Chapter 6

In a number of enzymatic kinetic resolutions a fast and stereoselective reaction of one enantiomer of the racemic substrate takes place, while the other is not converted even after prolonged reaction.27 The time dependency of conversion and ee values of the substrates were determined by chiral GC analysis employing n-dodecane as the internal standard (Figure 3). When the kinetic resolution of 1c was performed using the optimized conditions shown in Table 1 but for longer reaction time, we observed that the transformation virtually ceases around 50% conversion providing 99% ee for the recovered acetate 1c, illustrating a near-perfect selectivity in the palladium catalyzed kinetic resolution as well (Figure 3). It is also remarkable that the reaction proceeds with complete regioselectivity towards the formation of the 3-substituted product 3c (Table 1, entry 5) instead of the 5-substituted product 4c which would be expected based on the common reactivity pattern of 2-trimethylsilyloxyfuran.24

Figure 3. Plot of conversion (%) versus time (min) and plot of ee (%) versus time (min) for the palladium-catalyzed kinetic resolution of 1c (Table 1, entry 6). C = conversion of substrate; ee = enantiomeric excess of recovered acetate; T = reaction time.

6.3.2 Substrate scope and efficiency in the palladium-catalyzed kinetic resolution

The successful realization of this palladium catalyzed kinetic resolution has enabled us to introduce a wide range of racemic unsymmetrical and symmetrical allylic acetates under optimized conditions. As revealed in Table 2, both the kinetic resolution and the enantioselective substitution of the allylic acetates in the reaction with 2-trimethylsilyloxyfuran proceeded with high regioselectivities affording the highly enantioenriched recovered acetates and 3-substituted furanone products 3 in good yields. When unsymmetrical recovered acetates 1d and 1e with electron-withdrawing or -donating groups at the para-position of phenyl ring were investigated, excellent regio- and enantioselectivities were maintained (Table 2, entries 2-3). After approximately 49%

142


conversion of allylic acetate 1f, the reaction with TMSOF also led to both recovered acetate and product in excellent enantioselectivities (Table 2, entry 4).

Next we turned our attention to dialkyl substituted allylic acetates for the kinetic resolution. Although the recovered acetates showed a slightly lower enantiomeric excess than the aryl-substituted allylic acetates, the 3-substituted furanone products 3g and 3h were obtained with 99% ee and excellent regioselectivity both with respect to butenolide and unsymmetrical disubstituted allyl fragments (Table 2, entries 5,6). It is important to note that this reaction proceeds very well with both aromatic and alkyl substituted unsymmetrical substrates providing impressive selectivities in both cases.

Kinetic resolution and substitution of the symmetrical dimethyl-substituted substrate 1i proceeded with a slight decrease in enantioselectivity both for recovered acetate (S)-1i and product 3i. The low yield may be ascribed to the high volatility of recovered acetate and product. In addition, treatment of racemic cyclohexenyl acetate 1j under the optimized conditions gave the corresponding product 3j almost exclusively with excellent optical purity, while the acetate was also recovered in 99% ee with (R) configuration (Table 2, entry 8).28

On the contrary, racemic 1,3-diphenylallyl acetate 1k provided 3-substituted product 3k with full conversion in 87% ee and poor regioselectivity (3k/4k = 3:1; Table 2, entry 9). It turned out that the reaction of this common model substrate for allylic alkylation did not follow the kinetic resolution pathway anymore. This result was in accordance with the observation that sterically more encumbered substrates often gave lower enantioselectivity with the Pd(0)/L1 catalyst.29 The class of C2-diphosphine Trost ligands usually yield Pd fragments with a large bite angle where a chiral concave “pocket” is presumably formed.30 Cyclic substrates, in favor of such chiral “pocket” of Trost ligands, were often obtained with a high level of enantiomeric excess. Nonetheless, more sterically hindered substrates such as 1,3-diphenylallyl acetate gave rise to moderate enantioselectivity.

143

Chapter 6

Table 2. Substrate scope for kinetic resolution.a

entry convb

(%)

time

(h) 1

acetate 1 3/4b 3

product 3 sf

ee %c yield %d ee %c yield %d,e

1 52 7 1c 99(S) 43 >99/1 3c 99(R)g 47 116

2 52 7 1d 99 42 >99/1 3d 99 47 116

3 53 7 1e 99 38 >99/1 3e 99 46 80

4 49 7 1f 94 44 >99/1 3f 98 41 >200

5 48 7 1g 94 36 22/1 3g 99 39 >200

6h 46 9 1h 92 44 >99/1 3h 99 36 87

7 41 12 1i 91 18 14/1 3i 88 25 25

8 52 7 1j 99(R)i 33 37/1 3j 99 35 116

9 100 7 1k - - 3/1 3k 87 55 -

a Reaction conditions: 1/2a/(R,R)-L1/Pd2(dba)3·CHCl3 = 1:1:0.15:0.05, 0.175 mM of 1 in DCM at 0 oC, 0.5 h for addition of allylic acetates 1 by syringe pump. b The conversion and the ratio of regioisomers were determined by GC analysis using n-dodecane as internal standard. c Determined via chiral HPLC and chiral GC analysis. d Isolated yield. e No trace of SN2’ product was observed. f s = kfast/kslow = ln[(1-C) (1- ees)]/ln[(1-C)(1+ ees)] (C = conversion; ees = enantiomeric excess of recovered substrate). g The absolute configuration of 3c was assigned based on X-ray analysis of a single crystal. h The reaction was performed at room temperature with 2 equiv of 2a. i The absolute configuration of 1i was assigned by comparison of optical rotation with known compound.28

144


As noted in the introduction, the ee’s of starting material and product change as a function of conversion. It is often useful to characterize kinetic resolution reactions not in terms of the ee obtained but rather in terms of selectivity factor s that is the relative reaction rates of the two enantiomeric substrates. The relationship between the conversion of the reaction (C) and the ee of the of the unreacted substrate (ees) formed is straightforward and listed as s factor in Table 2. In general, this Pd-catalyzed kinetic resolution was observed to proceed with apparently very high selectivity for a broad range of substrates. Noteworthy, the use of substrates 1f and 1g led to a significant increase in selectivity to give s > 200 (Table 2, entries 4-5). Theoretically it means that 99% ee of recovered acetates could be achieved at only 51% conversion. In a sharp contrast, when 1,3-dimethylallyl acetate 1i was used under standard conditions, a decrease in selectivity was observed (s = 25; Table 2, entry 7). The relative low s factor may be attributed to the insufficient enantioselective control of Trost ligand on the symmetrically allylic substrates with small substitutions. Cyclohexenyl acetate 1j gave approximately the same selectivity as substrates 1c-e. Overall, the observation of such high selectivity factors reflects high efficiency of the catalyst system for the palladium-catalyzed kinetic resolution of allylic acetates, providing practical access to a series of enantioenriched allylic acetates and 3-substituted furanones.

6.3.3 Determination of absolute configuration

In order to establish the absolute structure of the product 3c, a solution of 3c and Cr(CO)3(CH3CN)3 in THF was heated for 24 h (Scheme 10).31 After removing the solvents under vacuum, the crude product was purified by flash chromatography on silica gel and then recrystallized from Pentane/EtOAc to yield orange crystals.

Scheme 10. Pd-catalyzed AAA of unsymmetrical substrates with silyl enol ethers as nucleophiles.

The absolute configuration of substrate 3c was determined by X-ray crystal structure analysis of the corresponding chromium complex of 3c (Figure 4). By assuming that the substitution of allylic acetates 1c-i with TMSOF in the presence of Pd/L1 complex all proceed with the same sense of asymmetric induction, we assigned the R configuration to the 3-substituted furanone products 3c-i and 3k. Given the fact that the recovered allylic

145

Chapter 6

acetates were obtained with S configuration suggesting that the (R)-enantiomer of the substrates were consumed, this palladium kinetic resolution took place with net retention of configuration at carbon stereogenic center. Furthermore, the S configuration was assigned to cyclic products 3j on the basis of the R configuration for the recovered acetates and net retention during the allylic substitution process.

Figure 4. ORTEP diagram of chromium complex of 3c.

6.3.4 Mechanistic investigation

To gain further insight into key structural parameters and mechanistic features, different methyl substituted 2-silyloxyfurans were investigated (Schemes 11). When the 3-position at the furan ring was blocked by a methyl group, the allylation reaction underwent exclusively through attack at the 5-position affording a 4:1 mixture of diastereomers with the major isomer 4m showing 86% ee (Scheme 11a). A moderate enantiomeric excess (46% ee) was observed in the recovered acetate. Interestingly, treatment of 5-substituted 2-silyloxy furans with unsymmetrical acetate did not lead to olefin isomerization, providing a 1:1 mixture of diastereomers in 33% total yield (Scheme 11b).

146


Scheme 11. Allylic alkylation of substituted 2-silyloxyfuran 2b.

A remarkable shift in selectivity was observed, when we carried out the reaction with allyl

acetate 1l, that is the regioisomer of 1c (Scheme 12). Instead of exclusive formation of 3c

with 99% ee, suprisingly the reaction only provided a 9:1 diastereomer mixture of 4l, in

which the 3-substituted product was not observed. Furthermore, almost no enantiomeric

excess was detected from the recovered starting material.

Scheme 12. Allylic alkylation of 1c and 1l with 2a.

147

Chapter 6

To further understand the mechanism of the reaction, we carried out model studies and DFT calculations.32 Based on the studies on the conformation of Pd/(R,R)-L1 complex reported by Lloyd-Jones, Norrby and co-workers,33 we performed a conformational search on the Pd-olefin complexes using both enantiomers of 1c (see Experiment Section). These results indicate that the acetate carbonyl of enantiomer (R)-1c is forming a hydrogen bond with the amide hydrogen of ligand L1 on the concave side of catalyst Pd/(R,R)-L1 (Figure 5a), whereas the same stabilization for enantiomer (S)-1c is absent (Figure 5b). The energy difference of about 11 kcal/mol between these (η2-allyl)Pd complexes would explain the result of the kinetic resolution in which the R substrate has been completely consumed. A similar result has been observed by Lloyd-Jones, Norrby and coworkers.33 In the neutral pre-ionization of η2-cyclic ester complexes, they found that the acetate carbonyl of (S)-enantiomer accepted a hydrogen bond from the amide hydrogen on the concave side of Pd complex, whereas no corresponding stabilization is available for (R)-enantiomer. This suggests that only one enantiomer of acetate can be selectively ionized due to the stabilization of the leaving acetate anion through hydrogen bonding.

Figure 5. B3LYP structures of (a) Pd/(R,R)-L1/(R)-1c, (b) Pd/(R,R)-L1/(S)-1c and (c) product 3c coordinated with complex Pd/(R,R)-L1 (Arrow indicates H-bond).

In addition, the DFT calculations displayed that the most stable product of the reaction is the one obtained from allylic alkylation at the 3-position on the furanone ring (bearing conjugated double bond) with the R configuration. We also observed that there is hydrogen bonding between the oxygen of the carbonyl group of the furanone product 3c and the amide hydrogen on the concave side of Pd complex (Figure 5c).

It has been described, for the Pd-catalyzed allylic alkylation of malonate derivatives with this particular ligand (R,R)-L1, that the hydrogen bonding interaction between the enolate

148


oxygen and the amide hydrogen can direct the enolate carbon to the closest enantioface of the η3-allyl complex.33 We envision that hydrogen bonding (also observed in the final product, see Figure 5c) between the oxygen anion of the incoming enolate and the amide hydrogen of the catalyst (to which the carbonyl oxygen of the acetate leaving group was interacting) controls the stereoselectivity of the nucleophilic attack (Figure 6). That is the removal of the acetate leaving group and the delivery of the nucleophile proceeds via an identical enantioface selection pathway. Key is a selective acetate-enolate exchange, suggesting that the whole process takes place with net retention, which is in perfect agreement with the obtained experimental results.

Figure 6. Proposed catalytic cycle.

This result is in full accordance with the proposal of Lloyd-Jones and Norrby,33 where they identified that hydrogen-bond interaction of one N-H unit in the Pd-coordinated complex can substantially accelerate both ionization and nucleophilic attack. Moreover, this

149

Chapter 6

hydrogen-bond pre-orients the allyl unit for ionization and also directs the orientation of nucleophile delivery.34 Most probably in the palladium complex also a subsequent olefin isomerization of the butenolide takes place which will give rise to the final product.35

6.4 Conclusions In summary, we have developed a palladium-catalyzed kinetic resolution of 1,3-disubstituted unsymmetrical allylic acetates and a concomitant allylic alkylation, using silyl enol ethers as nucleophiles, to access the important enantiomerically enriched 3-substituted-γ-butenolides. The reaction proceeds smoothly under mild conditions and provides both the recovered allylic acetates and 3-substituted furanones in high yield with excellent chemo-, regio- and enantioselectivity. This reaction proceeds without any additives, suggesting the acetate anion generated in situ in the catalytic reaction may activate the silyloxfuran. Various methyl-substituted trimethylsiloxyfurans react regioselectively to form the optically enriched products, disclosing the effect of furanyl substituents on the catalytic process. These allylation products containing conjugated or non-conjugated double bonds might be further converted to an array of important building blocks.

