Enantioselective cobalt-catalysed transformations

Enantioselective Cobalt-catalysed Transformations

Catalysis Series

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Titles in the series:1: Carbons and Carbon Supported Catalysts in Hydroprocessing2: Chiral Sulfur Ligands: Asymmetric Catalysis3: Recent Developments in Asymmetric Organocatalysis4: Catalysis in the Refining of Fischer–Tropsch Syncrude5: Organocatalytic Enantioselective Conjugate Addition Reactions:

A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules6: N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Syn-

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Amorphous Boron Alloys35: Enantioselective Cobalt-catalysed Transformations

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Enantioselective Cobalt-catalysed Transformations

By

Hélène PellissierCNRS, FranceEmail: [email protected]

Catalysis Series No. 35

Print ISBN: 978-1-78801-462-5PDF ISBN: 978-1-78801-509-7EPUB ISBN: 978-1-78801-515-8Print ISSN: 1757-6725Electronic ISSN: 1757-6733

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© Hélène Pellissier 2018

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vii

Catalysis Series No. 35Enantioselective Cobalt-catalysed TransformationsBy Hélène Pellissier© Hélène Pellissier 2018Published by the Royal Society of Chemistry, www.rsc.org

Foreword

The science of synthesis has transformed our world and opened a gateway to a molecular universe filled with previously unimaginable opportunities. Our improving ability to make molecules has profoundly changed how we think about nature's chemome, enabling access to natural materials often of otherwise limited availability and at the same time providing new structures with improved or totally new functions. Our significantly advanced ability to make molecules has now also placed emphasis on which molecules to make and the importance of achieving function through synthesis-informed design (function oriented synthesis). Collectively, these advances have enhanced our understanding of chemistry and in so doing they have significantly and beneficially impacted research, medicine, materials science, energy, environ-mental stewardship, our economy and our quality of life. Synthetic access to molecules and thus molecular function has more generally opened new frontiers in all of science from molecular anthropology to molecular zoology and all disciplines in between.

The reach of synthesis relies on and is inexorably determined by the dis-covery and invention of new reactivities and reactions. This is clearly evi-dent from the number of molecules once considered impossible to make that are now often routinely and step-economically prepared through the creative use of our ever-expanding reaction lexicon. While tracing its roots to the 18th century, organometallic chemistry and especially transition metal chemistry have figured significantly in advancing our molecule-making expertise. By modulating pi and sigma bond reactivities, transition metals in particular have changed how we think about bond formation. The once limited and historically recognized reactivity of functional groups, for exam-ple, has now been changed and vastly expanded as their reactivities are often enhanced or totally changed by interactions with transition metals. Vast

Forewordviii

new opportunities and choices are now made possible for green chemistry, improving step economy and bringing molecular construction closer to the ideal synthesis.

In this book, Hélène Pellissier, who has authored numerous noteworthy contributions to reaction science, provides an impressively comprehensive and insightful overview of enantioselective cobalt-catalyzed transforma-tions. Building on her scholarly review (Chemical Reviews 2014) of the field a few years ago, this considerably updated and expanded analysis serves as a superb survey of the remarkable reach of cobalt-catalyzed transformations and the many and varied strategies to control their absolute stereochemical outcome. From cobalt-catalyzed cycloadditions and cyclizations to reduc-tions, condensations, coupling reactions, epoxide ring opening and oligo-merizations and beyond, this tome captures the richness of organocobalt chemistry and its increasing impact on stereocontrolled synthesis. It is at once a celebration and recognition of the impressive achievements of those in the cobalt chemistry field and a forerunner of things to come.

The structure of each chapter in this book commendably provides a brief historical perspective and an information-rich summary of contemporary progress punctuated by representative contributions, mechanistic analyses, and insightful conclusions. The graphical presentations are superbly to the point, adding to the readability of this work. This book also benefits greatly from its perspective as well as its up-to-date nature, serving as a “must read” for those in the field as well as for those interested in emerging trends in organometallic chemistry. It is noteworthy and reflective of the growth of the field that not too many years ago, the field of organometallic chemistry was ambitiously addressed by some in single books. Now even enantioselective transformations of cobalt could fill many.

Like other transition metals, cobalt-based reagents and catalysts have had and continue to have a striking impact on the practice of synthesis and on our understanding of molecular reactivity. This book is a snapshot of the state of the science and a comprehensive collection of cobalt based reactions. It serves at the same time as a reference point and inspirational foundation for future advances in the field. Cobalt chemistry and more generally, metal catalysis, are shaping our approach to synthesis and with that the beneficial impact of synthesis on science and society.

Paul A. WenderBergstrom Professor of Chemistry

Stanford University

ix


Abbreviations

Acac AcetylacetoneAr ArylBDPP 2,4-Bis(diphenylphosphino)pentaneBINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthylBINOL 1,1′-Bi-2-naphtholBIPHEP 2,2′-Bis(diphenylphosphino)-1,1′-biphenylBn BenzylBoc Tert-butoxycarbonylBOPA Bis(oxazolinylphenyl)amineBTFEP 1,3-Bis(2,2,2-trifluoroethoxy)propan-2-olBz BenzoylCAN CericammoniumnitrateCbz BenzyloxycarbonylCHIRAPHOS 2,3-Bis(diphenylphosphine)butaneCod CyclooctadieneCy CyclohexylDBFOX 4,6-Dibenzofurandiyl-2,2′-bis-(4-phenyloxazoline)DBU 1,8-Diazabicyclo[5.4.0]undec-7-eneDCE 1,2-Dichloroethanede diastereomericexcessDIOP 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)

butaneDIPAMP 1,2-[(2-Methoxyphenyl)phenylphosphino]ethaneDIPEA DiisopropylethylamineDMAP 4-(N,N′-Dimethylamino)pyridineDME DimethoxyethaneDMF DimethylformamideDMSO Dimethylsulfoxide

Abbreviationsx

DNP 2,4-DinitrophenolateDpen 1,2-DiphenylethylenediamineDPPA Diphenylphosphorylazide(R,R,S,S)-DUANPHOS (1R,1′R,2S,2′S)-2,2′-Di-tert-butyl-2,3,2′,3′-tetrahydro-

1H,1H’-(1,1′)biisophospindolylDUPHOS 1,2-Bis(phospholano)benzeneEDTA Ethylenediaminetetraaceticacidee enantiomericexcessEWG Electron-withdrawingL LigandMAO MethylaluminoxaneMes Mesityl(2,4,6-trimethylphenyl)MOM MethoxymethylMS MolecularsievesMTBE Methyltert-butyletherNaph NaphthylNCS N-ChlorosuccinimideNFSI N-FluorbenzenesulfonimideNMI N-MethylimidazoleNMO N-Methylmorpholine-N-oxideNORPHOS 2,3-Bis(diphenylphosphino)-bicyclo[2.2.1]hept-5-eneOct OctylPent PentylPG ProtectinggroupPhth PhthalimidoPin PinacolatoPINAP 4-[2-(Diphenylphosphino)-1-naphthalenyl]-N-[1-phenylethyl]-

1-phthalazinaminePPN Bis(triphenylphosphine)iminiumPPN-DNP Bis-triphenylphosphineiminium2,4-dinitrophenolate(R)-PROPHOS (R)-(+)-1,2-bis(diphenylphosphino)propanePYBOX Pyridine-bisoxazolineQUINOX 2-(4,5-Dihydro-2-oxazolyl)quinoliner.t. roomtemperatureSalen N,N′-Ethylenebis(salicylideneiminato)SIPAD 7,7′-Bis(2-pyridinecarboxamido)-1,1′-spirobiindaneSIQAD 7,7′-Bis(2-quinolinecarboxamido)-1,1′-spirobiindaneTADDOL α,α,α′,α′-Tetraaryl-1,3-dioxolan-4,5-dimethanolTBAF Tetra-n-butylammoniumfluorideTBS Tert-butyldimethylsilylTEA TriethylamineTEMPO 2,2,6,6-TetramethylpipedinyloxylTetraphenyl-carbpi (Cyclopropaquinolinylideneimino)isoindoleTf TrifluoromethanesulfonylTHF TetrahydrofuranTHFA TetrahydrofurfurylalcoholTIPS Triisopropylsilyl

xiAbbreviations

TMS TrimethylsilylTol TolylTPS TriphenylsilylTs 4-Toluenesulfonyl(tosyl)VALNOP N-Diphenylphosphino-2-(diphenylphosphinoxymethyl)pyrrolidineXyl-P-Phos 2,2′,6,6′-Tetramethoxy-4,4′-bis[di(3,5-dimethylphenyl)

phosphino]-3,3′-bipyridine

xiii


Contents

Chapter 1 Enantioselective Cobalt-catalysed [2+1] Cycloadditions 1

1.1 Introduction 1 1.2 Cyclopropanations 1 1.2.1 IntermolecularCyclopropanations 1 1.2.2 IntramolecularCyclopropanations 20 1.3 AziridinationsandEpoxidations 22 1.3.1 Aziridinations 22 1.3.2 Epoxidations 26 1.4 Conclusions 28 References 29

Chapter 2 Other Enantioselective Cobalt-catalysed Cycloadditions 34

2.1 EnantioselectiveCobalt-Catalysed(Hetero)-Diels–AlderCycloadditions 34

2.1.1 Diels–AlderCycloadditions 34 2.1.2 Hetero-Diels–Alder

Cycloadditions 36 2.2 EnantioselectiveCobalt-Catalysed

1,3-DipolarCycloadditions 40 2.3 EnantioselectiveCobalt-catalysed[2+2+2]

and[2+2+1]Cycloadditions 46

Contentsxiv

2.3.1 [2+2+2]Cycloadditions 46 2.3.2 [2+2+1]Cycloadditions 50 2.4 OtherEnantioselectiveCobalt-Catalysed

Cycloadditions 53 2.5 Conclusions 55 References 57

Chapter 3 Enantioselective Cobalt-catalysed Cyclisations Through Domino Reactions 62

Conclusions 70 References 72

Chapter 4 Miscellaneous Enantioselective Cobalt-catalysed Cyclisations 75

4.1 UsingSalenLigands 75 4.2 UsingBiphosphineLigands 84 4.3 UsingPorphyrinLigands 86 4.4 UsingOtherLigands 88 4.5 Conclusions 92 References 93

Chapter 5 Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Reduction Reactions 95

5.1 ReductionsofCarbonylCompoundsandDerivatives 95

5.1.1 BorohydrideReductions 95 5.1.2 Hydrosilylations 105 5.1.3 Hydrogenations 109 5.2 ReductionsofAlkenes 111 5.2.1 ReductionswithBoraneDerivatives 111 5.2.2 Hydrosilylations 119 5.2.3 Hydrogenations 120 5.3 Conclusions 124 References 126

Chapter 6 Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Ring–Opening Reactions 129

6.1 HydrolyticandAlcoholyticRing–OpeningofEpoxides 129

6.2 Ring–OpeningofEpoxidesbyAminesandCarbamates 140

xvContents

6.3 Ring–OpeningofEpoxidesThrough(Co)polymerisation 143

6.4 Conclusions 146 References 147

Chapter 7 Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Michael and (Nitro)-Aldol Reactions 155

7.1 MichaelReactions 155 7.1.1 MichaelAdditionstoα,β-Unsaturated

CarbonylCompoundsandDerivatives 155

7.1.2 MichaelAdditionstoNitroolefins 160 7.2 (Nitro)-AldolReactions 167 7.3 Conclusions 175 References 175

Chapter 8 Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed 1,2-Nucleophilic Additions to Carbonyl Compounds and Derivatives 178


Chapter 9 Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Cross-coupling Reactions 188


Chapter 10 Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Hydrovinylation Reactions 196


Chapter 11 Synthesis of Chiral Acyclic Compounds Through Miscellaneous Enantioselective Cobalt-catalysed Reactions 204

11.1 α-Functionalisationsandα-AlkylationsofCarbonylCompounds 204

11.2 Carbonyl-eneReactions 207

Contentsxvi

11.3 OtherReactions 209 11.4 Conclusions 215 References 216

General Conclusion 218

Subject Index 220

1


1.1 IntroductionReactions forming multiple bonds and stereocentres represent important tools for the efficient assembly of complex molecular structures.1 Of the many families of reactions discovered over the past century, cycloadditions hold a prominent place in the area of current synthetic methodologies and the research activity in this field shows no signs of abatement.2 Among the metals used to catalyse cycloadditions,1,2a,b,3 cobalt has been found to be highly efficient in enantioselectively promoting the formation of carbo- and heterocycles of different ring sizes and especially three-membered chiral products.

1.2 Cyclopropanations1.2.1 Intermolecular Cyclopropanations

1.2.1.1 With Salen Cobalt ComplexesOrganic chemists have always been fascinated by the strained structure of the cyclopropane subunit,4 which is found in a wide variety of naturally occurring compounds, such as terpenes, pheromones, fatty acid metab-olites and unusual amino acids.5 This fact has inspired chemists to find novel approaches to their synthesis, and thousands of cyclopropane com-pounds have already been prepared.6 In this context, the cyclopropana-tion of alkenes based on the transition-metal-catalysed decomposition of

ChApTeR 1

Enantioselective Cobalt-catalysed [2+1] Cycloadditions

Chapter 12

diazoalkanes has been widely developed.7 Indeed, the synthesis of cyclopro-panes by transition-metal-mediated carbene transfer from aliphatic diazo compounds to carbon–carbon double bonds is not only a major method for the preparation of cyclopropanes, with them most of the time exhibiting a trans-configuration, but is also among the most developed and general methods available to the synthetic organic chemist.7c,e, f The asymmetric synthesis of cyclopropanes has remained a challenge,4d,7i,8 but it has been attempted since it was demonstrated that members of the pyrethroid class of compounds were found to be effective insecticides.9 Since the first enan-tioselective copper-catalysed cyclopropanation reported by Nozaki and co-workers in 1966,10 many groups have tried to find more efficient catalysts, and the most spectacular advances were reported by Aratani et al., who dis-covered, through extensive evaluation of a large number of ligands, a chiral (salicylaldiminato)copper(ii) complex which allowed enantioselectivities of up to 95% ee to be achieved.11 ever since, other highly effective and stereo-controlled syntheses of functionalised cyclopropanes have been reported, in particular, with catalysts based on copper,12 rhodium, and ruthenium.13 Moreover, cobalt complexes have been shown to be reactive catalysts for α-diazoester decomposition, leading to a metal carbene that could convert alkenes into cyclopropanes. Although the early work in this area established that chiral cobalt(ii) complexes were catalytically active, the low levels of diastereo- and enantiocontrol have limited their use in synthesis for a long time.14 The first highly enantioselective intermolecular cobalt-catalysed cyclopropanation reaction was reported by Nakamura et al. in 1978.15 It employed 3 mol% of bis[(−)-camphorquinone-α-dioximato]cobalt(ii) com-plex as a catalyst, allowing enantioselectivities of up to 88% ee to be achieved in combination with excellent yields (90–95%), for example in the synthe-sis of neopentyl trans-2-phenylcyclopropanecarboxylate. ever since, many other chiral cobalt catalysts have been successfully applied to promote these transformations, often derived from salen or porphyrin chiral ligands. For example, Katsuki et al. introduced novel chiral salen cobalt(iii) complexes to induce trans-selective cyclopropanation reactions.7a,16 The optimal trans- selective cobalt complex was demonstrated to be cobalt(iii) catalyst 1. As shown in Scheme 1.1, it promoted the decomposition of tert-butyl diazoac-etate in the presence of styrene derivatives to yield the corresponding trans- cyclopropanes with both excellent diastereoselectivities (90–94% de) and enantioselectivities (92–96% ee).

In 1999, Yamada et al. demonstrated that chiral 3-oxobutylideneaminato-cobalt(ii) complexes,17 such as 2 employed at a 5 mol% catalyst loading in ThF as solvent at 40–50 °C (Scheme 1.2), were efficient promotors of the same trans-selective reaction of monoaryl-substituted alkenes with tert-butyl diaz-oacetate.18 The addition of a catalytic amount of N-methylimidazole (NMI) was found to increase the rate of the reaction, as well as the enantioselectiv-ity. The scope of the reaction was, however, limited to aryl-monosubstituted alkenes, resulting in the formation of the corresponding chiral trans- cyclopropanes in high yields (85–99%) and good trans-diastereoselectivities

Scheme 1.1 Trans-selective cyclopropanation of aromatic alkenes with tert-butyl diazoacetate.

Scheme 1.2 Trans-selective cyclopropanation of mono- and 1,1-disubstituted alkenes with ethyl and tert-butyl diazoacetates.

Chapter 14

(64–82% de) combined with excellent enantioselectivities (92–96% ee). Indeed, the reaction of 1,1-disubstituted alkenes led to the corresponding enantiopure trisubstituted cyclopropane derivatives with only low diaste-reocontrol (6% de). The authors also found that the diastereoselectivity in the cyclopropanation of styrene decreased to 66% de when methyl diazoac-etate was used. A theoretical analysis of the reaction pathway using a den-sity functional theory method revealed that the axial donor ligand produced two prominent effects.19 One was that the activation energy for the forma-tion of the cobalt carbene was reduced and that the activation energy for the cyclopropanation step was increased. The other was that the distance of the carbene carbon above the plane was shortened during the cyclopro-panation step. From these results, the axial donor ligand effects, enhancing the reactivity and improving the diastereo- and enantioselectivities, in the 3-oxobutylideneaminatocobalt(ii)-catalysed asymmetric cyclopropanation could be explained. In relation to the axial donor ligand effect, the same authors showed that these highly enantioselective cyclopropanations could also be performed in environmentally friendly alcoholic and aqueous sol-vents.20 Indeed, the tetradentate ligand of the β-ketoiminatocobalt complex produces a rigid square planar structure around the cobalt atom and the structure of the complex is almost independent from the solvent. hence, the coordination of donor solvent at a vacant axial position would directly lead to the activation of the carbene carbon located at the other axial posi-tion. It is generally considered that metal–carbene carbon bonds in carbene complexes for cyclopropanation should be double-bonded; however, the authors reported theoretical and FT-IR analyses revealing that the cobalt–carbon bond of the 3-oxobutylideneaminato or the salen–cobalt–carbene complexes was characterised as a single bond.21 Furthermore, dinuclear salen complexes, such as 3 (Scheme 1.2), represent a new type of effective catalyst for asymmetric cyclopropanation. This is due to the fact that the substrates are invariably subjected to chiral induction by the chiral back-bone as they approach the complex platform. In 2005, Gao et al. applied this type of catalysts to the cyclopropanation of styrene with ethyl diazoace-tate, which led to the formation of trans-cyclopropane as the major product with moderate diastereoselectivity (48% de), albeit in a high yield (92%).22 Good enantioselectivities of 88% ee for the trans-product and 94% ee for the minor cis-product were obtained when performing the reaction at 25 °C in dichloromethane, using a 5 mol% catalyst loading.

In 1999, Katsuki et al. succeeded in designing rare cis-selective catalysts based on the salen scaffold, such as cobalt complex 4 (Scheme 1.3).23 The reaction of various aromatic mono- and disubstituted alkenes with ethyl and t-butyl diazoacetates proceeded very well in the presence of NMI, pro-viding the corresponding cis-cyclopropanes in good to quantitative yields, good to excellent diastereoselectivities of up to 98% de, and excellent enantioselectivities of up to 99% ee. In this study, the authors investigated the catalytic efficiency of cobalt(ii) salen complexes in comparison with the corresponding ruthenium(NO) salen complexes, showing that even if

5Enantioselective Cobalt-catalysed [2+1] Cycloadditions

Scheme 1.3 Cis-selective cyclopropanation of mono- and 1,1-disubstituted aromatic alkenes with ethyl and tert-butyl diazoacetates.

Chapter 16

excellent enantio- and cis-selectivities were achieved using the ruthenium catalysts, the yields of cyclopropanes were unsatisfactory because of a self-coupling of the diazo compounds that occurred competitively, as also mentioned by Zhang et al. for cobalt porphyrins.24 however, a drawback of this methodology was the limitation of its scope to aryl-substituted alkenes, as shown in Scheme 1.3. In 2007, the same authors investigated other cobalt(ii) complexes with chiral pentadentate salen ligands bear-ing imidazole or pyridine derivatives as the fifth coordinating group in the same cyclopropanation reaction.25 Catalyst 5, bearing an imidazole, proved to be the most efficient catalyst for promoting good to high cis-dias-tereoselectivity (78–98% de) in the reaction of monosubstituted aromatic alkenes with t-butyl diazoacetate to give the corresponding cis-cyclopro-panes, as shown in Scheme 1.3. Moreover, these products were obtained in excellent yields (93% to quantitative) combined with uniformly high enantioselectivities (93–96% ee), as shown in Scheme 1.3. On the other hand, the authors found that the reaction of disubstituted alkenes, such as α-methylstyrene, provided only a low cis-diastereoselectivity of 10% de and a moderate yield of 45%, albeit combined with an excellent enantioselec-tivity (96–97% ee). These reactions were performed with 5 mol% of catalyst 5 in toluene at room temperature.

Approaches to enantiopure trifluoromethyl-substituted cyclopropanes, which constitute important building blocks for drug discovery, still remain rare. In this context, in 2011, Carreira et al. reported a novel enantioselec-tive cobalt-catalysed route to these chiral products based on the cyclopro-panation of styrenes with in situ generated trifluoromethyl diazomethane.26 After screening another type of cobalt catalyst derived from (S,S)-1,2-cyclo-hexyldiamine and 2,3-dihydroxybenzaldehydes, these authors selected novel catalyst 6, bearing a combination of electron-donating and elec-tron-withdrawing substituents on benzaldehydes, as the optimal catalyst. As shown in Scheme 1.4, the cyclopropanation of a range of styrenes with CF3Ch2Nh3Cl in the presence of catalyst 6 provided the corresponding chi-ral trans-disubstituted cyclopropanes in moderate to high yields (49–95%), with high diastereoselectivities (84 to >98% de) and enantioselectivities (84–94% ee). The scope of this methodology was extended to 1,1-disubstituted styrenes, which furnished the corresponding trisubstituted cyclopropanes in uniformly high enantioselectivities (87–97% ee), albeit with generally lower diastereoselectivities (34–80% de). It must be noted that catalyst 6 constituted the first of its type that was active in asymmetric cyclopro-panation with an in situ generated diazoalkane under extreme conditions (aqueous acidic, oxidative media).

Later in 2014, novel C2-symmetric cobalt(ii) salen complex 7 was used by White and Shaw to promote the enantioselective cyclopropanation of a range of 1,1-disubstituted alkenes with ethyl diazoacetate (Scheme 1.5).27 The pro-cess was performed in dichloromethane at room temperature in the pres-ence of a potassium thioacetate additive, affording the corresponding chiral


trisubstituted cyclopropanes as almost single diastereomers (90–>96% de) in uniformly high yields (89–97%) and enantioselectivities (90–98% ee). This novel methodology was applied as a key step in the short and efficient syn-thesis of the dual serotonin–epinephrine reuptake inhibitor (+)-synosutine, as illustrated in Scheme 1.5.

It must be noted that only limited examples of catalytic asymmetric cyclopropanations of aromatic double bonds have been reported so far. In this context, the dearomatisation of a series of electron-deficient nitro-gen heterocycles was recently reported for the first time by Chen et al. on the basis of enantioselective cobalt-catalysed cyclopropanations.28 The reactions of different types of fused heteroaromatic substrates were promoted by 7.5 or 15 mol% of cobalt(ii) salen complex 8 in chloro-benzene at 45 °C in the presence of N-methylimidazole as an additive. For example, the reaction of various imidazopyrazine derivatives 9 with ethyl diazoacetate led to the corresponding tricyclic chiral products 10 exhibiting the cis-configuration as the major diastereomers with high diastereoselectivity (84–90% de). As shown in Scheme 1.6, these chiral polynitrogenated heterocycles were obtained in moderate to high yields (45–91%) and enantioselectivities (60–92% ee). The scope of the pro-cess was extended to incorporate the imidazopyridazines 11 which led, by reaction with ethyl diazoacetate, to the corresponding cis-heterocyclic cyclopropanes 12 as the major diastereomers in moderate to good yields

Scheme 1.4 Trans-selective cyclopropanation of styrenes with CF3Ch2Nh3Cl.

Chapter 18

Scheme 1.5 Cyclopropanation of 1,1-disubstituted alkenes catalysed with ethyl diazo-acetate and the synthesis of (+)-synosutine.


(47–89%) and diastereoselectivities (60–90% de) along with high enan-tioselectivities (84–98% ee), as summarised in Scheme 1.6. Other fused heteroaromatic substrates were compatible with the reaction conditions, such as 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine 13, which provided the desired product 14 in 92% yield, with both high cis-diastereoselectivity (90% de) and enantioselectivity (92% ee), as shown in Scheme 1.6.

Scheme 1.6 Cyclopropanations of various fused heteroaromatic substrates with ethyl diazoacetate.

Chapter 110

1.2.1.2 With Porphyrin Cobalt ComplexesIn addition to salen-derived cobalt catalysts, cobalt(ii) porphyrin com-plexes29 have been proved by Zhang et al. to be general and efficient promo-tors for the diastereo- and enantioselective cyclopropanation of alkenes.24 For example, cobalt(ii) D2-symmetric porphyrins derived from chiral cyclopropanecarboxamide with tunable electronic, steric and chiral envi-ronments, such as 15, were successfully investigated at a 1 mol% catalyst loading in toluene at room temperature in the cyclopropanation of styrene with ethyl and t-butyl diazoacetates, resulting in the formation of the cor-responding trans-cycloadducts in high yields, diastereo- and enantiose-lectivities, as shown in Scheme 1.7.30 The authors showed that the use of 4-(N,N′-dimethylamino)pyridine (DMAp) as an additive allowed the enan-tioselectivities to be doubled and the production of the trans-isomer to be boosted, suggesting a significant trans influence of the potential coordi-nating ligands on the metal centre.31 A comparison between this catalytic system and iron, ruthenium and rhodium porphyrins, demonstrated that the common diazoacetate dimerisation side reaction was minimised within the cobalt systems, thus providing higher yields of cyclopropanes. More-over, cobalt-catalysed cyclopropanations did not require the slow addition of diazo reagents, a practical protocol that is atypical when using metal catalysts other than cobalt. In 2007, the scope of this methodology was extended to a broad range of styrene derivatives bearing various substitu-ents on the phenyl ring, such as methoxy, methyl, t-butyl, bromide, chloride, fluoride, acetate and trifluoromethyl groups, yielding the corresponding cyclopropanes in good yields and with diastereo- and enantioselectivities of up to >99% de and 98% ee, respectively.32 Through comparative studies, the authors demonstrated the superiority of cobalt over iron by performing the reactions with the same porphyrin ligand. Indeed, low to good yields (1–77%) associated with poor enantioselectivities (of up to 28% ee) were obtained with the corresponding iron complex. In addition, the authors found that similar reactions could be efficiently catalysed by vitamin B12 derivatives, such as aquocobalamin,33 which provided the corresponding cis-dominant cyclopropanes in excellent yields, albeit with moderate enan-tioselectivities (of up to 68% ee). A major advantage of the cobalt catalytic system is the complete suppression of diazoalkane dimerization (provid-ing undesired corresponding alkenes), which constitutes a problem, com-plicating the use of copper and most ruthenium and rhodium catalysts, and necessitating the use of syringe pumps. Over the last few years, a novel type of highly modular and readily accessible pincer ligands, chiral bis(pyr-idylimino)isoindoles, were developed by Gade et al. to induce chirality in cobalt-catalysed intermolecular cyclisations of aromatic alkenes with ethyl diazoacetate.34 Whereas the chirally modified pyridyl units acted as stereo-directing elements, the appropriate substitution pattern in the backbone provided a protective hedge against rearside attack on the metal centre. Their versatility as efficient stereodirecting ligands has been demonstrated


Scheme 1.7 Trans-selective cyclopropanation of mono- and 1,1-disubstituted alkenes with ethyl and tert-butyl diazoacetates.

Chapter 112

by the high enantioselectivities of up to 94% ee that were achieved for cyclopropanes arising from the corresponding monosubstituted alkenes, as shown in Scheme 1.7. In 2008, other cobalt chiral bis(binaphthyl) por-phyrin complexes, such as catalyst 16 (Scheme 1.7), were developed by Gallo et al. to promote the cyclopropanation of mono- and disubstituted alkenes with ethyl diazoacetate, giving the corresponding cyclopropanes.35 Good yields and low to moderate enantioselectivities of up to 71% ee were observed for the trans-major diastereomers combined with moderate dias-tereoselectivities (32–68% de), whereas low to high enantioselectivities of up to 90% ee were obtained for the cis-minor diastereomers.

While a number of catalytic systems worked exceptionally well with styrene derivatives and some electron-rich olefins, the asymmetric cyclo-propanation of electron-deficient olefins containing electron-withdraw-ing groups, such as α,β-unsaturated carbonyl compounds and nitriles, were proven to be a challenging problem presumably due to the electro-philic nature of the metal–carbene intermediates in the catalytic cycles. In this context, in 2007 Zhang et al. investigated the asymmetric cyclopro-panation of more challenging substrates, such as electron-deficient non- styrenic olefins, with ethyl and t-butyl diazoacetates using cobalt(ii) catalyst 15.36 Moderate to high yields (66–94%) combined with high trans-diastere-oselectivities of up to 98% de were achieved for a range of formed trans- cyclopropanated products, making this catalyst one of the most selective for the asymmetric cyclopropanation of olefins in general. The reactions were performed in toluene at room temperature in the presence of DMAp as an additive and only 1 mol% of catalyst 15. It must be noted that generally the lowest diastereo- and enantioselectivities were observed for the formation of 1,2-cyclopropane cyanoesters (24–52% de and 73–95% ee, respectively), whereas cyclopropanes derived from α,β-unsaturated ketones, esters or amides were obtained in uniformly high diastereoselectivities (90–98% de) in combination with enantioselectivities of up to 97% ee. Moreover, asymmetric cyclopropanation using acceptor/acceptor-substituted diazo reagents remains, however, a major challenge because of their inherent low reactivity and perceived poor enantioselectivity. In 2008, Zhang et al. applied a family of cobalt(ii) D2-symmetric porphyrins, derived from chi-ral cyclopropanecarboxamide with tunable electronic, steric and chiral environments, in the cobalt-catalysed cyclopropanations of styrenes with α-nitrodiazoacetates.37 Among these cobalt complexes, catalyst 15 proved to be the optimal catalyst, producing the corresponding chiral cis-cyclopro-pane α-nitroesters in moderate to excellent yields (51–98%), good to almost complete cis-diastereoselectivities (80–>98% de), and good to high enanti-oselectivities ranging from 82% to 95% ee, as shown in Scheme 1.8. It must be noted that typically challenging substrates, such as aliphatic alkenes, were also successfully converted into the corresponding cyclopropanes with low to good diastereoselectivities (12–84% de), moderate to good enantioselectivities (75–88% ee) combined with moderate to high yields (42–92%). It is interesting to note that, in this study, the cis-cyclopropanes


were the major diastereomers generated in contrast with most of the other studies in which the major products exhibited a trans-configuration.

Later in 2009, the same authors also reported the asymmetric cyclopro-panation of aliphatic as well as aromatic alkenes with another unusual diazo reagent, succinimidyl diazoacetate.38 The reaction was catalysed by 5 mol% of the same cobalt(ii) D2-symmetric chiral cyclopropyl porphyrin 15 in DMAp at room temperature, resulting in the formation of a range of chiral trans-cyclopropane succinimidyl esters in low to high yields (33–90%) and excellent trans-diastereo- and enantioselectivities of >98% de and 89–98% ee, respectively (Scheme 1.9). These results constituted the first asymmetric cyclopropanation of alkenes with succinimidyl diazoacetate and, moreover, it must be noted that the resulting chiral products constituted valuable syn-thons for the general synthesis of important chiral cyclopropyl carboxamide derivatives.

Scheme 1.8 Cis-selective cyclopropanation of alkenes with α-nitrodiazoacetates.

Chapter 114

In the context of asymmetric cobalt-catalysed cyclopropanations of alkenes with unusual diazo reagents, the same authors also developed a closely related methodology for the trans-cyclopropanation of alkenes with α-cyanodiazoacetates such as tert-butyl α-cyanodiazoacetate.39 In this case, the reaction was performed in hexane at −20 °C in the presence of 1 mol% of catalyst 15 (Scheme 1.10). even higher enantioselectivities of up to 99% ee were achieved for the corresponding densely functionalised chiral cyclo-propanes, which can be used in a myriad of potential synthetic and biologi-cal applications, in particular as precursors for chiral α-cyclopropyl-β-amino acids. Remarkably, a general almost complete trans-diastereoselectivity of >98% de was reached in all cases of the substrates studied, in combination with good to excellent yields (72–99%). It must be noted that this cobalt(ii)-based system represented the first successful example of using this class of acceptor/acceptor-substituted diazo reagents for the asymmetric cyclopro-panation processing of aliphatic as well as aromatic alkenes.

In 2011, the same authors developed the asymmetric cyclopropenation of terminal aromatic alkynes bearing varied steric and electronic proper-ties with various acceptor/acceptor-substituted diazo compounds, such as α-cyanodiazoacetates and α-cyanodiazoacetamides, which provided the corresponding chiral trisubstituted cyclopropenes in moderate to high yields (42–97%), and high enantiocontrol of the all-carbon quaternary ste-reogenic centre with enantioselectivities of 80–99% ee (Scheme 1.11).40 In this case, the reactions were performed in trifluorotoluene as solvent at room temperature or 40 °C with 1 mol% of the related chiral porphyrin cat-alyst 17. Under these reaction conditions, a remarkable degree of tolerance

Scheme 1.9 Trans-selective cyclopropanation of alkenes with succinimidyl diazoacetate.


of this catalyst toward various functionalities, including ChO, Oh, and Nh2 groups, was demonstrated.

In addition, the same authors successfully developed the cobalt-catalysed asymmetric cyclopropanation of alkenes with a range of other unusual diazo compounds, such as diazosulfones.41 In this aim, they designed the novel chiral porphyrin 18 that has enhanced rigidity and polarity of the chiral envi-ronment as a result of both intramolecular hydrogen bonding interactions and the use of cyclic structures. The application of this chiral porphyrin as a cobalt ligand to promote the asymmetric cyclopropanation of a range of aromatic and electron-deficient aliphatic alkenes with various diazosulfones provided the corresponding chiral cyclopropyl sulfones in good to excellent yields of up to 99%, excellent trans-diastereoselectivities of >98% de in almost all cases of the substrates studied, and general excellent enantioselectivities (90–97% ee) with one exception of lower diastereo- and enantioselectivities of 58% de and 61% ee, respectively, in the case of using acrylonitrile as the alkene substrate and N2ChTs as the diazo reagent. Remarkably, this nice novel one-pot practical protocol was atypical, because for many other cat-alytic cyclopropanation systems the slow addition of the diazo compounds was necessary to avoid the competitive carbene dimerisation side reaction. The results are shown in Scheme 1.12.

In 2017, Zhang et al. employed the chiral amidoporphyrin cobalt complex 15 to develop the first asymmetric cyclopropanation of alkenes using tert-butyl

Scheme 1.10 Trans-selective cyclopropanation of alkenes with tert-butyl α-cyanodiazoacetate.