Preliminary studies indicate that hydrogen bonding interactions with the chiral ligand might play a key role in the control of regio- and enantioselectivity. The presented findings on the unusual reactivity of 2-trimethylsilyloxyfuran (TMSOF), the mechanistic implications as well as extension of this highly selective catalytic methodology to simple enol silane could lead to a variety of further studies.


Column chromatography was performed on silica gel (Silica-P flash silica gel from Silicycle, size 40-63 μm). TLC was performed on silica gel 60/Kieselguhr F254. Components were visualized by UV and stained with a solution of a mixture of KMnO4 (10 g) and K2CO3 (10 g) in H2O (500 mL). Mass spectra were recorded on a AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H and 13C NMR were recorded on a Varian AMX400 (400 and 100.6 MHz, respectively) or a Varian VXR300 (300 and 75 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C).

150


Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Optical rotations were measured in CHCl3 on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL). Conversion of the reaction were determined by GC (GC, HP6890: MS HP5973) with an HP5 column (Agilent Technologies, Palo Alto, CA). The regioselectivity of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Enantioselectivities were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector or by capillary GC analysis (HP 6890, Chiraldex G-TA column (30 m x 0.25 mm), Chiraldex B-PM column (30 m x 0.25 mm), or CP-Cyclodextrin-β-2,3,6-M-19 column (50 m x 0.25 mm)) using flame ionization detector.

All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. All solvents were reagent grade and were dried and distilled prior to use, if necessary. Tetrahydrofuran and diethylether were distilled over Na/benzophenone. Toluene and dichloromethane were distilled over calcium hydride. All the ligands, palladium catalysts and silyl enol ether 2a were purchased from Acros and Sigma-Aldrich.

Substrates 1a,36 1b37 and silyl enol ether 2b38 were prepared following literature procedures. Racemic products were synthesized by reaction of silyl enol ether 2 (1.2 mmol) with the corresponding allylic substrates (0.6 mmol) at room temperature in CH2Cl2 in the presence of Pd2(dba)3·CHCl3 (5 mol %) and PPh3 (15 mol %).

General procedure for the synthesis of racemic allylic acetates (1c-l):

Allylic alcohols were synthesized by reaction of the α,β-unsaturated aldehydes with the corresponding Grignard reagent at 0 °C in CH2Cl2 or reduction from corresponding ketone in the presence of sodium borohydride. The alcohols were used directly for the following reactions without further purification. Acetic anhydride (2.0 equiv) was added at 0 ºC to a solution of allylic alcohol (1.0 equiv), NEt3 (2.0 equiv) and DMAP (10 mol %) in dry CH2Cl2 (0.2 M). The reaction mixture was allowed to warm to room temperature and stirred at this temperature until the total consumption of the starting material. The reaction was quenched with saturated brine and the organic layer was separated. The aqueous layer was extracted with diethyl ether and the combined organics were washed with saturated

151

Chapter 6

OAc

Cl

aqueous NaHCO3, dried over Na2SO4 and the solvent was removed in vacuum. Futher purification was achieved by Kugelrohr distillation.

General procedure for Pd-catalyzed kinetic resolution of allylic substrates with silyl enol ethers:

To a dry Schlenk tube containing Pd2(dba)3·CHCl3 (0.0175 mmol, 18 mg) was added a solution of Trost ligand (R,R)-L1 (0.0525 mmol, 38 mg) in dry DCM (1 mL). After stirring at room temperature for 15 min, a solution of trimethylsilyloxyfuran (0.35 mmol, 60 μL) in dry DCM (0.5 mL) was added dropwise. After the mixture had been stirred for another 15 min at room temperature, a solution of acetate (0.35 mmol) and n-dodecane (30 μL, internal standard) in dry DCM (0.5 mL) were added via syringe pump over 0.5 h maintaining the temperature below 0 ºC. Reaction progress was followed by GC and GC-MS. After completion of the reaction, the solvent was removed under vacuum. The crude product was purified by flash chromatography on silica gel using different mixtures of pentane/Et2O as eluents. Toluene:Et2O 95:5 was used for TLC to distinguish the resulted regioisomers. The absolute configuration depicted for all the products is assumed to be the same to that of 3c, as determined by X-ray crystallography.

(−)-(S)-(E)-4-Phenylbut-3-en-2-yl acetate ((S)-1c)

Colourless oil, 43% yield, 99% ee. [α]20D = −96.5 (c 0.8, CHCl3). [lit.26 (R

isomer, 94% ee): [α]20D = +120.2 (c 1.14, CHCl3)]. The physical data were

identical in all respects to those previously reported.38 Enantiomeric excess was determined by chiral HPLC or chiral GC analysis, Chiralpak OB-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 210 nm), retention times: tR (major) 20.81 min, tR (minor) 23.33 min. Chiral CP-Cyclodextrin-β-2,3,6-M-19 column (50 m x 0.25 mm), (initial temp. 50 °C, gradient 10 °C/min to 160 °C, 160 °C isothermic for 15 min), retention time: tR (major) 24.53 min.

(−)-(S)-(E)-4-(4-Chlorophenyl)but-3-en-2-yl acetate ((S)-1d)

Colourless oil, 42% yield, 99% ee. [α]20D = −116 (c 2.8, CHCl3). [lit.26

(R isomer, 94% ee): [α]20D = +132.3 (c 0.92, CHCl3)]. The physical data

were identical in all respects to those previously reported.39 Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 210 nm), retention time: tR (major) 12.57 min.

OAc

152


(−)-(S)-(E)-4-(4-Methoxyphenyl)but-3-en-2-yl acetate ((S)-1e)

Colourless oil, 38% yield, 99% ee. [α]20D = −85 (c 2.8, CHCl3). [lit.26

(R isomer, > 99% ee): [α]20D = +125.9 (c 1.10, CHCl3)]. The physical

data were identical in all respects to those previously reported.39 Enantiomeric excess was determined by chiral HPLC, Chiralpak

OB-H (n-heptane/i-propanol = 95/5, 0.5 mL/min, 262 nm), retention time: tR (major) 43.49 min.

(−)-(S)-(E)-4-(2-Methoxyphenyl)but-3-en-2-yl acetate ((S)-1f)

Colourless oil, 44% yield, 94% ee. [α]20D = −108 (c 3.5, CHCl3). 1H NMR

(400 MHz, CDCl3) δ 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.32 – 7.16 (m, 1H), 6.98 – 6.88 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 6.22 (dd, J = 16.1, 6.8 Hz, 1H), 5.64 – 5.40 (m, 1H), 3.85 (s, 3H), 2.07 (s, 3H), 1.42 (t, J = 5.6 Hz,

3H). 13C NMR (100.6 MHz, CDCl3) δ 170.3, 156.9, 129.3, 128.9, 127.0, 126.5, 125.3, 120.6, 110.8, 71.5, 55.4, 21.4, 20.4. HRMS (ESI+, m/z): calcd for C15H17O3 [M+H]+: 245.11722, found 245.11578. Enantiomeric excess was determined by chiral HPLC, Chiralpak OJ-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 210 nm), retention times: tR (major) 22.53 min, tR (minor) 19.14 min.

(−)-(S)-(E)-Hept-3-en-2-yl acetate ((S)-1g)


(400 MHz, CDCl3) δ 5.74 – 5.64 (m, 1H), 5.45 (ddt, J = 15.4, 6.8, 1.3 Hz, 1H), 5.30 (dq, J = 6.5 Hz, 1H), 2.03 (s, 3H), 2.01 – 1.95 (m, 2H), 1.45 –

1.33 (m, 2H), 1.28 (d, J = 6.4 Hz, 2H), 0.87 (dt, J = 13.9, 6.8 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 170.6, 133.1, 129.6, 71.2, 34.2, 22.1, 21.4, 20.3, 13.6. HRMS (ESI+, m/z): calcd for C11H17O2 [M+H]+: 181.12231, found 181.12086. Enantiomeric excess was determined by chiral GC analysis, Chiraldex G-TA column (30 m x 0.25 mm), (initial temp. 50 °C, gradient 10 °C/min to 170 °C), retention times: tR (major) 25.74 min, tR (minor) 26.88 min.

(−)-(S)-(E)-4-Cyclohexylbut-3-en-2-yl acetate ((S)-1h)

Colourless oil, 44% yield, 92% ee. [α]20D = −13 (c 2.8, CHCl3). [lit.26 (R

isomer, 95% ee): [α]20D = +71.1 (c 0.97, CHCl3)]. The physical data were

identical in all respects to those previously reported.5 Ee was determined

OAc

OAc

OAc

H3CO

153

Chapter 6

by chiral GC analysis, Chiraldex B-PM column (30 m x 0.25 mm), (initial temp. 50 °C, gradient 2 °C/min to 100 °C, 100 °C isothermic for 30 min, gradient 5 °C/min to 160 °C), retention times: tR (major) 61.78 min, tR (minor) 62.85 min.

(−)-(S)-(E)-Pent-3-en-2-yl acetate ((S)-1i)

Colourless oil, 18% yield, 91% ee. [α]20D = −94 (c 0.1, CHCl3). [lit.39 (S

isomer): [α]20D = −65.5 (c 1.2, EtOH)]. The physical data were identical in all

respects to those previously reported.28 Enantiomeric excess was determined by chiral GC analysis, Chiraldex G-TA column (30 m x 0.25 mm), (initial temp. 50 °C, gradient 10 °C/min to 170 °C), retention times: tR (major) 8.63 min, tR (minor) 10.02 min.

(+)-(R)-Cyclohex-2-en-1-yl acetate ((R)-1j)

Colourless oil, 33% yield, 99% ee. [α]20D = +202 (c 0.9, CHCl3). [lit.28 (R isomer,

99% ee): [α]20D = +199.0 (c 2.40, CH2Cl3)]. The physical data were identical in all

respects to those previously reported.40 Enantiomeric excess was determined by chiral GC analysis, Chiraldex G-TA column (30 m x 0.25 mm), (initial temp. 60 °C, gradient 5 °C/min to 170 °C), retention times: tR (major) 27.89 min, tR (minor) 28.97 min.

(E)-1-Phenylbut-2-en-1-yl acetate (1l)

Pale yellow oil, 55% yield, 8% ee. [α]20D = +0.1 (c 1.0, CHCl3). The

physical data were identical in all respects to those previously reported.40 Enantiomeric excess was determined by chiral GC analysis, Chiraldex B-PM column (30 m x 0.25 mm), (initial temp. 50 °C, gradient 2 °C/min to

100 °C, 100 °C isothermic for 30 mins, gradient 5 °C/min to 160 °C), retention times: tR (major) 60.58 min, tR (minor) 60.89 min.

(−)-(R)-(E)-3-(4-Phenylbut-3-en-2-yl)furan-2(5H)-one ((R)-3c)

Colourless oil, 47% yield, 99% ee. [α]20D = −17.5 (c 3.0, CHCl3). 1H

NMR (400 MHz, CDCl3) δ 7.40 – 7.18 (m, 5H), 7.14 (dd, J = 3.0, 1.5 Hz, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.28 (dd, J = 15.9, 7.3 Hz, 1H), 4.76 (t, J = 1.5 Hz, 2H), 3.45 (dd, J = 11.1, 4.0 Hz, 1H), 1.39 (d, J = 7.0 Hz,

3H). 13C NMR (100.6 MHz, CDCl3) δ 173.3, 143.8, 137.5, 136.9, 130.7, 130.0, 128.4, 127.3, 126.1, 77.3, 33.8, 18.6. HRMS (ESI+, m/z): calcd for C14H15O2 [M+H]+: 215.10666, found 215.10579. Enantiomeric excess was determined by chiral HPLC, Chiralpak AS-H

O

O

OAc

154


(n-heptane/i-propanol = 97/3, 0.5 mL/min, 254 nm), retention times: tR (major) 29.51 min, tR (minor) 25.34 min.

(−)-(R)-(E)-3-(4-(4-Chlorophenyl)but-3-en-2-yl)furan-2(5H)-one ((R)-3d)


NMR (400 MHz, CDCl3) δ 7.30 – 7.23 (m, 1H), 7.15 (dd, J = 3.0, 1.6 Hz, 1H), 6.43 (d, J = 15.3 Hz, 1H), 6.24 (dd, J = 15.9, 7.3 Hz, 1H), 4.78 (bs, 2H), 3.45 (dd, J = 14.2, 7.1 Hz, 1H), 1.38 (d, J = 7.0

Hz, 1H). 13C NMR (100.6 MHz, CDCl3) δ 173.2, 143.8, 137.5, 135.4, 132.9, 131.5, 129.0, 128.6, 127.4, 70.1, 33.9, 18.6. HRMS (ESI+, m/z): calcd for C14H14ClO2 [M+H]+: 249.06768, found 249.06563. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 210 nm), retention time: tR (major) 49.45 min. In accordance with the results obtained in the kinetic resolution of 1c, the absolute configuration of this compound is assumed to be (R), analogous to compound 3c.

(−)-(R)-(E)-3-(4-(4-Methoxyphenyl)but-3-en-2-yl)furan-2(5H)-one ((R)-3e)


NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.6 Hz, 2H), 7.14 (dd, J = 3.0, 1.7 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.42 (d, J = 15.8 Hz, 1H), 6.13 (dd, J = 15.9, 7.3 Hz, 1H), 4.78 (t, J = 1.7 Hz, 2H), 3.80 (s, 3H), 3.43 (m, 1H), 1.37 (d, J = 7.0 Hz, 3H). 13C NMR (100.6

MHz, CDCl3) δ 173.4, 159.1, 143.6, 138.0, 129.7, 129.5, 128.6, 127.3, 113.9, 70.1, 55.3, 33.9, 18.8. HRMS (ESI+, m/z): calcd for C15H17O3 [M+H]+: 245.11722, found 245.11543. Enantiomeric excess was determined by chiral HPLC, Chiralpak OD (n-heptane/i-propanol = 99/1, 1 mL/min, 254 nm), retention time: tR (major) 41.76 min. In accordance with the results obtained in the kinetic resolution of 1c, the absolute configuration of this compound is assumed to be (R), analogous to compound 3c.

(+)-(R)-(E)-3-(4-(2-Methoxyphenyl)but-3-en-2-yl)furan-2(5H)-one ((R)-3f)

Colourless oil, 41% yield, 99% ee. [α]20D = +3.1 (c 2.6, CHCl3). 1H

NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.21 (td, J = 8.3, 1.7 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 16.0 Hz, 1H), 6.30 (dd, J = 16.0, 7.3 Hz, 1H), 4.77 (s, 2H), 3.84 (s, 3H), 3.57 – 3.36 (m, 1H), 1.39 (d, J = 7.0 Hz,

O

O

Cl

O

OOCH3

3

155

Chapter 6

3H). 13C NMR (100.6 MHz, CDCl3) δ 173.4, 156.5, 143.7, 138.1, 131.3, 128.4, 126.6, 126.0, 124.9, 120.6, 110.8, 70.1, 55.4, 34.3, 18.8. HRMS (ESI+, m/z): calcd for C15H17O3 [M+H]+: 245.11722, found 245.11578. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 210 nm), retention times: tR (major) 39.78 min. In accordance with the results obtained in the kinetic resolution of 1c, the absolute configuration of this compound is assumed to be (R), analogous to compound 3c.

(−)-(R)-(E)-3-(Hept-3-en-2-yl)furan-2(5H)-one ((R)-3g)


(400 MHz, CDCl3) δ 7.06 (d, J = 1.4 Hz, 1H), 5.50 (dd, J = 10.3, 5.8 Hz, 2H), 4.75 (t, J = 1.7 Hz, 2H), 3.28 – 3.11 (m, 1H), 2.06 – 1.87 (m, 2H),

1.42 – 1.29 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.5, 143.3, 138.4, 131.0, 70.0, 34.5, 33.5, 22.4, 19.0, 13.6. HRMS (ESI+, m/z): calcd for C11H17O2 [M+H]+: 181.12231, found 181.12086. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (heptane/i-propanol = 98/2, 0.5 mL/min, 210 nm), retention times: tR (major) 29.07 min, tR (minor) 27.68 min. In accordance with the results obtained in the kinetic resolution of 1c, the absolute configuration of this compound is assumed to be (R), analogous to compound 3c.

(−)-(R)-(E)-3-(4-Cyclohexylbut-3-en-2-yl)furan-2(5H)-one ((R)-3h)


(400 MHz, CDCl3) δ 7.05 (t, J = 1.5 Hz, 1H), 5.45 (p, J = 15.6 Hz, 2H), 4.75 (t, J = 1.7 Hz, 2H), 3.19 (dd, J = 9.4, 3.9 Hz, 1H), 2.03 – 1.84 (m, 1H), 1.76 – 1.56 (m, 5H), 1.24 (d, J = 7.0 Hz, 6H), 1.13 – 0.99 (m, 2H).

13C NMR (100.6 MHz, CDCl3) δ 173.5, 143.2, 138.6, 137.0, 128.3, 67.0, 40.5, 33.5, 33.0, 26.1, 26.0, 19.0. HRMS (ESI+, m/z): calcd for C14H21O2 [M+H]+: 221.15361, found 221.15185. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 210 nm), retention times: tR (major) 24.45 min, tR (minor) 21.89 min. In accordance with the results obtained in the kinetic resolution of 1c, the absolute configuration of this compound is assumed to be (R), analogous to compound 3c.

O

O

O

O

156


(−)-(R)-(E)-3-(Pent-3-en-2-yl)furan-2(5H)-one ((R)-3i)


(400 MHz, CDCl3) δ 7.05-7.06 (m, 1H), 5.59 – 5.42 (m, 2H), 4.76 (bs, 2H), 3.26 – 3.14 (m, 1H), 1.67 (d, J = 4.9 Hz, 3H), 1.24 (d, J = 7.0 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.5, 143.3, 138.3, 132.0, 125.6, 70.0, 33.5,

18.9, 17.8. HRMS (ESI+, m/z): calcd for C9H13O [M+H]+: 153.09101, found 153.09053. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 254 nm), retention times: tR (major) 40.03 min, tR (minor) 44.57 min. In accordance with the results obtained in the kinetic resolution of 1c, the absolute configuration of this compound is assumed to be (R), analogous to compound 3c.

(−)-(S)-3-(Cyclohex-2-en-1-yl)furan-2(5H)-one ((S)-3j)

Colourless oil. Yield: 35%. ee: 99%. [α]20D = −47.2 (c 1.5, CHCl3). 1H NMR

(400 MHz, CDCl3) δ 7.08 (d, J = 1.6 Hz, 1H), 5.87 (m, 1H), 5.63 (m, 1H), 4.77 (t, J = 1.7 Hz, 2H), 3.19 (s, 1H), 2.00 (m, 3H), 1.67 – 1.47 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.7, 144.6, 137.7, 129.5, 126.7, 70.1, 32.2, 27.3, 24.9,

19.9. HRMS (ESI+, m/z): calcd for C10H13O2 [M+H]+: 165.09101, found 165.08968. Enantiomeric excess was determined by chiral HPLC, Chiralpak OB-H (heptane/i-propanol = 98/2, 0.5 mL/min, 210 nm), retention time: tR (major) 54.16 min. In accordance with the results obtained in the kinetic resolution of 1c, the absolute configuration of this compound is assumed to be (S).

(−)-(R)-(E)-3-(1,3-Diphenylallyl)furan-2(5H)-one ((R)-3k)

Pale yellow oil, 55% yield, 92% ee. [α]20D = −51 (c 0.7, CHCl3). 1H

NMR (400 MHz, CDCl3) δ 7.46 – 7.21 (m, 10H), 7.18 (d, J = 1.3 Hz, 1H), 6.52 (dd, J = 15.9, 7.1 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 4.84 (dt, J = 4.0, 1.7 Hz, 2H), 4.67 (d, J = 7.1 Hz, 1H); 13C NMR (100.6 MHz,

CDCl3) δ 172.7, 146.0, 139.9, 136.6, 136.3, 132.0, 128.8, 128.7, 128.5, 128.1, 127.7, 127.2, 126.4, 70.1, 45.1. HRMS (ESI+, m/z): calcd for C19H16O2Na [M+Na]+: 299.10425, found: 299.10376. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (n-heptane/i-propanol = 95/5, 0.5 mL/min, 210 nm), retention times: tR (major) 16.52 min, tR (minor) 23.32 min. In accordance with the results obtained in the kinetic resolution of 1c, the absolute configuration of this compound is assumed to be (R), analogous to compound 3c.

O

O

O

O

O

O

157

Chapter 6

(+)-(E)-5-(1,3-Diphenylallyl)furan-2(5H)-one (4k)

Pale yellow oil, 13% yield. [α]20D = +42 (c 0.7, CHCl3). 1H NMR (400

MHz, CDCl3) δ 7.48 (dd, J = 5.8, 1.5 Hz, 1H), 7.42 – 7.11 (m, 10H), 6.60 (d, J = 15.8 Hz, 1H), 6.41 (dd, J = 15.8, 8.5 Hz, 1H), 6.08 (dd, J = 5.8, 2.0 Hz, 1H), 5.53 – 5.20 (m, 1H), 3.88 (dd, J = 8.5, 6.0 Hz, 1H). 13C NMR (100.6 MHz, CDCl3) δ 154.5, 138.1, 136.5, 133.7, 128.8,

128.6, 128.2, 127.9, 127.5, 126.4, 126.3, 122.8, 85.4, 52.3. HRMS (ESI+, m/z): calcd for C19H17O2 [M+H]+: 277.12231, found: 277.12022.

(+)-(E)-5-(4-Phenylbut-3-en-2-yl)furan-2(5H)-one (4l)

Colourless oil, 16% yield, 34% ee. [α]20D = +40 (c 1.9, CHCl3). 1H NMR

(400 MHz, CDCl3) δ 7.45 (dd, J = 5.8, 1.5 Hz, 1H), 7.39 – 7.28 (m, 5H), 6.49 (d, J = 16.0 Hz, 1H), 6.16 (dd, J = 5.8, 2.0 Hz, 1H), 6.09 (dd, J = 15.9, 7.7 Hz, 1H), 5.11 – 5.01 (m, 1H), 2.87 (dd, J = 11.9, 6.7 Hz, 1H), 1.18 (d, J = 6.9 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.0, 154.6,

136.6, 132.2, 128.6, 128.2, 127.7, 126.2, 122.6, 86.4, 39.9, 15.3. HRMS (ESI+, m/z): calcd for C14H15O2 [M+H]+: 215.10666, found: 215.06861. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 254 nm), retention times: tR (major) 40.03 min, tR (minor) 44.57 min.

(−)-(E)-3-Methyl-5-(4-phenylbut-3-en-2-yl)furan-2(5H)-one (5)


(400 MHz, CDCl3) δ 7.45 – 7.10 (m, 5H), 6.85 – 6.70 (m, 1H), 5.72 (ddd, J = 15.3, 7.5, 1.6 Hz, 1H), 5.64 – 5.49 (m, 1H), 5.12 – 4.98 (m, 1H), 3.40 (t, J = 7.5 Hz, 1H), 1.86 (s, 3H), 1.76 – 1.65 (m, 3H). 13C NMR (100.6 MHz, CDCl3) δ 174.1, 147.6, 139.6, 130.7, 129.0, 128.7, 128.1, 127.2,

83.5, 52.8, 29.7, 18.1, 10.6. HRMS (ESI+, m/z): calcd for C15H17O2 [M+H]+: 229.12231, found 229.12047. Enantiomeric excess was determined by chiral HPLC, Chiralpak AD-H (n-heptane/i-propanol = 99/1, 0.5 mL/min, 210 nm), retention times: tR (major) 36.74 min, tR (minor) 28.67 min.

O

O

O

O

O

O

158


Preparation and characterization of chromium complex of 3c:

A solution of 3c (0.37 mmol) and Cr(CO)3(CH3CN)3 (0.41 mmol) in THF (5 mL) was refluxed for 24 h, and then the solvents were removed in vacuum. The crude product was purified by flash chromatography on silica gel using n-pentane/Et2O as eluents.

Recrystallization from n-pentane/EtOAc gave orange crystals, m.p. = 107 oC. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 22.7 Hz, 1H), 6.24 (dd, J = 15.9, 7.0 Hz, 1H), 6.03 (d, J = 15.9 Hz, 1H), 5.48 – 5.34 (m, 3H), 5.24 (t, J = 5.8 Hz, 1H), 4.79 (s, 2H), 3.65 – 3.32 (m, 1H), 1.37 (d, J = 6.9 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 235.2, 173.2, 144.5, 136.9, 133.9, 126.6, 105.7, 93.2, 90.8, 90.6, 90.1, 70.2, 33.6, 18.4.