Chapter 116

α-formyldiazoacetate.42 Indeed, complex 15 was found to be an effective cat-alyst for the activation of tert-butyl α-formyldiazoacetate, which reacted with both aromatic and aliphatic olefins with varying electronic properties to give the corresponding synthetically useful 1,1-cyclopropaneformylesters in moderate to quantitative yields (61–99%) and good to excellent enantioselec-tivities (77–99% ee). As illustrated in Scheme 1.13, these products were gen-erated in toluene at 40 °C in generally high trans-diastereoselectivities of up to >98% de except for 1,1,2-cyclopropaneformylester nitrile (R = CN) and the 1,1,2-cyclopropaneformyldiesters (R = CO2Me, CO2et), which were obtained with much lower diastereoselectivities (2–22% de).

Scheme 1.11 Cyclopropenation of alkynes with α-cyanodiazoacetates and α-cyanodiazoacetamides.


Scheme 1.12 Trans-selective cyclopropanation of alkenes with diazosulfones.

Scheme 1.13 Trans-selective cyclopropanation of alkenes with tert-butyl α-formyldiazoacetate.

Chapter 118

In the same year, donor-substituted diazo reagents, in situ generated from sulfonyl hydrazones in the presence of a base, such as Cs2CO3, were demon-strated for the first time by the same authors as suitable radical precursors for the enantioselective cobalt-catalysed cyclopropanation of alkenes.43 As shown in Scheme 1.14, a related chiral amidoporphyrin cobalt complex 19 was found to be an efficient catalyst capable of activating the N-tosyl hydra-zone 20a for asymmetric cyclopropanation of a broad range of alkenes, afford-ing, in methanol at 40 °C, the corresponding chiral trans-cyclopropanes in

Scheme 1.14 Trans-selective cyclopropanations of alkenes with sulfonyl hydrazones.


moderate to high yields (41–90%), diastereoselectivities (50–92% de) and enantioselectivities (77–99% ee). This catalytic system was also applied to the reaction between various arylsulfonyl hydrazones 20b–g and styrene, leading to the corresponding products in good to high yields (75–91%), uni-formly excellent trans-diastereoselectivities (90–>98% de) and moderate to excellent enantioselectivities (68–99% ee), as shown in Scheme 1.14 (second reaction scheme).

1.2.1.3 With Other Cobalt ComplexesIn 2008, excellent enantioselectivities (91–94% ee) combined with both high trans-diastereoselectivities (88–92% de) and yields (92–97%) were described by Gade et al. using another type of chiral cobalt catalyst, [Co(tetra-phenyl-carbpi) (OAc)] 21, in the cyclopropanation of monosubstituted alkenes with ethyl diazoacetate.34 The reaction was performed with a cat-alyst loading of 2 mol% in toluene at room temperature (Scheme 1.15). Not unexpectedly, this catalyst system was shown to be less efficient in the reaction of 1,1-disubstituted alkenes which provided the correspond-ing chiral trisubstituted cyclopropanes in lower yields (71–78%), and

Scheme 1.15 Trans-selective cyclopropanation of alkenes with ethyl diazoacetate catalysed by [Co(tetraphenyl-carbpi) (OAc)].

Chapter 120

trans-diastereoselectivities (≤50% de), as well as lower enantioselectivities (80–88% ee). These results constituted, however, the first study of chiral bis(pyridylimino)isoindole ligands in enantioselective catalysis using 3d-metal complexes.

1.2.2 Intramolecular CyclopropanationsAlthough not as well studied, intramolecular versions of the enantioselective cobalt-catalysed cyclopropanation of alkenes have been developed by sev-eral groups. For example in the 2000s, Katsuki et al. reported the synthesis of novel chiral salen cobalt(ii) complexes that proved to be very efficient for the intramolecular cyclopropanation of various (E)-2-alkenyl α-diazoacetates in the presence of NMI.44 As shown in Scheme 1.16, the cyclopropanation of (E)-(aryl)allyl diazoacetates into the corresponding chiral bicyclic products proceeded in good to excellent enantioselectivities of up to 98% ee using cat-alysts 22ab, while lower enantioselectivities (68% ee) were obtained in the case of the (Z)-(aryl)allyl diazoacetates. Later in 2008, Gade et al. employed another type of chiral cobalt catalyst, [Co(tetraphenyl-carbpi) (OAc)] 21, to the same intramolecular cyclopropanation, providing the products as single dias-tereomers in good yields and good to high enantioselectivities (65–94% ee), as shown in Scheme 1.16.34

Later, in 2014, these reactions were reinvestigated by Zhang et al. using chiral amidoporphyrin cobalt complex 15 as a catalyst.45 In the presence of DMAp as an additive in dichloromethane at room temperature, a series of (E)-2-alkenyl α-diazoacetates were converted into the corresponding chiral [3.1.0]bicyclic products as single diastereomers (>98% de) in moderate to excellent yields (62–95%) combined with moderate to good enantioselectivi-ties (63–86% ee), as shown in Scheme 1.17.

earlier in 2011, novel cobalt(ii) porphyrin complex 23, derived from a chiral cyclopropanecarboxamide containing two contiguous stereocentres, was designed by Zhang et al. and further applied as a promotor in an orig-inal asymmetric intramolecular cyclopropanation of a range of α-acceptor- substituted allylic diazoacetates 24.46 This highly efficient novel methodol-ogy, for the first time, allowed the transformation of α-acceptor-substituted diazoacetates into enantioenriched 3-oxabicyclo[3.1.0]hexan-2-one deriva-tives 25 bearing three contiguous stereocentres with multiple functional-ities. As shown in Scheme 1.18, moderate to quantitative yields (73–99%) combined with excellent trans-diastereoselectivities of up to >98% de and moderate to excellent enantioselectivities (73–99% ee) were obtained for the cyclopropanation of a range of cinnamyl diazoesters bearing a sub-stituent at the α-position, which was an acceptor functional group such as a cyano, a nitro or an ester group, achieving the best results, but also a hydrogen or methyl group, which provided enantioselectivities of 99 and 73% ee, respectively. In addition to cinnamyl diazoesters, a series of allylic α-cyanodiazoacetates were successfully converted into the corresponding chiral bicyclic products in moderate to quantitative yields (51–99%), high


Scheme 1.16 Intramolecular cyclopropanation of (E)/(Z)-2-alkenyl α-diazoacetates catalysed by a salen cobalt(ii) complex and [Co(tetraphenyl-carbpi) (OAc)].

Chapter 122

trans-diastereoselectivities (>98% de) and good to excellent enantioselectivities (78–98% ee).

1.3 Aziridinations and Epoxidations1.3.1 AziridinationsAziridines are among the most fascinating intermediates in organic synthe-sis, acting as the precursors for many complex molecules due to the strain incorporated in their skeletons. The high strain energy associated with the aziridine ring enables easy cleavage of the C–N bond. Therefore, aziridines can either undergo ring-cleavage reactions with a range of nucleophiles or cycloaddition reactions with dipolarophiles, providing access to a wide range of important nitrogen-containing products.4b,d,47 however, they are less widely used in synthesis than their oxygen counterparts, partly because there are fewer efficient methods for aziridination relative to epoxidation.

Scheme 1.17 Intramolecular cyclopropanation of (E)-2-alkenyl α-diazoacetates cata-lysed by a porphyrin cobalt(ii) complex.


This is particularly true when enantioselective methods are considered.48 Obtaining optically active aziridines has become of major importance in organic chemistry for many reasons, including the antitumor and anti-biotic properties, among other biological activities, of a great number of aziridine-containing compounds.49 Nitrogen-atom transfer to alkenes is a particularly appealing strategy for the generation of aziridines because of the ready availability of the olefinic starting materials and the direct nature of such a process.

In addition to catalytic systems using copper, rhodium or ruthenium,50 in 2008, Zhang et al. demonstrated that cobalt was able to promote the asym-metric aziridination of styrenes using diphenylphosphoryl azide 26 as the nitrene source, affording the corresponding N-phosphorylated aziridines.51

Scheme 1.18 Intramolecular cyclopropanation of α-acceptor-substituted allylic diazo acetates catalysed by a porphyrin cobalt(ii) complex.

Chapter 124

The reaction was carried out in the presence of D2-symmetric chiral porphy-rins, such as 15, and was applied to a wide variety of styrenes, giving the corresponding enantioenriched aziridines in good yields combined with moderate enantioselectivities of up to 53% ee, as shown in Scheme 1.19. A higher enantioselectivity of 71% ee was reached by using 20 mol% of the same catalyst in the presence of DMAp as an additive in dichloromethane solvent, albeit combined with a low yield of 20%.

Later in 2014, the related chiral D2-symmetric amidoporphyrin cobalt cat-alyst 27 was applied by the same authors to promote the asymmetric azirid-ination of styrenes with another phosphoryl azide.52 This novel catalyst was compatible in benzene at 35 °C for a range of variously substituted styrenes, which provided by reaction with bis(2,2,2-trichloroethyl)phosphoryl azide 28, the corresponding chiral N-phosphorylaziridines in moderate to quan-titative yields (64–99%) and low to good enantioselectivities (23–85% ee), as shown in Scheme 1.20.

Scheme 1.19 Aziridination of styrenes with a diphenylphosphoryl azide.


earlier in 2009, enantioselectivities of up to 94% ee were reported by the same authors in the asymmetric aziridination of a range of aromatic, as well as aliphatic, monosubstituted alkenes with trichloroethoxysulfonyl azide 29 using cobalt(ii)-chiral rigid and polar porphyrin 18 catalysts.53 The process provided the corresponding chiral aziridines in both high yields (82–93%) and enantioselectivities (80–99% ee) when monosubstituted aromatic alkenes were used as the substrates, whereas monosubstituted aliphatic alkenes produced the corresponding aziridines in lower yields (26–42%) but with comparable high enantioselectivities (91–94% ee), as shown in Scheme 1.21. The scope of this methodology could be extended to aliphatic dienes, such as 2,3-dimethylbutadiene, which afforded the corresponding disubstituted aziridine in 53% yield and 87% ee. It must be highlighted that this work presented the first highly effective and enantioselective catalytic system for asymmetric aziridination of a broad range of olefins, without needing additional functionalities in the substrates for secondary binding interactions.

In 2017, chiral D2-symmetric amidoporphyrin cobalt catalyst 23 was applied by the same authors to develop the first enantioselective radical aziridination of allyl azidoformates.54 The reaction, when performed in chlorobenzene at

Scheme 1.20 Aziridination of styrenes with bis(2,2,2-trichloroethyl)phosphoryl azide.

Chapter 126

40 or 80 °C, led to the corresponding chiral aziridine/oxazolidinone-fused bicyclic products as single diastereomers (99% de) in excellent yields (>90–99%) and moderate to excellent enantioselectivities (70–>99% ee), as shown in Scheme 1.22.

1.3.2 EpoxidationsChiral epoxides constitute key building blocks for the synthesis of a num-ber of important products.4b,d,5c In particular, the asymmetric epoxidation of α,β-unsaturated carbonyl compounds represents a challenging transfor-mation in synthesis.55 In this context, Belokon et al. have described the use of chiral positively charged cobalt complex 30 for catalysing the asymmet-ric epoxidation of chalcones with h2O2 under phase transfer conditions.56 Indeed, treatment of a variety of chalcones with a 30% aqueous solution of h2O2 in the presence of 10 mol% of catalyst 30 and t-BuOK as a base in methyl tert-butyl ether (MTBe) at room temperature led to the correspond-ing chiral epoxides with moderate to complete conversions (50–99%) and moderate enantioselectivities (35–55% ee), as shown in Scheme 1.23.

Scheme 1.21 Aziridination of alkenes with trichloroethoxysulfonyl azide.

Scheme 1.22 Intramolecular aziridination of allyl azidoformates.

Scheme 1.23 epoxidation of chalcones.

Chapter 128

1.4 ConclusionsThis chapter illustrates how enantioselective cobalt catalysis is growing rap-idly in the development of enantioselective ecological and economical for-mations of three-membered (hetero)cycles, generally performed under mild conditions with low catalyst loadings, illustrating the power of these green catalysts, with lower costs and unique properties, in reaching remarkable enantioselectivities, even if this field is still in its infancy. For example, a steadily growing number of asymmetric cobalt-catalysed cyclopropanations have been developed, based on the extraordinary ability of cobalt catalysts to adopt unexpected reaction pathways.

Indeed, since the first highly enantioselective cobalt-catalysed cyclopro-panation reaction described by Nakamura in 1978, a range of chiral cobalt complexes, predominantly based on salen or porphyrin chiral ligands, have been successfully applied to these reactions. Using salen cobalt complexes, excellent enantioselectivities of up to 99% ee were reported for trans- selective as well as rarer cis-selective cyclopropanations of mono- but also 1,1-disub-stituted alkenes using alkyl diazoacetates. An unusual diazo compound pre-cursor, CF3Ch2Nh3Cl, also provided high enantioselectivities of up to 94% ee in the asymmetric synthesis of trans-disubstituted cyclopropanes. Fur-thermore, a very rare example of the catalytic asymmetric cyclopropanation of aromatic double bonds was recently reported with the dearomatisation of a range of electron-deficient nitrogen heterocycles, such as imidazopy-razine, imidazopyridazine and 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine derivatives, leading to many chiral polynitrogenated heterocycles with up to 98% ee. The second type of chiral cobalt complexes derived from por-phyrin ligands also successfully promoted the trans-selective cyclopropana-tions of mono- and 1,1-disubstituted alkenes with usual alkyl diazoacetates, with excellent enantioselectivities of up to 98% ee. Notably, the special use of porphyrin cobalt complexes has led to innovative methodologies based on the use of a variety of unusual diazo compounds. Among them are the first asymmetric trans-selective cyclopropanation of alkenes with succin-imidyl diazoacetates, with 97% ee, the first enantioselective trans- selective cyclopropanation of alkenes with α-formyldiazoacetates, with 99% ee, and the first enantioselective cobalt-catalysed trans-selective cyclopro-panation of alkenes using donor-substituted diazo reagents, such as those derived from sulfonyl hydrazones, achieving 99% ee. Comparable enantio-selectivities were also reported using other unusual diazo reagents for the trans-cyclopropanation of aliphatic and aromatic alkenes, such as α-cyan-odiazoacetates, constituting the first successful example of using acceptor/acceptor-substituted diazo reagents. Moreover, rare examples of the cis- selective cyclopropanation of alkenes have been reported, among them that involving α-nitrodiazoacetate as a diazo compound, which was performed with 95% ee. The use of porphyrin cobalt complexes also allowed the devel-opment of asymmetric cyclopropenations of terminal aromatic alkynes bearing varying steric and electronic properties, with α-cyanodiazoacetates


and α-cyanodiazoacetamides, providing chiral trisubstituted cyclopropenes with high enantiocontrol of the all-carbon quaternary stereogenic centre, with enantioselectivities of up to 98% ee. In the area of the intramolecular versions of cobalt-catalysed cyclopropanations, that of a range of α-acceptor- substituted allylic diazoacetates allowed for the first time the transformation of α-acceptor-substituted diazoacetates into enantioenriched 3-oxabicy-clo[3.1.0]hexan-2-one derivatives bearing three contiguous stereocentres with multiple functionalities, with enantioselectivities of up to 99% ee. In the field of asymmetric cobalt-catalysed aziridinations, important results have also been described using porphyrin cobalt chiral catalysts. For exam-ple, the first highly effective and enantioselective aziridination of a broad range of aromatic and aliphatic alkenes, not especially exhibiting additional functionalities in the substrates for secondary binding interactions, with trichloroethoxysulfonyl azide was developed, with up to 99% ee. The same excellent level of enantioselectivity was also reported for the first enantiose-lective cobalt-catalysed intramolecular aziridination of allyl azidoformates. All of these novel procedures have greatly improved the structural scope and synthetic utility of cobalt-catalysed enantioselective [2+1] cycloaddi-tions, providing enantioselective access to various functionalised important three-membered (hetero)cyclic compounds with remarkable enantioselec-tivities, often reaching 99% ee. In the near future, progress is expected on the investigation of other types of catalyst systems, which have been limited to salen and porphyrin derivatives so far. This would probably allow cycload-ditions of even more challenging substrates, such as highly substituted sub-strates, to be achieved. Furthermore, the development of more applications in the total synthesis of natural products and bioactive compounds are also awaited. Great efforts are also expected in the field of asymmetric cobalt- catalysed epoxidations, which has been very underdeveloped thus far. even over a century after the synthesis of the first cyclopropane derivative, the synthesis of chiral three-membered rings, widespread in natural and bio-logically active compounds, remains a considerable challenge. however, a bright future is undeniable, with the development of novel environmentally friendly catalytic systems based on a more abundant first–row transition metal, such as cobalt.

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34


2.1 Enantioselective Cobalt-Catalysed (Hetero)-Diels–Alder Cycloadditions

2.1.1 Diels–Alder CycloadditionsFew reactions can compete with the Diels–Alder cycloaddition with respect to the degree of structural complexity that can be achieved in a single syn-thetic step.1 Extensively studied over many decades, this versatile reaction remains one of the most frequently employed synthetic methods for the ste-reospecific construction of six-membered ring systems. The high regio- and stereoselectivities typically displayed by this pericyclic process and its ease of execution have contributed toward its popularity.2 Its thermal uncatalysed versions sometimes require harsh reaction conditions in order to be success-ful, and consequently a number of methods have been developed to over-come this obstacle, such as transition-metal catalysis.3 In recent years, many chiral catalysts, in addition to chiral auxiliaries, have been developed for achieving asymmetric products with very high levels of selectivity.3,4 Among them, however, only very few excellent works focussing on asymmetric Diels–Alder reactions induced by chiral cobalt complexes have been reported so far. As an example, in 1998 Kanemasa et al. employed a cationic chiral aqua complex derived from a trans-chelating tridentate ligand, (R,R)-4,6-diben-zofurandiyl-2,2′-bis-(4-phenyloxazoline) (DBFOX/Ph) and cobalt(ii) per-chlorate to induce the Diels–Alder cycloaddition of cyclopentadiene with

ChAPTEr 2

Other Enantioselective Cobalt-catalysed Cycloadditions

35Other Enantioselective Cobalt-catalysed Cycloadditions

3-acryloyl-2-oxazolidinone.5 As shown in Scheme 2.1, the corresponding cyc-loadduct was achieved in excellent yield (97%), high endo-diastereoselectivity (94% de) and remarkable enantioselectivity (99% ee).

Later, rawal et al. designed highly efficient chiral salen cobalt(iii) com-plexes, such as 1, to promote the Diels–Alder cycloaddition reaction between a carbamate-substituted diene and α,β-unsaturated aldehydes.6 As illustrated in Scheme 2.2, the corresponding chiral cycloadducts were formed in high to quantitative yields (78–>99%) and high to excellent enantioselectivities (85–98% ee). Notably, these reactions were conveniently performed at 0 °C or even at room temperature, under an air atmosphere, using a minimum amount of solvent. A drawback of the process was, however, its narrow scope, since only one diene and a few simple aldehydes were compatible.

A number of total syntheses of important natural products involve an asymmetric Diels–Alder reaction as a key step, among them that of the anti-biotic (−)-platencin. This novel synthesis, reported by Nicolaou et al. in 2009, is based on the related enantioselective Diels–Alder cycloaddition of a func-tionalised diene with a α,β-unsaturated aldehyde catalysed by closely related chiral salen cobalt(iii) catalyst 2, providing the corresponding densely func-tionalised cycloadduct in both excellent yield (97%) and enantioselectivity (96% ee), as shown in Scheme 2.3.7 This key, almost enantiopure product, was further converted through nine steps into the final (−)-platencin.

In 2011, the same salen catalyst 2 was employed by Brimble et al. to pro-mote a Diels–Alder cycloaddition to synthesise a chiral functionalised cyclo-hexene, which constituted a key intermediate in the asymmetric synthesis of

Scheme 2.1 Diels–Alder reaction of cyclopentadiene with 3-acryloyl-2-oxazolidinone.

Chapter 236

a tetracyclic alkaloid methyllycaconitine analogue.8 As shown in Scheme 2.4, the reaction occurred between another functionalised α,β-unsaturated alde-hyde and a dienamine to give the corresponding key cycloadduct constituting the B ring of the natural product in good yield (81%) with an enantioselectiv-ity of 80% ee. The subsequent elaboration to form the A, E and F rings of the final product was achieved by sequential Dieckmann, Mannich and Wacker-type cyclisations to afford tetracyclic methyllycaconitine analogues.

2.1.2 Hetero-Diels–Alder CycloadditionsThe asymmetric hetero-Diels–Alder reaction is one of the most efficient syn-thetic methodologies for the regio- and stereoselective construction of chi-ral six-membered heterocycles.3a,9 It must be noted that very few examples of enantioselective cobalt-catalysed hetero-Diels–Alder reactions have been reported so far. Among them, in 1998 Wu et al. described the enantioselective hetero-Diels–Alder cycloaddition of 1-(2-benzyloxyethyl)-3-(tert-butyldimeth-ylsilyl)oxy-1,3-butadiene with methyl glyoxylate catalysed by 10 mol% of a chiral salen cobalt(ii) catalyst 3, which provided the corresponding cycload-duct in 75% yield with an excellent endo:exo ratio of >99 : 1, albeit combined with a moderate enantioselectivity of 52% ee.10 In 2004, the same catalyst

Scheme 2.2 Diels–Alder reaction of a carbamate-substituted diene with α,β-unsatu-rated aldehydes.


was applied by Jurczak et al. to induce the high-pressure (10–11 kbar) Diels–Alder cycloaddition of 1-methoxybuta-1,3-diene with tert-butyldimethylsily-loxyacetaldehyde to provide the corresponding cis-cycloadduct in 52% yield with a cis-diastereoselectivity of 90% de and an enantioselectivity of 94% ee (Scheme 2.5).11 In this study, the authors compared the catalytic efficiency of salen cobalt(ii) catalyst 3 with the corresponding chromium(iii)Cl salt under the same high-pressure conditions, and found that use of the cobalt cata-lyst resulted in higher enantioselectivities and lower yields and comparable cis-selectivity in comparison with the chromium catalyst.

Earlier, Yamada et al. developed novel chiral salen cobalt(iii) complexes as effective catalysts for the enantioselective hetero-Diels–Alder cycloaddi-tion of various aryl and alkyl aldehydes with 1-methoxy-[3-(tert-butyldimeth-ylsilyl)oxy]-1,3-butadiene (Scheme 2.6).12 Among these catalysts, cationic cobalt(iii) triflate complex 4 proved to be the optimal catalyst for providing the corresponding chiral cycloadducts in good to high yields (69–94%) and high general enantioselectivities (81–94% ee), as shown in Scheme 2.6. The

Scheme 2.3 Diels–Alder reaction of a functionalised dienamine with a α,β-unsatu-rated aldehyde in the total synthesis of (−)-platencin.

Chapter 238

addition of molecular sieves to the reaction was found to improve both the yield and enantioselectivity of the reaction. The authors also investigated various other metal complexes of the optically active 3-oxobutylideneami-nato ligand. The use of titanium(iv), aluminum(iii), copper(ii), chromi-um(iii), manganese(iii), nickel(ii), as well as oxovanadium(iv) complexes led to (almost) racemic cycloadducts obtained in low yields, whereas the corresponding cobalt(ii) catalyst provided a good enantioselectivity of 62% ee associated with an excellent yield of 96% under the same non-optimised reaction conditions. These authors reported a theoretical analysis of this

Scheme 2.4 Diels–Alder reaction of a carbamate-substituted diene with a function-alised α,β-unsaturated aldehyde in the total synthesis of methyllycaco-nitine analogues.


Scheme 2.5 high-pressure hetero-Diels–Alder reaction of 1-(2-benzyloxyethyl)-3- (tert-butyldimethylsilyl)oxy-1,3-butadiene with methyl glyoxylate.

Scheme 2.6 hetero-Diels–Alder reaction of 1-methoxy-[3-(tert-butyldimethylsilyl)oxy]-1,3-butadiene with aldehydes.

Chapter 240

reaction, which revealed the crucial role of the aldehyde coordination as an axial ligand on the spin states and Lewis acidity of the cobalt complexes, leading to an improving in the enantioselectivity.13 Moreover, they showed that an increase in the cationic character of the cobalt atom resulted in a decrease in the activation energy, and that a spin transition between the trip-let and singlet states occurred in the cobalt(iii) catalytic cycle, according to a density functional theory (DFT) study.

2.2 Enantioselective Cobalt-Catalysed 1,3-Dipolar Cycloadditions

The 1,3-dipolar cycloaddition, also called the huisgen cycloaddition,14 is a classic reaction in organic chemistry consisting of the reaction of a dipolaro-phile with a 1,3-dipolar compound that allows the production of five-mem-bered heterocycles.15 The transition state of the concerted 1,3-dipolar cycloaddition reaction is controlled by the frontier molecular orbitals of the substrates. hence, the reaction of dipoles with dipolarophiles involves either a hOMO-dipole/LUMO-dipolarophile interaction (normal-electron-demand reaction), or a LUMO-dipole/hOMO-dipolarophile reaction (inverse-elec-tron-demand reaction), depending on the nature of the dipole and the dipo-larophile. In some cases, when the frontier molecular orbital energies of the dipole and the dipolarophile are very similar, a combination of both modes of interactions can occur. These interactions can also be referred to as either exo or endo, where the endo transition state is stabilised by small secondary π-orbital interactions or via an exo-transition state lacking such a stabilisa-tion. however, steric effects can also be important factors for the endo/exo selectivity and override the secondary orbital interactions.16 Depending on the substitution pattern in the reacting partners, the stereochemical outcome of the process gives rise to either the endo- or exo-cycloadducts. Moreover, the presence of a metal, such as a Lewis acid, in 1,3-dipolar cyc-loaddition reactions can alter both the orbital coefficients of the reacting atoms and the energy of the frontier orbitals of both the 1,3-dipole or the dipolarophile, depending on the electronic properties of these reagents or the Lewis acid. In particular, the coordination of a Lewis acid to one of the two partners of the cycloaddition is of fundamental importance for asym-metric 1,3-dipolar cycloadditions, since the metal can catalyse the reaction. Furthermore, the Lewis acid may also have an influence on the selectivity of the cycloaddition reaction, since the regio-, diastereo-, and enantioselectiv-ity can all be controlled by the presence of a metal–ligand complex. A vari-ety of enantioselective versions of this reaction have successfully used chiral cationic cobalt(iii) complexes as chiral catalysts. For example, Yamada et al. have employed highly efficient catalyst 5 for the enantioselective 1,3-dipo-lar cycloaddition reaction between α,β-unsaturated aldehydes with nitrones (Scheme 2.7).17 Even in the case of α-substituted α,β-unsaturated aldehydes, the corresponding cycloadducts were obtained completely regioselectively, endo-selectively, and in good to high enantioselectivities of up to 92% ee. As


shown in Scheme 2.7, the ratio of regioisomers was in the region of >99 : 1 in almost all cases of the substrates studied, as well as the endo/exo ratio. Later, the same authors employed a closely related cationic cobalt(iii) cat-alyst to promote the enantioselective 1,3-dipolar cycloaddition reaction of dihydrofuran with nitrones bearing an electron-withdrawing group, which

Scheme 2.7 1,3-Dipolar cycloaddition of nitrones with α,β-unsaturated aldehydes.

Chapter 242

led to the corresponding cycloadducts in moderate to high yields (40–87%), high to excellent endo-selectivity (28–>98% de), albeit combined with low to moderate enantioselectivities (6–73% ee).18

In 2004, Kanemasa et al. employed another type of chiral cobalt catalyst derived from a trans-chelating tridentate ligand, tetraphenyl-DBFOX/Ph, and Co(BF4)2 to promote the enantioselective 1,3-dipolar cycloaddition of N-ben-zylideneaniline N-oxide with α-bromoacrolein at room temperature.19 As shown in Scheme 2.8, the corresponding cycloadduct was obtained in 92% yield with remarkable diastereo- and enantioselectivities of >98% de and 98% ee, respectively.

In the same year, Tang et al. reported the first example of an enantiose-lective cycloaddition between various nitrones and alkylidene malonates.20 This reaction was promoted by a chiral cobalt catalyst in situ generated from Co(ClO4)2·6h2O and chiral trioxazoline 6, providing the corresponding chi-ral isoxazolidines with both high enantioselectivities and high exo-dias-tereoselectivities of up to >98% de and 98% ee, respectively (Scheme 2.9). Surprisingly, the authors found that by simply changing the temperature of the reaction, both the cis- and trans-cycloadducts could be prepared with high enantioselectivities. Indeed, performing the process at 0 °C led to trans-products whereas the corresponding cis-products were produced when the reaction was carried out at −40 °C. On the basis of experimental studies, it was demonstrated that the reaction to form cis-isoxazolidines was revers-ible and subject to kinetic control at −40 °C. In the case of the reaction at 0 °C, the cycloaddition was subject to thermodynamic control, favoring the trans-isomers.

Scheme 2.8 1,3-Dipolar cycloaddition of N-benzylideneaniline N-oxide with α-bromoacrolein.


Scheme 2.9 1,3-Dipolar cycloaddition of nitrones with alkylidene malonates.

Chapter 244

Later in 2017, Feng and Liu investigated the 1,3-dipolar cycloaddition of nitrones with methyleneindolinones by using a chiral N,N′-dioxide ligand such as 7.21 As shown in Scheme 2.10, the use of a combination of 10 mol% of Co(BF4)2(6h2O) and 10 mol% of ligand 7 as a catalytic system in ethyl ace-tate at 0 °C allowed the [3+2] cycloaddition of a wide variety of nitrones with methyleneindolinones to give the corresponding chiral multisubstituted spiroisoxazolidines, exhibiting three contiguous quaternary/tertiary stereo-centres in almost all cases, as single diastereomers (>90% de) in moderate to quantitative yields (45–99%) and uniformly high enantioselectivities (90–99% ee). In only four cases of substrates (r3 = p-IC6h4 or Cy, r4 = Me or p-Tol), the diastereoselectivities of the reaction were slightly lower (80–88% de).

In 2012, Cheng et al. reported an enantioselective cobalt-catalysed reduc-tive [3+2] cycloaddition of various alkynes with cyclic enones, which led to the corresponding chiral bicyclic tertiary alcohols with high regioselectivity (Scheme 2.11).22 When the reaction was promoted by a chiral cobalt com-plex in situ generated from CoI2 and (R,R,S,S)-Duanphos in the presence of Zn as a mild reducing agent in 1,4-dioxane, it allowed a range of chiral cyc-loadducts to be achieved in good yields (50–76%) and moderate to excellent

Scheme 2.10 1,3-Dipolar cycloaddition of nitrones with methyleneindolinones.


Scheme 2.11 1,3-Dipolar cycloaddition of alkynes with cyclic enones.

Chapter 246

enantioselectivities (64–>99% ee). The process was initiated by the reduction of the cobalt(ii) catalyst formed from CoI2 and (R,R,S,S)-Duanphos by zinc into the corresponding cobalt(i) species, which then coordinated the alkyne and the enone to undergo the cycloaddition. A reaction mechanism that accounts for the absolute configuration of the (S,S)-product arising from the reaction of diphenylacetylene with 2-cyclohexenone has been proposed by the authors and is depicted in Scheme 2.11. The reaction was likely initiated by the reduction of cobalt(ii) to cobalt(i) species A by zinc dust. The reaction proceed via the coordination of the alkyne in the equatorial position and the cyclic enone with its Si face in the axial position of the cobalt(i) centre to form intermediate B followed by oxidative cyclisation to give the cobal-tacyclopentene intermediate C. Selective protonation at the α-carbon to the keto group of C generates intermediate D. Then, a carbonyl insertion into the cobalt–carbon bond results in the formation of the cobaltalkoxide E. reduc-tion of the latter by zinc dust provides intermediate F and regenerates the cobalt(i) species. Finally, the hydrolysis of F in air affords the final product.

In a recent example, Feng and Liu developed highly efficient catalytic asymmetric [3+2] cycloadditions of 5-alkoxyoxazoles with azodicarboxylates performed in dichloromethane at 35 °C in the presence of another type of chiral cobalt catalysts derived from chiral N,N′-dioxides.23 The latter was in situ generated from 10 mol% of Co(BF4)2(6h2O) and the same quantity of chiral N,N′-dioxide 8 or 9. As shown in Scheme 2.12, the catalytic systems tolerated a range of variously substituted 5-alkoxyoxazoles, which led to the corresponding multisubstituted chiral 1,2,4-triazolines in moderate to quan-titative yields (70–99%) and high enantioselectivities (82–98% ee).

2.3 Enantioselective Cobalt-catalysed [2+2+2] and [2+2+1] Cycloadditions

2.3.1 [2+2+2] CycloadditionsThe transition metal-catalysed [2+2+2] cycloaddition of unsaturated motifs, such as alkynes and alkenes, constitutes the most atom-economical and fac-ile protocol for the construction of functionalised arenes.24 Among these pro-cesses, the enantioselective [2+2+2] cycloaddition is a fascinating protocol for the construction of chiral cyclic skeletons.25 In 1990, Lautens26 and Brun-ner27 independently reported, almost at the same time, the first highly enanti-oselective cobalt-catalysed [2+2+2] cycloadditions performed in the presence of chiral phosphines. These processes occurred between norbornadiene and acetylenic compounds, leading to the formation of the corresponding chi-ral monosubstituted deltacyclenes in good yields and enantioselectivities of up to 98% ee. The effective catalysts were obtained upon reduction of Co(a-cac)3 with Et2AlCl in the presence of chiral ligands, such as (S,S)-Chiraphos or (+)-Norphos, respectively. Using (S,S)-Chiraphos as a chiral ligand, Lautens et al. reported yields of up to 85% in combination with enantioselectivities of up to 91% ee, while using (+)-Norphos, Brunner obtained a quantitative yield


combined with an enantioselectivity of >98% ee for the deltacyclene arising from the reaction of norbornadiene with phenylacetylene. Later, Buono et al. demonstrated that these reactions could be catalysed by a new catalytic system [CoI2/Zn/L*] based on chiral organophosphorus bidentate ligands (L*) such as (S)-(+)-ValNOP.28 As shown in Scheme 2.13, a range of variously monofunctionalised deltacyclenes could be achieved from the correspond-ing acetylenic and propargylic compounds in low to quantitative yields (24–99%) and high to excellent enantioselectivities of up to >97% ee. The authors demonstrated that both the yields and enantioselectivities were highly depen-dent on the reaction temperature, with the best results reached at around 14 °C. The authors proposed the two-step process depicted in Scheme 2.13 to explain the formation of the products. It involves the reversible formation of two diastereomeric five pentacoordinated cobalt intermediates G and ent-G, which can equilibrate according to Berry pseudorotation,29 and the Turn-stile rotation mechanism.30 The low energy barriers for the interconversion between G and ent-G, associated with the high energy difference between these highly substituted structures as a result of the substitution patterns, could be responsible for the high enantioselectivity observed.

Scheme 2.12 1,3-Dipolar cycloaddition of 5-alkoxyoxazoles with azodicarboxylates.

Chapter 248

The synthesis of axially chiral biaryls has attracted much attention over the last few decades due to the emergence of a large number of natural products containing structures exhibiting a stereogenic biaryl axis, chiral auxiliaries, and ligands. In this context, Gutnov et al. investigated the cobalt-catalysed asymmetric [2+2+2] cycloaddition of alkynes with nitriles such as 2-substi-tuted 1-naphthonitriles.31 To promote this reaction, the authors screened tartrate-derived and methyl-derived chiral cobalt(i) complexes and it was found that catalyst 10 was the optimal catalyst for the reaction. Therefore, in the presence of 10 mol% of this catalyst in ThF at 20 °C, the reaction of 2-substituted 1-naphthonitriles with two equivalents of alkynes led to the

Scheme 2.13 [2+2+2] Cycloaddition of norbornadiene with alkynes.


corresponding 2-arylpyridines in low yields (3–11%) and moderate enan-tioselectivities (40–64% ee). When 2-substituted 1-naphthonitriles were reacted with dialkynes, the corresponding 2-arylpyridines were achieved in even lower enantioselectivities of (7–33% ee). On the other hand, the same authors developed a novel route to axially chiral 1-aryl-5,6,7,8-tetrahydro-quinolines on the basis of a cobalt-catalysed [2+2+2] cycloaddition occurring between 1-aryl-1,7-octadiynes and nitriles.32 As shown in Scheme 2.14, the process was catalysed by planar chiral (1-neomenthylindenyl)cobalt(cod) complex 10 under photochemical conditions, allowing the formation of various axially chiral 2-arylpyridines to be achieved from the reaction of the corresponding 1-naphthyldiynes with a range of differently functionalised nitriles. Thus, various enantioenriched tetrahydroquinolines were formed in low to good yields (9–86%) and low to high enantioselectivities (22–94% ee). Moreover, the authors investigated the synthesis of biaryls possessing a five-membered ring annulated at the pyridine moiety and found that the size of the ring was too small to prevent the slippage of the rings around the biaryl axis due to the presence of the ring nitrogen, and consequently no enantioselectivity was observed in this case.

Later in 2016, hapke et al. investigated the related chiral bisphosphite cobalt complex 11 under comparable heating conditions (50 °C) with various nitriles, which led to the formation of the corresponding biaryl products in

Scheme 2.14 Photochemical [2+2+2] cycloaddition of naphthyldiynes with nitriles.

Chapter 250

the presence of 5 or 10 mol% catalyst loading (Scheme 2.15).33 In this case, the products were obtained in lower yields (20–22%) and moderate to good enantioselectivities (66–80% ee), demonstrating that the photochemical acti-vation improved the yields compared to the thermal reaction.

Furthermore, these authors described the first enantioselective cobalt-ca-talysed intramolecular [2+2+2] cycloaddition of triynes, depicted in Scheme 2.16.34 The reaction was promoted in ThF at 25 °C by catalyst 12, derived from the (R,R)-N-PINAP ligand, and led to the formation of variously sub-stituted chiral tricyclic products in moderate to excellent yields (32–>95%), and low to moderate diastereo- (10–46% de), and enantioselectivities (7–78% ee). The substrate scope of the process included malonate- as well as ether-bridged triynes.

2.3.2 [2+2+1] CycloadditionsOver the past two decades, the Pauson–Khand reaction, allowing the prepa-ration of a 2-cyclopentenone on the basis of a [2+2+1] cyclocarbonylation of an alkyne with an alkene to be achieved, has attracted great attention from the synthetic chemistry community.35 Since the discovery of the first cata-lytic version reported in 1990,36 various types of chiral metal catalysts based on iron, nickel, titanium, zirconium, ruthenium, rhodium, and iridium have been applied to promote enantioselective Pauson–Khand reactions and reac-tion pathways involving milder conditions have been developed so far.37 More-over, the scope of the olefin substrates has been widened by the discovery

Scheme 2.15 Thermal [2+2+2] cycloaddition of a naphthyldiyne with nitriles.


of alkene equivalents, such as dimethyl(pyridyl) (vinyl)silane, o-(dimethyl-amino)phenyl vinyl sulfoxide, and 2,3-disubstituted 1,3-butadiene. Nowa-days, the Pauson–Khand reaction is recognised as one of the most important reactions in the synthetic arsenal for the preparation of five-membered compounds, including cyclopentenones.38 In 2000, hiroi et al. reported the first example of a catalytic asymmetric synthesis of 2-cyclopentenone deriv-atives based on the use of cobalt catalysts derived from chiral phosphines.39 As shown in Scheme 2.17, the intramolecular Pauson–Khand reaction of 1,6-enynes (X = C(CO2Me)2) under a carbon monoxide atmosphere, using (S)-BINAP as the most effective ligand of Co2(CO)8, provided the corresponding 2-cyclopentenone derivatives in moderate yields (31–53%) and enantioselec-tivities (63–90% ee). The scope of the reaction was extended to sulfonamides (X = NSO2-p-Tol) which led under the same reaction conditions to the corre-sponding bicyclic products in low to moderate yields (13–54%) with mod-erate to high enantioselectivities (62–94% ee) (Scheme 2.17). Later, Gibson et al. investigated the mechanism of this reaction, isolating and identifying through X-ray crystallographic analysis a hexacarbonyldicobalt(0) complex in which BINAP is bound to just one of the two cobalts as a precatalyst.40 In 2002, Buchwald and Sturla demonstrated that moderate enantioselectivities of up to 75% ee were obtained in comparable reactions using chiral aryl bis-phosphite ligands.41 In 2004, enantioselectivities of up to >91% ee combined with high yields of up to 95% were reported by Consiglio et al. employing (R)-MeO-BIPhEP as a chiral ligand of Co2(CO)8 in the cyclocarbonylation of 4,4-bis(carboethoxy)hex-6-en-1-yne.42

Scheme 2.16 Intramolecular thermal [2+2+2] cycloaddition of triynes.

Chapter 252

In 2015, riera and Verdaguer reported the synthesis of chiral cobalt com-plexes derived from novel P-stereogenic aminodiphosphane ligands to be investigated as promoters in the enantioselective Pauson–Khand reaction of norbornadiene with terminal alkynes (Scheme 2.18).43 Among these novel catalysts, complex 13 was recognised as the first catalytic system with useful levels of enantioselection (up to 97% ee) for the reaction between norbor-nadiene and trimethylsilylacetylene (r = TMS). Indeed, when this reaction was catalysed with 10 mol% of catalyst 13 in toluene at 100 °C under CO

Scheme 2.17 First intramolecular Pauson–Khand reaction of 1,6-enynes.

Scheme 2.18 Pauson–Khand reaction of norbornadiene with terminal alkynes.


pressure (1 atm), it afforded the corresponding product in moderate yield (39%), albeit with a remarkable enantioselectivity (97% ee). Other trialkyl-silyl-substituted acetylenes also provided good to high enantioselectivities (72–90% ee) when using either catalyst 13 or the related catalyst 14, while much lower enantioselectivities (≤40% ee) were obtained in the reaction of alkyl-substituted acetylenes.

2.4 Other Enantioselective Cobalt-Catalysed Cycloadditions

In 1993, Lautens et al. reported the first enantioselective cobalt-catalysed [4+2+2] cycloaddition of various 2-substituted buta-1,2-dienes with norbor-nadiene.44 This reaction was performed in the presence of 2 mol% of Co(a-cac)2 as a precatalyst in combination with a chiral phosphine ligand and a reducing agent, such as Et2AlCl (4 equivalents). Among several chiral phos-phine ligands investigated, including (R)-Prophos, (S,S)-Chiraphos, and (S,S)-Me-Duphos, (R)-Prophos was found to be the optimal ligand, allowing moderate to good enantioselectivities (71–79% ee) to be achieved. As shown in Scheme 2.19, the reaction was performed in benzene and afforded the cor-responding cycloadducts in moderate to good yields (40–66%). The yields were probably limited due to the competing polymerisation of the dienes under the reaction conditions. On the other hand, very little change in the enantioselectivity of the reaction was observed regardless of the nature of the substituent on the diene.

Scheme 2.19 The first cobalt-catalysed [4+2+2] cycloaddition.

Chapter 254

The importance of optically active β-lactones as versatile chiral synthons underscores current research efforts for developing novel catalytic enantiose-lective methods, among which the asymmetric [2+2] cycloaddition between aldehydes and ketenes appears to be the most elegant.45 For reactive enolis-able aliphatic aldehydes, such as benzyloxyacetaldehyde, catalysts with an excellent level of asymmetric induction are still needed. In this context, Lin et al. have designed the novel Lewis acid/Lewis base bifunctional catalyst 15 based on a covalent attachment of quinine to a salen cobalt(ii) complex.46 This novel mixed chiral catalyst was found to display a remarkable bifunc-tional catalytic activity in the enantioselective [2+2] cycloaddition of 2-ben-zyloxyacetaldehyde with ketene to give the corresponding β-lactone (Scheme 2.20). This important versatile synthon was generated in an excellent yield (91%) with complete enantioselectivity (>99% ee). In this study, the authors screened metals other than cobalt for the desired bifunctional catalytic activ-ity, finding that complexes derived from the same ligand and titanium(iv), iron(iii), nickel(ii), copper(ii), and chromium(iii) did not afford the desired β-lactone.

In 2008, Buono et al. described the first enantioselective cobalt-catalysed [6+2] cycloaddition between cycloheptatriene and alkynes, providing the corresponding chiral [4.2.1]bicyclononatrienes in good yields (86–89%) and moderate to high enantioslectivities (47–92% ee).47 As shown in Scheme 2.21, these results were achieved by promoting the process in the

Scheme 2.20 [2+2] Cycloaddition.


presence of 10 mol% of the chiral phosphoramidites 16 and 17 derived from 3,3′-disubstituted (R)-BINOL derivatives combined with 5 mol% of CoI2 in 1,2-dichloroethane (DCE) at 40 °C. The chiral phosphoramidites 16 and 17 were selected as optimal ligands from a series of chiral biden-tate phosphines and monodentate phosphoramidites. Later, these authors developed novel P-stereogenic triaminophosphines featuring an indoline or a 1,2,3,4-tetrahydroquinolidine pattern, which were further investigated as chiral ligands in the same cobalt-catalysed [6+2] cycloaddition, albeit providing moderate enantioselectivities of up to 52% ee.48 A vibrational circular dichroism study afforded the absolute configuration of the novel chiral cycloadducts.

2.5 ConclusionsThis chapter collects together examples of enantioselective cobalt-catalysed cycloadditions, other than [2+1] cycloadditions. Despite the extraordinary ability of green and economic cobalt catalysts to adopt unexpected reaction pathways, it must be recognised that the field of enantioselective cobalt-cata-lysed miscellaneous cycloadditions other than [2+1] ones is still in its infancy. For example, in the area of asymmetric (hetero)-Diels–Alder reactions, only a few excellent results have been reported so far. Among them, the Diels–Alder cycloaddition of cyclopentadiene with 3-acryloyl-2-oxazolidinone was per-formed in the presence of a bisoxazoline chiral ligand resulting in a quanti-tative yield combined with both excellent diastereo- and enantioselectivities

Scheme 2.21 [6+2] Cycloaddition of cycloheptatriene with alkynes.

Chapter 256

of 94% de and 99% ee, respectively. Various salen cobalt(iii) complexes have also allowed very high enantioselectivities of up to 98% ee to be achieved in the asymmetric Diels–Alder reaction of carbamate-substituted dienes with α,β-unsaturated aldehydes in quantitative yields. Moreover, slightly lower enantioselectivities of up to 96% ee were reported using this type of catalyst in a Diels–Alder cycloaddition between functionalised dienam-ines and α,β-unsaturated aldehydes applied to the total synthesis of (–)-pla-tencin. A closely related catalyst was employed in a successful example of a hetero-Diels–Alder reaction between 1-methoxy-[3-(tert-butyldimethylsilyl)oxy]-1,3-butadiene and aldehydes, resulting in enantioselectivities of up to 94% ee. On the other hand, the field of enantioselective cobalt-catalysed 1,3-dipolar cycloadditions has encountered more success than that of the Diels–Alder reactions. Indeed, a steadily growing number of highly effective examples of these processes have been described using various types of chi-ral ligands, including salen derivatives, bis- and trisoxazolines, N,N′-dioxides and biphosphines. Thus, 1,3-dipolar cycloadditions between nitrones and α,β-unsaturated aldehydes have been developed in the presence of a salen cobalt(iii) complex with 92% ee. The use of a chiral bisoxazoline derived from 4,6-dibenzofurandiyl-2,2′-bis-(4-phenyloxazoline) (DBFOX) applied to the enantioselective 1,3-dipolar cycloaddition of N-benzylideneaniline N-oxide with α-bromoacrolein was achieved with both remarkable diaste-reo- and enantioselectivities of >98% de and 98% ee, respectively. Moreover, the first example of enantioselective cycloadditions between nitrones and alkylidene malonates was promoted by a chiral trioxazoline-derived cobalt catalyst, leading to enantiopure isoxazolidines (>98% de and 98% ee). recently, the 1,3-dipolar cycloaddition of nitrones with methyleneindoli-nones was reported, using a chiral N,N′-dioxide ligand to afford chiral mul-tisubstituted spiroisoxazolidines, exhibiting three contiguous quaternary/tertiary stereocentres in almost all cases, as single diastereomers (>90% de) with uniformly high enantioselectivities (90–99% ee). The same type of catalyst was also applied to promote highly efficient catalytic asymmetric [3+2] cycloadditions of 5-alkoxyoxazoles with azodicarboxylates, providing multisubstituted chiral 1,2,4-triazolines with up to 98% ee. Furthermore, a chiral biphosphine, (R,R,S,S)-Duanphos, was successfully applied to pro-mote the enantioselective cobalt-catalysed reductive [3+2] cycloaddition of various alkynes with cyclic enones to give the corresponding chiral bicyclic tertiary alcohols with high regioselectivity and enantioselectivities of up to >99% ee. Concerning other types of asymmetric cobalt-catalysed cyc-loadditions, a few examples of highly effective [2+2+2] cycloadditions have been described, such as that occurring between norbornadiene and alkynes to afford variously monofunctionalised chiral deltacyclenes with high to excellent enantioselectivities of up to >97% ee when performed with (S)-(+)-ValNOP as a ligand. A second interesting example was the photochemical [2+2+2] cycloaddition of naphthyldiynes with nitriles achieved with up to 94% ee using a planar chiral (1-neomenthylindenyl)cobalt(cod) complex. Several successful [2+2+1] cycloadditions have also been described, such as


the first intramolecular Pauson–Khand reaction of 1,6-enynes performed in the presence of (S)-BINAP as a cobalt ligand with enantioselectivities of up to 94% ee. higher enantioselectivities of up to 97% ee were reported for the Pauson–Khand reaction of norbornadiene with terminal alkynes using P-stereogenic aminodiphosphane ligands. In addition, the design of a novel Lewis acid/Lewis base bifunctional catalyst based on the covalent attach-ment of quinine to a salen cobalt(ii) complex allowed the enantioselective [2+2] cycloaddition of 2-benzyloxyacetaldehyde with ketene to give the corre-sponding enantiopure β-lactone (>99% ee). Finally, the first enantioselective cobalt-catalysed [6+2] cycloaddition between cycloheptatriene and alkynes, providing the corresponding chiral [4.2.1]bicyclononatrienes in good yields and enantioselectivities of up to 92% ee was also recently reported using chiral phosphoramidite ligands. Despite these excellent results, progress is expected in the near future in the field of enantioselective cobalt-cata-lysed cycloadditions of miscellaneous types with the investigation of other types of cobalt catalyst systems, the extension of the scopes of the reactions to even more challenging substrates, as well as the development of more applications in the total synthesis of natural and/or biologically active com-pounds. Inspired by the early successes of the Pauson–Khand reaction or [2+2+2] cycloadditions, and by the lower costs and toxicity of cobalt catalysts in comparison with those of the other transition metals, more environmen-tally friendly and economical cobalt-catalysed cycloadditions have received a growing attention over the last two decades. Decidedly, the development of cycloadditions promoted by novel environmentally friendly catalytic sys-tems, based on a more abundant first–row transition metal such as cobalt, is blossoming.

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62


A domino reaction was defined by Tietze as a process in which two or more bond-forming transformations occur based on functionalities formed in the previous step and, moreover, no additional reagents, catalysts or additives can be added to the reaction vessel, nor can reaction conditions be changed.1 The use of these fascinating one-pot reactions2 in organic synthesis is increas-ing constantly, since they allow the synthesis of a wide variety of complex molecules, including natural products and biologically active compounds, through economically favourable processes that avoid the use of costly and time-consuming protection–deprotection processes, as well as the purifi-cation of intermediates.1,3 Actually, the forerunner of the cobalt-catalysed domino processes was that developed by the group of Vollhardt in 1986 in their excellent synthesis of steroids initiated by a [2+2+2] cycloaddition.4 Ever since, a number of cobalt-catalysed domino reactions have been developed and research into asymmetric catalytic versions has dramatically increased, especially in organocatalysed processes.5 Among enantioselective metal- catalysed domino reactions, an enantioselective cobalt-catalysed multicom-ponent process initiated by a Diels–Alder cycloaddition was developed by Hilt et al., in 2006.6 As shown in Scheme 3.1, the process involved a Diels–Alder reaction between a 1-boron-functionalised 1,3-diene and a terminal alkyne, followed by an allylboration reaction with para-nitrobenzaldehyde to give the corresponding chiral multifunctionalised domino product in good yield (87%) and enantioselectivity (78% ee). The product, exhibiting a stereogenic

CHApTEr 3

Enantioselective Cobalt-catalysed Cyclisations Through Domino Reactions

63Enantioselective Cobalt-catalysed Cyclisations Through Domino Reactions

quaternary centre next to a stereogenic secondary alcohol functionality, was regio- and diastereoselectively (>99% de) formed using a combination of CoBr2 with the chiral biphosphine ligand, (S,S)-Norphos.

In the same year, Sudalai and paraskar developed a novel enantioselec-tive cobalt-catalysed domino reductive cyclisation reaction of substituted γ-azido-α,β-unsaturated esters to afford the corresponding γ-lactams in high yields (82–93%).7 As shown in Scheme 3.2, the process was promoted by a catalytic amount of CoCl2 combined with chiral oxazoline 1 in the presence of NaBH4 as the reducing agent. It provided the corresponding γ-lactams with moderate to excellent enantioselectivities (51–98% ee).

The scope of this methodology was extended to a γ-cyano-α,β-unsaturated ester, which under similar reaction conditions afforded the corresponding δ-lactam in an almost quantitative yield (99%) with a good enantioselectiv-ity of 86% ee (Scheme 3.3). The utility of these reactions (Schemes 3.2 and 3.3) were demonstrated by their applications to the total syntheses of (R)-baclofen, (R)-rolipram, and (R)-4-fluorophenylpiperidinone, a key inter-mediate for (−)-paroxetine.

Scheme 3.1 A three-component domino Diels–Alder/allylboration reaction.

Chapter 364

Chiral tetrahydroquinoline derivatives are widely used in organic synthesis and the pharmaceutical chemistry due to their significant building blocks and important biological activities. Traditional methodologies for the forma-tion of these linchpins mainly include the povarov reaction and the reduction of quinolines. As an alternative straightforward approach to afford tetrahy-droquinolines, a tandem hydride transfer/cyclisation process, which involves the formation of a zwitterionic intermediate via a 1,5-hydride transfer, has been developed. As an example, a highly enantioselective synthesis of tetra-hydroquinolines was developed by Feng et al. in 2011 via a cobalt-catalysed domino 1,5-hydride transfer/cyclisation reaction.8 As shown in Scheme 3.4, a chiral catalyst in situ generated from l-proline-derived N,N′-dioxide 2 and Co(BF4)2·6H2O was applied to the asymmetric intramolecular hydride transfer- initiated cyclisation reaction of a series of o-dialkylamino-substituted alkylidene malonate derivatives to provide the corresponding biologically interesting tetrahydroquinolines in moderate to quantitative yields (60–99%) and good to high enantioselectivities (79–90% ee). The mechanism of the process involved the formation of a zwitterionic intermediate A, through intramolecular hydride transfer, which subsequently cyclised to give the final

Scheme 3.2 Domino reductive cyclisation reaction of γ-azido-α,β-unsaturated esters.

Scheme 3.3 Domino reductive cyclisation reaction of a γ-cyano-α,β-unsaturated ester.


Scheme 3.4 A domino 1,5-hydride transfer/cyclisation reaction.

Chapter 366

product (Scheme 3.4). A possible transition state model depicted in Scheme 3.4 was proposed by the authors to explain the absolute configuration of the products. In this model, the oxygens of N,N′-dioxide, amide oxygens, and the alkylidene malonate coordinated to cobalt(ii) in a hexadentate manner. The carbanion preferred to attack the Re face rather than the Si face of the imine because the latter was strongly shielded by the nearby anthracenyl ring, which resulted in the S-configured product.

Since the first catalytic domino Michael/aldol reaction was reported by Noyori et al. in 1996,9 many examples of domino reactions, includ-ing a Michael addition, have been developed. Among them, a number of enantioselective domino reactions initiated by a Michael addition have been promoted by chiral metal catalysts.3k,l,n,o,10 As an example, in 2011 Feng et al. reported the efficient asymmetric synthesis of 4H-chromene derivatives based on a domino Michael/cyclisation reaction of cyclohex-ane-1,3-dione with ethyl 2-cyano-3-arylacrylates.11 The process was pro-moted by a chiral cobalt complex in situ generated from Co(OAc)2

.4H2O and chiral salen ligand 3 derived from (R,R)-1,2-diphenylethane-1,2-di-amine and 3,5-di-tert-butylsalicylaldehyde. A series of additives includ-ing acids, bases, alcohols and phenols were investigated to improve the reactivity and enantioselectivity of the reaction, and the authors found that the enantioselectivities were optimal when using 3,5-dinitrosalicylic acid at 22.5 mol%. A range of chiral 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene derivatives, exhibiting extensive biological and pharmaco-logical activities, were obtained with moderate to good yields (46–81%) combined with good to high enantioselectivities (69–89% ee), following successive Michael addition, cyclisation, protonation of the imine inter-mediate B, which regenerated the chiral salen-complex, and a final tau-tomerisation, as depicted in Scheme 3.5. The results, obtained with a wide range of ethyl 2-cyano-3-phenylacrylates, showed that the electronic nature of the substituent in the aromatic ring (r1) had an obvious effect on the yield and enantioselectivity of the process. Generally, electron-withdrawing substituents provided better yields than electron-donating substituents, except in the case of the 3-methoxy phenyl substituent. Moreover, most of the substrates with substituents in the para position at r1 led to products with higher enantioselectivities. Furthermore, the 2-naphthyl substrate (r1 = 2-Naph, r2 = Et) also yielded the corresponding domino product in good yield (64%) with an enantioselectivity of 81% ee, while an heteroar-omatic substrate, such as a 2-thienyl derivative (r1 = 2-thienyl, r2 = Et), resulted in a lower enantioselectivity (69% ee) along with a yield of 75%.

Although the concept of bifunctional asymmetric catalysts has been well established in transition-metal catalysis and organocatalysis, respectively, the recent emergence of cooperative catalysis between metals and small organic molecules has provided alternative ways of asymmetric reaction optimizations, where two distinctive catalysis modes are controlled by either one or two chiral (or achiral) components of the reaction. Furthermore, such


a combination of multiple catalyst systems has opened up new avenues for developing cooperative catalytic systems, where the respective catalyst sys-tem alone fails to deliver sufficient catalyst reactivity and selectivity. Over the last few years, there has been an explosion in the number of multiple-cata-lyst systems developed for various organic transformations.5a,e,12 This novel methodology is particularly adapted to enantioselective domino reactions, allowing the rapid and economic one-pot construction of highly function-alised chiral molecules from simple and readily available starting materi-als. A recent example of an enantioselective domino reaction catalysed by

Scheme 3.5 A domino Michael/cyclisation reaction.

Chapter 368

a combination of a chiral cobalt catalyst and an achiral organocatalyst was described by Oh and Kim, in 2011.13 The process consisted of a domino aldol/cyclisation reaction between aromatic as well as aliphatic aldehydes and methyl α-isocyanate, to give the corresponding chiral trans-oxazolines (Scheme 3.6). By using a chiral cobalt complex in situ generated from CoI2 and brucine amino diol 4 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base with achiral thiourea 5, a range of chiral oxazolines were achieved in good to high yields (65–85%), and trans-diastereo- and enantioselectivities of up to >90% de and 98% ee, respectively, as shown in Scheme 3.6. The key to the success in this process lies in the strong anion-binding interaction between the isocyanide substrate and thiourea 5, which potentially disturbs the intrinsic cobalt-isocyanide complexation (Scheme 3.6). The reaction is applicable to a range of aromatic, heteroaro-matic, and aliphatic aldehydes with the lowest enantioselectivities found in the reactions of 2-thiophenecarboxaldehyde (84% ee) and pivaldehyde (74% ee), while high diastereoselectivities were maintained (>90% de). Moreover, the limitation of the current cooperative catalysis lie with the ortho- and meta-substituted benzaldehydes, for which low levels of enantioselectivity were obtained in the range of 20–50% ee, but with always excellent diastere-oselectivities of >90% de.

In 2017, Ge et al. developed the first enantioselective cobalt-catalysed domino hydroboration/cyclisation reaction of 1,6-enynes with pinacolbo-rane.14 The cobalt catalyst was in situ generated from Co(acac)2 and chiral bisphosphine ligand 6 in toluene at room temperature. A variety of oxygen-, nitrogen- and carbon-tethered 1,6-enynes underwent asymmetric reaction with HBpin, yielding the corresponding vinyl-substituted boronate esters, containing chiral tetrahydrofuran, pyrrolidine or cyclopentane moieties, in moderate to high yields (39–87%) with uniformly excellent enantioselectivi-ties (90–99% ee), as illustrated in Scheme 3.7.

On the other hand, the authors found that enynes containing ortho-sub-stituted aryl groups (r1 = o-Tol, 2-Naph) reacted with HBpin in THF solvent, resulting in the formation of the corresponding alkyl boronate esters in high yields (86–88%) and enantioselectivities (88–90% ee), as shown in Scheme 3.8. Furthermore, this anti-Markovnikov hydroboration/cyclisation process tolerated O-tethered 1,6-enynes bearing two substituents at the propargylic position, as well as N- and C-tethered 1,6-enynes, affording the correspond-ing products in moderate to high yields (50–91%) and high enantioselectivi-ties (86–98% ee), as shown in Scheme 3.8.

In the same year, an asymmetric three-component domino hydrosilyla-tion/hydrogenation reaction of terminal aryl alkynes with Ar2SiH2 and H2 was developed by Lu et al.15 The reaction was promoted by 5 mol% of chiral cobalt catalyst 7 in the presence of the reducing agent NaBHEt3 in diethylether at 0 °C, providing the corresponding chiral silanes in good to excellent yields (74–97%) and enantioselectivities (78–>99% ee), as shown in Scheme 3.9. Mechanistic studies demonstrated that the regioselectivity of the reaction was controlled by the alkyne hydrosilylation step, while the


Scheme 3.6 A domino aldol/cyclisation reaction.

Chapter 370

enantioselectivity was generated through the asymmetric hydrogenation of the resulting vinyl silanes.

ConclusionsThis small chapter collects the rare, albeit generally highly efficient, exam-ples of enantioselective cobalt-catalysed domino reactions that have been developed in the presence of various types of chiral ligands, including salen

Scheme 3.7 Synthesis of vinyl boronate esters through domino hydroboration/cycli-sation reaction of 1,6-enynes with pinacolborane.

Scheme 3.8 Synthesis of alkyl boronate esters through domino hydroboration/cycli-sation reaction of 1,6-enynes with pinacolborane.


derivatives, N,N′-dioxides, oxazolines, biphosphines, or amino diols. Among them, is a novel enantioselective cobalt-catalysed domino reductive cycli-sation reaction of substituted γ-azido-α,β-unsaturated esters to afford the corresponding γ-lactams, with enantioselectivities of up to 98% ee using a chiral oxazoline ligand. The success of this methodology was demonstrated by its application to the total syntheses of the biologically important prod-ucts, (R)-baclofen, (R)-rolipram, and (R)-4-fluorophenylpiperidinone, a key intermediate for (−)-paroxetine. Another example involved a highly enan-tioselective synthesis of tetrahydroquinolines based on a cobalt-catalysed domino 1,5-hydride transfer/cyclisation reaction of o-dialkylamino-substi-tuted alkylidene malonate derivatives performed in the presence of a l-pro-line-derived N,N′-dioxide ligand, which afforded biologically interesting tetrahydroquinolines in up to 90% ee. In another area, an efficient asymmet-ric synthesis of 4H-chromene derivatives, with up to 89% ee, was reported based on a domino Michael/cyclisation reaction of cyclohexane-1,3-dione with ethyl 2-cyano-3-arylacrylates catalysed with a chiral salen cobalt com-plex. Another type of enantioselective domino reaction, such as the domino aldol/cyclisation reaction of aldehydes with methyl α-isocyanate, allowed chiral trans-oxazolines to be achieved in up to 98% ee and >90% de when performed through multicatalysis involving a chiral cobalt complex derived

Scheme 3.9 The three-component domino hydrosilylation/hydrogenation reaction of terminal aryl alkynes with Ar2SiH2 and H2.

Chapter 372

from a brucine amino diol combined with an achiral thiourea. In addition, the first enantioselective cobalt-catalysed domino hydroboration/cyclisa-tion reaction of 1,6-enynes with pinacolborane was recently developed by employing a chiral bisphosphine ligand, resulting in chiral vinyl-substi-tuted boronate esters containing chiral tetrahydrofuran, pyrrolidine, and cyclopentane moieties with uniformly excellent enantioselectivities (90–99% ee). When enynes were used with ortho-substituted aryl groups, the process afforded chiral alkyl boronate esters with enantioselectivities of up to 90% ee, while even higher enantioselectivities of up to 98% ee were achieved in the reaction of O-tethered 1,6-enynes bearing two substituents at the propargylic position, as well as N- and C-tethered 1,6-enynes. Finally, enantioselectivities of up to >99% ee were achieved in the asymmetric three-component domino hydrosilylation/hydrogenation reaction of termi-nal aryl alkynes with Ar2SiH2 and H2 catalysed by a chiral pyridine-oxazoline cobalt(iii) cobalt complex. Despite these excellent results and the extraor-dinary ability of cobalt catalysts to adopt unexpected reaction pathways, it must be noted that the field of enantioselective cobalt-catalysed domino reactions is still in its infancy. In the near future, more types of domino reactions are expected to be developed as well as their applications in the total synthesis of natural and/or biologically active compounds. Other types of ligands will also have to be investigated. Efforts are also expected in the field of multicatalysis, which is blossoming. On the basis of the lower cost and toxicity of cobalt catalysts in comparison with other transition metals, the development of novel enantioselective cobalt-catalysed domino reac-tions seems close at hand.

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M. Kanai, N. Kato, E. Ichikawa and M. Shibasaki, Synlett, 2005, 1491; (c) D. H. paull, C. J. Abraham, M. T. Scerba, E. Alden-Danforth and T. Leckta, Acc. Chem. Res., 2008, 41, 655; (d) Z. Shao and H. Zhang, Chem. Soc. Rev., 2009, 38, 2745; (e) C. Zhong and X. Shi, Eur. J. Org. Chem., 2010, 2999; (f ) M. rueping, r. M. Koenigs and I. Atodiresei, Chem.–Eur. J., 2010, 16, 9350; (g) J. Zhou, Chem.–Asian J., 2010, 5, 422; (h) L. M. Ambrosini and T. H. Lambert, ChemCatChem, 2010, 2, 1373;

Chapter 374

(i) S. piovesana, D. M. Scarpino Schietroma and M. Bella, Angew. Chem., Int. Ed., 2011, 50, 6216; ( j) N. T. patil, V. S. Shinde and B. Gajula, Org. Biomol. Chem., 2012, 10, 211; (k) A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3, 633; (l) Z. Du and Z. Shao, Chem. Soc. Rev., 2013, 42, 1337.

13. H. Y. Kim and K. Oh, Org. Lett., 2011, 13, 1306. 14. S. Yu, C. Wu and S. Ge, J. Am. Chem. Soc., 2017, 139, 6526. 15. J. Guo, X. Shen and Z. Lu, Angew. Chem., Int. Ed., 2017, 56, 615.

75


4.1 Using Salen LigandsThe prevalence of five-membered carbo- and heterocycles in natural prod-ucts and other bioactive compounds has provided a major impetus for the development of efficient methods for their construction. In 1999, Yokota et al. reported the asymmetric cyclisation of a meso-diepoxide through hydra-tion using chiral salen cobalt(iii) complexes.1 As shown in Scheme 4.1, the treatment of meso-1,2 : 4,5-dianhydro-3-O-methylxylitol with water in the presence of (R,R)-Jacobsen's salen(Co) catalyst 1 led to the exclusive forma-tion of the d-enantiomer of 1,4-anhydro-3-O-methyl-d-arabinitol in 78% yield and an excellent enantioselectivity of >99% ee (Scheme 4.1). By using the (S,S)-enantiomer of catalyst 1, the corresponding l-enantiomer was formed with the same enantioselectivity and in an even better yield of 88%. It must be noted that a remarkably low catalyst loading of 0.5 mol% was employed in this process which used just water as a reagent at room temperature. Appli-cation of this methodology to other meso-diepoxides, such as 1,2 : 5,6-dian-hydro-3,4-di-O-methylallitol or 1,2 : 5,6-dianhydro-3,4-di-O-methylgalactitol, led, however, to mixtures of the corresponding optically active five- and six-membered cyclic compounds which were, however, both obtained in excellent enantioselectivities (92–97% ee).

In the same year, Jacobsen et al. reported the use of the same cobalt catalyst 1 to promote the intramolecular desymmetrisation of meso-epoxy alcohols 2a–c into the corresponding almost enantiopure bicyclic products 3a–c.2 As shown in Scheme 4.2, the treatment of epoxy alcohol 2a by catalyst 1 under hydrolytic conditions led to the corresponding bicyclic product 3a in both

ChApTer 4

Miscellaneous Enantioselective Cobalt-catalysed Cyclisations

Chapter 476

Scheme 4.1 Cyclisation of a meso-diepoxide.

Scheme 4.2 Intramolecular cyclisations of meso-epoxy alcohols.

77Miscellaneous Enantioselective Cobalt-catalysed Cyclisations

excellent yield (96%) and enantioselectivity (98% ee). Similarly, gem-bishy-droxymethylcyclopentene oxide 2b smoothly cyclised under the same reaction conditions into the corresponding bicyclic ring system 3b in 86% yield and 95% ee. Moreover, meso epoxy diol 2c underwent an exclusive 4-exo ring closure to afford the corresponding enantiopure oxetane 3c in 45% yield, while meso-epoxy diol 2d underwent a cobalt-catalyzed payne rearrange-ment to provide the 1,2-anhydrothreitol product 3d in 81% yield and 96% ee (Scheme 4.2). This novel methodology allowed the synthesis of almost enan-tiopure cyclic and bicyclic ethers ranging from three- to seven-membered rings under mild conditions.

Later in 2001, Katsuki and Uchida employed chiral cationic salen cobalt(iii) complex 4 to promote the asymmetric Baeyer–Villiger reaction of 3-substituted cyclobutanones using hydrogen peroxide as a terminal oxidant (Scheme 4.3).3 When the reaction was performed in ethanol as a solvent at 0 °C in the presence of a 5 mol% catalyst loading, it afforded the correspond-ing chiral 3-aryl butyrolactones in good yields (75–85%) and enantioselec-tivities (75–78% ee). In 2002, the same authors described the synthesis of novel salen cobalt(iii) complexes bearing a chiral ethane-1,2-diamine moi-ety considered to take a square planar geometry.4 These cobalt catalysts were investigated to promote the same Baeyer–Villiger oxidation of 3-aryl as well as 3-alkyl cyclobutanones into the corresponding chiral lactones in the pres-ence of hydrogen peroxide. Among a range of cobalt complexes investigated, all with a chiral binaphthalenediamine unit, catalyst 5 bearing electron- withdrawing F-atoms was found to be optimal, providing enantioselectivities of 69–79% ee (Scheme 4.3). Although this process is actually a ring-expansion reaction and not a real cyclisation methodology, it was decided to maintain it in this chapter since it affords cyclic compounds.