Computational details:

To the optimized structure of ligand (R,R)-L1,33 the (R)- or (S)-enantiomer of 1c was added and a conformational analysis was carried out with the Hyperchem software package41 at the PM3 level of theory. The 6 lowest energy conformations were refined at the DFT B3LYP level employing a mixed basis set (in particular the LANL2DZ basis,42 as downloaded from the BSE website,43 was used for the Pd and the 6-31G(d,p) for all the other elements). For these DFT calculations, the Firefly QC package (partially based on the GAMESS US source code )44 was used.45 Finally, the conformation with the lowest DFT energy was considered for further discussions. On the basis of the lowest DFT energy conformation of the Pd/(R,R)-L1/(R)-1c complex, products 3 and 4 were calculated in the same way.

6.6 References 1 For reviews on the Pd-AAA reaction, see: a) B. M. Trost, D. L.Van Vranken, Chem. Rev. 1996, 96,

395-422; b) G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336-345; c) B. M. Trost, M. L.

Crawley, Chem. Rev. 2003, 103, 2921-2943; d) B. M. Trost, J. Org. Chem. 2004, 69, 5813-5837; e)

A. Pfaltz, W. J. Drury, Proc. Natl. Acad. Sci. USA 2004, 101, 5723-5726. f) B. M. Trost, M. R.

Machacek, A. Aponick, Acc. Chem. Res. 2006, 39, 747-760; g) J. T. Mohr, B. M. Stoltz, Chem. Asia.

J. 2007, 2, 1476-1491; h) Z. Lu, S. M. Ma, Angew. Chem. Int. Ed. 2008, 47, 258-297.

2 For selected examples of palladium-catalyzed asymmetric allylic alkylation, see: a) B. M. Trost, D.

L.Van Vranken Angew. Chem. Int. Ed. 1992, 31, 228-230; b) D.–C. Peter Von Matt, A. Pfaltz,

Angew. Chem. Int. Ed. 1993, 32, 566-568; c) H. Steinhagen, M. Reggelin, G. Helmchen, Angew.

Chem. Int. Ed. 1997, 36, 2108-2110; d) T. Hayashi, M. Kawatsura, Y. Uozumi, J. Am. Chem. Soc.

Cr(CO)3

O

O

159

Chapter 6

1998, 120, 1681-1687; e) U. Bremberg, M. Larhed, C. Moberg, A. Hallberg, J. Org. Chem. 1999, 64,

1082-1083; f) S. L. You, X. L. Hou, L. X. Dai, X. Z. Zhu, Org. Lett. 2001, 3, 149-151; g) M.

Ogasawara, K. Yoshida, T. Hayashi, Organometallics 2001, 20, 3913-3917; h) T. Hayashi, A. Okada,

T. Suzuka, M. Kawatsura, Org. Lett. 2003, 5, 1713-1715; i) N. Oohara, K. Katagiri, T. Imamoto,

Tetrahedron: Asymmetry 2003, 14, 2171-2175; j) G. A. Molander, J. P. Burke, P. J. Carroll, J. Org.

Chem. 2004, 69, 8062-8069; k) J. W. Faller, J. C. Wilt, J. Parr, Org. Lett. 2004, 6, 1301-1304; l) H.

Yorimitsu, K. Oshima, Angew. Chem. Int. Ed. 2005, 44, 4435-4439; m) B. M. Trost, A. Aponick, J.

Am. Chem. Soc. 2006, 128, 3931-3933; n) R. Shintani, W.-L. Duan, T. Hayashi, J. Am. Chem. Soc.

2006, 128, 5628-5629; o) T. Imamoto, M. Nishimura, A. Koide, K. Yoshida, J. Org. Chem. 2007, 72,

7413-7416; p) B. M. Trost, D. A. Thaisrivongs, J. Am. Chem. Soc. 2008, 130, 14092-14093; q) W.

Liu, D. Chen, X. Z. Zhu, X. L. Wan, X. L. Hou, J. Am. Chem. Soc. 2009, 131, 8734-8735; r) X.

Caldentey, M. A. Pericas, J. Org. Chem. 2010, 75, 2628-2644.

3 For general reviews on the palladium catalysed dynamic kinetic asymmetric transformations, see: a)

B. M. Trost, D. R. Fandrick, Aldrichim. Acta. 2007, 40, 59-72. For selected examples of dynamic

kinetic resolution, see: b) G. R. Cook, P. S. Shanker, K. Pararajasingham, Angew. Chem. Int. Ed.

1999, 38, 110-113; c) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121, 3543-3544; d) B. M.

Trost, J. Dudash, E. J. Hembre, Chem.-Eur. J. 2001, 7, 1619-1629; e) B. M. Trost, B. S. Brown, E. J.

McEachern, O. Kuhn, Chem.-Eur. J. 2003, 9, 4442-4451; f) A. Parvulescu, D. De Vos, P. Jacobs,

Chem. Commun. 2005, 5307-5309; g) M. J. Kim, W. H. Kim, K. Han, Y. K. Choi, J. Park, Org. Lett.

2007, 9, 1157-1159; h) A. N. Parvulescu, P. A. Jacobs, D. E. De Vos, Chem.-Eur. J. 2007, 13,

2034-2043; i) I. Mangion, N. Strotman, M. Drahl, J. Imbriglio, E. Guidry, Org. Lett. 2009, 11,

3258-3260.

4 For general reviews on the kinetic resolution, see: a) H. B. Kagan, J. C. Fiaud, Top. Stereochem.

1988, 18, 249-330; b) G. R. Cook, Curr. Org. Chem. 2000, 4, 869-885; c) J. M. Keith, J. F. Larrow,

E. N. Jacobsen, Adv. Synth. Catal. 2001, 343, 5-26; d) D. E. J. E. Robinson, S. D. Bull, Tetrahedron:

Asymmetry 2003, 14, 1407-1446; e) E. Vedejs, M. Jure, Angew. Chem. Int. Ed. 2005, 44,

3974-4001.

5 T. Hayashi, A. Yamamoto, Y. Ito, J. Chem. Soc., Chem. Commun. 1986, 1090-1092.

6 S. Ramdeehul, P. Dierkes, R. Aguado, P. C. J. Kamer, P. W. N. M. van Leeuwen, J. A. Osborn,

Angew. Chem. Int. Ed. 1998, 37, 3118-3121.

7 a) H.-J. Gais, H. Eichelmann, N. Spalthoff, F. Gerhards, M. Frank, G. Raabe, Tetrahedron:

Asymmetry 1998, 9, 235-248. b) M. Frank, H.-J. Gais, Tetrahedron: Asymmetry 1998, 9, 3353-3357.

c) H.-J. Gais, T. Jagusch, N. Spalthoff, F. Gerhards, M. Frank, G. Raabe, Chem.-Eur. J. 2003, 9,

4202-4221. d) B. J. Lüssem, H.-J. Gais, J. Am. Chem. Soc. 2003, 125, 6066-6067.

160


8 For selected examples of palladium-catalyzed kinetic resolution, see: a) S. Ramdeehul, P. Dierkes,

R. Aguado, P. C. J. Kamer, P. W. N. M. van Leeuwen, J. A. Osborn, Angew. Chem. Int. Ed. 1998, 37,

3118-3121; b) B. M. Trost, E. J. Hembre, Tetrahedron Lett. 1999, 40, 219-222; c) B. Dominguez, N.

S. Hodnett, G. C. Lloyd-Jones, Angew. Chem. Int. Ed. 2001, 40, 4289-4291; d) B. J. Lussem, H. J.

Gais, J. Am. Chem. Soc. 2003, 125, 6066-6067; e) B. L. Lei, C. H. Ding, X. F. Yang, X. L. Wan, X.

L. Hou, J. Am. Chem. Soc. 2009, 131, 18250-18251; f) R. K. Rao, G. Sekar, Tetrahedron:

Asymmetry, 2011, 22, 948-954.

9 H. J. Gais, O. Bondarev, R. Hetzer, Tetrahedron Lett. 2005, 46, 6279-6283.

10 D. G. Blackmond, J. Am. Chem. Soc. 2000, 123, 545-553.

11 R. Naasz, PhD thesis, University of Groningen (The Netherlands), 2002.

12 H. B. Kagan, J. C. Fiaud in Topics in Stereochemistry, Vol. 14 (Eds.: E. L. Eliel, S. H. Wilen,) Wiley,

New York, 1987, pp 249-330.

13 For reviews on the palladium-catalyzed allylic alkylations of enolates, see: a) M. Braun, T. Meier,

Synlett 2006, 661-676; b) M. Braun, T. Meier, Angew. Chem. Int. Ed. 2006, 45, 6952-6955.

14 B. M. Trost, E. Keinan, Tetrahedron Lett. 1980, 21, 2591-2594.

15 I. Minami, K. Takahashi, I. Shimizu, T. Kimura, J. Tsuji, Tetrahedron 1986, 42, 2971-2977.

16 C. Carfagna, L. Mariani, A. Musco, G. Sallese, R. Santi, J. Org. Chem. 1991, 56, 3924-3927.

17 D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 15044-15045.

18 J. Tsuji, I. Minami, I. Shimizu, Chem. Lett. 1983, 1325-1326.

19 É. Bélanger, K. Cantin, O. Messe, M. Tremblay, J.-F. Paquín, J. Am. Chem. Soc. 2007, 129,

1034-1035.

20 M. Seto, J. L. Roizen, B. M. Stoltz, Angew. Chem. Int. Ed. 2008, 47, 6873-6876.

21 T. Graening, J. F. Hartwig, J. Am. Chem. Soc. 2005, 127, 17192-17193.

22 For selected examples of palladium-catalyzed allylic alkylations with preformed or in situ-

generated enolates: a) B. M. Trost, G. M. Schroeder, J. Am. Chem. Soc. 1999, 121, 6759-6760; b)

M. Braun, F. Laicher, T. Meier, Angew. Chem. Int. Ed. 2000, 39, 3494-3497; c) J. T. Mohr, D. C.

Behenna, A. M. Harned, B. M. Stoltz, Angew. Chem. Int. Ed. 2005, 44, 6924-6927; d) X. X. Yan, C.

G. Liang, Y. Zhang, W. Hong, B. X. Cao, L. X. Dai, X. L. Hou, Angew. Chem. Int. Ed. 2005, 44,

6544-6546; e) B. M. Trost, J. Y. Xu, J. Am. Chem. Soc. 2005, 127, 17180-17181; f) M. Braun, T.

Meier, F. Laicher, P. Meletis, M. Fidan, Adv. Synth. Catal. 2008, 350, 303-314; g) P. Meletis, M.

Patil, W. Thiel, M. Braun, Chem.-Eur. J. 2011, 17, 11243-11249.

23 J. Boukouvalas, J. Sperry, M. A. Brimble, 2-trimethylsilyloxyfuran in e-EROS Encyclopedia of

161

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Reagents for Organic Synthesis, (Eds.: L. A. Paquette, D. Crich, P. L. Fuchs, P. Wipf ), John Wiley

& Sons, Weinheim, 2008.

24 For selected examples of the use of 2-trimethylsilyloxyfuran (TMSOF) as nucleophile to build

γ-butenolides, see: a) S. P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc. 2003,

125, 1192-1194; b) R. K. Boeckman, J. E. Pero, D. J. Boehmler, J. Am. Chem. Soc. 2006, 128,

11032-11033; c) Y. Q. Jiang, Y. L. Shi, M. Shi, J. Am. Chem. Soc. 2008, 130, 7202-7203; d) V.

Liautard, V. Desvergnes, K. Itoh, H. W. Liu, O. R. Martin, J. Org. Chem. 2008, 73, 3103-3115; e) L.

C. Wieland, E. M. Vieira, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131, 570-576; f)

R. P. Singh, B. M. Foxman, L. Deng, J. Am. Chem. Soc. 2010, 132, 9558-9560.

25 C. W. Jefford, A. W. Sledeski, J. Boukouvalas, Helv. Chim. Acta 1989, 72, 1362-1370.

26 S. Akai, R. Hanada, N. Fujiwara, Y. Kita, M. Egi, Org. Lett. 2010, 12, 4900-4903.

27 a) C. H. Wong, G. M. Whitesides, Enzymes in Synthetic Organic Chemistry, Elsevier, London, 1994;

b) A. D. Cuiper, M. L. C. E. Kouwijzer, P. D. J. Grootenhuis, R. M. Kellogg, B. L. Feringa, J. Org.

Chem. 1999, 64, 9529-9537; c) H. van der Deen, A. D. Cuiper, R. P. Hof, A. van Oeveren, B. L.

Feringa, R. M. Kellogg, J. Am. Chem. Soc. 1996, 118, 3801-3803.

28 The absolute configuration was determined by comparison of the rotation to that reported in the

literature: T. Fukazawa, Y. Shimoji, T. Hashimoto, Tetrahedron:Asymmetry 1996, 7, 1649-1658.

29 G. Helmchen, U. Kazmaier, S. Forster, in Catalytic Asymmetric Synthesis, 3rd ed, (Ed.: I. Ojima),

Wiley-VCH, New York, 2010, pp 497-641.