Later in 2009, Jacobsen and Loy described an enantioselective intramole-cular opening of 3-substituted oxetanes catalysed by chiral salen cobalt(iii) complexes to afford the corresponding chiral functionalised tetrahydrofu-rans.5 When the oxetanes were activated by the monomeric salen cobalt cata-lyst 1, they provided the corresponding tetrahydrofurans in good to excellent yields (76–98%) and enantioselectivities of up to 99% ee, as shown in Scheme 4.4. The scope of the reaction of oxetanes with O-centered nucleophiles was examined with a variety of oxetanes bearing nucleophilic appendages. Thus, a series of substituted ethanol derivatives underwent ring-opening with good to excellent enantioselectivities (84–99% ee). Alkyl and phenyl substitution at the 3-position of the oxetane was tolerated, affording products bearing quaternary stereocentres. In particular, the ring-opening of phenolic sub-strates provided chiral dihydrobenzofurans.

The halolactonisation of unsaturated carboxylic acids, in particular its asymmetric version, constitutes a powerful chemical process in synthetic organic chemistry, which can not only build small to large lactone rings but also functionalise olefinic double bonds. The stereochemistry of this reaction can be controlled by either chiral substrates or catalysts. While substrate- controlled halolactonisation has been investigated in detail, the generation

Scheme 4.3 Baeyer–Villiger reaction of 3-aryl(alkyl) cyclobutanones.

Scheme 4.4 Intramolecular opening of oxetanes.


of chirality using a chiral catalyst remains to be further investigated. In this context, in 2009 Gao et al. developed a range of chiral salen cobalt complexes, such as 6, to be investigated as chiral catalysts in the asymmetric iodolac-tonisation of 4-substituted-4-pentenoic acid derivatives, affording the cor-responding iodolactones in low to good enantioselectivities (22–83% ee), as shown in Scheme 4.5.6 Indeed, a range of substrates having various sub-stituents such as sterically bulky, electron-rich and electron-deficient, and aromatic and aliphatic groups reacted under these conditions, demonstrat-ing that this protocol was amenable to a broad range of substrates. how-ever, introducing an electron-rich methoxy group onto a phenyl substituent (r = p-MeOC6h4) markedly decreased the enantioselectivity of the reaction (22% ee). On the other hand, the use of electron-deficient Br instead of MeO groups tended to increase the enantioselectivity (73% ee). This influence was attributed to the probable different stability of the intermediate iodonium ion, as affected by the electronic property of the substituents.

Later in 2011, these authors extended the scope of this methodology to the asymmetric iodolactonisation of 5-substituted-4-pentenoic acid deri vatives.7 Under the same reaction conditions, both moderate to good yields (48–67%) and enantioselectivities (53–74% ee) were obtained for the formed iodolactones arising from the corresponding (E)-5-substitut-ed-4-pentenoic acid derivatives (Scheme 4.6), whereas the (Z)-5-substitut-ed-4-pentenoic acid derivatives led to the corresponding iodolactones in enantioselectivities of lower than 12% ee. In this study, the authors com-pared the catalytic efficiency of cobalt(ii) salen complex 6 to the correspond-ing manganese(iii), chromium(iii), and aluminum(iii) chiral complexes, and

Scheme 4.5 Iodolactonisation reaction of 4-substituted-4-pentenoic acid derivatives.

Chapter 480

found that the latter catalysts provided much lower enantioselectivities than cobalt catalyst 6 (0–4% ee instead of 27% ee using 6 under similar non- optimised reaction conditions).

In another context, the asymmetric Darzens condensation of α-haloam-ides with benzaldehydes has been investigated by North et al., using a range of cobalt complexes of novel C1-symmetrical salen chiral ligands derived from amino acids, such as (S)-alanine, (S)-phenylalanine, (R)-phenylglycine, and (S)-valine.8 even if the corresponding epoxides were obtained in good to excellent yields (72–97%) as mixtures of cis- and trans-diastereomers, low to moderate enantioselectivities of up to 44% ee were observed for both these two diastereomers. In 2007, the same authors also investigated these reac-tions using chiral salen cobalt(ii) complexes derived from diaminocyclohex-ane, such as 7, which provided comparable enantioselectivities of up to 47% ee combined with moderate diastereoselectivities (14–42% de) and good to excellent yields (71–95%), as shown in Scheme 4.7.9 This cobalt(ii) complex was demonstrated to give much better enantioselectivities than the corre-sponding copper, titanium, oxovanadium, as well as nickel catalysts.

Several groups have studied the kinetic resolution of racemic terminal epoxides based on a coupling with carbon dioxide to give the correspond-ing chiral five-membered cyclic carbonates. Various chiral cobalt complexes have been investigated to promote this reaction, providing moderate to high enantioselectivities of up to 92% ee, albeit often combined with mod-erate conversions. For example, Jing et al. have synthesised multichiral cobalt(iii) complexes of bis(1,1′-2-hydroxy-2′-alkoxy-3-naphthylidene)-1,2-cyclohexanediamine (BINAD), which were further investigated as catalysts in the coupling of carbon dioxide with various terminal epoxides to provide the corresponding chiral cyclic carbonates.10 Low to high enantioselectivi-ties (6–89% ee) in combination with low yields (5–33%) were obtained when the reaction was performed in the presence of phenyltrimethylammonium tribromide as a co-catalyst. Chiral heterobimetallic cobalt(ii) salen com-plexes were also proven by Kim and co-workers to be capable of providing chiral cyclic propylene carbonate in 25% yield and 89% ee from the reaction of propylene oxide with carbon dioxide.11 In this case, the authors showed that using quaternary ammonium salts as co-catalysts led to lower enantio-selectivities. More recently, comparable results were reported by Lu et al.

Scheme 4.6 Iodolactonisation reaction of 5-substituted-4-pentenoic acid derivatives.


using multichiral cobalt(iii) complex 8 in the presence of 200 equivalents of ammonium salts as co-catalysts, such as 9. The best result (35% yield, 92% ee) achieved under these conditions for the formation of propylene carbonate 10a from the reaction of propylene oxide 11a with carbon diox-ide, is shown in Scheme 4.8.12 The authors assumed that the nucleophilic co-catalyst played an important role in the product selectivity and enantio-selectivity of the reaction. Therefore, in the presence of less than 1 equivalent of this co-catalyst, the reaction did not afford the required cyclic chiral car-bonate 10a, but linear polypropylene carbonate 12. As shown in Scheme 4.8, the Co(iii) complex initiated the coupling reaction by coordinating the epox-ide, which was followed by attack by the co-catalyst, leading to the epoxide ring-opening and formation of a cobalt-bound alkoxide. The insertion of carbon dioxide into the cobalt–O bond formed a metal-bound carboxylate, which provided the production of the cyclic carbonate 10a via a back-biting pathway (Scheme 4.8). It must be noted that this process employed a very low catalyst loading of 0.05 mol%. In 2004, Yamada et al. described the incor-poration of carbon dioxide in N,N-diphenylaminomethyloxirane induced by optically active chiral ketoiminatocobalt(ii) complexes in the presence of a catalytic amount of a base such as trimethylsilyldiethylamine.13 Under opti-mal conditions, the corresponding cyclic carbonate was formed in 49% yield and 86% ee. In addition, reactions of terminal epoxides with carbon dioxide

Scheme 4.7 Darzens condensation of α-haloamides with aromatic aldehydes.

Chapter 482

Scheme 4.8 Formation of cyclic propylene carbonate through kinetic resolution of propylene epoxide with carbon dioxide.


were performed in ionic liquids. For example, Jing et al.14 and Kim et al.,15 have independently undertaken these reactions with chiral salen cobalt(iii) complexes and immobilised chiral cobalt(ii) salen catalysts, which provided moderate enantioselectivities of up to 60 and 65% ee, respectively. It must be noted that the treatment of terminal epoxides with carbon dioxide can also lead to the formation of polycarbonate products. The product selectivity in the formations of cyclic carbonates or acyclic polycarbonates can be con-trolled by altering the temperature, CO2 pressure, and the nature of the co-catalyst used, or not, and its loading.

Later in 2016, Jing et al. designed novel chiral oligomers of spiro–salen cobalt complexes, which were further investigated as catalysts in the same reaction of the racemic epoxides 11a–c with carbon dioxide.16 The use of optimal catalyst 13 in the presence of TBAF as an additive allowed at 25 °C the corresponding chiral cyclic carbonates 10a–c to be synthesised in mod-erate conversions (38–45%) and enantioselectivities (54–61% ee), as shown in Scheme 4.9. Notably, this stable catalyst could be recycled up to five times without loss of activity and enantioselectivity.

Scheme 4.9 Kinetic resolution of epoxides with CO2 in the presence of a chiral oligo-meric spiro–salen cobalt complex.

Chapter 484

4.2 Using Biphosphine LigandsTransformation of organic halides into various organic compounds cata-lysed by transition metals by means of oxidative addition has been recog-nised as an important tool in organic synthesis. In this context, in 2007 Cheng et al. reported a highly efficient cyclisation of o-iodobenzoates with aldehydes induced by cobalt bidentate phosphine complexes.17 An asym-metric version of this process was developed using a cobalt complex of (S,S)-Dipamp 14 in the presence of zinc powder allowing the reduction of cobalt(ii) to cobalt(i). As shown in Scheme 4.10, various aromatic alde-hydes underwent cyclisation with methyl 2-iodobenzoate in ThF at 75 °C to provide the corresponding (S)-phthalides in high yields (80–89%) and good to excellent enantioselectivities (70–98% ee). This methodology opened up a novel route to these important chiral five-membered lactones, which are present in a large number of biologically active compounds and are also key intermediates for the synthesis of natural products. The authors showed that 2-iodobenzoates did not react under the same reaction condi-tions with aldehydes, probably due to their lower reactivity relative to that of the 2-iodobenzoates. To explain the results, the authors proposed the mechanism depicted in Scheme 4.10 in which the reduction of cobalt(ii) to cobalt(i) by zinc metal likely initiated the catalytic reaction. Oxidative addition of methyl 2-iodobenzoate with the cobalt(i) species yielded an o-metalated methylbenzoate complex A with both the o-carbon atom and the ester oxygen atom bound to the cobalt(iii) center. Coordination of the aldehyde molecule to the cobalt center adjacent to the o-metalated methyl benzoate group to give intermediate B, followed by insertion of the cobalt–carbon bond to the aldehyde afforded the cobalt–alkoxide intermediate C. Intramolecular nucleophilic addition of the coordinated alkoxy group in intermediate C to the ester group gave the final product and a cobalt(iii) species. The latter cobalt(iii) species was reduced by zinc metal to regener-ate the active cobalt(i) species.

In another area, the hydroacylation reaction, consisting of the catalytic addition of an aldehyde C–h bond across an unsaturated bond, represents an atom-efficient synthetic approach to synthesising carbonyl compounds.18 These reactions are generally catalysed by rhodium complexes, however, rare examples employing cobalt catalysts have been recently developed. Among them, Yoshikai and Yang reported the enantioselective intramole-cular hydroacylation of 2-alkenylbenzaldehydes promoted by a chiral cobalt catalyst in situ generated from 10 mol% of CoCl2 and the same quantity of (R,R)-BDpp as a ligand (Scheme 4.11).19 performed in acetonitrile at 25 °C in the presence of 50 mol% of zinc as a reductant, the process led to differently substituted chiral indanones in both high yields (81–95%) and enantioselec-tivities (81–97% ee).

In order to extend the scope of this catalytic system to substrates bearing trisubstituted alkenes, these authors found that the use of CoBr2 instead of CoCl2 as a precatalyst and performing the reaction in DMF at 80 °C instead of


Scheme 4.10 Cyclisation of o-iodobenzoates with aldehydes.

Chapter 486

acetonitrile at 25 °C allowed optimal results to be achieved (Scheme 4.12).20 Indeed, the enantioselective intramolecular hydroacylation of a wide range of trisubstituted alkenes using a combination of only 5 mol% of CoBr2 and 5 mol% of (R,R)-BDpp in DMF at 80 °C led to the corresponding chi-ral 2,3-disubstituted indanones in moderate to quantitative yields (66–99%), combined with moderate to excellent diastereoselectivities (54–>90% de) and enantioselectivities (63–97% ee). Interestingly, the level of enantioselecti vity was independent of the stereochemistry (E/Z ratio) of the alkenyl group of the starting material.

4.3 Using Porphyrin LigandsCobalt-based metalloradical catalysis was, for the first time, successfully applied by Zhang et al. to develop the asymmetric intramolecular C–h alkylation of acceptor/acceptor-substituted diazo reagents, such as

Scheme 4.11 Intramolecular hydroacylation of 2-alkenylbenzaldehydes.

Scheme 4.12 Intramolecular hydroacylation of trisubstituted alkenes.


α-methoxycarbonyl-α-diazosulfones.21 Indeed, based on the design and synthesis of novel D2-symmetric chiral amidoporphyrin as a chiral ligand, the corresponding cobalt-based metalloradical system 15 was found capa-ble of promoting at room temperature in benzene the radical intramolec-ular C–h alkylation of α-methoxycarbonyl-α-diazosulfones with a broad range of electronic properties, which afforded the corresponding chiral trans-five-membered sulfolane derivatives in high yields (86–99%), dias-tereoselectivities (86–94% de), and enantioselectivities (78–94% ee). As shown in Scheme 4.13, the catalytic system has a remarkable degree of functional group tolerance, since the substrate could include allylic and allenic groups, among others.

Scheme 4.13 radical intramolecular C–h alkylation of α-methoxycarbonyl-α- diazosulfones.

Chapter 488

Another cobalt–porphyrin catalyst 16 was used by De Bruin et al. to pro-mote the asymmetric intramolecular ring-closing C–h bond amination of an azide into the corresponding chiral pyrrolidine.22 As shown in Scheme 4.14, when performed in toluene at 100 °C, the radical reaction provided this prod-uct in low yield (22%) and modest enantioselectivity (46% ee).

4.4 Using Other LigandsOver the years, the Nazarov reaction has been increasingly refined to allow the synthesis of a range of five-membered carbocycles, including naturally occurring ones and bioactive products. Usually, this reaction involves the use of cross-conjugated dienones, treatment of which with a Lewis or Brøn-sted acid induces the formation of a pentadienyl cation that undergoes 4π electrocyclisation to give an allyl cation, followed by proton migration to give, finally, a cyclopentenone.23 Somewhat surprisingly, it was not until the end of 2003 that asymmetric catalytic versions of the Nazarov cyclisation began to surface in the literature.24 In addition to scandium, copper, nickel and iron chiral complexes have been involved in enantioselective versions of the Nazarov reaction and it was only in 2010 that Itoh et al. investigated

Scheme 4.14 Intramolecular ring-closing C–h bond amination of an azide.


cobalt complexes derived from chiral pybox-type ligands.25 Indeed, these authors succeeded in demonstrating the cobalt-catalysed asymmetric Nazarov reaction of divinyl ketones using a chiral cobalt complex in situ generated from Co(ClO4)2·6h2O and a (S,S)-ip-pybox ligand. As shown in Scheme 4.15, the corresponding enantioenriched functionalised cyclo-pentenones were achieved in moderate to good yields (23–70%) and low to moderate enantioselectivities (8–63% ee). In some cases of the substrates, better enantioselectivities of up to 93% ee were reached using iron instead of cobalt catalysts.

In another context, in 2014 Feng et al. reported the enantioselective cobalt-catalyzed Darzens reactions of N-protected isatins with phenacyl bro-mides in order to synthesise potentially bioactive spiroepoxyoxindoles.26 The optimal catalyst system for this process was constituted by a combination of 11 mol% of Co(acac)2 and 10 mol% of chiral N,N′-dioxide ligand 17. The reactions were performed at −30 °C in a 3 : 1 mixture of ThF/acetone as a sol-vent in the presence of a mixture of K3pO4 and K2hpO4 as a base. Under these conditions, the reaction of a range of N-protected isatins with phenacyl bro-mides led to the corresponding chiral spiroepoxyoxindoles as single diaste-reomers (98% de) in low to excellent yields (18–96%) and enantioselectivities (47–95% ee), as illustrated in Scheme 4.16.

In 2015, Gong et al. demonstrated that the sodium salts of anionic chi-ral cobalt complexes were highly promising catalysts for the asymmetric

Scheme 4.15 The Nazarov reaction.

Chapter 490

povarov reaction of 2-azadienes with various dienophiles.27 For example, 10 mol% of catalyst 18 was found to promote the enantioselective povarov reaction between 2-azadienes and 2,3-dihydrofuran in n-hexane at −40 °C to give the corresponding chiral tetrahydroquinolines exhibiting three con-tiguous stereocentres in moderate to excellent yields (40–93%), uniformly excellent endo-diastereoselectivity (88–>90% de) and low to very high enanti-oselectivities (23–90% ee), as shown in Scheme 4.17.

The scope of this methodology was extended to N-Cbz-2,3-dihydropyrrole, which reacted with 2-azadienes under the same reaction conditions to pro-vide the corresponding chiral tetrahydroquinolines with high yields (94–99%), diastereoselectivities (84–>90% de) and enantioselectivities (82–86% ee), as shown in Scheme 4.18.

Moreover, other dienophiles were tolerated, such as ethyl vinyl ether, which led to the desired products as almost single diastereomers (>90% de)

Scheme 4.16 Darzens reaction of isatins with phenacyl bromides.


Scheme 4.17 povarov reaction of 2-azadienes with 2,3-dihydrofuran.

Scheme 4.18 The povarov reaction of 2-azadienes with N-Cbz-2,3-dihydropyrrole.

Chapter 492

in moderate yields (44–64%) and high enantioselectivities (88–89% ee), as illustrated in Scheme 4.19.

4.5 ConclusionsThis chapter collects together enantioselective cobalt-catalysed cyclisa-tion reactions that have been developed in the presence of various types of chiral cobalt complexes derived from salen ligands, biphosphines, por-phyrins, N,N′-dioxides, oxazolines, and amino diols. The use of various salen cobalt complexes has allowed these different types of reactions to be achieved with excellent enantioselectivities. Among them, are rear-rangements of meso-epoxides into chiral cyclic compounds, such as the treatment of meso-1,2 : 4,5-dianhydro-3-O-methylxylitol with water in the presence of (R,R)-Jacobsen's cobalt catalyst, leading exclusively to the formation of an enantiopure d-enantiomer of 1,4-anhydro-3-O-methyl-d- arabinitol in 78% yield. The same catalyst was also successfully applied to promote the intramolecular desymmetrisation of meso-epoxy alcohols into the corresponding almost enantiopure bicyclic products with up to 98% ee in 96% yield. Another type of salen cobalt complex was found to effi-ciently catalyse the asymmetric intramolecular opening of 3-substituted oxetanes into the corresponding chiral functionalised tetrahydrofurans with enantioselectivities of up to 98% ee. A second variety of chiral ligands, such as biphosphines, were applied to develop other highly efficient cycli-sation reactions. For example, (S,S)-Dipamp was used as a ligand to pro-mote the enantioselective cobalt-catalysed cyclisation of o-iodobenzoates with aldehydes, providing the corresponding (S)-phthalides with up to 98%

Scheme 4.19 The povarov reaction of 2-azadienes with ethyl vinyl ether.


ee. excellent enantioselectivities of up to 97% ee were also described using another chiral biphosphine, (R,R)-BDpp, in the enantioselective intramo-lecular hydroacylation of 2-alkenylbenzaldehydes to afford differently sub-stituted chiral indanones in high yields. The scope of this process could be extended to a wide range of trisubstituted alkenes, thus providing chiral 2,3-disubstituted indanones in diastereo- and enantioselectivities of up to >90% de and 97% ee, respectively. A third type of chiral ligands, porphy-rins, provided good results when applied to promote the asymmetric intra-molecular C–h alkylation of acceptor/acceptor-substituted diazo reagents, such as α-methoxycarbonyl-α-diazosulfones, to give the corresponding chiral trans-five-membered sulfolane derivatives in high yields combined with diastereo- and enantioselectivities of up to 94% de and 94% ee, respec-tively. The use of other types of ligands also led to interesting high lev-els of enantioselectivity in a variety of cyclisation reactions. For example, a chiral N,N′-dioxide ligand efficiently promoted enantioselective cobalt- catalysed Darzens reactions of N-protected isatins with phenacyl bromides to afford potentially bioactive spiroepoxyoxindoles as single diastereomers with enantioselectivities of up to 95% ee. In another area, the enantiose-lective povarov reaction between 2-azadienes and 2,3-dihydrofuran to give the corresponding chiral tetrahydroquinolines exhibiting three contigu-ous stereocentres with uniformly excellent endo-diastereoselectivity (88–>90% de) and enantioselectivities of up to 90% ee was achieved using an anionic cobalt complex. The same reaction conditions could be applied to the povarov reactions of 2-azadienes with other dienophiles, such as N-Cbz-2,3-dihydropyrrole with 86% ee and ethyl vinyl ether with 89% ee. On the basis of the extraordinary ability of cobalt catalysts to adopt unex-pected reaction pathways, it is obvious that the use of other types of chiral ligands will probably allow in the near future the development of miscella-neous asymmetric cyclisation reactions. The application of these reactions to the total synthesis of naturally occurring and biologically active com-pounds will have to be further developed, since many of them include cyclic structures. Moreover, considering the green aspect of cobalt in comparison with other transition metals, the development of novel enantioselective cobalt-catalysed cyclisation reactions is highly expected.

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19. J. Yang and N. Yoshikai, J. Am. Chem. Soc., 2014, 136, 16748. 20. J. Yang, A. rérat, Y. J. Lim, C. Gosmini and N. Yoshikai, Angew. Chem., Int.

Ed., 2017, 56, 2449. 21. X. Cui, X. Xu, L.-M. Jin, L. Wojtas and X. p. Zhang, Chem. Sci., 2015, 6,

1219. 22. p. F. Kuijpers, M. J. Tiekink, W. B. Breukelaar, D. L. J. Broere, N. p. van Leest,

J. I. van der Vlugt, J. N. h. reek and B. de Bruin, Chem.–Eur. J., 2017, 23, 7945.

23. (a) C. Santelli-rouvier and M. Santelli, Synthesis, 1983, 429; (b) S. e. Denmark, in Comprehensive Organic Synthesis, ed. L. A. paquette, pergamon press, Oxford, 1991, vol. 5, p. 751; (c) K. L. habermas and S. e. Denmark, Org. React., 1994, 45, 1; (d) h. pellissier, Tetrahedron, 2005, 61, 6479.

24. G. Liang, S. N. Gradl and D. Trauner, Org. Lett., 2003, 5, 4931. 25. M. Kawatsura, K. Kajita, S. hayase and T. Itoh, Synlett, 2010, 1243. 26. Y. Kuang, Y. Lu, Y. Tang, X. Liu, L. Lin and X. Feng, Org. Lett., 2014, 16,

4244. 27. J. Yu, h.-J. Jiang, Y. Zhou, S.-W. Luo and L.-Z. Gong, Angew. Chem., Int. Ed.,

2015, 54, 11209.

95


5.1 Reductions of Carbonyl Compounds and Derivatives

5.1.1 Borohydride ReductionsThe reduction of carbonyl compounds is one of the most direct approaches to obtain optically active alcohols from ketones.1 To achieve these reactions, sodium borohydride is the most conventional reducing agent to use due to its stability, high selectivity and ease of handling. While optically active semi-corrin cobalt(ii) complexes were synthesised by Pfaltz et al. in 1989 to promote the highly enantioselective 1,4-reduction with sodium borohy-dride,2 no application to the 1,2-reduction version was reported until 1995, when the group of Mukaiyama reported the first enantioselective borohy-dride 1,2-reduction of ketones catalysed by optically active cobalt complexes.3 As shown in Scheme 5.1, the reduction of a range of aromatic ketones was successfully achieved using pre-modified borohydride arising from NaBH4, tetrahydrofurfuryl alcohol (THFA) and ethanol.4 When promoted by chiral (β-oxoaldiminato) cobalt(ii) complex 1, it led to the corresponding alcohols in high, often quantitative, yields (76–>98%) and generally high enantiose-lectivities (77–97% ee). Later in 2007, this process was reinvestigated by the

CHAPTer 5

Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Reduction Reactions

Chapter 596

same authors who demonstrated that chloroform not only acted as the sol-vent in the reaction, it was also the activator of the cobalt complex.5 There-fore, a catalytic amount of chloroform was sufficient to induce the process in tetrahydrofuran (THF).

In the same area, in 2006, Yamada et al. proposed a novel route to synthesise chiral ortho-fluorinated benzhydrols based on the related enantioselective

Scheme 5.1 First borohydride 1,2-reduction of aromatic ketones.

97Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed

borohydride reduction of the corresponding ortho-fluorinated benzophe-nones (Scheme 5.2).6 In this case, the process was catalysed by an even more sterically hindered chiral cobalt(ii) complex 2, providing both high yields (75–95%) and enantioselectivities (87–97% ee), as shown in Scheme 5.2. The chelation between the fluorine atom and the carbonyl oxygen was shown to enhance the differentiation between the two aryl groups of the benzophe-nones during the enantioselective reduction. The scope of the process was successfully extended to aryl alkyl ketones. These processes allow novel routes to optically active benzhydrols, which are some of the most important frameworks of pharmaceutical compounds.

earlier in 2000, the same authors successfully developed the enantiose-lective borohydride reduction of various acyclic aromatic 1,3-dicarbonyl compounds based on the use of another chiral (β-oxoaldiminato) cobalt(ii) complex, 3. As illustrated in Scheme 5.3, a range of almost enantiopure 1,3-diaryl-1,3-propanediols were conveniently prepared from the corre-sponding symmetrical 1,3-diketones in both uniformly excellent yields (93–>99%) and enantioselectivities (96–99% ee), albeit combined with mod-erate to good diastereoselectivities (52–80% de).7 The further cyclisation of these diols allowed an easy route to enantiopure C2-symmetrical cyclic amines to be achieved.8

Scheme 5.2 Borohydride reduction of ortho-fluorinated benzophenones.

Chapter 598

In 2001, the same authors described the first asymmetric borohydride reduction of acyclic 2-substituted-1,3-diketones using catalyst 2.9 Uniformly excellent diastereoselectivities of 98–99% de were obtained in combination with good to excellent yields (73–97%) and remarkable enantioselectivities (97–99% ee) for the formed optically active 2-substituted-1,3-diaryl-3-hydroxy-propanones, as shown in Scheme 5.4.

Scheme 5.3 Borohydride reduction of symmetrical 1,3-diaryl-1,3-diketones.

Scheme 5.4 Borohydride reduction of 1,3-diaryl-2-alkyl-1,3-diketones.


In the same year, using catalyst ent-3 in the presence of only 0.4 equiv-alents of sodium borohydride, the authors developed a highly chemo-, diastereo-, and enantioselective reduction of various asymmetrical 1,2-dial-kyl-3-phenyl-1,3-diketones, which led to the corresponding anti-aldol-type compounds in moderate yields (41–48%) and both excellent diastereo- and enantioselectivities of 94–99% de and 95–98% ee, respectively, as shown in Scheme 5.5.10

As an extension of this methodology, in 2002 the same authors described the enantioselective reduction of 2-alkyl-3-aryl-2-ketoesters achieved in the presence of 4 mol% of the same catalyst ent-3 in the presence of a base, such as MeONa, to perform the process under dynamic kinetic resolution11 in the presence of 1.2 equivalents of sodium borohydride.12 The correspond-ing optically active anti-2-alkyl-3-hydroxy esters were synthesised in high yields (82–93%), and high diastereo- and enantioselectivities of 83–92% de and 90–95% ee, respectively. In 2003, the same authors reinvestigated these reactions using cobalt catalyst 3.13 In addition to remarkable enantio-selectivities (97–99% ee) combined with good to quantitative yields (68–97%), a generally excellent diastereoselectivity of 99% de was obtained for the produced anti-2-substituted-3-hydroxy esters (Scheme 5.6). Catalyst 3 was also involved in the enantioselective borohydride reduction of various other carbonyl derivatives, including 2-phenacylpyridine, which provided the corresponding chiral amine in 94% yield and 92% ee (Scheme 5.6).14 This process constituted the key step in the synthesis of sedamine. Further-more, enantiomeric catalyst ent-3 was applied to the enantioselective boro-deuteride reduction of p-methyl benzaldehyde, giving the corresponding

Scheme 5.5 Borohydride reduction of asymmetrical 1,2-dialkyl-3-phenyl-1,3-dike - tones.

Chapter 5100

primary alcohol in quantitative yield, with an isotopic purity of >95% and an enantioselectivity of 77% ee.15

Later in 2008, the same authors developed an atropo-enantioselective boro-hydride reduction of biaryl lactones evolving through dynamic kinetic resolu-tion to afford the corresponding chiral opened biaryl products.16 As shown in Scheme 5.7, when the reaction was catalysed by chiral β-ketoiminatocobalt(ii) complex 4, these products were achieved in good to excellent yields (64–96%) and enantioselectivities (80–93% ee). A fast equilibrium between the atro-po-isomers of the biaryl lactones 5-P and 5-M was demonstrated from HPLC analysis. Indeed, the biaryl axis in the lactones remained configuration-ally unstable and produced atropo-enantiomers in equilibrium. The chiral hydride could recognize one of these two atropo-enantiomers (5-M) and selectively attack it to afford the corresponding final axially chiral biaryl com-pounds, which were configurationally stable.

Another application of catalyst 3 was reported by the same authors for the efficient preparation of C2-symmetrically chiral ferrocenyl diols through enantioselective borohydride reduction of the corresponding

Scheme 5.6 Borohydride reductions of 2-alkyl-3-aryl-2-ketoesters and 2-phenacylpyridine.


1,1′-diacylferrocenes.17 As shown in Scheme 5.8, a range of enantiopure C2-symmetrical ferrocenyldiols were achieved in high yields (69–94%) and moderate to excellent dl:meso ratios (80 : 20 to 99 : 1).

The enantioselective reduction of N-diarylphosphinyl imines was also investigated, leading to the corresponding chiral amines in good to high yields (81–97%) and enantioselectivities (91–99% ee) when promoted by closely related catalysts employed at less than 1 mol% of catalyst loading.18 The best results obtained for the reduction of N-diphenylphosphinyl imines into chiral amines with catalyst 1 are collected in Scheme 5.9.

In the course of studying cobalt-catalysed enantioselective borohydride reductions of various ketones,19 the same authors also demonstrated that tetralone derivatives could be reduced into the corresponding alcohols by treatment with NaBH4 in the presence of the same cobalt catalyst 1 in mod-erate to high yields (37–92%) and enantioselectivities (67–91% ee) under continuous-flow conditions (Scheme 5.10).20 In 2006, these authors demon-strated, on the basis of experimental and theoretical studies, that the key reactive intermediate of borohydride reduction catalysed by Schiff base− cobalt(ii) complexes in chloroform was a dichloromethylcobalt hydride with a sodium cation, for example that depicted in Scheme 5.10 for the present reaction.4d Thus, the initial cobalt(ii) catalyst (1) was converted in chloroform

Scheme 5.7 Borohydride reduction of biaryl lactones through dynamic kinetic resolution.

Scheme 5.8 Borohydride reduction of 1,1′-diacylferrocenes.

Scheme 5.9 Borohydride reduction of N-diphenylphosphinyl imines.


into the corresponding dichloromethylcobalt hydride 6 with a sodium cation intermediate. Indeed, chloroform was not only a suitable solvent, but it also served as an activator for the cobalt complex to generate this essential reac-tive dichloromethycobalt hydride with the sodium cation intermediate that catalysed the borohydride reduction.

Although the aryl carbonyl derivatives are suitable substrates for achiev-ing high enantioselectivities in the borohydride reduction, the enantio-selective reduction of aliphatic ketones still needed to be developed. In this context, the same authors have recently designed a novel in situ generated cobalt(iii) complex 7 exhibiting a 1-chlorovinyl group.21 They demonstrated that this active complex 7 was derived from catalyst ent-1 by treatment with sodium borohydride in 1,1,1-trichloroethane. As shown in Scheme 5.11, catalyst ent-1 first generated the corresponding intermediate

Scheme 5.10 Borohydride reduction of tetralones under continuous-flow conditions.

Chapter 5104

Scheme 5.11 Borohydride reductions of aliphatic ketones.


dichloroethyl–cobalt complex 8, which was further converted into the active cobalt complex 7 via the elimination of hydrogen chloride due to the acidity of the terminal methyl group. The active complex 7 then underwent the classic mechanism of borohydride reduction of ketones.4d This in situ gen-erated catalyst was found to provide moderate to high enantioselectivities (61–90% ee) in the enantioselective reduction of various aliphatic ketones 9a–e including dialkyl ketones and 1-adamantyl ketones 9f–h into the cor-responding alcohols 10a–h, along with low to excellent yields (16–97%). Very recently, the same authors demonstrated that the corresponding reus-able and recyclable cobalt system could also efficiently induce chirality in comparable reactions.22

Always in the area of salen cobalt catalysts, it must be noted that in 1999, Kim et al. investigated the catalytic activity of novel chiral salen cobalt com-plexes immobilised on mesoporous MCM-41 by grafting in the enantiose-lective borohydride reduction of aromatic ketones.23 These complexes were synthesised from 3-aminopropyltrimethoxysilane and 2,6-diformyl-4-tert- butylphenol through a multi-grafting method, which presented the advan-tage that the ligand preferentially binds at locations on the MCM-41 surface accessible for the substrate during the catalytic reaction. A relatively high enantioselectivity was obtained as compared with the corresponding homo-geneous salen catalysts. In 2015, Lu et al. demonstrated that cobalt catalysts other than salen complexes, such as complex 11 derived from a chiral imino-pyridine oxazoline ligand, could promote the highly enantioselective hyd-roboration of aryl ketones with HBPin under mild conditions.24 As shown in Scheme 5.12, the reaction of a range of aryl ketones in the presence of 2.5 mol% of catalyst 11 and NaBHet3 as a reductant in diethylether at room temperature led to the corresponding chiral alcohols in good to quantitative yields (71–>99%) and moderate to excellent enantioselectivities (63–>99% ee). In addition to aryl alkyl ketones, diaryl ones could also be hydroborated with up to 90% ee, while dialkyl ketones provided the corresponding products in lower enantioselectivities (17–64% ee).

5.1.2 HydrosilylationsAlthough asymmetric hydrogenation constitutes a successful strategy to pre-pare optically active alcohols and amines, the asymmetric 1,2-hydrosilylation of carbon–heteroatom bonds catalysed by chiral transition metals complexes has emerged as a desirable alternative to asymmetric hydrogenation due to its mild reaction conditions and manipulative simplicity.25 Over the past two decades, a variety of chiral transition metal catalysts, especially those based on titanium, zinc, tin, copper and iron, have been broadly applied to promote enantioselective 1,2-hydrosilylation reactions with moderate to excellent enantioselectivities. On the other hand, the asymmetric hydrosilylation of ketones mediated by cobalt has received relatively moderate attention, since the pioneering works reported by Brunner and Amberger in 1991.26 In this early work, in situ generated chiral cobalt(i)/pyridinyloxazoline complexes

Chapter 5106

provided moderate enantioselectivities of up to 56% ee in the hydrosilyla-tion of acetophenones with diphenylsilane. A breakthrough came in 2010 when Nishiyama and co-workers reported the highly efficient cobalt(ii) com-plex of chiral bis(oxazolinylphenyl)amine 12, allowing enantioselectivities of up to 98% ee to be achieved.27 As shown in Scheme 5.13, a range of alkyl aryl ketones were successfully converted into the corresponding alcohols, by reaction with (etO)2MeSiH followed by hydrolytic work up, in uniformly excellent yields (95–99%) and high enantioselectivities in almost all cases of the substrates studied. Indeed, with the exception of 1-acetyl naphthalene, which provided the lowest enantioselectivity of 60% ee, other ketones, such as variously substituted phenyl ketones or 2-acetyl naphthalene derivatives, provided higher enantioselectivities (87–98% ee).

Later in 2012, Gade et al. designed a novel family of chiral C2 symmet-ric tridentate monoanionic N,N,N-pincer ligands based on the 1,3-bis(2- pyridylimino)isoindoline framework to be investigated as cobalt ligands in the asymmetric hydrosilylation of several aryl methyl ketones with tertiary

Scheme 5.12 Borohydride reduction of aryl ketones in the presence of a cobalt com-plex derived from a chiral iminopyridine oxazoline ligand.


silanes, such as (etO)2MeSiH.28 As shown in Scheme 5.14, the tetracoordi-nated chiral cobalt alkyl complexes 13ab proved to be highly efficient pro-moters of this reaction, since the corresponding alcohols were obtained in moderate to quantitative yields (58–>99%) and low to high enantioselec-tivities (25–91% ee) after subsequent hydrolytic work up. Various substi-tuted phenylmethylketones and naphthylmethylketones were successfully employed as substrates to establish the substrate scope. It was shown that electron-rich as well as electron-poor groups at the 3,4- or 5-position had no effect on the productivity and enantioselectivity of the catalytic hydrosilyla-tion. On the other hand, substitution at the aromatic ring at the 2-position to the keto group led to a significant decrease in activity and enantioselec-tivity of the reaction, while 2,6-disubstituted acetophenones underwent no catalytic reduction at all. Whereas backbone substitution in the ligand had no significant effect on the catalytic performance, substitution at the chiral center in the wingtips of the pincers seemed to influence the catalyst stability and performance.

earlier in 2011, another asymmetric hydrosilylation of aryl alkyl ketones was described by Chan et al.29 This process employed PhSiH3 as the hydride donor, and a cobalt catalyst in situ generated from a chiral dipyridylphos-phine, (S)-Xyl-P-Phos, and Co(OAc)2·4H2O. It constituted the first effective cobalt(ii)-diphosphine-catalysed hydrosilylation system, providing a range

Scheme 5.13 Hydrosilylation of alkyl aryl ketones in the presence of a chiral bis-(oxazolinylphenyl)amine ligand.

Chapter 5108

of chiral alcohols in generally low to quantitative yields (6–99%) and mod-erate to excellent enantioselectivities (51–94% ee) after subsequent hydro-lytic work up, as shown in Scheme 5.15. It must be noted that the reaction activities were dependent on the electronic nature of the substituents on the arene ring of the substrates. For example, only a trace of reaction product was synthesised for acetophenone or p-methylacetophenone. Nonetheless, the aryl alkyl ketones embodying the electron-withdrawing substituents on the phenyl group were apparently more conducive to both faster reaction rates and higher enantioselectivities. Moreover, it was found that the positioning of the substituents on the phenyl ring of the ketones had a dramatic effect on the reaction outcomes. For example, acetophenone with an NO2 group sub-stituted at either the para- or meta-position resulted in a quantitative yield and high enantioselectivities (85–89% ee), while the corresponding sterically hindered ortho-substituted reagent provided a low yield (6%) and a moderate enantioselectivity of 51% ee.

In 2016, Lu and Chen reported enantioselectivities of up to >99% ee in the enantioselective hydrosilylation of simple aryl alkyl ketones promoted by a chiral cobalt catalyst in situ generated from CoCl2 and the novel chiral iminophenyl oxazolinylphenylamine ligand 14 in dichloromethane at room

Scheme 5.14 Hydrosilylation of alkyl aryl ketones catalysed by tetracoordinated chi-ral cobalt alkyl complexes.


temperature (Scheme 5.16).30 The reaction involved (etO)3SiH as a reducing agent and NaBHet3 as the activating agent of the precatalyst. It led to a range of optically active aromatic alcohols in good to quantitative yields (71–98%) and uniformly excellent enantioselectivities (90–>99% ee). Notably, in most cases, very low catalyst loadings were employed, since only 0.5 mol% of CoCl2 combined with 0.8 mol% of ligand 14 was sufficient enough to achieve excellent results.

5.1.3 HydrogenationsThe enantioselective metal-catalysed hydrogenation of ketones is a direct method to prepare optically active alcohols, which constitute important intermediates in organic synthesis. Along with expensive and toxic metal complexes based on ruthenium, rhodium and iridium, chiral cobalt com-plexes have been rarely applied to the hydrogenation of ketones and, more-over, with only moderate enantioselectivities. In this context, Li et al. recently reported the synthesis of novel chiral cobalt complex 15 containing a chiral PNNP-type ligand, which was further investigated to promote the hydroge-nation of various aromatic ketones.31 employed at only a 2 mol% catalyst

Scheme 5.15 Hydrosilylation of alkyl aryl ketones in the presence of a chiral dipyr-idylphosphine ligand.

Chapter 5110

loading in methanol at 100 °C in the presence of KOH as a base, the reac-tion afforded a range of chiral aromatic alcohols in low to quantitative yields (31–99%) combined with low to excellent enantioselectivities (35–92% ee), as shown in Scheme 5.17.

When this reaction was promoted by the enantiomeric catalyst ent-15, it led to the opposite enantiomeric products in comparable yields (35–98%) combined with slightly higher enantioselectivities (54–95% ee), as shown in Scheme 5.18. It must be noted that this study represented the first example of a cobalt-catalysed enantioselective hydrogenation of ketones using molec-ular hydrogen.

Scheme 5.16 Hydrosilylation of aryl ketones in the presence of a chiral iminophenyl oxazolinylphenylamine ligand.


5.2 Reductions of Alkenes5.2.1 Reductions with Borane Derivatives

5.2.1.1 Borohydride Conjugate ReductionsIn 1989, Pfaltz et al. reported the enantioselective conjugate reduction of (E)-α,β-unsaturated carboxylates with sodium borohydride promoted by cat-alytic amounts (1–1.2 mol%) of chiral cobalt semicorrin complexes, such as that in situ generated from CoCl2 and chiral ligand 16.2 The corresponding

Scheme 5.17 Hydrogenation of aromatic ketones with chiral cobalt complex 15 con-taining a chiral PNNP-type ligand.

Scheme 5.18 Hydrogenation of aromatic ketones with chiral cobalt complex ent-15.

Chapter 5112

chiral esters were achieved in both good to high yields (84–97%) and enantio-selectivities (73–96% ee), as illustrated in Scheme 5.19.

Later, the same authors extended the same catalyst system to the highly enantioselective conjugate reduction of (E)-α,β-unsaturated carboxamides.32 Uniformly excellent enantioselectivities (92–99% ee) combined with high to quantitative yields (87–99%) were achieved for the corresponding formed amides using cobalt catalyst 16, as shown in Scheme 5.20. Furthermore, a remarkably lower catalyst loading of 0.12 mol% constituted a supplementary attractive attribute to this exceptional process.

Among the various primary and secondary amides studied, the corre-sponding (Z)-isomers were also examined under similar reaction conditions. As shown in Scheme 5.21, they led to the corresponding chiral amides in comparable and remarkable enantioselectivities (93–97% ee) and yields (96–99%).32 In 2003, Yamada et al. reinvestigated these reactions using chiral β-ke-toiminato cobalt(ii) complexes. For example, using catalyst 1 (Scheme 5.1) at a 2 mol% catalyst loading in tetrahydrofurfuryl alcohol led to enantioen-riched amides in moderate to excellent yields of 41–98%, combined with low to moderate enantioselectivities (27–60% ee),33 while using 0.075 to 0.5 mol% of catalyst 17 (Scheme 5.21) provided chiral amides in good to high yields (69–99%) and better enantioselectivities (49–91% ee).34 It is reasonable to assume that a cobalt–enolate equivalent derived from the α,β-unsaturated carboxamide was generated as a reactive intermediate (Scheme 5.21). The latter was subsequently protonated by ethanol in an enantioselective manner to afford the final chiral carboxamide.

In 2005, reiser et al. introduced the use of more readily available chi-ral azabis(oxazoline) ligands in an enantioselective conjugate reduction of

Scheme 5.19 First conjugate reduction of (E)-α,β-unsaturated carboxylates in the presence of a bidentate nitrogen chiral ligand.


α,β-unsaturated esters with sodium borohydride.35 Several differently substi-tuted chiral ligands were screened and the phenyl-substituted ligand 18 was selected as the optimal ligand, allowing high to excellent enantioselectivities (92–97% ee) to be achieved in combination with high yields (85–89%) for the conjugate reduction of various aromatic as well as aliphatic α,β-unsaturated

Scheme 5.20 Conjugate reduction of (E)-α,β-unsaturated carboxamides in the pres-ence of a bidentate nitrogen chiral ligand.

Scheme 5.21 Conjugate reduction of (Z)-α,β-unsaturated carboxamides in the pres-ence of bidentate nitrogen and a salen chiral ligand.

Chapter 5114

esters into the corresponding esters (Scheme 5.22). Moreover, the scope of this methodology was successfully extended to the reduction of other Michael acceptors, such as γ-butyrolactones and α,β-unsaturated amides, which afforded the corresponding reduced products in moderate to high yields of 54–65% and 81–88%, respectively, in combination with enantiose-lectivities of up to 86% ee and 95% ee, respectively.

Later in 2010, Fraile et al. reported a study on the recycling possibil-ities for chiral azabis(oxazoline)-cobalt complexes as catalysts for the enantioselective conjugate addition of NaBH4 to ethyl (E)-3-phenylbut-2-enoate.36 They demonstrated that the best method for recycling was the use of a liquid–liquid biphasic system. In this context, the use of a cobalt complex of chiral ditopic azabis(oxazoline) 19 in 1,3-bis(2,2,2-trifluoroe-thoxy)propan-2-ol (BTFeP) as a solvent was shown to allow the conjugated reduction of the substrate with an excellent enantioselectivity of 96% ee to be achieved in combination with a quantitative yield (99%), as shown in Scheme 5.23. Moreover, the authors found that this catalytic system could be re-used for 5 runs.

In 2015, a novel cobalt complex 20 derived from a chiral diamidine ligand was demonstrated by Kitamura et al. to catalyse the asymmetric NaBH4 conjugate reduction of C3-disubstituted 2-propenoates to give the corre-sponding chiral esters in both high yields (72–98%) and enantioselectiv-ities (84–>98% ee).37 Notably, the process employed, under mild reaction conditions (25 °C), a low catalyst loading of only 1 mol% of complex 20 (Scheme 5.24). In all cases of the substrates, the reaction provided excellent enantioselectivities (94–>98% ee) excepted for C3-diaryl substituted ones (r1 = Ph, r2 = p-MeOC6H4 or p-F3CC6H4), which led to the corresponding products in slightly lower enantioselectivities (84–88% ee). Generally, the

Scheme 5.22 Conjugate reduction of α,β-unsaturated esters in the presence of a chi-ral azabis(oxazoline) ligand.


substrates exhibiting an E-configuration led to the corresponding (R)-en-antiomers while the Z-diastereomeric substrates provided the opposite enantioselectivity.

5.2.1.2 HydroborationsThe catalytic asymmetric hydroboration of alkenes constitutes an effi-cient atom-economical method for the synthesis of chiral alkylboronic acid derivatives, which are important intermediates in synthesis as they are able to be converted into various functional groups via consecutive

Scheme 5.23 Conjugate reduction of ethyl (E)-3-phenylbut-2-enoate in the presence of a chiral ditopic azabis(oxazoline) ligand.

Scheme 5.24 Conjugate reduction of C3-disubstituted 2-propenoates catalysed by a cobalt complex derived from a chiral diamidine.

Chapter 5116

carbon–carbon and carbon–heteroatom bond formation reactions.38 Due to the difficulty in differentiating between two enantiotopic faces in prochi-ral substrates, the asymmetric hydroboration of 1,1-disubstituted alkenes is still challenging. Along with rhodium, iridium, copper and iron catalysts, chiral cobalt complexes have been found to be even more active promotors for the asymmetric hydroborations of 1,1-disubstituted alkenes. For exam-ple, Huang et al. have reported excellent enantioselectivities of 92–99% ee when these reactions were catalysed in THF at 25 °C with only 0.5 mol% of novel cobalt(ii) complex 21, derived from a chiral iminopyridine–oxaz-oline ligand (Scheme 5.25).39 Indeed, the asymmetric hydroboration of a wide range of 1,1-disubstituted aryl alkyl alkenes with HBPin afforded the corresponding chiral α-alkyl-β-pinacolatoboranes with exclusive anti- Markovnikov regioselectivity in high yields (69–98%) and uniformly excel-lent enantioselectivities (92–99% ee). However, when the reaction condi-tions were applied to the asymmetric hydroboration of 1,1-diarylethenes, much lower enantioselectivities were observed (8–54% ee) in combination with low to good yields (19–84%).

Comparable reactions were also performed by the same authors in the presence of the cobalt complex 22 derived from another chiral iminopyri-dine–oxazoline ligand.40 In this case, the process employed NaBHet3 as an activating agent at room temperature in toluene or under solvent-free con-ditions. A range of 1,1-disubstituted aryl alkyl alkenes reacted with HBPin to provide the corresponding chiral α-alkyl-β-pinacolatoboranes with an exclusive anti-Markovnikov regioselectivity in moderate to excellent yields

Scheme 5.25 Hydroboration of 1,1-disubstituted aryl alkyl alkenes catalysed by a cobalt(ii) complex derived from a chiral iminopyridine–oxazoline.


(45–96%) and enantioselectivities (53–>99% ee), as shown in Scheme 5.26. Notably, uniformly excellent enantioselectivities (95–>99% ee) were obtained in the reaction of almost all of the substrates except for ortho-substituted styrenes (Ar = o-Tol or o-FC6H4, r = Me, 66–84% ee) and naphthyl-substituted alkenes (Ar = 1-Naph, r = Me, 53% ee).

Since no examples of the enantioselective hydroboration of vinylsilanes had been previously reported, the same authors successfully applied cata-lyst 22 to develop the first asymmetric hydroboration of α-silyl alkenes.41 As shown in Scheme 5.27, the reaction of the latter with HBPin in the presence of 5 mol% of catalyst 22 and NaBHet3 as a reductant in toluene at 25 °C led regioselectively to the corresponding chiral anti-Markovnikov products in good yields (76–82%) and enantioselectivities (80–85% ee).

Another closely related cobalt catalyst 23 was used by the same authors for the asymmetric anti-Markovnikov hydroboration of challenging sterically hindered styrenes.42 When 5 mol% of this catalyst was employed in the pres-ence of NaBH(s-Bu)3 in THF at 25 °C, the hydroboration with HBPin led to the corresponding products in moderate to high yields (47–86%) and enantiose-lectivities (57–95% ee), as shown in Scheme 5.28.

Scheme 5.26 Hydroboration of 1,1-disubstituted aryl alkyl alkenes catalysed by a cobalt complex derived from another chiral iminopyridine–oxazoline ligand.

Chapter 5118

Scheme 5.27 Hydroboration of α-silyl alkenes catalysed by a cobalt complex derived from a chiral iminopyridine–oxazoline ligand.

Scheme 5.28 Hydroboration of sterically hindered styrenes catalysed by a cobalt complex derived from a chiral iminopyridine–oxazoline ligand.


In addition, these authors discovered that by using another cobalt cat-alyst in situ generated from CoCl2 and chiral oxazoline aminopyridine ligand 24 under the same reaction conditions, the process led to enantio-meric products. As shown in Scheme 5.29, these products were obtained in slightly lower yields (35–81%) and moderate to high enantioselectivities (65–95% ee).

5.2.2 HydrosilylationsIn 2010, Nishiyama et al. reported moderate to good enantioselectivities in the cobalt-catalysed asymmetric conjugate hydrosilylation of enones with (etO)2MeSiH using chiral bis(oxazolinylphenyl)amine ligands.27 As shown in Scheme 5.30, the hydrosilylation of α,β-unsaturated ketones provided the cor-responding reduced ketones in high yields (90–93%) and moderate to good enantioselectivities (65–75% ee) using a combination of Co(OAc)2 with chiral ligand Bopa-dpm. The authors selected this cobalt catalyst as the optimal one

Scheme 5.29 Hydroboration of sterically hindered styrenes in the presence of a chi-ral oxazoline aminopyridine ligand.

Chapter 5120

among a range of complexes including related nickel, copper and iron ones. While nickel and copper acetates did not show the expected catalytic activity for the present reaction, cobalt(ii) acetate strongly promoted the reaction in comparative high yields and with higher enantioselectivities than its iron counterpart.

In 2017, Lu et al. developed an enantioselective Markovnikov-type hydro-silylation of alkenes with PhSiH3 to provide the corresponding chiral dihy-drosilanes.43 The process was promoted at room temperature by 1 mol% of cobalt complex 25 derived from a chiral iminopyridine oxazoline ligand in the presence of NaOt-Bu in diethylether. The reaction was found to be suitable for a wide range of both aryl and aliphatic alkenes with excellent functional group tolerability, allowing a variety of chiral dihydrosilanes to be synthesised in moderate to high yields (53–97%) with high enantioselec-tivities (81–>99% ee), as illustrated in Scheme 5.31. In particular, uniformly remarkable enantioselectivities (98–>99% ee) were achieved in the reaction of vinylarenes, while aliphatic alkenes led to the corresponding products in lower enantioselectivities (81–87% ee) and yields (53–91% vs. 62–94%). Moreover, using the opposite enantiomeric ligand, the authors obtained the opposite enantiomers of the silanes.

5.2.3 HydrogenationsThe asymmetric hydrogenation of alkenes is one of the most prominent and well-established methods for the synthesis of enantiomers and has found numerous applications in the pharmaceutical, agrochemical and

Scheme 5.30 Conjugate hydrosilylation of α,β-unsaturated ketones.


fine-chemical industries. The vast majority of catalysts used in these pro-cesses are based on precious metals with ruthenium, rhodium and iridium catalysts being the most common.44 replacing these expensive and toxic elements with more abundant and environmentally compatible first–row transition metals such as cobalt is attractive and an area gaining renewed attention. In this context, in 1981 Ohgo et al. investigated the asymmetric hydrogenation of alkenes using dimethylglyoximatocobalt(ii) complexes in the presence of quinine, which provided only low to moderate optical yields (7–49% ee).45 Later in 2012, Chirik et al. employed enantiopure C1-symmet-ric bis(imino)pyridine cobalt complexes for the asymmetric hydrogenation of geminal-disubstituted olefins.46 Chiral C1-symmetric bis(imino)pyri-dine cobalt chloride, methyl, hydride and cyclometalated complexes were investigated as catalysts for the enantioselective hydrogenation of a range of styrenes. Among these complexes, C1-symmetric bis(imino)pyridine cobalt methylmetalated complex 26, in which one imine is anchored by a large 2,6-diisopropylphenyl ring and the other is derived from enantiopure (S)-2-cyclohexyl ethylamine, was proved to be the optimal catalyst to pro-vide hydrogenated products in low to excellent yields (5–>98%) combined with moderate to excellent enantioselectivities (66–>98% ee), as shown in Scheme 5.32. It was noted that a higher activity was observed for less

Scheme 5.31 Hydrosilylation of alkenes.

Chapter 5122

hindered substrates, and that introduction of electron-donating and elec-tron-withdrawing groups at the 4-position of the styrene had little impact on the activity, but generally increased the enantioselectivity, except for fluoro- and trifluoromethyl derivatives. The best results were achieved for phenylated alkenes with enantiomeric excesses of 80–98% ee, with the more sterically crowded olefins producing higher selectivity, albeit with reduced activity. Importantly, the presence of coordinating functionalities on the ole-fin was not required for a high enantiomeric excess.

Later in 2015, the same authors applied the same catalyst system to pro-mote the asymmetric hydrogenation of cyclic alkenes in toluene at 25 °C.47 As shown in Scheme 5.33, moderate to high yields (41–98%) and uniformly excellent enantioselectivities (91–99% ee) were achieved in the reaction of substituted benzo-fused five- and six-membered alkenes to give the cor-responding products. The stereochemical outcome of the reaction was dependent on both the ring size and exo/endo disposition of the C=C bond to be hydrogenated. For example, while endocyclic alkenes 27 led to enantiomers 28, exocyclic alkenes 29 generally yielded the opposite enan-tiomers 30 in high yields (84–97%). Moreover, better enantioselectivities were obtained in the hydrogenation of endocyclic alkenes (91–99% ee vs. 53–85% ee).

In 2016, Lu et al. reported the first highly enantioselective hydrogenation of 1,1-diarylalkenes promoted by a combination of a metal and a chiral base ligand.48 As shown in Scheme 5.34, this reaction was catalysed in toluene

Scheme 5.32 Hydrogenation of styrenes.


at room temperature with 5 mol% of chiral cobalt complex 22, exhibiting a chiral oxazoline iminopyridine ligand in the presence of NaBHet3 as a reducing agent. It led to the corresponding chiral 1,1-diarylethanes in high to quantitative yields (77–>99%) and moderate to excellent enantioselectiv-ities (58–>99% ee). A unique o-chloride effect was observed to achieve high enantioselectivity. Indeed, 1-(2′-chlorophenyl)-1-arylethenes provided the best enantioselectivities (85–>99% ee). Furthermore, a wide range of other substituents could also be present along with this chloride atom on the phenyl ring, as well as on the second aryl group. The utility of this protocol was related to the easy dechlorination of the products by treatment with HCO2NH4 on Pd/C.

Scheme 5.33 Hydrogenations of endo- and exocyclic alkenes.

Chapter 5124

In another area, there have been only a few reports on the asymmetric hydrogenation of β-enamino esters, especially using chiral cobalt catalysts. Among them, Cabrera and Amezquita-Valencia investigated these reactions in 2014 in the presence of different ligands including (R)-BINAP and its derivatives, (R,R)-DIOP, (R,R)-Me-DuPhos and (R)-PrOPHOS.49 The authors demonstrated that a combination of Co2(CO)8 with (R)-BINAP was the optimal catalytic system for the asymmetric hydrogenation of a range of β-enamino esters, since the corresponding chiral amino esters were obtained in high yields (82–93%), albeit with low enantioselectivities (4–43% ee), as shown in Scheme 5.35.

5.3 ConclusionsThe uniformly excellent enantioselectivities described in this chapter well reflect the wide possibilities of chiral cobalt catalysts of various types to promote all types of enantioselective reduction reactions spanning from those of carbonyl compounds and their derivatives to those of the alkenes. They involve borohydride reductions, hydrosilylations and hydrogenations, but also hydroborations in the case of alkenes as substrates. Since the first

Scheme 5.34 Hydrogenation of 1,1-diarylethenes.


enantioselective borohydride 1,2-reduction of ketones was reported in 1995 by Mukaiyama using chiral (β-oxoaldiminato) cobalt(ii) complexes, which afforded the corresponding alcohols in high enantioselectivities of up to 97% ee, many cobalt complexes of this type have been success-fully applied to the borohydride reduction of a range of carbonyl com-pounds and their derivatives. Therefore, excellent enantioselectivities were achieved in almost all cases of many types of substrates, such as ortho- fluorinated benzophenones (97% ee), symmetrical 1,3-diaryl-1,3-diketones (99% ee), 1,3-diaryl-2-alkyl-1,3-diketones (99% ee), asymmetrical 1,2-dial-kyl-3-phenyl-1,3-diketones (98% ee), 2-alkyl-3-aryl-3-ketoesters (99% ee), 2-phenacylpyridine (92% ee), biaryl lactones (93% ee), 1,1′-diacylferrocenes (>99% ee), N-diphenylphosphinyl imines (99% ee), tetralones (91% ee) and even more challenging aliphatic ketones (90% ee). Moreover, cobalt cata-lysts other than chiral (β-oxoaldiminato) cobalt(ii) complexes, such as ones derived from chiral iminopyridine oxazoline ligands have been successfully applied to promote the borohydride reduction of aryl ketones with up to >99% ee. In the area of enantioselective cobalt-catalysed hydrosilylations of ketones, a variety of ligands, such as chiral bis(oxazolinylphenyl)amines, chiral C2 symmetric tridentate monoanionic N,N,N-pincer ligands based on the 1,3-bis(2-pyridylimino)isoindoline framework, chiral dipyridylphos-phine ligands, and chiral iminophenyl oxazolinylphenylamine ligands, have resulted in enantioselectivities of 91–>99% ee. In addition, the area of asymmetric cobalt-catalysed reductions of aromatic ketones through hydrogenation has encountered success with enantioselectivities of up to 95% ee achieved using cobalt complexes containing chiral PNNP-type ligands. Concerning the asymmetric reduction of alkenes, many excellent

Scheme 5.35 Hydrogenation of β-enamino esters.

Chapter 5126

results have been described, in particular in the area of borohydride conju-gate reductions of (E)-α,β-unsaturated carbonyl compounds, since the first one reported by Pfaltz in 1989 concerning (E)-α,β-unsaturated carboxylates as substrates reduced in the presence of cobalt semicorrin chiral complexes with up to 96% ee. For example, enantioselective borohydride conjugate reductions of α,β-unsaturated carboxamides were successfully developed in the presence of bidentate nitrogen chiral ligands and salen ligands with enantioselectivities of up to >98% ee and 97% ee, respectively. More-over, asymmetric borohydride conjugate reductions of α,β-unsaturated esters have been achieved with comparable excellent enantioselectivities (96–>98% ee) using chiral azabis(oxazoline) ligands, chiral ditopic aza-bis(oxazoline) ligands, and chiral diamidine ligands. The reduction of sim-ple alkenes through hydroboration has also provided remarkable results, such as that of the 1,1-disubstituted aryl alkyl alkenes reacted with different cobalt(ii) complexes derived from chiral iminopyridine–oxazoline ligands with up to >99% ee or that of sterically hindered styrenes catalysed by cobalt complexes derived from the same type of ligands or chiral oxazoline amin-opyridine ligands with up to 95% ee. Another type of reduction of alkenes, the enantioselective Markovnikov-type hydrosilylation with PhSiH3, led to enantiopure dihydrosilanes (>99% ee) using derived chiral iminopyridine oxazoline ligands. Finally, the field of asymmetric cobalt-catalysed hydro-genations of alkenes has also been widely developed, providing uniformly excellent enantioselectivities of up to >99% ee. For example, styrenes have been reduced with enantioselectivities of up to >98% ee by employing C1-symmetric bis(imino)pyridine cobalt methylmetalated complexes. The same type of catalysts was also applied to the enantioselective hydrogena-tion of endo- and exocyclic alkenes with up to 99% ee. In addition, cobalt complexes exhibiting a chiral oxazoline iminopyridine ligand allowed the hydrogenation of 1,1-diarylethenes with up to >99% ee. In the near future, further developments in the field of asymmetric cobalt-catalysed reductions are expected by applying other types of chiral ligands and also in the exten-sion of the substrate scopes of the reactions. Furthermore, according to the remarkable enantioselectivities achieved in all of these types of reduction reactions, their application to the total synthesis of natural and/or biologi-cally active products will be undoubtedly developed.

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129


6.1 Hydrolytic and Alcoholytic Ring–Opening of Epoxides

Despite the increased industrial demand for enantiomerically pure com-pounds, to date only a few asymmetric catalytic processes have been used for commercial applications,1 among them, rare exceptions are catalytic kinetic resolutions.2 Indeed, kinetic resolution, as one of the most pow-erful tools in asymmetric catalysis, has found wide applications in both academia and industry, complementing approaches such as asymmetric synthesis and classical resolution.3 A wide number of reactions evolved through kinetic resolution have been developed with high efficiency, such as the nucleophilic ring-opening reactions of racemic epoxides.4 For exam-ple, the hydrolytic kinetic resolution constitutes the simplest methodology for the synthesis of enantiopure epoxides and diols.5 This methodology, first reported by Jacobsen in 1997, employs water as the sole reagent, small amounts of solvent, and often low loadings (0.2–2 mol%) of recyclable chi-ral cobalt(iii)-based complexes,6 and has allowed many building blocks

ChApTer 6

Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Ring–Opening Reactions

Chapter 6130

for the synthesis of complex natural products and pharmaceuticals to be achieved.7 Indeed, the Jacobsen methodology, for enantioselective epoxide ring-opening by water or other nucleophiles, is one of the most import-ant developments in non-enzymatic catalytic kinetic resolution, especially for the hydrolytic ring-opening of epoxides. Therefore, hydrolytic kinetic resolution based on the use of Jacobsen's chiral salen Co(iii) complexes, such as catalyst 1, (and also chiral salen Cr(iii) complexes) has emerged as a powerful and widely used method for resolving a wide range of terminal racemic epoxides, often affording both epoxides and their corresponding ring-opened 1,2-diols in very high enantioselectivities. The use of alkyl-, halo alkyl-, aryl-, vinyl-, and alkynyl-epoxides, including epoxides contain-ing various functional groups, such as sulfones, esters or dialkylphospho-nates affords the corresponding chiral diols, as well as chirally recovered epoxides, in enantioselectivities of 99% ee (Scheme 6.1).2d,8,9 Most of the time, catalyst loadings of as low as 0.01 mol% were sufficient to reach these excellent results. It must be noted that examples of the hydrolytic kinetic resolution of epoxides bearing two stereocentres still remain rare. In one example, a resolved epoxypentenol species was generated in 48% yield and 98% ee and further employed as a key intermediate in the total synthesis of (5S,7R)-kurzilactone.10 Another example was reported by Sudalai et al. who applied the same methodology to a series of benzyloxy- and azido- epoxides, providing a practical way to synthesise a wide range of enantio-pure syn- or anti-alkoxy- and azido-epoxides, along with the corresponding diols.11 To demonstrate its utility, this methodology was employed in the concise enantioselective synthesis of bioactive molecules, such as (S,S)- reboxetine and (+)-epi-cytoxazone. In addition, the efficient total synthe-ses of patulolide C and 11-epipatulolide C,12 and that of (+)-boronolide13

Scheme 6.1 hydrolytic kinetic resolution of epoxides through the Jacobsen methodology.


have been independently described by Sharma and Babu and Kumar and Naidu, respectively, on the basis of the same methodology. Several other biologically active products, such as cryptocarya diacetate,14 yene-polyol macrolide rK-397,15 and macroviracin A16 have involved successful hydro-lytic kinetic resolutions of epoxides bearing at least two stereocentres in their syntheses.

In the same area, the enantiomeric catalyst ent-1 was applied by Sudalai et al. in 2014 to promote hydrolytic kinetic resolution, which constituted the key step of the concise total synthesis of (+)-l-733,060, a potent and selective neurokinin-1 substance p receptor antagonist.17 As shown in Scheme 6.2, this synthesis began with the hydrolytic kinetic resolution of a racemic azido epoxide with water performed in the presence of only 0.5 mol% of the (S,S)-salen–cobalt(iii) acetate complex ent-1, which afforded the corresponding diol in 48% yield and 98% ee, along with the recovered (R,R)-epoxide in 47% yield. Subsequently, the formed diol was converted through eight supple-mentary steps into (+)-l-733,060 in an overall yield of 19%.

Scheme 6.2 hydrolytic kinetic resolution of an azido epoxide catalysed with a salen cobalt complex and an overview of the total synthesis of (+)-l-733,060.

Chapter 6132

Later in 2017, the same authors described the total synthesis of the naturally occurring and biologically active alkaloid DAB-1, the key step of which was the hydrolytic kinetic resolution of another racemic azido epoxide promoted by 1 mol% of catalyst 1 (Scheme 6.3).18 This provided the corresponding almost enantiopure azido diol in 50% yield, which was further converted into the expected DAB-1 through five supplementary steps in an overall yield of 18%.

A related catalyst 2 was employed by the same authors for the phenolic ring-opening of racemic azido (Y = N3) and benzyloxy (Y = OBn) epoxides.19 As shown in Scheme 6.4, the reaction of a range of racemic anti-azido and -benzyloxy epoxides with variously substituted phenols in the presence of 4.4 mol% of catalyst 2 in methyl tert-butyl ether (MTBe) at 25 °C led to the cor-responding chiral anti-1-aryloxy-3-azido or benzyloxy-2-alcohols in moderate to excellent yields (35–98%) and enantioselectivities (68–99% ee). In the case of the use of azido epoxides as substrates, a wide range of phenols bearing either electron-donating or electron-withdrawing groups reacted efficiently, delivering the corresponding products in good to high yields and enantiose-lectivities, whereas benzyloxy epoxides underwent the reaction only when electron-deficient phenols were used.

The utility of this methodology was demonstrated in its application to the total synthesis of the β-blocker ICI-118,551 using an enantiopure anti-1-aryloxy-3-azido product thus formed (99% ee) as an intermediate (Scheme 6.5).19

Scheme 6.3 hydrolytic kinetic resolution of another azido epoxide catalysed with a salen cobalt complex and an overview of the total synthesis of DAB-1.


Scheme 6.4 phenolic ring-opening of azido and benzyloxy epoxides catalysed with a salen cobalt complex.

Scheme 6.5 An overview of the total synthesis of ICI-118,551.

Chapter 6134

Among the advantages of the hydrolytic kinetic resolution methodology are its broad applicability over a range of simple as well as functionalised terminal epoxides, high enantioselectivity, remarkable practical appeal and low catalyst loading. Unsurprisingly, the generality and broad substrate specificity of hydrolytic kinetic resolution has been exploited for the pro-duction of a wide range of chiral synthons for the synthesis of natural prod-ucts and bioactive compounds.20,21 Detailed mechanistic investigations on hydrolytic kinetic resolution using monomeric salen metal catalysts have revealed second-order kinetic dependence on catalyst concentration, and point to a cooperative mechanism of catalysis.8a Various strategies have been explored for overcoming the entropic price of bringing two catalyst mole-cules together in the rate-limiting transition state, thereby enhancing the catalytic efficiency in the hydrolytic kinetic resolution. In this context, cat-alysts derived from cyclic ligands that contain more than one metal centre in close proximity to one another might display enhanced reactivity relative to conventional monomeric salen catalyst systems. Successful approaches identified to date include construction of covalently-linked dimers. For each dimeric catalyst, enhanced reactivity relative to monomeric catalysts has been demonstrated.22 For example, a recyclable dimeric homochiral salen Co(iii) complex 3 (Scheme 6.6) developed by Kureshy et al.,23 a chiral bime-tallic Co(iii) salen-calix[4]arene hybrid,24 and a chiral macrocyclic dinuclear salen cobalt complex,25 both developed by Kleij et al., as well as various dimeric chiral salen cobalt complexes activated by InCl3, GaCl3 or BF3 and developed by Kim et al., have allowed remarkable enantioselectivities of up to 98% ee for the corresponding diols and >99% ee for the recovered epox-ides to be obtained.26

Scheme 6.6 hydrolytic kinetic resolution of epoxides catalysed with a dimeric salen Co(iii) complex.