30 B. M. Trost, D. L. Van Vranken , C. Bingel , J. Am. Chem. Soc. 1992, 114, 9327-9343.

31 J. Pan, J. Wang, M. M. B. Holl, J. W. Kampf, A. J. Ashe, Organometallics 2006, 25, 3463-3467.

32 a) C. T. Lee, W. T. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785-789; b) A. D. Becke, J. Chem.

Phys. 1993, 98, 5648-5652; c) P. J. Stephens, F. J. Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys.

Chem. 1994, 98, 11623-11627.

33 C. P. Butts, E. Filali, G. C. Lloyd-Jones, P.-O. Norrby, D. A. Sale, Y. Schramm, J. Am. Chem. Soc.

2009, 131, 9945-9957.

34 For selected exmples that ligand may direct regioselective allylic substitution by hydrogen-bond

donation to the nucleophile, see: a) C. Wang, N. Pahadi, J. A. Tunge, Tetrahedron 2009, 65,

5102-5109; b) G. S. Mahadik, S. A. Knott, L. F. Szczepura, S. J. Peters, J. M. Standard, S. R.

Hitchcock, J. Org. Chem. 2009, 74, 8164-8173; c) M. H. Katcher, A. Sha, A. G. Doyle, J. Am.

Chem. Soc. 2011, 133, 15902-15905.

35 It is still not clear when the double bond migration take place. Isomerization of butenolides

162


promoted by hydrogen bond has been described, see: Y. Wu, R. P. Singh, L. Deng, J. Am. Chem.

Soc. 2011, 133, 12458-12461.

36 B. M. Trost, J. Richardson, K. Yong, J. Am. Chem. Soc. 2006, 128, 2540-2541.

37 B. Plietker, Angew. Chem. Int. Ed. 2006, 45, 1469-1473.

38 D. A. Evans, L. Kvaerno, T. B. Dunn, A. Beauchemin, B. Raymer, J. A. Mulder, E. J. Olhava, M.

Juhl, K. Kagechika, D. A. Favor, J. Am. Chem. Soc. 2008, 130, 16295-16309.

39 J. C. Mckew, M. J. Kurth, J. Org. Chem. 1993, 58, 4589-4595.

40 T. Hayashi, A. Yamamoto, T. Hagihara, J. Org. Chem. 1986, 51, 723-727.

41 HyperChem(TM) v. 8, Hypercube, Inc., 1115 NW 4th Street, Gainesville, Florida 32601, USA.

42 J. V. Ortiz, P. J. Hay, R. L. Martin, J. Am. Chem. Soc. 1992, 114, 2736-2737.

43 a) D. Feller, J. Comp. Chem. 1996, 17, 1571-1586; b) K. L. Schuchardt, B. T. Didier, T. Elsethagen,

L. Sun, V. Gurumoorthi, J. Chase, J. Li, T. L. Windus, J. Chem. Inf. Model. 2007, 47, 1045-1052.

44 Alex A. Granovsky, Firefly version 7.1.G, http://classic.chem.msu.su/gran/firefly /index.html.

45 All the DFT calculations were carried out at the Millipede cluster of the Donald Smits Center for

Information Technology, University of Groningen.

Chapter 7

Enantioselective Synthesis of 5-Substituted

Furanones Through Palladium-catalyzed

γ-Allylation of 2-Trimethylsilyloxyfuran

Palladium-catalyzed γ-allylation of 2-trimethylsilyloxyfuran (TMSOF) with allylic carbonate to access the γ-substituted β,γ-unsaturated furanone in the presence of enantiopure phosphinooxazoline (PHOX) ligand is described. Control experiments and 31P NMR studies helped to propose the mechanism of the reaction.

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7.1 Introduction

7.1.1 Mechanism of the palladium-catalyzed allylic alkylation (Pd-AAA) with different types of nucleophiles

Due to the importance of palladium-catalyzed asymmetric allylic alkylation with carbon nucleophiles as a fruitful and versatile method for carbon-carbon bond formations, significant efforts have been made to understand the mechanism of this reaction.1, 2 As shown in most cases, a carbanion with a pKa value lower than 20 serves as “soft” nucleophile, which often adds directly to a terminal carbon on a π-allyl ligand of a palladium complex.3 Thus the combination of malonates with allylic substrate became the standard procedure in the palladium-catalyzed allylic alkylation to evaluate the performance of a chiral ligand.3 An outer-sphere allylic alkylation process was generally expected as the soft nucleophile directly adds to the carbons of allylic termini and substitutes the (η3-allyl)palladium complex (Scheme 1).4

Scheme 1. Outer-sphere mechanism for palladium-catalyzed allylic alkylation of “soft” nucleophiles.

Besides the outer-sphere mechanism, literature precedent for the palladium-catalyzed allylic alkylation suggest that an inner-sphere mechanism might proceed with a “hard” nucleophile (pKa value more than 20).1a, 2 In this case, the nucleophilic attack occurs at the palladium center followed by a subsequent bond-forming reductive elimination which constitutes an inner-sphere process (Scheme 2).

Scheme 2. Inner-sphere mechanism for palladium-catalyzed allylic alkylation of “hard” nucleophiles.

165

Enantioselective Synthesis of 5-Substituted Furanones

7.1.2 Phosphinooxazoline (PHOX) ligands in the palladium-catalyzed asymmetric allylic alkylation

Introduced by Pfaltz,5 Helmchen6 and Williams,7 the phosphinooxazoline (PHOX) ligands have emerged as privileged ligands for the Pd-AAA and have been extensively explored in a variety of this type of reactions.8 Simple PHOX ligands have served particularly well in reactions with acyclic substrates.5 As depicted in Scheme 3, very high enantiomeric excess was obtained with the (S)-t-Bu-Phox ligand upon use of 1,3-diphenylallyl acetate as substrate.5

Scheme 3. Phosphinooxazoline (PHOX) ligand in the palladium-catalyzed asymmetric allylic alkylation using dimethyl malonate as nucleophile.5 BSA = N,O-bis(trimethylsilyl)acetamide.

Scheme 4. Allylic alkylation of “soft” nucleophiles via (η3-allyl) palladium complexes containing a PHOX ligand.

Mechanistic studies carried out by Helmchen and co-workers indicated that a similar outer-sphere allylic alkylation mechanism proceeds with soft nucleophiles on the basis of PHOX-ligand-derived palladium complex (Scheme 4).9 According to their results, two enantiomeric products can be formed through the reaction between the rapid equilibrating diastereomeric π-allyl intermediates and “soft” nucleophile such as malonate. Further evidence strongly suggested the attack of the nucleophile preferentially at the allylic terminal C trans to P of the exo isomer.9, 10 The X-ray structures of (η3-allyl)palladium complexes disclosed that the repulsive electronic interaction between the ligand and the

166

Chapter 7

allylic moiety is smaller for the exo than the endo diastereomer, providing insights into the reason why the exo isomers is more stable than the endo isomer.11

7.1.3 Mechanistic investigations of palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of ketone enolates

Palladium-catalyzed decarboxylative asymmetric alkylation12 as a highly chemo-, regio- and enantioselective process for the synthesis of ketones bearing a quaternary stereogenic α-carbon center has been independently reported by Stoltz13 and Trost.14 The solution for a successful allylic alkylation of non-stabilized enolates relies on their in situ generation. Both research groups have shown that allyl enol carbonates can serve as suitable precusors (Table 1). Since then, this reaction has been intensively explored for its scope and applications.15, 16 The promising synthetic applications of this palladium-catalyzed decarboxylative AAA reaction have also triggered extensive mechanistic investigations. As β-keto carboxylates with quaternary stereocenters smoothly undergo decarboxylative allylation, it suggests that the decarboxylation likely preceeds carbon-carbon bond formation and that ketone enolates are possibly true intermediates. An interesting mechanistic study was carried out by Trost et al. using deuterium-labeled substrates,4 pointing to the existence of ketone enolates in solution.

167


Table 1. Enantioselective allylation through in situ generation of enolates from enol carbonates and allyl β-keto esters.13,14 L = ligand, dba = dibenzylideneacetone.

Previous studies indicated that the reaction between the unstabilized ketone enolate including potassium,17 lithium,18 tin,19 zinc20 and boron enolates20 and π-allyl palladium complex might go through an outer-sphere mechanism. In the palladium-catalyzed decarboxylative asymmetric allylic alkylation of enol carbonates, it’s likely that the C-C bond forming occurs when the in situ generated palladium enolate species attacks the π-allyl palladium complex, which would also imply the possible transient formation of a free enolate during the reaction.4 In the case of Stoltz, all three different classes of substrates gave allylic alkylation products in similar yields and practically identical ee values, suggesting a single mechanism converged at or before the formation of the ketone enolate intermediates.13, 15c The existence of a free enolate with a single PHOX palladium π-allyl species was simulated using computational studies.21

168

Chapter 7

Scheme 5. Enantioselective Tsuji allylation could be performed on three different classes of substrates with similar results.

Stoltz’s group presented their theoretical work on the mechanism of palladium-catalyzed DAAA,21 in which they claimed the penta-coordinated π-allyl palladium enolate complex was as stable as the charge separated palladium enolate. These computational results constitute strong evidence for an inner-sphere mechanism instead of a common outer-sphere mechanism, whereby the product was generated after 7-membered double vinylogous reductive elimination of the (η1-allyl)palladium enolate complex (Figure 1).

Figure 1. 7-Membered double vinylogous reductive elimination indicated by DFT simulation.21

Subsequent 31P NMR spectroscopy studies on the palladium-catalyzed DAAA revealed a long-lived singular intermediate for different substrate variants.22 The authors proceeded to isolate and characterize the carboxylate complexes corresponding to those NMR detectable intermediates (Figure 2). Carboxylate complex 1 represented the resting state of the catalyst, indicating that the rate limiting step of the allylic alkylation of allyl β-ketoester substrate is decarboxylation.22 A similar neutral complex 2 was also synthesized where the phosphorus atom and the acetate group have a trans relationship.22 Carboxylate complex 1 and 2 shed light on the existence and proposed structure of putative palladium enolate (Figure 3), which is recognized as the key intermediate for

169


palladium-catalyzed DAAA reaction in the presence of PHOX ligand.22, 23 Computational studies further disclosed that the observed enantioselectivity supported the inner-sphere mechanism involving the formation of a 5-coordinate Pd species that undergoes a ligand rearrangement, which is selective with regard to the prochiral faces of the intermediate enolate.21, 24

Figure 2. X-ray structure of carboxylate complex 1 and 2.22 Complex 1 is the resting state of the catalytic cycle. The molecular structure is shown with 50% probability ellipsoids.

N

O

Ph2Pt-BuPd

O

Figure 3. Structure of putative enolate complex from DFT calculation of the intermediate (η1-allyl)palladium enolate prior to C-C bond-forming by reductive elimination.21, 22

7.1.4 Palladium-catalyzed γ-arylation of dienolates

The palladium-catalyzed arylation of enolates represents an extremely versatile method for the formation of carbon-carbon bonds.25 However, the palladium-catalyzed arylation of dienolates of unsaturated carbonyl compounds has been less explored (Scheme 6).26-29 Despite the fact that the resulted γ-aryl-α,β-unsaturated carbonyl motifs are important building blocks,30 the development of coupling of dienolates with haloarenes suffered

170

Chapter 7

from certain limitations: 1) lower nucleophilicity for the dienolates compared to enolates, 2) the generation of regioisomeric products and the potential condensation for the active products.

Scheme 6. Regioselective dienolate arylation.28

Miura and co-workers reported that the unfunctionalized α,β-unsaturated ketones and aldehydes react with aryl bromides under basic conditions selectively at the γ-position using Pd(OAc)2/PPh3-based catalyst.26 An important advance for this transformation was published by Buchwald and Hyde, demonstrating that γ-substituted α,β- or β,γ-unsaturated ketones27 and lactones28 undergo selective γ-arylation with aryl chlorides and bromides to allow for a facile construction of quaternary centers (Scheme 7).

Scheme 7. γ-Arylation of unsaturated ketone. dppe = 1,2-Bis(diphenylphophino)ethane.

In 2010, Hartwig’s group revealed the first palladium-catalyzed coupling of aryl halides with silyl ketene acetals derived from acyclic α,β-unsaturated esters to form the γ-arylation product (Scheme 8).29

171


Scheme 8. γ-Arylation of silyl ketene acetal with bromobenzene. TES = triethylsilyl.

An inner-sphere mechanism involving transmetallation, the formation of the palladium-catalyzed dienolate complex and subsequent reductive elimination was proposed by the same authors (Scheme 9).29 The promoting effect of zinc chloride was explained helping to labilize the halide on palladium instead of the Lewis acid property of zinc chloride, facilitating the formation of palladium dienolate complex.

Scheme 9. Potential mechanism for the coupling of silyl ketene acetal with bromobenzene. dba = Dibenzylideneacetone.