Bimetallic chiral salen cobalt catalysts containing transition-metal salts have also been demonstrated by Kim et al. to be highly efficient and enanti-oselective in the hydrolytic kinetic resolutions of various epoxides.27 enan-tioselectivities of up to 99% ee for the recovered epoxides combined with enantioselectivities of up to >85% ee for the corresponding ring-opened products and very high catalytic activity could be reached (40–50% yields). Another means for fixing or linking two or more Co(salen) units in close proximity to decrease the catalyst requirements, by making the reaction pseudo first-order with respect to the Co(salen) units, was in the discovery of oligomeric Co(salen) catalyst systems, which exhibited extremely high reactivities and enantioselectivities in the hydrolytic kinetic resolution of a variety of terminal epoxides under neat conditions with exceptionally low catalyst loadings (0.01 mol%).8h,28 Despite these important advances, the discovery of easily recovered and recycled catalysts was needed. In this context, the immobilisation of salen cobalt(iii) complexes on various sup-ports,29 such as polymers,30 gold colloids,31 mesoporous silica,32 or zeolite,33 was recently reported by several authors along with its successful applica-tion in the hydrolytic kinetic resolution of epoxides, providing remarkable enantioselectivities of up to >99% ee. In addition, pozzi et al. have demon-strated that the hydrolytic kinetic resolution of epoxides was feasible under fluorous biphasic conditions.34 It was shown that the nature of the counter anion had a dramatic effect on the catalytic activity of heavily fluorinated chiral salen cobalt(iii) complexes. For example, excellent enantioselectivi-ties of up to 99% ee for both the diols and the epoxides were obtained in the fluorous biphasic hydrolytic kinetic resolution of terminal epoxides when fluorinated anions were introduced. On the other hand, the ring-opening of epoxides can also be performed through dynamic kinetic resolution.35 Therefore, Kunz et al. developed new composite materials, which ideally combine polymer functionalisation with the good mass-transfer properties of the monolithic carriers.36 This unique combination led to the synthesis of versatile materials for organic synthesis, which could be used in a flow-through mode. Based on these monolithic materials with different polymer functionalities, an example of dynamic kinetic resolution is depicted in Scheme 6.7, consisting of the ring-opening of epibromohydrin with water catalysed by complex 4, providing the corresponding chiral bromo alcohol in 76% yield and 91% ee.

Later in 2015, Sun et al. designed novel macroporous helical silica-sup-ported salen cobalt complexes to be investigated in water as chiral cat-alysts in related reactions.37 Among them, catalyst 5, prepared from an (S)-amino alcohol-doped silica and a (R,R)-salen cobalt complex, was found to be the optimal catalyst when used at a 2 mol% catalyst loading in the presence of n-Bu4NBr as an additive. These conditions allowed the recovery of (R)-1,2-epoxybutane (r = et) in moderate yield (46%) and high enantioselectivity (91% ee) along with the formation of the correspond-ing chiral diol in comparable yield (49%) and enantioselectivity (91% ee),

Chapter 6136

as shown in Scheme 6.8. Moreover, styrene oxide (r = ph) was also com-patible with the catalyst system, providing the recovered (R)-epoxide in 50% yield and 95% ee along with the corresponding diol in 46% yield and 89% ee.

earlier in 2014, Jacobsen et al. reported the synthesis of novel cyclic oligomeric salen cobalt catalysts to be applied to promote related reac-tions.38 Among them, oligomeric chiral complex 6 employed at remark-ably low catalyst loadings (0.0003 to 0.04 mol%) was selected as the optimal catalyst to prepare a series of enantiopure terminal (S)-epoxides in moderate yields (35–44%) at 23 °C starting from the corresponding racemic ones (Scheme 6.9, first reaction scheme). The efficiency of this catalyst was also applied to the regioselective phenolytic ring-opening of terminal epoxides performed at the same temperature in acetonitrile (Scheme 6.10, second reaction scheme). Indeed, the ring-opening of epox-ides with phenols, bearing a broad range of electron-withdrawing and electron-donating substituents at the ortho, meta, and para positions, was accomplished with catalyst loadings of lower than 0.1 mol% in nearly all cases. The corresponding chiral alcohols were formed in uniformly excel-lent yields (79–97%) and enantioselectivities (97–>99% ee). Moreover, the regioselective ring-opening of epoxides with aliphatic alcohols could be performed under comparable reaction conditions, providing a range of chiral monoprotected 1,2-diols in high to quantitative yields (80–>99%) and remarkable enantioselectivities (98–>99% ee), as shown in Scheme 6.9 (third reaction scheme).

The hydrolysis of meso-epoxides derived from cyclic alkenes represents an attractive approach to chiral diols that are not accessible via asymmetric

Scheme 6.7 polymer-supported hydrolytic dynamic kinetic resolution of epibromohydrin.


alkene dihydroxylation. In this context, the same authors showed that oligomeric salen cobalt complex 6 employed at a 1 or 2.5 mol% catalyst loading was a highly efficient catalyst for the hydrolytic desymmetrisa-tion of a variety of cyclic meso-epoxides (Scheme 6.10).38 Indeed, the corre-sponding chiral trans-1,2-diols were obtained in good to quantitative yields (76–>99%) and generally excellent enantioselectivities (96–99% ee). A lower enantioselectivity of 72% ee was observed in the case of a seven-membered substrate (X = (Ch2)3).

The same year, the synthesis of another type of oligomeric salen cobalt complex was reported by Schulz et al.39 These chiral calix-salen cobalt com-plexes were investigated as catalysts to promote the asymmetric hydrolytic ring-opening of epibromohydrin. As illustrated in Scheme 6.11, the use of the optimal cyclic tetramer complex 7 at a 2 mol% catalyst loading in ThF at room temperature allowed, through dynamic kinetic resolution, the cor-responding diol to be obtained with complete conversion (>99%) and high enantioselectivity (92% ee). Importantly, the catalyst could be easily recov-ered from the reaction mixture by simple filtration and reused in other runs

Scheme 6.8 hydrolytic kinetic resolution of terminal epoxides catalysed with a macroporous helical silica-supported salen cobalt complex.

Chapter 6138

Scheme 6.9 hydrolytic, phenolytic and alcoholytic ring-openings of terminal epox-ides catalysed with an oligomeric salen cobalt complex.


to produce the diol with steady enantioselectivity values (89–95% ee), albeit with decreased conversions (63–95%).

Later in 2016, the same authors reinvestigated this reaction using a com-bination of chiral oligomeric cobalt- and manganese-based calix-salen complexes as catalysts.40 As shown in Scheme 6.12, when the asymmetric ring-opening of epibromohydrin was performed at room temperature in ThF solvent in the presence of 1 mol% of cobalt catalyst 8 and the same quantity of manganese catalyst 9, it afforded the corresponding chiral diol in both excellent yield (97%) and enantioselectivity (92% ee). In this study, the authors showed that using an equimolar combination of these chiral cata-lysts proved to be more enantioselective than using the cobalt system alone. Furthermore, as heterogeneous complexes, the catalytic mixture could be easily recovered by simple filtration and reused in up to eight runs with

Scheme 6.10 hydrolytic desymmetrisation of meso-epoxides catalysed with an oligomeric salen cobalt complex.

Scheme 6.11 hydrolytic ring-opening of epibromohydrin catalysed with a tetram-eric calix-salen cobalt complex.

Chapter 6140

reasonable stability in terms of activity (82–97% conversion) and enantio-selectivity (82–90% ee).

In 2015, Thakur et al. reported the synthesis of dinuclear salen cobalt complex 10, incorporating Y(OTf)3, which was further investigated as a chiral catalyst in the hydrolytic kinetic resolution of terminal epoxides.41 employed at only 0.2 mol% of catalyst loading, it showed higher reactivity and enantioselectivity than its monomer analogue since a range of termi-nal (S)-epoxides could be recovered with uniformly excellent enantioselec-tivities (97–>99% ee) and moderate yields (42–46%), as shown in Scheme 6.13. One advantage of this catalyst was its water tolerance, due to the moisture stability of Y(OTf)3.

6.2 Ring–Opening of Epoxides by Amines and Carbamates

epoxides can also be resolved through ring-opening by nucleophiles other than water, such as amines,42 carbamates, imides, phenol derivatives,8b,43 alcohols,44 azides,8b,45 fluoride,46 carboxylic acids,47 or carbon nucleophiles,48 allowing access to many important chiral functionalised compounds.49

Scheme 6.12 hydrolytic ring-opening of epibromohydrin catalysed with a combina-tion of oligomeric calix-salen cobalt and manganese catalysts.


Among them, chiral β-amino alcohols constitute valuable intermediates in the synthesis of a variety of biologically active compounds and play a very significant role in asymmetric catalysis.50 Various efficient methods have been reported for their synthesis; noteworthy among them is the asymmet-ric ring-opening aminolytic kinetic resolution of racemic terminal epoxides with alkyl/arylamines using different catalysts.2b,51 In particular, carbamates have shown excellent results in the ring-opening of epoxides through kinetic resolution. As an example, Bartoli et al. have used a chiral salen cobalt(iii) complex 11, previously developed by Jacobsen's group, to open terminal epoxides with carbamate Nh2Boc, providing the corresponding Boc-pro-tected 1,2-amino alcohols in moderate yields (41–44%) with an exceptionally high enantioselectivity of >99% ee, as shown in Scheme 6.14.52 Notably, the selectivity factors were found to be >500 for all of the examples examined. This protocol was later extended to the enantioselective preparation of 5-sub-stituted oxazolidinones, which are known to be valuable structural motifs of medicinally active drugs.53 In 2009, Kureshy et al. reported the use of highly efficient recyclable salen cobalt(iii) complexes in ionic liquids in the cata-lytic kinetic resolution of aryloxy/terminal epoxides with carbamates, which

Scheme 6.13 hydrolytic kinetic resolution of terminal epoxides catalysed with a dinuclear salen cobalt complex incorporating Y(OTf)3.

Chapter 6142

provided high regio- and enantioselectivities of >99% ee for both the amino alcohols and the recovered epoxides.54

In 2016, mesoporous silica-supported salen cobalt complex 12 was designed by Islam and Bhaumik.55 This material showed an excellent cat-alytic activity for the regio- and enantioselective asymmetric ring-opening of terminal epoxides, using aromatic as well as cyclic aliphatic amines, to produce the corresponding chiral β-amino alcohols at ambient tempera-ture under solvent-free conditions (Scheme 6.15, first reaction scheme). These products were achieved in uniformly excellent yields (92–98%) and enantioselectivities (87–>99% ee). The scope of the process was extended to meso-epoxides, such as cyclohexene oxide, which led to the correspond-ing chiral products with high yields (87–97%) and good to excellent enan-tioselectivities (77–>99% ee), as shown in Scheme 6.15 (second reaction scheme). The advantages of this novel heterogeneous catalyst are its easy separation, recyclability and reusability for up to five times without a loss in both activity (≥85% yield) and enantioselectivity (≥88% ee).

In addition, the carbamolytic desymmetrisation of several cyclic meso- epoxides 13a–b through a ring-opening reaction with phenyl carbamate could be achieved at 50 °C using 1–2 mol% of oligomeric catalyst 6 (Scheme 6.16).38 Starting from the six-membered substrates 13a–b, the reaction led to the corresponding trans-4,5-disubstituted oxazolidinones 14a–b in high yields (84–94%) and excellent enantioselectivity (96% ee) through successive ring-opening and intramolecular cyclisation, while the five-membered sub-strates 13c–d (X = O, Ch2) provided the corresponding ring-opened products 15c–d in moderate yields (49–66%), albeit with remarkable enantioselectivity (>99% ee), as shown in Scheme 6.16.

Scheme 6.14 Kinetic resolution of epoxides through ring-opening by carbamates catalysed with a salen cobalt(iii) complex.


6.3 Ring–Opening of Epoxides Through (Co)polymerisation

Chiral cobalt catalysts have also been applied for the enantioselective polymerisation of monosubstituted epoxides in which chiral racemic mono-mers are kinetically resolved during polymerisation. This process provides

Scheme 6.15 Aminolysis of epoxides catalysed with a macroporous silica-supported salen cobalt complex.

Chapter 6144

two desirable products: enantiopure epoxides and stereoregular polyethers. In 2008, Coates et al. reported the first highly enantioselective polymerisa-tion catalyst for the kinetic resolution of monosubstituted epoxides.56 The employed chiral bimetallic cobalt(iii)catalyst 16 exhibited high levels of activity and enantioselectivity (81–>99% ee) for a range of ring-opened iso-tactic polyethers bearing alkyl, aryl and ether substituents (Scheme 6.17). It must be noted that the process employed bis(triphenylphosphine)iminium (ppN) acetate as a cocatalyst and a remarkable low catalyst loading of only 0.025 mol%.

Like most metal-catalysed systems employed to promote the coupling reaction of carbon dioxide and epoxides, cobalt-based catalysts are able to afford both cyclic carbonates and polycarbonate products. The product selectivity of these two processes can be controlled by different parameters, such as temperature, carbon dioxide pressure, nature of the cobalt catalyst used, and also by the use (or not) and nature of a nucleophilic co-catalyst and its relative loading.43k The copolymerisation of monosubstituted epox-ides with CO2 constitutes a powerful method for the synthesis of chiral poly-carbonates.57 A highly enantioselective version of this process was recently developed by Lu et al.58 In their study, the authors investigated the enantiose-lective copolymerisation of cyclohexene oxide with CO2 catalysed by chiral dissymmetrical salen cobalt(iii)NO3 complexes, such as catalyst 17, bearing bulky adamantyl and tert-butyl groups on the phenolate ortho positions, in the presence of bis(triphenylphosphine)iminium chloride (ppNCl) as a nuc-leophilic co-catalyst. This methodology allowed the synthesis of the corre-sponding chiral polycarbonate to be achieved in enantioselectivities of up to 96% ee, as shown in Scheme 6.18. It must be noted that this highly isotactic poly(cyclohexene carbonate) constituted the first semicrystalline CO2-based polycarbonate.

Scheme 6.16 Carbamolytic desymmetrisations of meso-epoxides catalysed with an oligomeric salen cobalt complex.


Scheme 6.17 polymerisation of epoxides.

Scheme 6.18 Copolymerisation of cyclohexene oxide with CO2 catalysed with a dis-symmetrical salen cobalt(iii)NO3 complex.

Chapter 6146

Later, Lu et al. reinvestigated this reaction using 10 mol% of dinuclear salen cobalt complex 18 in toluene at 0 °C in the presence of 20 mol% of bis-triphenylphosphine iminium 2,4-dinitrophenolate (ppN–DNp) as an ionic additive (Scheme 6.19).59 Under these reaction conditions, the chiral polycarbonate was obtained with enantioselectivities of up to 98% ee. The presence of the additive, bearing a bulky cation, was found to significantly improve both the catalytic activity and enantioselectivity of the reaction.

6.4 ConclusionsA wide number of asymmetric cobalt-catalysed nucleophilic ring-opening reactions of racemic epoxides have been successfully developed on the basis of salen cobalt complexes. Among them, the hydrolytic kinetic resolution of terminal epoxides has been widely investigated since the first report by Jacob-sen in 1997. This simple and practical process has advantages that allow the concomitant syntheses of enantiopure epoxides and diols. Uniformly excellent enantioselectivities of up to >99% ee have been described from the use of many types of salen cobalt catalysts, spanning from mononuclear

Scheme 6.19 Copolymerisation of cyclohexene oxide with CO2 catalysed with a dinuclear salen cobalt catalyst.


complexes to dimeric or oligomeric ones. excellent results were also obtained by employing macroporous helical silica-supported salen cobalt complexes in these reactions (95% ee). A polymer-supported hydrolytic dynamic kinetic resolution of epibromohydrin also provided a high enantioselectivity of 91% ee. enantioselectivities of >99% ee were also obtained in phenolytic and alco-holytic ring-openings of terminal epoxides catalysed with oligomeric salen cobalt complexes. Furthermore, this type of complex also provided the same level of enantioselectivity in the hydrolytic desymmetrisation of meso-epox-ides. On the basis of these remarkable results, many building blocks for the synthesis of complex natural products and pharmaceuticals have been pre-pared on the basis of hydrolytic kinetic resolutions. epoxides can also be resolved through ring-opening by nucleophiles other than water or alcohols, such as amines and carbamates, allowing access to chiral β-amino alcohols, which are valuable intermediates in the synthesis of a variety of biologically active compounds and play a very significant role in asymmetric catalysis. Again, enantioselectivities of >99% ee have been reported for the kinetic resolution of epoxides through ring-opening with carbamates catalysed by either monomeric salen cobalt(iii) complexes or their oligomeric salen cobalt counterparts. Furthermore, the aminolysis of epoxides catalysed with a macroporous silica-supported salen cobalt complex was achieved with 99% ee. In another area, epoxides could be opened through (co)polymerisation. The first highly enantioselective polymerisation catalyst, a chiral bimetallic cobalt(iii)catalyst was recently reported, for the kinetic resolution of mono-substituted epoxides, providing high levels of activity and enantioselectiv-ity (81–>99% ee) for a range of thus formed ring-opened isotactic polyethers bearing alkyl, aryl and ether substituents. Finally, the copolymerisation of cyclohexene oxide with CO2 into the corresponding chiral polycarbonate was catalysed with a dinuclear salen cobalt catalyst with 98% ee. In the near future, applications of these powerful and simple processes in total synthe-sis are expected, as well as the use of nucleophiles other than water, alcohols and amines.

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155


7.1 Michael Reactions7.1.1 Michael Additions to α,β-Unsaturated Carbonyl

Compounds and DerivativesThe conjugate additions of nucleophiles to electron-poor alkenes constitute a powerful tool in organic synthesis, allowing carbon–carbon and carbon–heteroatom bond-forming reactions to be easily achieved.1 Consequently, many different versions of these transformations including asymmetric ones have been developed, using a wide variety of conjugate acceptors, nucleophiles, and catalysts.2 Among the latter, chiral cobalt catalysts have provided excellent results since the pioneering works reported by Brunner et al. in 1984 in which a catalytic system, in situ generated from Co(acac)2 and (+)-1,2-diphenylethylenediamine as a chiral ligand, was found capable of promoting the addition of methyl 1-oxo-2-indanecarboxylate to methyl-vinylketone with an enantioselectivity of up to 66% ee.3 However, attempts to improve the enantioselectivity of the Michael addition of 1,3-dicarbonyl com-pounds by involving other chiral ligands, such as alkaloid or salicylaldimine

CHApTer 7

Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Michael and (Nitro)-Aldol Reactions

Chapter 7156

derivatives,3b,c proline-based ligands,4 or spirobiindane-containing ligands5 were unsuccessful for many years. In 1997, Feringa and de Vries reported the addition of diethylzinc to chalcone mediated by a chiral cobalt com-plex generated from Co(acac)2 and chiral amino alcohols.6 In this study, the best enantioselectivity of 83% ee was achieved using a (+)-camphor- based ligand. In 1998, slightly higher enantioselectivities of up to 89% ee were reported by pfaltz et al. using tert-butyl-substituted chiral bisoxaz-oline oxalamide ligands to promote the Michael addition of malonates to chalcone.7 In this work, tert-butyl-substituted chiral bisoxazoline oxalamide ligands were found capable of providing these good enantioselectivities as a function of the steric hindrance of the malonate derivatives, however, in low chemical yields (12–17%). Later in 2006, Zhou et al. designed two novel chiral C2-symmetric spiro nitrogen-containing ligands including pyridine or quinolone units, 7,7′-bis(2-pyridinecarboxamido)-1,1′-spirobiindane (SIpAD) and 7,7′-bis(2-quinolinecarboxamido)-1,1′-spirobiindane (SIQAD).5 These ligands were combined with Co(OAc)2 to in situ generate the correspond-ing complexes, which proved to be efficient catalysts in the enantioselective Michael addition of malonates to chalcones. The alkylation products were obtained in high yields (70–78%), albeit with moderate enantioselectivities ranging from 47% to 57% ee. In 2008, Itoh et al. reported enantioselectivi-ties of up to 95% ee for the asymmetric Michael addition of thiols to (E)-3- crotonoyloxazolidin-2-one using a catalytic system consisting of a combina-tion of Co(ClO4)2·6H2O with (S,S)-ip-pybox (Scheme 7.1).8 The process was performed in THF at −20 °C in the presence of 4 Å molecular sieves, pro-viding the corresponding Michael adducts in moderate to high yields. The best enantioselectivity of 95% ee was obtained in the reaction of sterically

Scheme 7.1 Michael addition of thiols to (E)-3-crotonoyloxazolidin-2-one.


hindered 2-methylbenzenethiol. In the same year, Ganzmann and Gladysz reported a low enantioselectivity of 33% ee combined with a yield of 78% for the Michael addition of dimethyl malonate to 2-cyclopenten-1-one pro-moted by Werner salts of a chiral tris(ethylenediamine)-substituted octa-hedral cation.9

In 2011, Nishimura and Hayashi investigated the cobalt-catalysed asym-metric conjugate alkynylation of α,β-unsaturated ketones.10 Having devel-oped a cobalt-based catalytic system to achieve the conjugate addition of silylacetylenes to enones using a bidentate diphenylphosphino(ethane) ligand, an asymmetric version was accomplished using chiral biphosphine ligand 1. In this context, several chiral β-alkynylketones were produced in moderate to high yields (53–93%) and enantioselectivities (79–91% ee) start-ing from the corresponding α,β-unsaturated ketones and (triisopropylsilyl)acetylene, as shown in Scheme 7.2.

Soon after, this catalytic system was applied by the same authors to pro-mote the asymmetric addition of terminal alkynes to extended conjugate systems such as α,β,γ,δ-unsaturated carbonyl compounds.10b However, a thorough screening of chiral biphosphine ligands led to the identification of (S,S)-et-Duphos as the optimal ligand. As shown in Scheme 7.3, the addi-tion of (triisopropylsilyl)acetylene to aliphatic dienoates and dienamides occurred exclusively in the δ-position, affording the corresponding 1,6-con-jugate adducts in good to quantitative yields (65–99%) and uniformly high enantioselectivities (88–99% ee). In addition, an α,β,γ,δ-unsaturated arene was found to be a good substrate in the alkynylation reaction, since the

Scheme 7.2 Michael addition of (triisopropylsilyl)acetylene to α,β-unsaturated ketones.

Chapter 7158

corresponding Michael adduct was obtained in 68% yield with an enantiose-lectivity of 88% ee. Control experiments proved the imperative need for zinc to form the products and the influence of the geometrical structure of the starting material on both the chemical and optical yields.

In 2014, Belokon et al. reported enantioselectivities of up to 96% ee in the enantioselective Michael addition of a glycine Schiff base to activated ole-fins promoted by positively charged chiral cobalt(iii) complexes, such as 2 or 3, prepared from Schiff bases derived from chiral diamines and salicy-laldehydes.11 As shown in Scheme 7.4, the process performed in the pres-ence of KOH as a base led to the corresponding chiral Michael products in good to quantitative yields (70–97%), low to complete diastereoselectivities (34–>99% de), and moderate to high enantioselectivities (60–96% ee). In addition to α,β-unsaturated esters, α,β-unsaturated nitriles and α,β-unsatu-rated ketones were compatible with the reaction conditions.

Later in 2015, Yamada and Tsubo described the enantioselective Michael addition of various dialkyl malonates to cyclic α,β-unsaturated ketones

Scheme 7.3 Michael addition of (triisopropylsilyl)acetylene to α,β,γ,δ-unsaturated carbonyl compounds.


promoted by 5 mol% of chiral salen cobalt(iii) catalyst 4 in the presence of a base such as CyONa.12 The corresponding products were obtained in low to quantitative yields (21–98%) and moderate to good enantioselectiv-ities (52–88% ee), as shown in Scheme 7.5. The catalytic system tolerated five-membered, six-membered, as well as seven-membered α,β-unsaturated ketones. Although the mechanism of the process was not detailed, the combination of the 1-chlorovinyl axial ligand with the sodium cation of the additive was confirmed as a crucial condition to achieve high reactivity and enantioselectivity. With the aim of extending the scope of the reaction, the same reaction conditions were applied to acyclic α,β-unsaturated ketones, which led to the corresponding Michael products, albeit in lower enantiose-lectivities (32–38% ee) combined with low yields (26–30%).

Another type of chiral cobalt catalyst, in situ generated from Co(BF4)2(6H2O) and chiral N,N′-dioxide ligands, such as 5 and 6, was applied in 2014 by Feng et al. to promote the enantioselective addition of cyclic β-ketoamides

Scheme 7.4 Michael addition of a glycine Schiff base to activated olefins.

Chapter 7160

to alkynones.13 The corresponding chiral Michael products were obtained as mixtures of Z- and E-diastereomers in high yields (80–99%) and moder-ate to high enantioselectivities (69–97% ee) for both diastereomers when using ligand 5 or 6 (Scheme 7.6). The Z/E ratios ranged from 52 : 48 to 78 : 22. The best enantioselectivities (92–97% ee) were obtained by using ligand 6.

7.1.2 Michael Additions to NitroolefinsIn 2010, Matsunaga and Shibasaki reported an efficient example of bifunc-tional cooperative asymmetric catalysis using a homodinuclear bis-Co(iii) Schiff base complex for the conjugate addition of β-ketoesters to nitroole-fins.14 Using a dinucleating Schiff base, several combinations of metals, such as copper, palladium, nickel, manganese, zinc or lanthanides, were investi-gated to identify the most powerful system for promoting enantioselective Michael addition. More or less success was achieved, since only a bisnickel system gave rise to Michael adducts with enantioselectivities of up to 74% ee. On the other hand, chiral bis-Co(iii) complex 7 was found to efficiently promote the addition of a range of cyclic as well as acyclic β-ketoesters to

Scheme 7.5 Michael addition of malonates to cyclic α,β-unsaturated ketones.


nitroalkenes, providing the corresponding nitro-Michael adducts in good to quantitative yields (73–>99%) combined with both good to excellent diaste-reo- and enantioselectivities of up to >94% de and 99% ee, respectively, as shown in Scheme 7.7. It must be noted that the best results were obtained when cyclic β-ketoesters were used as substrates. Indeed, lower diastereo-selectivities of 54% de were obtained in cases of acyclic β-ketoesters while a high yield (73%) and excellent enantioselectivity of 96% ee were reached. An interesting feature of this catalytic system was that it also worked in the absence of solvent and the catalyst loading could be decreased down to 0.1 mol%. Moreover, mechanistic studies and control experiments were car-ried out in order to confirm the cooperative intramolecular effect of the two cobalt centers. The postulated catalytic cycle for the reaction is depicted in Scheme 7.7. The authors assumed that the β-keto ester coordinates to the sterically less hindered outer Co-metal center of complex 7. Co-aryloxide (or Co-acetate) deprotonates the α-proton of the β-keto ester to generate a Co-enolate. The inner Co-metal center acts as a Lewis acid to activate the

Scheme 7.6 Michael addition of β-ketoamides to alkynones.

Chapter 7162

Scheme 7.7 Michael addition of β-ketoesters to nitroalkenes.


nitroalkene in a similar manner to that observed in the monomeric Co-salen system. 1,4-Addition via a bimetallic transition state followed by protonation affords the final products and regenerates the catalyst. In addition, these reaction conditions were also successfully applied to the enantioselective Michael addition of cyclic as well as acyclic β-ketoesters to alkynones, provid-ing the corresponding chiral enones with remarkable results, since a general diastereoselectivity of >94% de was obtained in all cases of the substrates studied in combination with good to excellent yields (83–96%) and high enantioselectivities (91–99% ee).15 In this study, catalyst screening allowed biscobalt complex 7 to be selected as the optimal catalyst among a range of other dinuclear chiral complexes based on nickel, copper, zinc, samarium, lanthanum, and palladium. For example, moderate enantioselectivities were obtained using the corresponding bisnickel catalyst, while rare-earth-metal complexes gave poor enantioselectivities, and the use of biszinc or biscopper catalysts resulted in racemic products.

In 2014, Feng et al. developed the enantioselective conjugate addition of cyclic β-ketoamides to nitroolefins promoted by cobalt catalysts in situ gen-erated from Co(BF4)2(6H2O) and chiral N,N′-dioxide ligands such as 8.13 The reaction afforded the corresponding densely functionalised chiral Michael products bearing a quaternary carbon centre as mixtures of two diastereo-mers in moderate to quantitative yields (51–98%) combined with low to moderate diastereoselectivities (8–44% de). The major diastereomers were achieved in uniformly excellent enantioselectivities (93–97% ee), while the minor ones were achieved in lower enantioselectivities (55–90% ee), as shown in Scheme 7.8. It was found that the electronic nature of the substit-uents (r1) on the aromatic ring of the indenone scaffold had no effect on the enantioselectivity and reactivity of the reaction.

In 2014, Kezuka et al. reported that chiral salen cobalt(ii) complex 9 was an effective catalyst for the enantioselective Michael addition of O-alkylhydroxyl-amines to nitroolefins to afford the corresponding chiral N-alkylhydroxyl- 1,2-nitroamines.16 As shown in Scheme 7.9, these products were achieved in moderate to quantitative yields (58–99%) and moderate to high enantiose-lectivities (56–91% ee) starting from either alkyl- or (hetero)aryl-substituted nitroalkenes. In most cases, the best enantioselectivities (82–91% ee) were achieved in the reaction of O-benzylhydroxylamine (r2 = Bn) with alkyl- substituted nitroalkenes (r1 = CH2Bn, n-Hept, (CH2)2OBn). This study repre-sented the first example of a transition-metal-catalysed asymmetric Michael addition of amines to nitroalkenes.

Werner complexes of cobalt(iii) and 1,2-diamines represent examples of substitution inert low-spin d6 complexes, and consequently are incapable of traditional-metal-based substrate activation. However, the coordinated NH groups of their chiral 1,2-diamine ligands constitute powerful hydro-gen-bond donors. Therefore, in the presence of this type of catalyst, the sub-strates are not activated by classical metal coordination, but rather by second coordination sphere hydrogen bonding involving the ligating NH2 groups. In this context, Gladysz et al. have investigated the use of inexpensive and

Chapter 7164

Scheme 7.8 Michael addition of cyclic β-ketoamides to nitroolefins.

Scheme 7.9 Michael addition of amines to nitroolefins.


readily available Werner complexes based on the D3-symmetric chiral trication [Co((S,S)-dpen)3]3+ (dpen = 1,2-diphenylethylenediamine) for the enantiose-lective Michael addition of dimethyl malonate to nitroolefins.17 Indeed, when this reaction was promoted by 10 mol% of catalyst 10 in acetone at 0 °C in the presence of TeA as a base, it led to the corresponding chiral nitroalkanes in uniformly excellent yields (93–98%) and high enantioselectivities (85–98% ee), as shown in Scheme 7.10. This study illustrated the possibility associated with enantioselective second coordination sphere-promoted catalysis.

These reactions were also performed by the same authors in the presence of another Werner cobalt complex 11 incorporating an additional functional-ity, such as a dimethylamino group.18 performed at −35 °C in dichlorometh-ane, the reactions of dialkyl malonates with aryl- as well as alkyl-substituted nitroalkenes catalysed with 10 mol% of complex 11 led to the correspond-ing chiral nitroalkanes in good to quantitative yields (72–98%) and excel-lent enantioselectivities (90–99% ee), as shown in Scheme 7.11. Generally very high enantioselectivities (93–99% ee) were obtained in the reaction of aryl-substituted nitroalkenes bearing electron-donating or electron-with-drawing substituents. particularly noteworthy were analogous additions to alkyl-substituted nitroalkenes, which also provided uniformly excellent enantioselectivities (90–94% ee).

In 2017, Song and Gong described the synthesis of novel imidazoline/oxazoline N,N′-bidentate chiral ligands derived from 2,2-dimethylmalonic acid, which were further applied to promote the first enantioselective cobalt- catalysed Michael addition of 2-acetyl azaarenes to β–CF3–β-disubstituted nitroolefins.19 When using 12 mol% of optimal chiral ligand 12 in combina-tion with 10 mol% of Co(acac)2 in MTBe at 20 °C, the process afforded the corresponding chiral products bearing a trifluoromethylated all-carbon qua-ternary centre in low to quantitative yields (24–98%) and moderate to excel-lent enantioselectivities (60–98% ee). As shown in Scheme 7.12, the reaction

Scheme 7.10 Michael addition of dimethyl malonate to nitroolefins.

Chapter 7166

Scheme 7.11 Michael addition of dialkyl malonates to nitroolefins.

Scheme 7.12 Michael addition of 2-acetyl azaarenes to β–CF3–β-disubstituted nitroolefins.


tolerated a wide variety of β–CF3–β-(hetero)aryl-disubstituted nitroalkenes and a range of 2-acetyl azaarenes containing thiazole, N-methylimidazole, pyrazine, benzothiazole, quinoxaline, benzoxazole, pyrimidine and quino-lone groups. For a nitroalkene containing a β-alkyl group (r = Bn), the reac-tivity was found to still be good (47–84% yield), but the stereocontrol was only moderate (66–78% ee).

7.2 (Nitro)-Aldol ReactionsAldol reactions are among the most widely studied and extensively used for the carbon–carbon bond formation, most notably for rapid access to poly-oxygenated compounds.20 The Henry reaction or nitro-aldol reaction is one of the most convenient reactions for direct carbon–carbon bond formation without any pretreatment to afford β-hydroxy-nitroalkanes from aldehydes and nitroalkanes. Since the first catalytic enantioselective version of this reaction reported in 1992 by Shibasaki et al. based on the use of heterobi-metallic lanthanide BINOL catalyst systems,21 various chiral catalyst systems have been successfully developed. For example, in 2004, Yamada et al. found that chiral ketoiminato cobalt complexes efficiently catalysed the enanti-oselective Henry reaction of aldehydes in the presence of a tertiary amine such as DIpeA.22 The most efficient catalyst 13 (Scheme 7.13) employed at a 5 mol% catalyst loading provided in dichloromethane low to quantitative yields (11–>99%) and moderate to high enantioselectivities (53–92% ee). The same authors obtained even better results for the reaction of aromatic alde-hydes with nitromethane using chiral salen cobalt complexes, such as 14 and 15, at a lower catalyst loading of 2 mol% in the presence of the same base, solvent and temperature. As shown in Scheme 7.13, a range of chiral β-nitro-alcohols were achieved in low to quantitative yields (36–>99%) and moderate to excellent enantioselectivities (62–98% ee).23

In 2008, these reactions were also investigated by Hong et al. using a newly designed self-assembled chiral dinuclear salen cobalt(ii) complex 17 in situ generated from the reaction of the corresponding salen cobalt(ii) complex 16 with Co(OAc)2·4H2O, self-assembled through hydrogen bonding (Scheme 7.14).24 The reaction provided, in the presence of DIpeA, the cor-responding chiral alcohols in moderate to quantitative yields (65–99%) and high enantioselectivities (81–96% ee), as shown in Scheme 7.14. The self- assembly through hydrogen bonding was confirmed from the X-ray structure and 1H NMr experiments.

Later in 2012, the same authors developed a diastereo- and enantiose-lective nitro-aldol reaction of aliphatic as well as aromatic aldehydes with nitroalkanes other than nitromethane, including nitroethane, nitropropane and TBSOCH2CH2NO2, to afford the corresponding Henry products bear-ing two stereocentres.25 When the process was promoted by novel chiral [(bisurea-salen)cobalt] catalyst 18, it provided low to high anti-selectivities (4–>96% de) combined with high enantioselectivities (85–99% ee), as shown in Scheme 7.15. The cooperative activation by the H-bonds of urea and the

Chapter 7168

Scheme 7.13 Henry reaction of aromatic aldehydes with nitromethane catalysed by salen cobalt(ii) complexes.


Lewis acid cobalt center is shown in Scheme 7.15. It must be noted that comparable results were achieved in both cases of aromatic and aliphatic aldehydes and, consequently, the use of this chiral urea–cobalt bifunctional catalyst successfully extended the substrate scope of anti-selective Henry reactions to previously unexplored aldehydes. Moreover, the synthetic utility

Scheme 7.14 Henry reactions of aromatic aldehydes with nitromethane catalysed by a self-assembled chiral dinuclear salen cobalt(ii) complex.

Chapter 7170

of this methodology was demonstrated by the concise asymmetric synthesis of (1R,2S)-methoxamine hydrochloride.

In 2014, Wang et al. reported the synthesis of novel C2-symmetric salen ligands bearing morpholine functional groups based on a BINOL framework to be investigated in the enantioselective cobalt-catalysed Henry reaction of aldehydes with nitromethane.26 Among them, ligand 19 was selected as the optimal one when used at a 6 mol% catalyst loading in a 2 : 1 mixture of methanol/THF at 15 °C in combination with 5 mol% of Co(OAc)2(4H2O). Under these conditions, nitromethane reacted with a range of aromatic as

Scheme 7.15 Henry reaction of aromatic and aliphatic aldehydes with other nitro-alkanes catalysed by a (bisurea–salen)cobalt(iii) complex.


well as aliphatic aldehydes to give the corresponding chiral Henry products in moderate to excellent yields (65–95%) and high enantioselectivities (81–97% ee), as shown in Scheme 7.16. It was found that changing the Lewis acid from cobalt to ytterbium resulted in a decrease in the enantioselectivities (10–87% ee).

In 2014, the Henry reaction of aromatic aldehydes with nitromethane was also investigated by Xu et al. using a novel type of chiral salen cobalt(iii) catalyst, 20.27 As shown in Scheme 7.17, the reaction was performed in tol-uene at −20 °C in the presence of DIpeA as a base and 5 mol% of cata-lyst 20. Under these conditions, a wide variety of chiral aromatic alcohols were obtained in moderate to quantitative yields (48–99%) and moderate to excellent enantioselectivities (70–98% ee). Better yields and enantio-selectivities were achieved for aromatic aldehydes functionalised at the ortho-position of the phenyl ring. This result suggests that the selective rec-ognition of ortho-substituted benzaldehydes is ascribed to the difference in the molecular size of the aromatic aldehydes and a possible aromatic– aromatic interaction between the phenyl rings of the ligand and the aro-matic ring of the aldehydes.

In 2016, Yashima et al. reported the synthesis of a novel double-helical bimetallic cobalt salen complex 21 stabilised by chiral amidinium-carboxylate

Scheme 7.16 Henry reaction of aldehydes with nitromethane in the presence of a BINOL-derived C2-symmetric salen ligand bearing morpholine moieties.

Chapter 7172

salt bridges to catalyse the asymmetric Henry reaction of o-methoxybenzal-dehyde and nitromethane.28 As shown in Scheme 7.18, the corresponding Henry product was obtained in both high yield (91%) and enantioselectivity (89% ee) when the reaction was performed with 4 mol% of this catalyst in dichloromethane at −30 °C in the presence of DIpeA as a base. The reactivity and enantioselectivity of the reaction were higher than those catalysed by the corresponding single strands, showing the key role of the chiral double-helical framework for the supramolecular bimetallic catalysis.

The direct catalytic asymmetric aldol reaction is a powerful and atom-economical method for synthesizing chiral β-hydroxy carbonyl com-pounds. Many catalysts, including metals and organocatalysts have been developed over the past decade to promote these reactions.29 For example in 2011, reiser et al. reported the highly efficient use of simple l-proline as a chiral ligand of cobalt to catalyse the enantioselective direct aldol reac-tion of a range of aromatic and aliphatic aldehydes with cyclic as well as acyclic ketones.30 The authors found that the efficiency of these reactions was significantly higher compared with the analogous classical proline- catalysed processes as well as with the other metal–proline complexes pre-viously employed. Indeed, the use of combinations of l-proline with zinc and nickel chlorides provided lower enantioselectivities (≤81% ee vs. 92% ee with cobalt chloride) while manganese, iron, magnesium or copper chlo-rides gave even lower enantioselectivities (37–75% ee). This novel protocol presented the advantage of being very simple through mixing inexpensive

Scheme 7.17 Henry reaction of aromatic aldehydes with nitromethane catalysed by a salen cobalt(iii) complex.


CoCl2 and l-proline in methanol at room temperature. In general, the best results for the formation of a number of chiral alcohols 22 were obtained in the case of using cyclic ketones as the substrates with various aromatic and aliphatic aldehydes, providing good to excellent yields (50–93%), with high diastereoselectivities of up to 96% de, and excellent enantioselectivities of up to 98% ee, as shown in Scheme 7.19. The scope of the methodology was extended to acyclic unsymmetrical ketones, which provided by reaction with aromatic aldehydes the corresponding chiral alcohols 23 in good to high yields (64–92%), and low to moderate diastereoselectivities (34–66% de), combined with moderate to high enantioselectivities (50–91% ee), as shown in Scheme 7.19. In some cases of substrates, the best enantioselec-tivities were reached by using DMSO instead of methanol as the solvent. The authors proposed that initially, two molecules of l-proline were bound through their carboxylate groups to cobalt(ii), giving rise to complex 24. The key catalytically active species could then function as the C2-symmet-rical cobalt–proline complex 25. Moreover, during the aldol reaction, a pH

Scheme 7.18 Henry reaction of o-methoxybenzaldehyde with nitromethane cata-lysed by a double-helical bimetallic cobalt salen complex.

Chapter 7174

value of 4–6 was measured, which was in agreement with the liberation of HCl during the catalyst formation.

In 2011, Duan et al. developed an approach to create an l-proline-function-alised cobalt-organic triangle to be used as a size-selective homogeneous cat-alyst for comparable reactions.31 This catalyst was generated by self-assembly through incorporating an l-proline moiety within a cobalto-helical triangle formed by assembling cobalt ions and two tridentate N2O units containing amide groups within a central benzene ring at the meta sites. Therefore, it included l-proline moieties as asymmetric catalytic sites and a helical-like cavity, and was proved to work as an asymmetric catalyst to prompt the aldol reaction of ortho-, meta-, and para-nitrobenzaldehydes with cyclohexanone with size-, diastereo- and enantioselectivity. Besides low yields (21–42%), the process afforded low to good diastereo- and enantioselectivities (0–83% de and 44–73% ee, respectively).

Scheme 7.19 Aldol reactions of aldehydes with cyclic and acyclic ketones.


7.3 ConclusionsThis chapter demonstrates that a wide variety of chiral cobalt catalysts are today capable of promoting a range of enantioselective Michael reactions as well as Henry reactions. Firstly, a number of highly efficient asymmetric additions of very different nucleophiles to α,β-unsaturated carbonyl com-pounds and derivatives have been reported with enantioselectivities of up to 99% ee. Among them, the Michael addition of thiols to (E)-3-crotonoyloxaz-olidin-2-one has been performed with up to 95% ee in the presence of (S,S)-ip-pybox as a ligand. The use of a simple chiral biphosphine has allowed the Michael addition of (triisopropylsilyl)acetylene to α,β-unsaturated ketones to be achieved in 91% ee, while even higher enantioselectivities of 99% ee were described for the Michael addition of (triisopropylsilyl)acetylene to α,β,γ,δ-unsaturated carbonyl compounds in the presence of (S,S)-et-Duphos as a ligand. Moreover, the Michael addition of glycine Schiff bases to acti-vated olefins were catalysed by positively charged chiral cobalt(iii) complexes with 96% ee and that of β-ketoamides to alkynones provided enantioselectiv-ities of 97% ee using a chiral N,N′-dioxide ligand. In addition to α,β-unsatu-rated carbonyl compounds and their derivatives, nitroalkenes have also been successfully subjected to enantioselective Michael addition to a wide variety of nucleophiles, including β-ketoesters with 99% ee using a dinuclear cobalt complex, cyclic β-ketoamides with 97% ee by employing a N,N′-dioxide chiral ligand, amines with 91% ee in the presence of a salen cobalt(ii) catalyst, and dialkyl malonates with 99% ee using Werner complexes. Furthermore, the enantioselective Michael addition of 2-acetyl azaarenes to β–CF3–β-disubsti-tuted nitroolefins was achieved with 98% ee in the presence of a imidazoline/oxazoline N,N′-bidentate chiral ligand. On the other hand, excellent results have also been described for enantioselective Henry reactions of aldehydes with nitroalkanes catalysed by a wide variety of salen cobalt complexes with up to 98% ee. In contrast, much fewer investigations have been undertaken in the area of the direct aldol reaction. Among them, are the enantioselec-tive aldol reactions of aldehydes with cyclic and acyclic ketones performed in the presence of simple l-proline as a ligand with up to 98% ee. In the near future, this last field of aldol condensations will have to be further devel-oped, while the many exceptional results achieved in both the Michael and Henry reactions will undoubtedly be applied in the total synthesis of import-ant products.

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8415.

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The formation of a carbon–carbon bond via nucleophilic addition of an organometallic reagent to a carbonyl substrate constitutes one of the most elementary transformations in organic synthesis and has been studied extensively over the past few decades.1 The dawn of organometallic chem-istry dates back to 1849 with Frankland's early work on organozinc com-pounds.2 By the turn of the 20th century, the routine use of organozinc reagents in organic synthesis had been largely supplanted by main-group organometallics due to the rapid growth of Grignard chemistry,3 and the development of practical routes to organolithium compounds.4 Actually, the first tentative step towards developing a procedure for enantioselective addition to carbonyl compounds dates back to 1940, in a report by Betti and Lucchi on the reaction of methylmagnesium iodide with benzaldehyde performed in the presence of N,N-dimethylbornylamine as a solvent to give 1-phenylethanol, albeit in a racemic mixture.5 In the 1950s, Wright et al. reported what appears to be the first successful enantioselective addition of

ChApTer 8

Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed 1,2-Nucleophilic Additions to Carbonyl Compounds and Derivatives


Grignard reagents to carbonyl compounds, using chiral ethers as cosolvents, resulting in low enantioselectivities of 17% ee.6 It was only later, in 1989, that enantioselectivities of up to 99% ee were reported by Ohno and Yosh-ioka for the first enantioselective titanium-promoted addition of diethylzinc to benzaldehyde using chiral trans-1,2-bis(trifluoromethanesulfonylamino)cyclohexane as a ligand.7 In 1994, Seebach and Weber described the first truly enantioselective catalytic alkyl and aryl additions to aldehydes employ-ing a highly reactive rTi(Oi-pr)3 reagent, which resulted in enantioselectiv-ities of up to 99% ee upon catalysis with a titanium TADDOLate complex.8 After these two latter remarkable pioneering works, chemists have shown a continuous interest in developing highly enantioselective catalysts for asymmetric nucleophilic additions to carbonyl compounds and derivatives, since these methodologies have the strategic synthetic advantage of form-ing new C–C bonds, and a new functionality (alcohol) with the concomitant creation of a stereogenic centre in a single transformation. It must be noted that this chapter includes enantioselective cobalt-catalysed 1,2-nucleop-hilic additions to carbonyl compounds and derivatives other than (nitro)-al-dol reactions, which are collected separately in Chapter 7. In 2001, Soai et al. described a rare example of “chiral-at-metal” catalysis performed with high enantiomeric excesses. Tetrahedral complexes bearing four different monodentate ligands or octahedral complexes with achiral bidentate ligands show this type of chirality and they are called “chiral-at-metal” complexes.

Indeed, in inorganic chemistry, a metal complex can be asymmetric at the metal centre as a function of its topology of coordination. Therefore, chiral octahedral cobalt complexes, such as (−)-546-K[Co(edta)·2h2O], were found to be able to promote the highly enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, leading to the formation of the correspond-ing pyrimidyl alkanol in a quantitative yield (99%) with an enantioselectiv-ity of up to 94% ee (Scheme 8.1).9 Using the (+)-546-K[Co(edta)·2h2O] chiral complex allowed the opposite enantiomer of the pyrimidyl alkanol to be obtained in 91% ee. however, one drawback of this process was the need for 50 mol% catalyst loading. This is of note, since these cobalt complexes are practically insoluble in toluene, the reaction likely occurs at the interface between the metal complex and the solvent. Therefore, the cobalt atom is not the true reaction centre, but is undeniably responsible for the enantiose-lectivity of the addition.

The addition of cyanide to a carbonyl compound to form a cyanohydrin is one of the fundamental carbon–carbon bond forming reactions in organic chemistry.10 Cyanohydrins contain two functional groups, a nitrile and an alcohol (or protected alcohol), which can be further and readily manipu-lated to produce a diverse range of 1,2-difunctional compounds, including many which are often found as components of important pharmaceuticals. Asymmetric cyanohydrin synthesis has come a long way over the last 100 years, with most progress having been made over the last decade using chiral complexes of various metals. As an example, in 2006, Belokon et al. reported an original system involving the use of negatively-charged complex ions in

Chapter 8180

asymmetric cyanosilylation.11 An advantage of the weakly coordinated achi-ral/chiral anion ion-pair system is the ability to retain a greater Lewis acid-ity in the cation, when compared to traditional metal complexes where the charge on the metal is compensated by strong first-sphere ligand metal coor-dination. Thus, chiral metal cations, such as Na+ or K+, which are not usu-ally considered as likely candidates for Lewis acids in catalytic cycles, can become efficient asymmetric catalysts in combination with weakly coordi-nated chiral anions. Therefore, inert complex 1, readily prepared from tryp-tophan, salicylaldehyde and K3[Co(CO3)3], was found to be the most efficient in a series of similar complexes investigated in the asymmetric cyanosilyla-tion of benzaldehyde with trimethylsilyl cyanide. The authors studied the effect of additives, such as triphenylphosphine, indole, water, tert-butanol, etc., and showed that in the presence of triphenylphosphine (0.1 mol%), the corresponding O-silylated mandelonitrile was obtained in 85% yield and 77% ee, as shown in Scheme 8.2. It is interesting to note that, in the presence of other cations, such as h+, Li+, Na+, Cs+, or Nh4

+, the reaction resulted in an almost racemic mixture of the product. Unfortunately, aldehydes other than benzaldehydes gave poor or no asymmetric induction.

Among various organometallic reagents, organoboron reagents have gained much attention due to their air and moisture stability, low toxicity and availability. Complexes of various metals, such as rhodium, palladium, platinum, nickel, copper and iron, have been successfully used to catalyse the reaction of organoboronic acids to aldehydes. Despite the fact that a wide number of publications dealing with this type of reaction are available in the literature, there have been few reports on the asymmetric versions of

Scheme 8.1 Addition of diisopropylzinc to pyrimidine-5-carbaldehyde.


these reactions. As an example, the first enantioselective cobalt-catalysed addition reaction of various phenylboronic acids to substituted aldehydes was described in 2010 by Cheng et al., affording the corresponding biologi-cally interesting substituted diarylmethanols in both high yields (82–99%) and enantioselectivities (86–99% ee).12 As shown in Scheme 8.3, the reac-tions were promoted by a cobalt catalyst in situ generated from CoI2 and (R,R)-BDpp as the ligand in the presence of K2CO3 as the base, and proved to be compatible with a wide range of phenylboronic acids and aromatic, heteroaromatic, and aliphatic aldehydes. The lowest enantioselectivities

Scheme 8.2 Cyanosilylation of benzaldehyde.

Scheme 8.3 Addition of phenylboronic acids to aldehydes.

Chapter 8182

(86 and 89% ee, respectively) were obtained in the cases of aldehydes bear-ing a 2-thienyl or a 1-naphthyl group in comparison with the other aryl or heteroaryl groups. It is interesting to note that even an aliphatic aldehyde, such as cyclohexanecarbaldehyde, yielded the corresponding alcohol in 84% yield and 97% ee.

In 2016, (S,S)-BDpp was used as a ligand by Zhao et al. to promote the first cobalt-catalysed enantioselective vinylation of activated carbonyl compounds such as α-ketoesters.13 Indeed, when the reaction of α-ketoesters with vinyl boronic acids was promoted by a combination of 12 mol% of the ligand (S,S)-BDpp and 10 mol% of CoI2 in ThF at 70 °C in the presence of K2CO3 as a base, it afforded the corresponding chiral tertiary allylic α-hydroxy esters in low to good yields (30–75%) and good to high enantioselectivities (78–92% ee), as illustrated in Scheme 8.4.

When (R,R′,S,S′)-Duanphos was used as ligand instead of (S,S)-BDpp in these reactions, the enantiomeric products were obtained under similar reaction conditions in comparable yields (40–75%) with slightly higher enan-tioselectivities (84–95% ee), as shown in Scheme 8.5.

Moreover, (R,R′,S,S′)-Duanphos was employed in combination with CoBr2 under the same reaction conditions to promote the first enantioselective cobalt-catalysed vinylation of isatins.13 As shown in Scheme 8.6, the addi-tion of vinyl boronic acids to variously substituted isatins led to the cor-responding functionalised tertiary alcohols in moderate to high yields (50–90%) and high enantioselectivities (84–94% ee). The utility of this novel methodology is related to the fact that the skeletons of chiral 3-alkenyl- 3-hydroxy oxindoles match the core structure of a large number of biologi-cally active entities.

The scope of the precedent methodology was extended to the first asym-metric cobalt-catalysed vinylation of imines.13 As illustrated in Scheme 8.7, when almost the same reaction conditions (10 mol% of (R,R′,S,S′)- Duanphos was used instead of the 12 mol% in Scheme 8.6) were applied to

Scheme 8.4 Vinylation of α-ketoesters in the presence of (S,S)-BDpp as a ligand.


the reaction between imines, such as substituted benzoxathiazine-2,2-dioxides, and vinyl boronic acids, the corresponding almost enantiopure cyclic allylic amines (98–>99% ee) were obtained in moderate to high yields (52–85%).

In 2017, Werner complexes, such as catalyst 2, were used by the same authors to promote enantioselective nucleophilic additions to imines in situ

Scheme 8.5 Vinylation of α-ketoesters in the presence of (R,R′,S,S′)-Duanphos as a ligand.

Scheme 8.6 Vinylation of isatins.

Chapter 8184

Scheme 8.7 Vinylation of benzoxathiazine-2,2-dioxides.

Scheme 8.8 Addition of malonates to imines derived from α-amido sulfones.


generated from α-amido sulfones.14 As shown in Scheme 8.8, 10 mol% of cobalt catalyst 2, in dichloromethane at 0 °C in the presence of K2CO3 as a base, promoted the addition of various dialkyl malonates to α-amido sulfones to give the corresponding chiral products in both very high yields (90–97%) and enantioselectivities (87–99% ee).

Furthermore, the addition of nitroalkanes to the same α-amido sulfones could be catalysed under the same reaction conditions by 10 mol% of a related Werner complex 3 to afford the corresponding chiral nitroalkanes in both high yields (89–93%) and enantioselectivities (79–91% ee), as shown in Scheme 8.9.14 Notably, when nitroethane (r3 = Me) was used as a nucleophile, the corresponding product was obtained as almost a single diastereomer (90% de) in 89% yield and 83% ee.

ConclusionsThis small chapter includes information about several types of enantiose-lective cobalt-catalysed 1,2-nucleophilic additions to carbonyl compounds and derivatives, such as the highly enantioselective addition of diisopro-pylzinc to pyrimidine-5-carbaldehyde, leading to the corresponding pyrim-idyl alkanol in 94% ee and quantitative yield using a chiral octahedral cobalt

Scheme 8.9 Addition of nitroalkanes to imines derived from α-amido sulfones.

Chapter 8186

complex. The use of (R,R)-BDpp as a ligand has allowed the first enanti-oselective cobalt-catalysed addition of various phenylboronic acids to substituted aldehydes to afford the corresponding biologically interesting substituted diarylmethanols in both high yields and enantioselectivities of up to 99% ee. The first cobalt-catalysed enantioselective vinylation of acti-vated carbonyl compounds, such as α-ketoesters, with vinyl boronic acids has been achieved, providing easy access to chiral tertiary allylic α-hydroxy esters with up to 92% ee in the presence of (S,S)-BDpp as a ligand. The enan-tiomeric products could also be obtained in up to 95% ee by performing the same reactions in the presence of (R,R′,S,S′)-Duanphos as a ligand. More-over, this ligand was applied to promote the first enantioselective cobalt- catalysed addition of vinyl boronic acids to variously substituted isatins to give the corresponding biologically interesting chiral tertiary alcohols in up to 94% ee. The scope of this methodology was also extended to develop the first asymmetric cobalt-catalysed vinylation of imines, such as substi-tuted benzoxathiazine-2,2-dioxides, with vinyl boronic acids to provide the corresponding almost enantiopure cyclic allylic amines (98–>99% ee). Another type of chiral cobalt catalysts, Werner complexes, were also proven to be effective promoters of enantioselective 1,2-nucleophilic additions of various dialkyl malonates to imines in situ generated from α-amido sul-fones, with enantioselectivities of up to 99% ee. A related Werner complex allowed the enantioselective addition of nitroalkanes to the same α-amido sulfones, with up to 91% ee. Finally, good enantioselectivities of 77% ee were observed in another type of 1,2-nucleophilic addition to aldehydes, in the asymmetric cyanosilylation of benzaldehyde with trimethylsilyl cya-nide, which was performed in the presence of a cobalt complex readily pre-pared from tryptophan, salicylaldehyde and K3[Co(CO3)3]. In spite of the limited number of these generally excellent results obtained for a variety of enantioselective nucleophilic 1,2-additions to carbonyl compounds and derivatives promoted by different types of complexes, including diphos-phines, Werner catalysts, and octahedral complexes among others, a lot of work is expected in the near future on the discovery of novel methodologies related to the extraordinary ability of cobalt catalysts to adopt unexpected reaction pathways. The investigation of other types of chiral ligands is also expected as well as applications to the total synthesis of natural and bio-active products.

References 1. (a) h. pellissier, Tetrahedron, 2015, 71, 2487; (b) S. Suga and M. Kitamura,

Compr. Chirality, 2012, 4, 328; (c) S. A. Buitrago and J. L. Leighton, Sci. Synth., 2011, 2, 401; (d) D. J. ramon and M. Yus, Sci. Synth., 2011, 2, 349; (e) M. hatano and K. Ishihara, Synthesis, 2008, 11, 1647; (f) h. Manabu, M. Takashi and I. Kazuaki, Curr. Org. Chem., 2007, 11, 127; (g) M. Yus and D. J. ramon, Recent Res. Dev. Org. Chem., 2002, 6, 2978; (h) p. Knochel and r. D. Singer, Chem. Rev., 1993, 93, 2117; (i) r. Noyori and M. Kitamura,


Angew. Chem., Int. Ed. Engl., 1991, 30, 49; ( j) D. A. evans, Science, 1988, 240, 420; (k) r. Noyori, S. K. Kawai, S. Okada and M. Kitamura, Pure Appl. Chem., 1988, 60, 1597.

2. e. Frankland, Ann. Chem. Pharm., 1849, 71, 171. 3. V. Grignard, C. R. Hebd. Sceances Acad. Sci., 1900, 130, 1322. 4. (a) W. Schlenk and J. holtz, Chem. Ber., 1917, 50, 262; (b) K. Ziegler and

h. Colonius, Justus Liebigs Ann. Chem., 1930, 479, 135; (c) G. Wittig, U. pockels and h. Droge, Chem. Ber., 1938, 71, 1903; (d) h. Gilman and A. L. Jacoby, J. Org. Chem., 1938, 3, 108; (e) h. Gilman, W. Langham and A. L. Jacoby, J. Am. Chem. Soc., 1939, 61, 106.

5. M. Betti and e. Lucchi, Chem. Abstr., 1940, 34, 2354. 6. h. L. Cohen and G. F. Wright, J. Org. Chem., 1953, 18, 432. 7. (a) M. Yoshioka, T. Kawakita and M. Ohno, Tetrahedron Lett., 1989, 30,

1657; (b) h. Takahashi, T. Kawakita, M. Yoshioka, S. Kobayashi and M. Ohno, Tetrahedron Lett., 1989, 30, 7095.

8. B. Weber and D. Seebach, Tetrahedron, 1994, 50, 7473. 9. I. Sato, K. Kadowaki, Y. Ohgo, K. Soai and h. Ogino, Chem. Commun.,

2001, 1022. 10. M. North, D. L. Usanov and C. Young, Chem. Rev., 2008, 108, 5146. 11. (a) Y. N. Belokon, V. I. Maleev, D. A. Kataev, I. L. Mal’fanov, A. G. Bulychev,

M. A. Moskalenko, T. F. Saveleva, T. V. Skrupskaya, K. A. Lyssenko, I. A. Godovikov and M. North, Tetrahedron: Asymmetry, 2008, 19, 822; (b) Y. N. Belokon, V. I. Maleev, I. L. Mal fanov, T. F. Saveleva, N. S. Ikonnikov, A. G. Bulychev, D. L. Usanov, D. A. Kataev and M. North, Russ. Chem. Bull., 2006, 55, 821.

12. J. Karthikeyan, M. Jeganmohan and C.-h. Cheng, Chem.–Eur. J., 2010, 16, 8989.

13. Y. huang, r.-Z. huang and Y. Zhao, J. Am. Chem. Soc., 2016, 138, 6571. 14. h. Joshi, S. K. Ghosh and J. A. Gladysz, Synthesis, 2017, 49, 3905.

188


Metal-catalysed coupling reactions are very efficient transformations for the elaboration of carbon–carbon bonds.1 In particular, asymmetric reductive coupling involving alkynes as substrates is a competent method for the syn-thesis of highly regio-, stereo- and enantioselective substituted alkenes. Vari-ous types of π-components, such as aldehydes, imines, epoxides and ketones, have been employed in the enantioselective coupling with alkynes using sev-eral metal complexes (nickel, rhodium or iridium). On the other hand, the asymmetric reductive coupling of alkynes with alkenes remains relatively less explored. As an example, in 2011, Cheng et al. developed an enantioselective synthesis of β-substituted cyclic ketones based on the cobalt-catalysed asym-metric reductive coupling of alkynes with cyclic enones.2 The reaction was promoted by a chiral cobalt complex in situ generated from CoI2 and (R,R)-BINAP, regioselectively leading to the corresponding chiral β-alkenyl cyclic ketones in good yields (63–81%) and enantioselectivities (85–96% ee) in the presence of zinc as the reducing agent, as shown in Scheme 9.1. The scope of the reaction was large with comparable results for symmetrical as well as unsymmetrical alkynes, including electron-deficient ones. It is noteworthy,

ChAPTer 9

Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Cross-coupling Reactions


however, that the process was not suitable for terminal alkynes but instead led to facile homocyclotrimerisation of the alkynes. The advantage of this reaction lies in the use of an air-stable catalyst, a mild reductive agent and a simple hydrogen source such as water.

Later in 2012, hayashi et al. reported the catalytic asymmetric addition of ter-minal alkynes, such as silylacetylenes, to oxa- and azabenzonorbornadienes, which provided the corresponding chiral 1,2,3,4-tetrahydro-2-alkynyl-1,4-ep-oxy(aza)naphthalenes (Scheme 9.2).3 Among a series of chiral ligands inves-tigated in this reaction, including (S,S)-Chiraphos, (S,S)-BDPP, (R,R)-BINAP, (R,R)-Dipamp and (S,S)–Me-Duphos, ligand (R,R)-QuinoxP* 1 was selected as the optimal one to provide generally excellent enantioselectivities of 90–99% ee, in combination with low to high yields (7–91%), as shown in Scheme 9.2. The authors proposed the initial formation of cobalt(i) acetate arising from the reduction of the starting cobalt(ii) diacetate by zinc pow-der. The latter formed an alkynylcobalt(i) complex and acetic acid. Then, the approach of this complex from the exo direction of the oxa(aza)benzonor-bornadiene allowed the final product to be obtained. It must be noted that this work constituted the first example of catalytic asymmetric addition of terminal alkynes to oxabenzonorbornadienes without ring-opening, which was achieved using a chiral phosphine–cobalt catalyst system. To explain the results, the authors proposed the catalytic cycle depicted in Scheme 9.2. It is initiated by the reduction of cobalt(ii) to cobalt(i) by zinc powder giving cobalt(i) acetate A, which undergoes a reaction with the terminal alkyne to

Scheme 9.1 reductive coupling of alkynes with cyclic enones.

Chapter 9190

Scheme 9.2 Coupling of alkynes with oxa- and azabenzonorbornadienes and a pro-posed catalytic mechanism for the reaction.


form an alkynylcobalt(i) B and acetic acid. The approach of the intermediate B from the exo direction of the oxabenzonorbornadiene followed by syn-car-bometalation generates the alkylcobalt(i) species C. Then, protonation of intermediate C with the terminal alkyne leads to the alkynylation product and regenerates the alkynylcobalt intermediate C.

Among other metal-catalysed coupling reactions, is the catalytic cross-cou-pling reaction of Grignard reagents with organic electrophiles, also called the Kumada coupling.4 Despite recent improvements to this methodology using catalyst systems based on nickel, palladium, cobalt, copper and iron, very few enantioselective versions allowed chiral products to be achieved in useful levels of enantioselectivity. The first highly enantioselective cobalt-ca-talysed Kumada cross-coupling reaction was reported by Zhong and Bian, in 2014.5 It occurred between α-bromo esters and aryl Grignard reagents in ThF at −80 °C in the presence of a combination of 10 mol% of CoI2 and 12 mol% of bisoxazoline 2 as the chiral ligand. It afforded a wide variety of chiral α-arylalkanoic esters in moderate to excellent yields (57–96%) and enantiose-lectivities (33–97% ee), as illustrated in Scheme 9.3.

Scheme 9.3 Kumada cross-coupling reaction of α-bromo esters with aryl Grignard reagents.

Chapter 9192

The synthetic utility of this novel procedure was demonstrated by its appli-cation to the total synthesis of the nonsteroidal anti-inflammatory drugs, (S)-fenoprofen and (S)-ar-turmerone, with the latter using ent-2 as a ligand (Scheme 9.4).

Later in 2016, this methodology was also applied by Bian et al. to the efficient and concise synthesis of two naturally occurring and biologically active products, (R)-ar-curcumene and (R)-4,7-dimethyl-1-tetralone (Scheme 9.5).6 Indeed, the key step of the synthesis was the cobalt-catalysed Kumada cross-coupling of the same α-bromo ester with p-tolylmagnesium bromide performed in the presence of chiral ligand 2 under the same reaction condi-tions as those described in Scheme 9.3, leading to the corresponding chiral benzyl ester in both high yield (88%) and enantioselectivity (92% ee). This product was subsequently converted into (R)-ar-curcumene through seven supplementary steps and (R)-4,7-dimethyl-1-tetralone through eight supple-mentary steps.

In the same year, Zhong et al. described the synthesis of novel chiral cyclopropane-based bisoxazolines that were investigated in enantioselective

Scheme 9.4 Synthesis of (S)-fenoprofen and (S)-ar-turmerone.


Kumada cross-couplings of α-bromo esters with aryl Grignard reagents.7 Among them, chiral bisoxazoline 3 was selected as the optimal ligand, and when combined at 12 mol% of catalyst loading with 10 mol% of CoBr2 in ThF at −80 °C, provided the corresponding chiral esters in moderate to high yields (79–93%) and moderate to good enantioselectivities (56–84% ee), as shown in Scheme 9.6.

Scheme 9.5 Synthesis of (R)-ar-curcumene and (R)-4,7-dimethyl-1-tetralone.

Scheme 9.6 Kumada cross-coupling reaction of α-bromo esters with aryl Grignard reagents in the presence of another bisoxazoline ligand.

Chapter 9194

To demonstrate the utility of this methodology, the anti-inflammatory drug (S)-ibuprofen was prepared with 98% ee, as illustrated in Scheme 9.7.

ConclusionsThis small chapter collects the rare known examples of enantioselective cobalt-catalysed cross-coupling reactions. Among them, is the regio- and highly enantioselective synthesis of chiral β-alkenyl cyclic ketones based on a cobalt-catalysed asymmetric reductive coupling of alkynes with cyclic enones performed with enantioselectivities of up to 96% ee in the presence of (R,R)-BINAP as a ligand. Another example is the first enantioselective coupling of terminal alkynes, such as silylacetylenes, with oxa- and azaben-zonorbornadienes developed using chiral QuinoxP* as the ligand, which provided the corresponding chiral 1,2,3,4-tetrahydro-2-alkynyl-1,4-ep-oxy(aza)naphthalenes with up to 99% ee. Another type of cobalt-catalysed asymmetric coupling reaction, such as the first enantioselective Kumada cross-coupling between aryl Grignard reagents and α-bromo esters, was achieved with enantioselectivities of up to 97% using a chiral bisoxazoline ligand. The synthetic utility of this novel procedure was demonstrated in its application in the total synthesis of several important biologically active products, such as the nonsteroidal anti-inflammatory drugs (S)-fenopro-fen, (S)-ar-turmerone and (S)-ibuprofen, as well as the natural bioactive products (R)-ar-curcumene and (R)-4,7-dimethyl-1-tetralone. On the basis of the limited number of results reported so far, it is obvious that a lot of work is expected in the near future to fill this gap. however, considering the extraordinary ability of cobalt catalysts to adopt unexpected reaction pathways, it is obvious that other enantioselective cross-coupling reactions catalysed by miscellaneous types of chiral cobalt complexes will be soon be discovered.

Scheme 9.7 Synthesis of (S)-ibuprofen.


References 1. (a) J. M. hammann, M. S. hofmayer, F. h. Lutter, L. Thomas and P. Kno-

chel, Synthesis, 2017, 49, 3887; (b) G. Cahiez and A. Moyeux, Chem. Rev., 2010, 110, 1435; (c) C. Gosmini, J.-M. Bégouin and A. Moncomble, Chem. Commun., 2008, 3221.

2. C.-h. Wei, S. Mannathan and C.-h. Cheng, J. Am. Chem. Soc., 2011, 133, 6942.

3. T. Sawano, K. Ou, T. Nishimura and T. hayashi, Chem. Commun., 2012, 48, 6106.

4. r. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417. 5. J. Mao, F. Liu, M. Wang, L. Wu, B. Zheng, S. Liu, J. Zhong, Q. Bian and P. J.

Walsh, J. Am. Chem. Soc., 2014, 136, 17662. 6. L. Wu, J.-C. Zhong, S.-K. Liu, F.-P. Liu, Z.-D. Gao, M. Wang and Q.-h. Bian,

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and J. Zhong, Tetrahedron: Asymmetry, 2016, 27, 663.

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The transition-metal-catalysed codimerisation of ethene with alkenes, also called the hydrovinylation reaction, is the addition of the elements of ethene (vinyl and hydrogen) across the double bond of a second alkene, offering great potential for practical synthetic applications.1 Only moderate success has been reported in the first cobalt-catalysed hydrovinylation reactions,2 and most of the time, these reactions are catalysed by nickel or palladium complexes, which are limited to the use of monodentate ligands.3 Inspired by the work of Hilt et al. reported in 2001, dealing with the cobalt-cata-lysed codimerisation of a range of 1,3-dienes and alkenes,4 in 2009, Vogt et al. explored the asymmetric cobalt-catalysed hydrovinylation of styrene with ethene, resulting in the formation of the corresponding chiral 3-phe-nyl-1-butene.5 The activation of [CoX2(phosphine)] complexes by alkylating agents, especially Et2AlCl, affords very active catalysts with unprecedented high selectivity for the formation of the expected codimers. Indeed, this product was obtained with more than 99% selectivity without a trace of dou-ble bond isomerisation. On the other hand, an enantioselectivity limited to 50% ee was obtained using chiral bis(amido-phosphine) ligands. Following this lead, in 2010, Sharma and RajanBabu reported the very efficient and

CHApTER 10

Synthesis of Chiral Acyclic Compounds Through Enantioselective Cobalt-catalysed Hydrovinylation Reactions


highly enantioselective hydrovinylation of a range of substituted unactivated linear 1,3-dienes with ethene, exclusively resulting in the formation of the corresponding chiral (Z)-1,4-adducts without any trace of the corresponding 1,2-regioisomers or any dimerisation products (Scheme 10.1).6 Among the chiral cobalt ligands investigated, commercially available (R,R)-DIOp and (S,S)-BDpp, were found to give the best results, in the presence of 15 mol% of AlMe3 as a catalyst activator, with almost quantitative yields achieved in all cases of the substrates studied and uniformly excellent enantioselectiv-ities (89–99% ee), as shown in Scheme 10.1. The reaction appeared to be quite general for dienes, including (E)-1,3-pentadiene. Substrates with func-tional groups, such as benzyl ether, were tolerated, also providing excellent enantioselectivities (96–99% ee) but not unexpectedly, reacted sluggishly (40% yield). Finally, a diene with phenyl conjugation gave essentially a race-mic product (<5% ee). The authors proposed the mechanism depicted in Scheme 10.1 to explain the results, in which a [(L*)Co(ii)–H]+ intermediate A is the catalytic species generated by the metathesis of the Al–Me/Co–Cl bonds and migratory insertion of an alkene into the Co–Me bond, followed by reductive elimination. Addition of the Co–H via an η4-diene complex B would produce a syn-anti-(allyl)Co-species C, which would undergo coupling with ethene to give E. Reductive elimination from E regenerates the catalyst, resulting in the formation of the final product.