7.2 Project Goal Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) using silyl enol ethers as nucleophiles represents one of most challenging problems in this field.31 The side reactions as well as insufficient regio- and diastereoselectivity has precluded the Pd-catalyzed allylic alkylation of silyl enol ethers from being generally applicable.31a As discussed in Chapter 6, our group has developed an efficient, stereocontrolled approach towards the synthesis of 3-substituted γ-butenolides through a near-perfect Pd-catalyzed kinetic resolution of 1,3-disubstituted unsymmetrical allylic acetates with 2-trimethylsilyloxyfuran (TMSOF) in the presence of Trost ligand.32 This reaction proceeds under mild conditions and provides the desired 3-substituted γ-butenolides with excellent regio- and enantioselectivity.

172

Chapter 7

As noticed, 2-trimethylsilyloxyfuran is considered as a stable, readily accessible synthon for the γ-anion of 2(5H)-furanones where the nucleophilic attack of TMSOF usually takes place exclusively at C-5.33 Thus we envisioned this novel methodology could be extended towards the asymmetric synthesis of 5-substituted butenolides simply by alternating different reaction conditions and ligands. In this case, the reaction might provide efficient access to highly functionalized 5-substituted γ-butenolides with up to two new adjacent stereocenters. Moreover, this process would also allow for further investigation to give more insight into the mechanism involved in the Pd-AAA reaction using silyl enol ethers as nucleophiles.

7.3 Results and Discussion 7.3.1 Screening of ligands and conditions

Under similar conditions as established in Chapter 6, we first examined the reaction of allylic carbonate 1a catalyzed by Pd2(dba)3·CHCl3 and commercially available PHOX type ligand L1, using 2-trimethylsilyloxyfuran (TMSOF) 2a as nucleophile (Scheme 10). The reaction went to completion without any additives in 16 h at room temperature, surprisingly, led to regioisomers of C-5 substituted non-conjugated β,γ-unsaturated furanone products 3a and 3b in a ratio of 2 to 1. The formation of a small amount of 1,3-diene from allylic carbonate 1b was also observed probably through β-hydride elimination of the π-allyl palladium complex.34 This result was in a sharp contrast to our previous observation that only regioisomeric products 3c and 3e, C-3 substituted 3c being the major isomer, were obtained in the presence of Trost type ligand.32 Instead, the carbon-carbon bond formation took place at the 5-position of dienolate precursor 2a and most surprisingly the reaction did not generate the conjugated system of 5-substituted furanone as expected from precedent literature.35 The exclusive formation of γ-substituted β,γ-unsaturated butyrolactone implied that the reaction proceeded with complete regioselectivity towards the C5 position of 2-trimethylsilyloxyfuran.

We then began screening reaction conditions with symmetrical 1,3-dimethylallyl carbonate 1b in order to facilitate the analysis of the reaction by suppressing the problem of regioselectivity associated to an unsymmetrical substrate. A small improvement on the yield was observed by changing the solvent from dichloromethane to 1,2-dichloroethane (Table 2, entries 1 and 2). We also found that other optimal PHOX ligands used for palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA), such as

173


ligand L2 led to lower conversion, producing a mixture of γ-substituted α,β- or β,γ-unsaturated butyrolactones (4a and 4b) as well as α-substituted butenolide 4c (Table 2, entries 3-4).

Scheme 10. Formation of β,γ-unsaturated butyrolactones through palladium-catalyzed enantioselective allylation of 2-trimethylsiloxyfuran (preliminary study).

As mentioned in the introduction, (S)-t-Bu-PHOX L3 was also recognized as an optimal ligand for effecting an asymmetric variant of the allylic alkylation5 and the decarboxylative alkylation.14, 15 However, the product 4a did not form in detectable amounts from the reaction of carbonate 1b with TMSOF in the presence of palladium catalyst system containing ligand L3, perhaps due to the poor solubility of the palladium catalyst system in 1,2-dichloroethane (Table 2, entry 5). Tetrahydrofuran (THF) was applied to address the solubility problem and the γ-substituted β,γ-unsaturated butyrolactone 4a was formed in a complete conversion with 72% yield and 80% ee. The formation of 1,3-diene product was observed. Although no major influence on the regio- and enantioselectivity was observed, the conversion was incomplete when switching to the palladium complex Pd2(dba)3 (Table 2, entry 6). The reaction conducted with a catalyst containg L1 using THF as solvent, provided the desired product with higher conversion but poor regioselectivity (Table 2, entry 7).

174

Chapter 7

Table 2. Screening of ligands and conditions in the palladium-catalyzed allylation of carbonate 1b.a

entry L solvent time

(h)

conv.b

(%) 4a/4b/4cb

ee(%) of

product 4ac

1 L1 CH2Cl2 24 80 only 4a 62

2 L1 ClCH2CH2Cl 24 85 only 4a 64

3 L2 ClCH2CH2Cl 24 51 78/10/12 64

4 L3 ClCH2CH2Cl 18 <5 - -

5 L3 THF 18 100d only 4a 80

6e L3 THF 18 67 only 4a 78

7 L1 THF 24 90 70/25/5 68

a Reaction conditions: 1b/2/L/Pd2(dba)3·CHCl3 = 1:2:0.15:0.05, 0.1 mM of 1b at rt. b The conversion and the ratio of regioisomers were determined by GC analysis using n-dodecane as internal standard. c Determined via chiral GC analysis. d The product was isolated with 72% yield. e The reaction was performed with 5 mol % of Pd2(dba)3 instead of Pd2(dba)3·CHCl3.

7.3.2 Mechanistic studies

After the optimized conditions were established, we then set out to explore the nature of allylic substrate with different leaving groups such as acetate or tert-butyl carbonate (Scheme 11). Surprisingly this reaction was unsuccessful, resulting only in the partial recovery of the starting material and the formation of 1,3-diene. This observation suggests that the tert-butyl carbonate or acetate generated in situ in the catalytic reaction do not activate the 2-trimethylsilyloxyfuran.

175


Scheme 11. Unsuccessful attempt for the synthesis of unsaturated butyrolactones through the reaction between 2a and 1c-d.

A summary of the effect of additives on the coupling of allylic carbonate 1b with 2-trimethylsilyloxyfuran (TMSOF) is shown in Table 3. Reactions of 1b with TMSOF 2a in the presence of tetra-n-butylammonium acetate and ZnF2 only gave trace amounts of the desired product (Table 3, entries 1-2). It’s noteworthy that the reaction with ZnCl2 proceeded to completion by providing γ-substituted α,β-unsaturated butyrolactone. This difference could likely be attributed to a general process involving the formation of zinc enolate and subsequent nucleophilic addition to the π-allyl palladium complex. This procedure would give rise to the standard product as the γ-substituted α,β-unsaturated butyrolactone.

Table 3. Effect of additive on the reaction of trimethylsilyloxyfuran 2a and carbonate 1b.a

entry additives time

(h)

conv.b

(%) 4a/4b/4cb

1 NBu4OAc 17 <5 -

2 ZnF2 18 <5 -

3 ZnCl2 18 100 6/84/10

a Reaction conditions: 1b/2/L3/Pd2(dba)3·CHCl3 = 1:2:0.15:0.05, 0.1 mM of 1b, 1 equiv of additive. b The conversion and the ratio of regioisomers were determined by GC analysis using n-dodecane as internal standard.

In order to get more insight into the reaction mechanism, several control experiments were carried out. PHOX ligands have been proven to be effective ligands for enantioselective

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intermolecular Heck reactions of cyclic olefins.36 The formation of product 4a could be attributed to a similar Heck type reaction of the double bond of TMSOF. However, in contrast to those previous studies, the coupling of substrate 2b or 2c with carbonate 1b did not provide product 4a under the optimized conditions (Scheme 12).

Scheme 12. Unsuccessful attempt towards an intermolecular Heck reaction.

The formation of product 4a could also be attributed to an isomerization of the double bond under the basic reaction conditions. To determine whether the product 4a was formed after double bond isomerization, reaction of γ-substituted α,β-unsaturated butyrolactone 4b was performed with stoichiometric amount of sodium methoxide as base that is closely related to intermediate during the reaction process (Scheme 13). It turned out that the addition of base does not help to shift the conjugate double bond in the furanone product 4b. Thus the possibility of a nucleophilic addition to the π-allyl Pd complex followed by isomerization was ruled out. Notably, if the reaction run for a long period of time product 4a starts isomerizing to 4b possessing the conjugated double bond i.e. the reverse isomerization is preferred.

Scheme 13. Unsuccessful attempt for the isomerization of product 4b.

7.3.3 31P NMR studies

The phosphorus atom present in the PHOX ligand makes it possible to monitor the reaction by 31P NMR. The combination of (S)-t-Bu-PHOX ligand L3 (δ = -6.48 ppm) with Pd2(dba)3·CHCl3 (3:1) at room temperature in THF-d8 for 30 minutes, led to a single new phosphorous resonance at δ = 18.22 ppm (Figure 4, Spectrum 1). Subsequent addition of 1 equivalent of 1,3-dimethylallyl carbonate 1b, resulted in a new peak at δ = 23.05 ppm

177


(Figure 4, Spectrum 2). Addition of 2-trimethylsilyloxyfuran appeared to shift the resonance at δ = 23.05 ppm to δ = 22.85 ppm and produced three resonances at δ = 21.86 ppm, 21.56 ppm, 21.19 ppm with a single long-lived resonance at δ = 20.89 (Figure 4, Spectrum 3). Moreover, the phosphorus signal came close to complete disappearance at δ = 18.22 ppm. As the reaction proceeded, the resonance at δ = 22.85 disappeared completely and the newly forming resonances at δ = 21.86 ppm, 21.56 ppm, 21.19 ppm also decreased. The resonance at δ = 20.89 remained, even after the reaction was completed.

Figure 4. 31P NMR studies of γ-allylation of TMSOF. 1) Spectrum of ligand L3 and Pd2(dba)3·CHCl3 in THF-d8 at room temperature after 30 min. 2) Spectrum after the addition of carbonate 1b into the above mixture for 30 min. 3) Spectrum after the addition of TMSOF for 1 h to form the product 4a. 4) Spectrum after the addition of TMSOF for 6 h to form the product 4a. 5) Spectrum after the completion of the reaction. Spectra were referenced to 85% aqueous H3PO4 at -6.48 ppm.

7.3.4 Proposed mechanism

A potential mechanistic picture for the transformation of 1b and 2a into 4a could be proposed based on the above information although full 31P NMR assignment could not be made yet (Scheme 14). The catalytic cycle would start from the coordination of the

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palladium catalyst A containing PHOX ligand L3 to the double bond of the allylic carbonate 1b. Subsequent oxidative addition by ionization of the leaving group of carbonate yields an intermediate including a positively charged π-allyl complex B after the loss of CO2. This intermediate is presumed to be a reactive cationic complex. 31P NMR study suggests that the intermediate B might be identified as corresponding to the resonance at δ = 23.05 ppm. After the addition of TMSOF to the reaction mixture, an enolate exchange process might occur as a consequence of the reaction between the methoxide and the TMSOF. The shift of the 31P NMR resonance from δ = 23.05 ppm to δ = 22.85 ppm would indicate such process. Inspired by the work of Stoltz and co-workers,21-24 it’s reasonable to propose that the palladium enolate may form a contact ion-pair or covalently bond where the formation of a σ-allyl Pd complex would be the key to the formation of an O-bound Pd enolate D. Based on literature reported for the palladium-catalyzed γ-arylation of dienolates,27-29 we assumed that the possible intermediate D could be in equilibrium with species F through the isomerisation from a O-bound palladium enolate to an C-bound palladium enolate. As the C(sp3)-C(sp3) reductive elimination is very slow at room temperature,37 we proposed that intermediate F might undergo an internal proton transfer affording intermediate G which is also favoured by a rearomatization process. Subsequent reductive elimination, now a faster process involving a C(sp2)-C(sp3) coupling, from palladium complex G would generate the desired product 4a after tautomerization and decomplexation of intermediate H. Moreover, the long-live intermediate observed through the 31P NMR at the resonance δ = 20.89 might be assigned to Pd complex H.

.

179


Scheme 14. Potential mechanism for palladium-catalyzed γ-allylation of TMSOF.

7.4 Conclusions In the presence of enantiopure PHOX ligand, palladium-catalyzed γ-allylation of 2-trimethylsilyloxyfuran (TMSOF) with allylic carbonate is found to be a novel method for the asymmetric synthesis of γ-substituted β,γ-unsaturated furanone. Our studies suggested that the solvent plays an important role in this reaction, i.e. tetrahydrofuran is the solvent of choice leading to the highest enantioselectivity for the resulted product. The importance of counteranion in the system have been demonstrated since the additives might prevent the formation of product via an enolate anion exchange. As reflected from the results of different additives, the potential enolate exchanging between the π-allyl palladium complex and 2-trimethylsilyloxyfuran is very sensitive to the additive addition. The control experiments exclude alternative processes involving the intermolecular Heck reaction as well as general outer-sphere allylic alkylation followed by double bond isomerization.

31P NMR investigation of the palladium-catalyzed γ-allylation reveals several intermediates, which appear to be part of the allylation phase of the mechanism. The carbon-carbon bond formation might undergo an “inner sphere” reductive elimination of the palladium enolate instead of the alternative “outer sphere” SN2-substitution.

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Unfortunately, studies on the scope of substrate, application of the 5-substituted β,γ-unsaturated furanone product as well as the deuterium labeling experiment could not be completed due to a lack of time.


Column chromatography was performed on silica gel (Silica-P flash silica gel from Silicycle, size 40-63 μm). TLC was performed on silica gel 60/Kieselguhr F254. Components were visualized by UV and stained with a solution of a mixture of KMnO4 (10 g) and K2CO3 (10 g) in H2O (500 mL). Mass spectra were recorded on a AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H and 13C NMR were recorded on a Varian AMX400 (400 and 100.6 MHz, respectively) or a Varian VXR300 (300 and 75 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Optical rotations were measured in CHCl3 on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL). Conversion of the reaction were determined by GC (GC, HP6890: MS HP5973) with an HP5 column (Agilent Technologies, Palo Alto, CA). The regioselectivity of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Enantioselectivities were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector or by capillary GC analysis (HP 6890, Chiraldex G-TA column (30 m x 0.25 mm)) using flame ionization detector.

All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. All solvents were reagent grade and were dried and distilled prior to use, if necessary. Tetrahydrofuran was distilled over Na/benzophenone. Dichloromethane and dichloroethane were distilled over calcium hydride. All the ligands including L1, L2, L3, palladium catalysts and silyl enol ether 2a were purchased from Acros and Sigma-Aldrich. Ligand L4 was synthesized according to a literature procedure reported by Pfaltz and co-workers.38 Substrates 1a,39 1b,40 1c41 and 1d42 were prepared following literature procedures.

181


General procedure for the synthesis of racemic γ-substituted β,γ-unsaturated furanone:

Racemic products were synthesized by reaction of silyl enol ether 2a (70 μL, 0.4 mmol) with the corresponding allylic substrates (0.2 mmol) at room temperature in dichloroethane (2 mL) in the presence of Pd2(dba)3·CHCl3 (10.4 mg, 0.01 mmol) and PHOX ligand L4 (9.9 mg, 0.03 mmol). The reaction mixture was allowed to stir at room temperature until the total consumption of substrates. The reaction mixture was then partioned with hexane and the resulted black precipitation was removed by filtration over silica and washed with dichloromethane. The combined organics were dried over Na2SO4 and the solvent was removed in vacuum. The crude product was purified by flash chromatography on silica gel using different mixtures of pentane/Et2O as eluents. Toluene:Et2O 95:5 was used for TLC to distinguish the different regioisomers.

General procedure for the synthesis of γ-substituted β,γ-unsaturated furanone through palladium-catalyzed γ-allylation of 2-trimethylsilyloxyfuran:

To a dry Schlenk tube containing Pd2(dba)3·CHCl3 (10.4 mg, 0.01 mmol) was added a solution of PHOX ligand L3 (11.6 mg, 0.03 mmol) in dry THF (1 mL). After stirring at room temperature for 30 min, a solution of a solution of allylic carbonate (0.2 mmol) and n-dodecane (20 μL, internal standard) in dry THF (1 mL) was added dropwise. After the mixture stirred for another 15 min at room temperature, 2-trimethylsilyloxyfuran (70 μL, 0.4 mmol) were then added in one portion. Reaction progress was followed by GC and GC-MS. After completion of the reaction, the reaction mixture was partioned with hexane and the resulted black precipitation was removed under filtration over silica and washed with dichloromethane. The collected solvent was then removed under vacuum and the crude product was purified by flash chromatography on silica gel using different mixtures of pentane/Et2O as eluents. Toluene:Et2O 95:5 was usd for TLC to distinguish the product regioisomers.

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Chapter 7

(E)-5-(4-Phenylbut-3-en-2-yl)furan-2(3H)-one (3a)

Pale yellow oil, using L1 as ligand in dichloromethane (see Scheme 10), 57% yield, 72% ee. 1H NMR (400 MHz, CDCl3) 7.30 (m, 5H), 6.50 (d, J = 16.0 Hz, 1H), 6.19 (dd, J = 15.9, 7.5 Hz, 1H), 5.18 (t, J = 1.0 Hz, 1H), 3.34 – 3.31 (m, 1H), 3.20 (s, 2H), 1.36 (d, J = 6.9 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 173.3, 143.8, 137.5, 136.9, 130.7, 130.0, 128.4,

127.3, 126.1, 77.3, 33.8, 18.6. Enantiomeric excess was determined by chiral HPLC, Chiralpak OD-H (n-heptane/i-propanol = 98/2, 0.5 mL/min, 254 nm), retention times: tR (major) 18.8 min, tR (minor) 20.5 min.

(E)-5-(Pent-3-en-2-yl)furan-2(3H)-one (4a)

Pale yellow oil, using L3 as ligand, 72% yield, 80% ee. 1H NMR (400 MHz, CDCl3) δ 5.57 (td, J = 12.7, 6.3 Hz, 1H), 5.41 (dd, J = 16.3, 7.1 Hz, 1H), 5.09 (t, J = 1.2 Hz, 1H), 3.15 (dd, J = 8.0, 7.1 Hz, 2H), 3.08 (s, 1H), 1.68 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 130.6,

127.1, 97.4, 36.5, 34.2, 18.1, 17.6. Enantiomeric excess was determined by chiral GC analysis, Chiraldex G-TA column (30 m x 0.25 mm), (initial temp. 60 °C, gradient 5 °C/min to 170 °C), retention times: tR (major) 27.2 min, tR (minor) 27.4 min.

Palladium-catalyzed γ-allylation of 2-trimethylsilyloxyfuran monitored by 31P NMR:

In a glove-box under nitrogen atmosphere, Pd2(dba)3·CHCl3 (5.2 mg, 0.005 mmol) and (S)-t-Bu-PHOX ligand L3 (5.8 mg, 0.015 mmol) was dissolved in THF-d8 (1 mL) in a 4 mL vial. This solution was stirring for 30 min at room temperature during which time a dark red-purple solution formed. This solution was then filtered through a pipette filter with cotton directly into an NMR tube and the NMR tube was then sealed with a septum and removed from the glove box. NMR spectrum 1 was taken at this time. After the NMR measurement, the reaction mixture was transferred from the NMR tube back to the 4 mL vial. (E)-methyl pent-3-en-2-yl carbonate 1b (14.4 mg, 0.1 mmol) dissolved in THF-d8 (0.5 mL) was then added to the reaction mixture via a pipette in one portion. After the solution was stirred for 30 min, the color of reaction changed from dark red-purple to rich orange. NMR spectrum 2 was taken at this time. After the addition of 2-trimethylsilyloxyfuran (70 μL, 0.4 mmol) for 1h at room temperature, NMR spectrum 3 was taken at this time. The reaction mixture was then stirred for 6 h, while the color of the

183


solution changed from orange to yellow-green. NMR spectrum 4 was taken at this time.

After the completion of the reaction indicated by GC, NMR spectrum 5 was taken.

7.6 References

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7 G. J. Dawson, C. G. Frost, J. M. J. Williams, S. J. Coote, Tetrahedron Lett. 1993, 34, 3149-3150.

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395-422; b) G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336-345; c) B. M. Trost, M. L.

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10 G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336-345.

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Chem. Int. Ed. 2006, 45, 6952-6955.

13 D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 15044-15045.

14 B. M. Trost, J. Xu, J. Am. Chem. Soc. 2005, 127, 2846-2847.

15 a) J. T. Mohr, B. M. Stoltz, Chem. Asian J. 2007, 2, 1476-1491; b) A. Y. Hong, B. M. Stoltz, Eur. J.

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14199-14223; g) D. C. Behenna, Y. Liu, T. Yurino, J. Kim, D. E. White, S. C. Virgil, B. M.

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20 I. Shimizu, J. Tsuji, J. Am. Chem. Soc. 1982, 104, 5844-5846.

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23 N. Sherden, Mechanistic investigations into the palladium-catalyzed decarboxylative allylic

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24 J. A. Keith, D. C. Behenna, N. Sherden, J. T. Mohr, S. Ma, S. C. Marinescu, R. J. Nielsen, J.

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34 J. Tsuji, T. Yamakawa, M. Kaito, T. Mandai, Tetrahedron Letters 1978, 19, 2075-2078.

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Asymmetry 1994, 5, 573-584.

Summary

187

Chiral butenolides and γ-butyrolactones are key structural and ubiquitous moieties in many natural products and biologically active compounds. The stereochemical information of those compounds is often found to be key to their effectiveness as bioactive compounds. Thus the catalytic asymmetric construction of butenolides and γ-butyrolactones has attracted considerable attention from organic chemists in recent years. This thesis describes different approaches aim at applying catalytic asymmetric allylic alkylation and conjugated addition to the construction of key carbon-carbon and carbon–heteroatom bonds in butenolides and γ-butyrolactones. In chapter 2, the development of an efficient catalytic asymmetric synthesis of chiral γ-butenolides based on the hetero-allylic asymmetric alkylation (h-AAA) in combination with ring closing metathesis (RCM) is described (Scheme 1). The synthetic potential of this h-AAA-RCM protocol was illustrated with the facile synthesis of (–)-whiskey lactone, (–)-cognac lactone, (–)-nephrosteranic acid and (–)-roccellaric acid.

Scheme 1. Catalytic asymmetric synthesis of γ-butenolides through h-AAA in combination with RCM.

Diversity oriented synthesis of various chiral cyclic and bicyclic esters is decribed in chapter 3 (Scheme 2). The attempted extention of copper catalyzed hetero-allylic asymmetric alkylation (h-AAA) by using functionalized Grignard reagents bearing an alkene or alkyne moiety is successfully achieved. Further transformation of the corresponding alkylation products through cyclization or cycloaddition provided a variety of highly functionalized chiral cyclic and bicyclic esters with excellent control of chemo-, regio- and stereoselectivity. The synthetic versatility of this methodology was illustrated by stereocontrolled installation of an all-carbon quaternary center on the bridgehead carbon of a carbon [5,5] bicyclic structure.

188

Summary

Scheme 2. Diversity oriented synthesis of various chiral cyclic and bicyclic esters through copper catalyzed hetero-allylic asymmetric alkylation using functionalized Grignard reagents.

Chapter 4 describes a highly efficient enantioselective synthesis of structurally diverse lactones based on the asymmetric conjugate addition of Grignard reagents to 2H-pyran-2-one and 5,6-dihydro-2H-pyran-2-one (Scheme 3). The synthetic applicability of the products from this catalytic C-C bond formation is demonstrated in the stereoselective synthesis of an optically active β-alkyl substituted aldehyde and β-bromo-γ-alkyl substituted alcohol, which are valuable chiral multifunctional synthons.

Scheme 3. Asymmetric conjugate addition of Grignard reagents to 2H-pyran-2-one and 5,6-dihydro-2H-pyran-2-one.

Chapter 5 describes the development of a novel catalytic asymmetric conjugate addition of organozinc reagents to β-phthalimino-α,β-unsaturated substrates (Scheme 4). Using copper/phosphoramidite complex, optically active β-phthalimino-β-alkyl substituted carbonyl compounds were obtained in high yields although with only moderate enantioselectivities (up to 43% ee). Such a protocol provides an alternative and efficient route towards the formation of chiral β-alkyl-β-amino acids.

189

Scheme 4. Asymmetric conjugate addition of organozinc reagents to β-phthalimino-α,β-unsaturated substrates.

In Chapter 6, the development of a palladium-catalyzed kinetic resolution of 1,3-disubstituted allylic acetates and a concomitant allylic alkylation using silyl enol ethers as nucleophiles is described (Scheme 5). The procedure proceeds under mild conditions and provides 3-substituted-γ-butenolides with excellent chemo-, regio- and enantioselectivity. Preliminary studies indicate that hydrogen bonding interactions with the chiral ligand might play a key role in the control of regio- and enantioselectivity. The unusual reactivity of 2-trimethylsilyloxyfuran (TMSOF) was also observed.

Scheme 5. Palladium-catalyzed kinetic resolution of 1,3-disubstituted allylic acetates using 2-trimethylsilyloxyfuran as nucleophiles.

Chapter 7, the final chapter of this thesis, extends the asymmetric synthesis of 5-substituted butenolides simply by alternating different reaction conditions and ligands which have been described in chapter 6. In the presence of enantiopure phosphinooxazoline (PHOX) ligand, palladium-catalyzed γ-allylation of 2-trimethylsilyloxyfuran (TMSOF) with allylic carbonate is found as a novel method for the asymmetric synthesis of γ-substituted β,γ-unsaturated furanone (Scheme 6). 31P NMR studies of the palladium-catalyzed γ-allylation reveal several intermediates, which appear to be part of the allylation phase of the mechanism. The carbon-carbon bond formation might undergo an “inner sphere” reductive elimination pathway of the palladium enolate instead of the alternative “outer sphere” SN2-substitution.

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Summary

2 2 3 3

2 2

S i-

2

i

Scheme 6. Enantioselective synthesis of 5-substituted furanones through palladium-catalyzed γ-allylation of 2-trimethylsilyloxyfuran.

Nederlandse Samenvatting

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Chirale butenolides en γ-butyrolactonen zijn belangrijke structurele elementen in veel natuurproducten en biologisch actieve stoffen. De stereochemische informatie in deze moleculen is vaak van cruciaal belang voor hun biologische activiteit. In de loop der jaren is onderzoek naar de asymmetrische katalytische synthese van butenolides en γ-butyrolactonen flink toegenomen. Dit proefschrift beschrijft verschillende benaderingen gericht op het toepassen van de asymmetrisch katalytische allylische alkylering en geconjugeerde additie in de synthese van eesentiële koolstof-koolstof en koolstof-heteroatoom bindingen van butenolides en γ-butyrolactonen.

In hoofdstuk 2 wordt de ontwikkeling van een efficiënte katalytisch asymmetrische synthese van chirale γ-butenolides beschreven, gebaseerd op de hetero-allylische asymmetrische alkylering (h-AAA) in combinatie met een ringsluiting cross-metathese reactie (RCM). Het synthetische potentieel van deze h-AAA-RCM was getoond middels eenvoudige synthese van (–)-wiskey lacton, (–)-cognac lacton, (–)-nephrosteranic acid en (–)-roccellaric acid (Schema 1).

Schema 1. Katalytisch asymmetrische synthese van γ-butenolides middels de h-AAA in combinatie met RCM.

Diversiteit georiënteerde synthese van verscheidende chirale cyclische en bicyclische esters is beschreven in hoofdstuk 3 (Schema 2). De gepoogde uitbreiding van de koper-gekatalyseerde h-AAA gebruikmakend van alkeen- of alkyn-houdende Grignard reagentia was succesvol. Verdere transformatie van het corresponderende alkyleringsproduct doormiddel van cyclisatie of cycloadditie reacties leverde een variëteit aan hoog gefunctionaliseerde chirale cyclische en bicyclische esters met excellente chemo-, regio- en stereoselectiviteit. De synthetische veelzijdigheid van deze methodologie wordt geïllustreerd door de stereogecontroleerde installatie van een all-carbon quaternair stereocentrum op het bruggenhoofd koolstof atoom van een koolstof [5,5] bicyclische structuur.

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Schema 2. Diversiteit georiënteerde synthese van verscheidende chirale cyclische en bicyclische esters middels de koper-gekatalyseerde hetero-allylische asymmetrische alkylering.

Hoofdstuk 4 beschrijft de zeer efficiënte enantioselectieve synthese van structureel diverse lactonen, gebaseerd op de asymmetrische geconjugeerde additie van Grignard reagentia aan 2H-pyra-2-non en 5,6-dihydro-2H-pyra-2-non (Scheme 3). De synthetische toepassing van de producten uit deze katalytische C-C binding formatie wordt gedemonstreerd in de stereoselectieve synthese van waardevolle chirale multifunctionele synthons als optisch actieve β-alkyl gesubstitueerde aldehydes en β-broom-γ-alkyl gesubstitueerde alcoholen.

3

3

2

2

R,S

Schema 3. Asymmetrisch geconjugeerde additive van Grignard reagentia aan 2H-pyra-2-non en 5,6-dihydro-2H-pyra-2-non.

Hoofdstuk 5 beschrijft de ontwikkeling van de katalytisch asymmetrische geconjugeerde additie van organozink reagentia aan β-phthalimino-α,β-onverzadigde substraten (Schema 4). Door het gebruik van een koper/fosforamidiet complex zijn optische actieve β-phthalimino-α,β-onverzadigde alkyl gesubstitueerde carbonyl-houdende stoffen vervaardigt in een goede opbrengst, maar met middelmatige enantioselectiviteiten (tot en met 43% ee). Dit protocol voorziet in een alternatief en efficiënte route naar de formatie van chirale β-alkyl-β-amino zuren.

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Schema 4. Asymmetrische geconjugeerde additive van organozink reagentia aan β-phthalimino-α,β-onverzadigde substraten.

In hoofdstuk 6 wordt de ontwikkeling van een palladium-gekatalyseerde kinetische resolutie van 1,3-digesubstitueerde allylische acetaten, en een gelijktijdige allylische alkylering met silyl enol ethers als nucleofiel, beschreven (Schema 5). De procedure vindt plaats onder milde reactie condities en levert 3-gesubstitueerde-γ-butenolides met excellente chemo-, regio-, en enantioselectiviteit. Voorlopige resultaten wijzen erop dat waterstofbruginteracties met het chirale ligand een belangrijke rol spelen in de controle van de regio-, en enantioselectiviteit. Een ongebruikelijke reactiviteit van 2-trimethylsiloxyfuran (TMSOF) is ook waargenomen.

Scheme 5. Palladium-gekatalyseerde kinetische resolutie van 1,3-digesubstitueerde allylische acetaten met 2-trimethylsiloxyfuran als nucleofiel.

Hoofdstuk 7, het laatste hoofdstuk van dit proefschrift, betreft de asymmetrische synthese van 5-gesubstitueerde butenolides door simpelweg het veranderen van de reactie condities en liganden beschreven in hoofdstuk 6. Er is waargenomen dat in de aanwezigheid van enantiozuiver fosfinooxazoline (PHOX) ligand de palladium-gekatalyseerde γ-allylering van 2-trimethylsiloxyfuran (TMSOF) met allylische carbonaten resulteren in een nieuwe methode is voor de asymmetrische synthese van γ-gesubstitueerde β,γ-onverzadigde furanonen. De 31P NMR studies van de palladium-gekatalyseerde γ-allylering onthulde verscheidende intermediëren die een rol lijken te spelen in de allylatiefase van de reactie. In de koolstof-koolstof binding vorming is de betrokkenheid van een “inner sphere”

195


reductieve eliminatie van het palladium enolaat meer waarschijnlijk dan dat van de “outer sphere” SN2-substitutie.

Scheme 6. Enantioselective synthese van 5-gesubstitueerde furanonen middels de palladium-gekatalyseerde γ-allylering van 2-trimethylsilyloxyfuran.

Acknowledgements

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After almost 5 years in Groningen，I just celebrated my 30th birthday and now it’s time to finish the period for a Ph.D. student. It would be impossible to finish all the work present in this thesis without the help of many excellent people. Therefore, it is my great pleasure to acknowledge all the people who supported and contributed to this thesis. First of all, I would like to express gratitude towards my supervisor, Prof. dr. Ben L. Feringa, for giving me the opportunity to be a part of his research group. I have learnt much from his meticulous scholarship, working enthusiasm and creative thinking. I am also grateful for his profound discussions on the research results and invaluable help with the preparation of all the articles and manuscripts. An indelible picture of the moment we spent in front of the blackboard was impressed upon my mind. Next, I would like to thank Prof. dr. Adriaan J. Minnaard who is always willing to help and to give suggestions. Thank you for all the valuable comments over the years and thank you for being part of my reading committee. I would also like to express thanks to other members of the reading committee, Prof. dr. Henk Hiemstra, Prof. dr. Andreas Pfaltz, for reading and evaluating the thesis as well as their comments and feedback in improving the manuscript. My sincere thanks to Dr. Martín Fañanás-Mastral for his daily guidance, extensive discussion as well as helpful suggestions. Martín, thanks for all the corrections for the manuscripts we published together over last 5 years and for reading all the details of this thesis. I benefited from your experience and rigorous attitude not only in performing reactions but also in understanding the principles and problems behind them. A big thanks goes to the professors in the Stratingh Institute for Chemistry while I was there as a Ph.D. candidate: Prof. dr. Wesley R. Browne, Prof. dr. Syuzanna R. Harutyunyan, Prof. dr. Sijbren Otto, Prof. dr. Gerard Roelfes, Prof. dr. Anna K. H. Hirsch. Thanks to all the people who helped me with analytical and technical support: Theodora (exact mass), Monique (HPLC’s and GC’s), Auke (Crystal structure), Martin (Crystal structure), Hilda, Tineke, Cristina and Alphons. Many thank to all my great lab mates (5114.223N and 5116.238Z) for providing very

198

Acknowledgements

friendly environment: Bjorn, Pieter, Nataša, Céline, Martín, Maria, Stella, Yining, Tatsuo, Robby, Xiaoyan, Lili, Jos, Paula, Anna, Diederik, Matea, Nathalie. Special thanks goes to Jeffrey Butter for the translation of English summary to Netherlandse samenvatting and for making all the fun in the lab. Furthermore, I would like to thank all the neighbors: Alena, Anne, Lachlan, Bea, Tati, Jerome, Jack, Yange, Dahui, Johannes, Tim, Manolo, Valentin, Annick, Carlos, Kriztof, Suresh, Thom, Petra, Anouk, Petra, Stefano, Kuang-yen, Arjen, Jort, Depeng, Jurica, Nopporn, Jiawen, Massimo, Jochem, Toon, Jiaobin, Romina. My thanks also go to the people from the Roelfes group (Qian, Lorina, Fiora, Jens, Rik, Jeffrey, Almudena and all the others), people from Wesley group (Shaghayegh, Jiajia, Pat, Hella, Francesco, Apparao, Davide and all the others), people from the Syuzi group (Francesca, Jiawei, Alaric, Emma, Aike and all the others), people from the Sijbren group (Saleh, Hugo, Mathieu, Piotr, Shuo, Jianwei, Yang, Elio, Asish, Andrea and all the others) and all the lab mates in the new building (Adi, Ashoka, Danny, Zhongtao, Peter, Yun, Leticia, Dorus, Milon, Kiran, Jeffrey, Peter, Miriam, Manuel, Santi, Bea, Felix, Claudia, Tiziana, Wim, Wiktor and all the others). Also a big thank you to all the members of the Stratingh Institute that I forgot to mention. During my stay I had the privilege to work with a number of talented post-docs, Ph.D. students. Here I would like to thank Yining and Giuseppe for their contribution in the chapter 6. For all the useful suggestions and funny meetings I would like to thank the entire subgroup of asymmetric catalysis. Special thanks to Prof. dr. Brian M. Stoltz for offering me the position to perform exchanging study at the California Institute of Technology. The most important thing I have learnt from there is how to conduct research with enthusiasm and patience. My thanks also goes to Jeff, Michele, Douglas, Hideki, Alex, Allen, Hosea, Kristy, Kun-liang, Yiyang and all the other members in the Stoltz group.

My life in the Netherlands would not have been so nice without all the friends. Although it would be too much to name all of them, a few people deserved to be mentioned: Jiajia Dong(董佳佳), Jiawen Chen(陈佳文), Beibei Zhang (张蓓蓓), Depeng Zhao (赵德鹏), Kun Yue (岳坤), Yun Liu(刘允), Stella Zhang, Wenjin Li (李文静), Zilin Yu (俞子陵), Jie Yin (殷杰), Wenqiang Zou (强哥), Lifei Zheng(二飞), 二飞嫂，Zhiyuan Zhao(小赵)，Fei Xiang (大飞)，Linyun Yu (俞凌云), Yuan Zhang (张渊), Ning Ding (丁宁), Lin Yuan (苑

199

琳), Yining Ji (季一宁)，Jia Gao (高佳)，Zheng Zhang (铮铮)， Rui Qing (秦瑞), Jianwei Li, Xiaoguang Du (晓光)，Xiaoming Liu (刘晓明), Bian Wu (吴边)，Qiqi (琪琪), Mengyuan Li (李梦媛). 感谢你们陪我走过了这一段美好时光！ Thanks to my family, especially my father and mother for their understanding and constant support! 真挚地感谢献给我的家人特别是我的父亲和母亲。谢谢你们赋予我如此美好的生命，

谢谢你们最无私的爱以及所给予的理解和支持。 Life should be varied and interesting, unexpected and changing…... 无论何时何地，生活总是让我们充满惊喜……

Bin Mao

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University of Groningen Catalytic asymmetric …Table of contents Chapter 1 Catalytic Asymmetric Synthesis of Butenolides and γ-Butyrolactones 01 1.1 Introduction 02 1.2 Lactone-derived