In 2012, the authors applied the same (S,S)-BDpp-based cobalt com-plex to promote the remarkable asymmetric hydrovinylation of 1-vinylcy-cloalkenes with ethene, which provided high regio- and enantioselectively, in the presence of more easily weighed out methylaluminoxane (MAO) in the place of the hydrocarbon solutions of Me3Al, to afford the correspond-ing chiral 1-alkylidene-2-vinylcycloalkanes.7 As shown in Scheme 10.2, these chiral products were produced in high yields (84–98%) in all cases of the substrates studied with uniformly remarkable enantioselectivi-ties (>98–>99% ee). The ratios between the expected 1,4-hydrovinylation adducts and the undesired 1,2-hydrovinylation regioisomers were between 85 : 15 and >99.5 : 0.5. For example, vinylcyclooctene, among several other substrates, exclusively gave the corresponding 1,4-adduct. The enhanced reactivity of the trisubstituted double bond in the electrophilic reactions should make these enantiopure 1,4-dienes valuable intermediates for syn-thetic applications.

In 2014, RajanBabu et al. developed the highly enantioselective hydrovinyla-tion of acyclic 1,3-dienes promoted by 10 mol% of cobalt catalyst 1 derived from the (R,R)-DIOp ligand.8 The reaction of various acyclic (E)-1,3-dienes with ethene (1 atm) was performed in the presence of AlMe3, or methylalumi-noxane, as an additive in dichloromethane at −45 or −20 °C, regioselectively leading to the corresponding chiral 1,4-hydrovinylation products bearing a Z-internal alkene (Scheme 10.3). These products were obtained in mod-erate to quantitative yields (40–>98%) combined with uniformly very high enantioselectivities (95–96% ee). The opposite enantiomeric products could be synthesised under comparable reaction conditions using (S,S)-DIOp as

Chapter 10198

Scheme 10.1 1,4-Hydrovinylation of substituted 1,3-dienes with ethene.

Scheme 10.2 1,4-Hydrovinylation of 1-vinylcycloalkenes with ethene.

Scheme 10.3 Hydrovinylations of acyclic 1,3-dienes with ethene.

Chapter 10200

the cobalt ligand in good to high enantioselectivities (74–94% ee) and with comparable yields (46–99%), as illustrated in Scheme 10.3 (second reaction scheme).

Chiral trialkylsilyl enol ethers constitute versatile intermediates for the synthesis of optically active carbonyl compounds. Nevertheless, there have still been few reports on broadly applicable catalytic methods for their syn-thesis. In 2015, RajanBabu et al. developed a general catalytic procedure for the highly chemo-, regio- and enantioselective synthesis of trialkylsi-lyl enol ethers exhibiting a vinyl-bearing chiral center at the β-position.9 The reactions were performed at room temperature in dichloromethane in the presence of 5 mol% of the cobalt catalyst ent-1 derived from the (S,S)-DIOp ligand and two equivalents of methylaluminoxane. As shown in Scheme 10.4, the reaction of various 1,3-siloxydienes with ethene (1 atm) regioselectively led to the corresponding branched 1,4-hydrovinylation chi-ral products in both remarkable yields (>90–96%) and enantioselectivities (>95–98% ee). These reactions were also promoted by cobalt catalyst 2, derived from another chiral bisphosphine, (S,S)-BDpp, providing the enan-tiomeric products in comparable yields (88–>95%) and good to excellent enantioselectivities (80–>95% ee), as shown in Scheme 8.4 (second reaction scheme).

In 2016, Schmalz et al. reported an efficient and practical protocol for the enantioselective cobalt-catalysed hydrovinylation of vinylarenes with ethene at low pressure (1.2 bar).10 The reactions were performed in dichloromethane using 5 mol% of a chiral cobalt catalyst in situ generated from CoCl2 and the TADDOL-derived phosphine–phosphite ligand 3 in the presence of 30 mol% of Et2AlCl as the activating agent. This regioselectively led to the formation of a wide range of chiral branched products in high yields (76–99%) and moderate to excellent enantioselectivities (44–99% ee), as shown in Scheme 10.5. Related reaction conditions were applied to the asymmetric hydrovinylation of β-alkyl-styrenes which regioselectively provided the corresponding 1,4-hydrovinylation chiral products in good to high yields (74–96%) and low to good enantioselectivities (16–84% ee), as shown in Scheme 10.5 (second reaction scheme). In both types of sub-strates, vinylarenes and β-alkyl-styrenes, an almost complete regioselectiv-ity was observed (≥98 : 2).

ConclusionsThis small chapter collects the first successes reported in the field of enan-tioselective cobalt-catalysed hydrovinylation reactions. Inspired by the early racemic work of Hilt, reported in 2001, dealing with the cobalt-catalysed codimerisation of 1,3-dienes with alkenes, the first asymmetric version was developed by Vogt in 2009, dealing with the enantioselective cobalt-catalysed hydrovinylation of styrene with ethene, providing the corresponding chiral 3-phenyl-1-butene in moderate enantioselectivities of up to 50% ee using a phosphine chiral cobalt complex. Following this lead, in 2010 Sharma and


RajanBabu reported the first highly efficient enantioselective hydrovinyla-tion of a range of substituted unactivated linear 1,3-dienes with ethene, lead-ing exclusively to the corresponding chiral (Z)-1,4-adducts with up to 99% ee, without any trace of the corresponding 1,2-regioisomers or any dimeri-sation products, using (R,R)-DIOp and (S,S)-BDpp as the cobalt ligands in the presence of AlMe3 as an additive. In 2012, the same group also used a (S,S)-BDpp-based cobalt complex to promote the remarkable asymmetric hydrovinylation of 1-vinylcycloalkenes with ethene, resulting in the forma-tion of chiral 1-alkylidene-2-vinylcycloalkanes with both high regio- and enantioselectivities of up to >99% ee in the presence of more easily weighed out methylaluminoxane in place of Me3Al. In 2014, the same group reported

Scheme 10.4 Hydrovinylations of 1,3-siloxydienes with ethene.

Chapter 10202

the highly enantioselective hydrovinylation of acyclic 1,3-dienes promoted by a cobalt catalyst derived from (R,R)-DIOp in the presence of AlMe3, or methylaluminoxane, as an additive, which regioselectively led to the corre-sponding chiral 1,4-hydrovinylation products bearing a Z-internal alkene, with up to 96% ee. In 2015, the same authors developed a general catalytic procedure for the highly chemo-, regio- and enantioselective synthesis of tri-alkylsilyl enol ethers exhibiting a vinyl-bearing chiral center at the β-position on the basis of an enantioselective hydrovinylation reaction between vari-ous 1,3-siloxydienes and ethane catalysed by a cobalt complex of (S,S)-DIOp, in the presence of methylaluminoxane as an additive, which afforded the corresponding branched 1,4-hydrovinylation chiral products in uniformly excellent enantioselectivities (>95–98% ee). Later in 2016, Schmalz reported an efficient and practical protocol for the enantioselective cobalt-catalysed

Scheme 10.5 Hydrovinylations of vinylarenes and β-alkyl-styrenes with ethene.


hydrovinylation of vinylarenes with ethane at low pressure, performed in the presence of Et2AlCl as an additive, regioselectively providing a wide range of chiral branched products in enantioselectivities of up to 99% ee. In spite of these rare but uniformly excellent results, efforts to better develop and apply the hydrovinylation reactions catalysed by chiral cobalt complexes in synthe-sis remain. In particular, the ligands investigated in these rare reactions are still limited to DIOp and BDpp, consequently other types of ligands will have to be researched in the near future.

References 1. (a) T. V. RajanBabu, Chem. Rev., 2003, 103, 2845; (b) T. V. RajanBabu, Syn-

lett, 2009, 853. 2. (a) L. S. pu, A. Yamamoto and S. Ikeda, J. Am. Chem. Soc., 1968, 90, 7170;

(b) S. M. pillai, G. L. Tembe and M. Ravindranathan, J. Mol. Catal., 1993, 84, 77; (c) G. Hilt and S. Lüers, Synthesis, 2002, 609; (d) C.-C. Wang, p.-S. Lin and C.-H. Cheng, Tetrahedron Lett., 2004, 45, 6203; (e) M. M. p. Grut-ters, C. Müller and D. Vogt, J. Am. Chem. Soc., 2006, 128, 7414.

3. D. Vogt, Angew. Chem., Int. Ed., 2010, 49, 7166. 4. (a) G. Hilt, F.-X. du Mesnil and S. Lüers, Angew. Chem., Int. Ed., 2001, 40,

387; (b) G. Hilt, M. Arndt and D. F. Weske, Synthesis, 2010, 1321; (c) M. Arndt, M. Dindaroglu, H.-G. Schmalz and G. Hilt, Synthesis, 2012, 44, 3534.

5. M. M. p. Grutters, J. I. van der Vlugt, Y. pei, A. M. Mills, M. Lutz, A. L. Spek, C. Müller, C. Moberg and D. Vogt, Adv. Synth. Catal., 2009, 351, 2199.

6. R. K. Sharma and T. V. RajanBabu, J. Am. Chem. Soc., 2010, 132, 3295. 7. J. p. page and T. V. RajanBabu, J. Am. Chem. Soc., 2012, 134, 6556. 8. (a) Y. N. Timsina, R. K. Sharma and T. V. RajanBabu, Chem. Sci., 2015, 6,

3994; (b) Y. N. Timsina, S. Biswas and T. V. RajanBabu, J. Am. Chem. Soc., 2014, 136, 6215.

9. S. Biswas, J. p. page, K. R. Dewese and T. W. RajanBabu, J. Am. Chem. Soc., 2015, 137, 14268.

10. S. Movahhed, J. Westphal, M. Dindaroglu, A. Falk and H.-G. Schmalz, Chem.–Eur. J., 2016, 22, 7381.

204


11.1 α-Functionalisations and α-Alkylations of Carbonyl Compounds

Chiral fluorinated organic compounds are well recognised as important materials in the field of biological and medicinal chemistry. Recently, several groups have demonstrated that chiral metal catalysts, based on titanium, ruthenium, palladium, copper, nickel or magnesium are effective in pro-moting the highly enantioselective α-fluorinations of β-ketoesters. In 2010, Itoh et al. demonstrated that cobalt could also be used in these reactions.1 Indeed, the cobalt-catalysed asymmetric α-fluorination of cyclic β-ketoesters with N-fluorobenzenesulfonimide (NFSI) was achieved using a chiral cobalt complex derived from Co(acac)2 and (R,R)-Jacobsen's salen ligand 1, which led to the corresponding α-fluorinated products in moderate to good yields (65–75%) and good to high enantioselectivities (75–90% ee), as shown in Scheme 11.1 (in the first reaction scheme). When an acyclic β-ketoester, such as ethyl 2-methyl-3-oxo-butanoate, was employed as a substrate, the reaction afforded the corresponding α-fluorinated product in both a lower yield (64%) and enantioselectivity (71% ee), as shown in Scheme 11.1 (in the second reaction scheme).

ChapteR 11

Synthesis of Chiral Acyclic Compounds Through Miscellaneous Enantioselective Cobalt-catalysed Reactions

205Synthesis of Chiral Acyclic Compounds Through Miscellaneous Enantioselective

as an extension of the precedent methodology, a chiral cyclic α-chlori-nated could be produced from the corresponding cyclic β-ketoester in 62% yield and 88% ee using CF3SO2Cl as the source of chloride using the same catalyst system in toluene at room temperature, as shown in Scheme 11.2.

In 2016, Gladysz et al. reported the use of Werner complex 2, based on the chiral trication [Co((S,S)-dpen)3]3+ (dpen = 1,2-diphenylethylenediamine), in promoting the enantioselective α-aminations of 1,3-dicarbonyl compounds and related substrates, such as cyanoketones, in acetonitrile at 0 °C.2 as shown in Scheme 11.3, the reaction of various cyclic β-ketoesters (X = CO2Me, CO2et) with di-tert-butyl azodicarboxylate, catalysed by 5 mol% of cobalt complex 2 in the presence of N-methylmorpholine as a base, afforded the corresponding chiral tertiary amines in high to quantitative yields (88–98%)

Scheme 11.1 α-Fluorinations of β-ketoesters.

Scheme 11.2 α-Chlorination of β-ketoesters.

Chapter 11206

and moderate to excellent enantioselectivities (72–>99% ee). Notably, the best enantioselectivities (91–>99% ee) were achieved for five- and six-membered ketones (n = 0–1) while a lower enantioselectivity (72% ee) was obtained in the reaction of a seven-membered substrate (n = 2).

the scope of this methodology was extended to an acyclic β-ketoester which underwent amination to give the corresponding enantiopure amine (>99% ee) in a quantitative yield (98%), as shown in Scheme 11.4. an α-cyano-cyclopentanone was also compatible (X = CN, n = 0), leading to the corre-sponding amine in 92% yield, albeit with a much lower enantioselectivity of 45% ee.

In 2008, North et al. described the synthesis of novel C1-symmetrical salen ligands, which were further investigated as chiral cobalt ligands in asymmetric reactions under phase-transfer conditions, such as the asym-metric alkylation of an alanine derivative with benzylbromide.3 as shown in Scheme 11.5, a good enantioselectivity of 80% ee combined with a good yield (83%) were achieved for the corresponding benzylated prod-uct using cobalt complex 3 as a catalyst. In this study, the authors also

Scheme 11.3 α-amination of 1,3-dicarbonyl compounds and α-cyanoketones.


obtained comparable results using the corresponding copper catalyst (91% yield, 81% ee).

11.2 Carbonyl-ene Reactionsthe carbonyl-ene reaction constitutes one of the most convenient meth-ods for carbon–carbon bond formation, which does not need any pretreat-ment of the carbonyl compounds such as enolisation, and the resulting

Scheme 11.4 α-amination of an acyclic β-ketoester.

Scheme 11.5 alkylation of an alanine derivative.

Chapter 11208

homoallylic alcohols can be further transformed into more functionalised products by taking advantage of the carbon–carbon double bonds. In par-ticular, the enantioselective carbonyl-ene reaction promoted by a Lewis acid is a direct route to optically active homoallylic alcohols. a variety of chiral complexes derived from metals, such as titanium, copper, scan-dium, chromium, and cobalt, and chiral ligands, such as BINOL, bisox-azolines, pybox, Schiff bases, etc. have been investigated as catalysts in these reactions. For example in 2001, chiral cationic cobalt(iii) complexes were used by Yamada et al. to promote the enantioselective carbonyl-ene reaction of glyoxal derivatives with a variety of alkenes.4 this reaction smoothly proceeded at −20 °C to afford the corresponding homoallylic alcohols in both moderate to high yields (60–93%) and high enantioselec-tivities (56–94%) when catalysed by cobalt complex 4, as shown in Scheme 11.6. the authors showed that, even in the presence of only 0.2 mol% of the cobalt catalyst, the reaction resulted in high yields (98–99%) and enan-tioselectivities (92–96% ee). the reaction temperature was found to have an effect on both the enantioselectivity and yield, since they were lower at room temperature and at 0 °C, while slightly improved at −40 and −60 °C instead of −20 °C.

In 2007, Rawal et al. reinvestigated this type of reaction using the more sterically hindered catalyst 5, in which bulky triisobutylsilyl substituents occupy the positions ortho to the phenolic oxygens.5 this complex cata-lysed the reactions of various 1,1-disubstituted, as well as trisubstituted, alkenes with ethyl glyoxylate at room temperature using catalyst loadings

Scheme 11.6 Carbonyl-ene reaction of 1,1-disubstituted alkenes with glyoxal deri vatives.


of as low as 0.1 mol%. the processes provided the corresponding homoal-lylic alcohols in moderate to quantitative yields (64–98%), and excellent diastereo- (92–94% de) and enantioselectivities (94–98% ee), as shown in Scheme 11.7.

11.3 Other Reactionsthe Friedel–Crafts reaction of aromatic compounds with aldehydes or ketones constitutes a fundamental reaction in organic chemistry, however, it must be recognised that its enantioselective catalytic version is still an un-explored field. In 2003, a chiral salen cobalt(ii) complex was used by Jurczak et al. to promote the high-pressure Friedel–Crafts reaction of 2-methylfuran with alkyl glyoxylates to afford the corresponding enantioenriched furfuryl alcohols (Scheme 11.8).6 When catalyst ent-1 was employed, these alcohols were achieved in moderate yields (47–50%) and moderate to good enantiose-lectivities (60–76% ee). Notably, this work represented the first example of an enantioselective Friedel–Crafts reaction catalysed by a chiral salen-type complex.

Scheme 11.7 Carbonyl-ene reaction of di- and trisubstituted alkenes with ethyl glyoxylate.

Chapter 11210

the Nicholas reaction is a versatile transformation involving the reaction of a cobalt carbonyl stabilised propargylic cation with different nucleo-philes, such as alcohols, amines, thiols, phosphines, hydrides, as well as carbon nucleophiles in the form of enol ethers, electron-rich aromatics, allyl silanes, allyl stannanes and trialkyl aluminum reagents.7 Complexation of the precursor propargylic alcohols with dicobalt octacarbonyl proceeds smoothly at room temperature, and the complex formed is subsequently treated with a Lewis acid, such as BF3(et2O), to generate a cation prior to addition of the nucleophile. Decomplexation is generally achieved oxida-tively, using cerium ammonium nitrate or iodine. asymmetric versions of the Nicholas reaction have in general involved the use of chiral nucleo-philes or chiral substrates. In 2008, Kann et al. reported the first asymmetric version of this reaction involving the use of racemic propargylic alcohols in conjunction with chiral ligands coordinated to cobalt, such as phosphor-amidite ligands.8 as shown in Scheme 11.9, the treatment of propargylic alcohols with Co2(CO)8 and two equivalents of chiral pyrrolidine-substi-tuted phosphoramidite ligand 6, followed by reaction with various nucleo-philes in the presence of a Lewis acid, such as BF3(Oet2), after decomposition through treatment with cerium ammonium nitrate, afforded the corre-sponding Nicholas products. the yields (30–90%) and enantioselectivities (12–70% ee) were found to fluctuate depending on the alcohol functionality and the nucleophiles used.

In 2015, Zhao et al. reported the first enantioselective cobalt-cata-lysed allylation of heterobicyclic alkenes, which employed potassium

Scheme 11.8 Friedel–Crafts reaction of 2-methylfuran.


allyltrifluoroborate as the allylating agent.9 among a series of chiral bis-phosphines investigated as the cobalt ligands, (S,S)-BDpp was found to be the optimal ligand, in combination with CoCl2. as shown in Scheme 11.10 (in the first reaction scheme), the reaction of various heterobicyclic alkenes with potassium allyltrifluoroborate performed in a 1 : 1 mixture of tetra-hydrofuran (thF) and 1,2-dichloroethane (DCe) at 70 °C led to the corre-sponding ring-opened chiral products in moderate to quantitative yields (66–90%) and uniformly excellent enantioselectivities (94–>98% ee). the extension of the scope of the reaction to less reactive non-benzofused substrates proved to be successful, since the corresponding product was obtained in 74% yield and 98% ee (Scheme 11.10, in the second reaction scheme).

In another context, in 2015 Yoshikai and Lee developed the enantiose-lective cobalt-catalysed C2-alkylation of Boc-protected indoles with aryl alkenes (Scheme 11.11).10 the catalyst was in situ generated from 20 mol% of

Scheme 11.9 enantioselective Nicholas reactions.

Chapter 11212

chiral phosphoramidite 7 as the ligand, 10 mol% of Co(acac)3 and 75 mol% of tMSCh2MgCl in thF at room temperature, allowing the corresponding chiral C2-alkylated indoles to be achieved in low to high yields (16–88%) and moderate to good enantioselectivities (68–87% ee).

Kinetic resolutions, based on the oxidation of a chiral secondary alcohol to a prochiral ketone, have been of considerable interest since the latter can be usually recycled into the racemic starting material through a simple hydride reduction.11 the first broadly applicable method for this purpose was reported by Noyori et al. under catalytic hydride transfer conditions similar to those employed for the asymmetric hydrogenation of ketones.12 Recently, cobalt-catalysed kinetic resolutions of secondary alcohols with molecular oxygen have been achieved. For example, in 2009 Yamada et al. reported good to high enantioselectivities of up to 96% ee for the aerobic kinetic resolution of various secondary benzylic alcohols 10 and 11 using the chiral ketoiminato-cobalt(ii) complexes 8 or 9 as catalysts (Scheme 11.12).13 In this catalytic sys-tem, styrene was employed as the oxygen acceptor to be converted into the corresponding ketone.

the use of another cobalt complex bearing Schiff base ligand 12 allowed the kinetic resolution of α-hydroxy ketones 13 and α-hydroxy esters 14 to be achieved in high selectivity factors of up to 47 and 31.9, respectively (Scheme 11.13).14

Chiral cobalt catalysts have also been applied in the resolution of other substrates, such as epoxides and N-benzyl α-amino acids. In this context, the

Scheme 11.10 allylations of heterobicyclic alkenes.


enantiomer of chiral Jacobsen's salen cobalt catalyst 15 (Figure 11.1) was employed by Gennari et al. to achieve a novel approach for the resolution of racemic N-benzyl α-amino acids in excellent yields and enantioselectiv-ities of up to 99% ee through liquid–liquid extraction.15 as a result of the resolution by extraction, one enantiomer (S) of the N-benzylated α-amino acid was predominately found in the aqueous phase, while the other enan-tiomer (R) was driven into the organic phase by complexation to cobalt. the complexed amino acid (R) was then quantitatively released by a reductive (cobalt(iii) into cobalt(ii)) counter-extraction with aqueous sodium dithi-onite or l-ascorbic acid in methanol. the reductive cleavage allowed recov-ery of the Co(ii) complex in good yield, which could be easily reoxidised to Co(iii) with air/acOh and reused with essentially no loss of reactivity and selectivity. Investigation into the nitrogen substitution indicated that the presence of a single benzyl group on the amino acid nitrogen was import-ant for obtaining high enantioselectivity in the extraction process. a range of racemic N-benzyl α-amino acids, such as N-benzyl-threonine, N-benzyl- valine, N-benzyl-leucine, N-benzyl-phenylalanine and N-benzyl-alanine could be resolved under these conditions with enantioselectivities of 96%, 94%, 99%, 93% and 66% ee, respectively. Moreover, the scope of this methodology was extended to the resolution of N-benzyl β3-amino acids, such as N-benzyl

Scheme 11.11 C2-alkylation of indoles with aryl alkenes.

Chapter 11214

β3-homophenylglycine, N-benzyl β3-homoalanine and N-benzyl β3-homov-aline, which were resolved in 93%, 93% and 90% ee, respectively. Finally, tokunaga et al. have shown that chiral salen cobalt complexes, such as the enantiomers of the catalysts ent-1 and 15, could also allow the hydrolytic kinetic resolution of cis-2-tert-butylcyclohexyl vinyl ether to be achieved with a good selectivity factor of 10.16

Scheme 11.12 Kinetic resolutions of secondary alcohols.


11.4 Conclusionsthis small chapter includes other types of enantioselective cobalt-catalysed transformations that could not be inserted in the other chapters. among them, various reactions have provided excellent results in term of enantio-selectivity. For example, asymmetric α-fluorinations and α-chlorinations

Scheme 11.13 Kinetic resolutions of α-functionalised secondary alcohols.

Figure 11.1 the structure of salen cobalt(iii) catalyst 15.

Chapter 11216

of β-ketoesters performed with salen cobalt complexes were achieved with enantioselectivities of 88–90% ee. In the same area, enantioselective α-ami-nations of 1,3-dicarbonyl compounds and α-cyanoketones catalysed by Wer-ner complexes resulted in >99% ee. Moreover, the asymmetric carbonyl-ene reaction of 1,1-disubstituted and trisubstituted alkenes with glyoxal deriv-atives, promoted by cationic salen cobalt complexes, were achieved with enantioselectivities of up to 98% ee. the first enantioselective cobalt-cata-lysed allylation of heterobicyclic alkenes, employing potassium allyltriflu-oroborate as the allylating agent, was also developed using (S,S)-BDpp as the ligand with up to 98% ee. a phosphoramidite ligand allowed the enan-tioselective cobalt-catalysed C2-alkylation of Boc-protected indoles with aryl alkenes to be achieved, with 87% ee. Finally, many kinetic resolutions based on the oxidation of a wide variety of chiral secondary alcohols were developed in the presence of chiral salen cobalt complexes along with the kinetic resolution of other substrates such as epoxides, N-benzyl α-amino acids, and cis-2-tert-butylcyclohexyl vinyl ether. On the basis of the extra-ordinary ability of cobalt catalysts to adopt unexpected reaction pathways, an increasing amount of novel methodologies will be undoubtedly devel-oped in the near future.

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General ConclusionThe production of chiral compounds has become a central theme in organic chemistry. Indeed, the broad utility of these products as single-enantiomer pharmaceuticals, in electronic and optical devices, as components in poly-mers, and as probes of biological functions, has made asymmetric synthesis an outstanding area of investigation. Nearly all natural products are chiral and their physiological and pharmacological properties depend upon their recognition by chiral receptors, which will interact only with molecules of the proper absolute configuration. Indeed, the use of enantiopure drugs is now a standard requirement and, consequently, the development of new asym-metric synthetic methods to obtain chiral compounds has become a key goal for pharmaceutical companies. More generally, the search for new method-ologies to prepare optically pure compounds constitutes one of the most active areas of research in organic synthesis. Of the methods available for preparing chiral compounds, catalytic asymmetric synthesis has attracted most attention. In particular, asymmetric transition-metal catalysis consti-tutes a powerful tool for performing reactions in a highly enantioselective fashion. The main efforts to develop new asymmetric transformations have focused predominantly on the use of a few metals, such as titanium, nickel, copper, ruthenium, rhodium, palladium, iridium, and more recently, gold. However, by the very fact that cobalt catalysts have lower costs associated with them in comparison with other transition metals, and the extraordinary ability of cobalt catalysts to adopt unexpected reaction pathways, an impres-sive number of enantioselective cobalt-promoted transformations have been developed over the three last decades, allowing the synthesis of many types of both chiral cyclic and acyclic products to be achieved, often under rela-tively mild conditions and with remarkable enantioselectivities. This book illustrates how much enantioselective cobalt catalysis has contributed to the

219General Conclusion

development of various types of enantioselective ecological and economical transformations. It collects together the major developments reported over the last three decades in the field of enantioselective reactions promoted by chiral cobalt catalysts, illustrating the power of these green catalysts to pro-vide all types of organic reactions, from basic ones to completely novel meth-odologies, such as domino reactions, for example.

The book is divided into 11 chapters, the first 4 of which deal with enan-tioselective cobalt-catalysed cyclisation reactions, while the following chap-ters 5–11 feature enantioselective cobalt-catalysed formations of acyclic chiral compounds. Chapters 1–4 successively include [2 + 1] cycloadditions, other types of cycloadditions, cyclisations through domino reactions, and miscellaneous cyclisations. Chapters 5–11 concern the synthesis of chiral acyclic compounds through enantioselective cobalt-catalysed transforma-tions, including successive reduction reactions, ring–opening reactions, Michael and (nitro)-aldol reactions, 1,2-nucleophilic additions to carbonyl compounds and derivatives other than (nitro)-aldol reactions, cross- coupling reactions, hydrovinylation reactions and miscellaneous reactions. This book demonstrates the diversity and impressive amount of enantioselective syn-thetic uses that have been found for cobalt chiral catalysts over the last three decades, spanning from basic organic transformations to completely novel methodologies.

The ever-growing need for environmentally friendly catalytic processes has prompted organic chemists to focus on more abundant and less toxic first–row transition metals such as cobalt to develop new catalytic systems to promote all type of organic reactions, including C–C bond formations, C–heteroatom bond formations, C–H functionalisations, oxidations and reduction reactions. A bright future is undeniable for more sustainable novel and enantioselective cobalt-promoted transformations. However, despite the impressive number of excellent results reported so far, many challenges remain, such as a better understanding of the mechanisms of the reactions, the investigation of other types of cobalt catalyst systems, which are still really limited in some cases, and the extension of the scopes of the reactions to even more challenging substrates, as well as the development of more applications in the total synthesis of natural and/or biologically active compounds. Efforts are also expected in the field of multicatalysis which is blossoming. Moreover, the further development of many types of reactions is highly desirable, such as 1,2-nucleophilic additions to carbonyl com-pounds and derivatives, cross-coupling reactions, hydrovinylations, epoxi-dations, aldol condensations and domino processes, which are still in their infancy. Considering the extraordinary ability of cobalt catalysts to adopt unexpected reaction pathways, an increasing number of novel methodolo-gies will be undoubtedly developed in the near future.

220

Subject Index

3-acryloyl-2-oxazolidinone, 35alkenes, reductions of

borane derivativesborohydride conjugate

reductions, 111–115hydroborations,

115–119hydrogenations, 120–124hydrosilylations, 119–120

2-alkenylbenzaldehydes, 86(E)-2-alkenyl α-diazoacetates, 22(E)/(Z)-2-alkenyl α-diazoacetates, 215-alkoxyoxazoles with

azodicarboxylates, 47allyl azidoformates, 27aziridinations, 22–26

Baeyer–Villiger reaction, 78benzaldehyde, 181benzoxathiazine-2,2-dioxides,

vinylation of, 184N-benzylideneaniline N-oxide, 421-(2-benzyloxyethyl)-3-(tert-

butyldimethylsilyl)oxy-1,3- butadiene with methyl glyoxylate, 39

biphosphine ligands, 84–86borohydride reductions, 95–105α-bromoacrolein, 42

carbon–carbon double bonds, 2carbonyl compounds and

derivativesα-amido sulfones, 184, 185

(S,S)-BDPP, 182benzaldehyde, 181benzoxathiazine-2,2-dioxides,

vinylation of, 184borohydride reductions,

95–105diisopropylzinc to pyrimidine-

5-carbaldehyde, 180(R,R′,S,S′)-DuanPhos, 183hydrogenations, 109–111hydrosilylations, 105–109isatins, vinylation of, 183phenylboronic acids to

aldehydes, 181chalcones, 27chiral acyclic compounds

α-alkylations of carbonyl compounds, 204–207

C2-alkylation, indoles with aryl alkenes, 213

carbonyl compounds and derivatives

α-amido sulfones, 184, 185(S,S)-BDPP, 182benzaldehyde, 181benzoxathiazine-2,2-diox-

ides, vinylation of, 184diisopropylzinc to

pyrimidine-5- carbaldehyde, 180

(R,R′,S,S′)-DuanPhos, 183isatins, vinylation of, 183phenylboronic acids to

aldehydes, 181

Subject Index 221

carbonyl-ene reactions, 207–209

cross-coupling reactionsalkynes with cyclic

enones, 189(R)-ar-curcumene, 193(S)-ar-turmerone, 192(R)-4,7-dimethyl-1-

tetralone, 193(S)-fenoprofen, 192(S)-ibuprofen, 194Kumada cross-coupling

reaction, 191, 193oxa- and azabenzonor-

bornadienes, 190Friedel–Crafts reaction,

209–210α-functionalisations,

204–207α-functionalised secondary

alcohols, 215heterobicyclic alkenes, 212hydrovinylation reactions

acyclic 1,3-dienes with ethene, 199

β-alkyl-styrenes with ethene, 202

1,4-hydrovinylation of 1-vinylcycloalkenes with ethene, 199

1,4-hydrovinylation of substituted 1,3-dienes with ethene, 198

1,3-siloxydienes with ethene, 201

vinylarenes, 202Michael reactions

(nitro)-aldol reactions, 167–174

nitroolefins, 160–167α,β-unsaturated carbonyl

compounds and derivatives, 155–160

Nicholas reactions, 211ring-opening of epoxides

alcoholytic, 129–140by amines and

carbamates, 140–143(co)polymerisation,

143–146hydrolytic, 129–140

salen cobalt(iii) catalyst, 215secondary alcohols, kinetic

resolutions of, 214chiral iminopyridine–oxazoline

ligand, 118chiral oxazoline aminopyridine

ligand, 119[Co(tetraphenyl-carbpi)

(OAc)], 21cross-coupling reactions

alkynes with cyclic enones, 189

(R)-ar-curcumene, 193(S)-ar-turmerone, 192(R)-4,7-dimethyl-1-tetralone,

193(S)-fenoprofen, 192(S)-ibuprofen, 194Kumada cross-coupling

reaction, 191, 193oxa- and azabenzonorborna-

dienes, 190α-cyanoketones, 206cyclic β-ketoamides, 164cyclisation, o-iodobenzoates with

aldehydes, 85[2+2] cycloaddition, 54[2+2+1] cycloadditions, 50–53[2+2+2] cycloadditions, 46–50[4+2+2] cycloaddition, 53[6+2] cycloaddition, 55cyclopropanations

α-acceptor-substituted allylic diazoacetates, 23

of alkynes with α- cyanodiazoacetates, 16

cis-selective cyclopropanationof alkenes with α-nitro-

diazoacetates, 13

Subject Index222

cyclopropanations (continued)of mono- and 1,1-disub-

stituted aromatic alkenes with ethyl, 5

tert-butyl diazoacetates, 5α-cyanodiazoacetamides, 161,1-disubstituted alkenes

catalysed with ethyl diazoacetate, 8

heteroaromatic substrates with ethyl diazoacetate, 9

intermolecularwith other cobalt

complexes, 19–20with porphyrin cobalt

complexes, 10–19with salen cobalt

complexes, 1–9intramolecular, 20–22, 21, 22, 23(+)-synosutine, 8and tert-butyl diazoacetates, 11trans-selective

cyclopropanationof alkenes with

diazosulfones, 17of alkenes with ethyl

diazoacetate, 19of alkenes with

succinimidyl diazoacetate, 14

of alkenes with sulfonyl hydrazones, 18

of alkenes with tert-butyl α-cyanodiazoacetate, 15

of alkenes with tert-butyl α-formyldiazoacetate, 17

aromatic alkenes with tert-butyl diazoacetate, 3

of mono- and 1,1-disub-stituted alkenes with ethyl, 3, 11

of styrenes with CF3CH2NH3Cl, 7

tert-butyl diazoacetates, 3

Darzens condensation, 81Darzens reaction, isatins with

phenacyl bromides, 90diazoalkanes, transition-metal-

catalysed decomposition of, 1–21,2-dichloroethane (DCE), 211Diels–Alder cycloadditions, 34–364-(N,N′-dimethylamino)pyridine

(DMAP), 10diphenylphosphoryl azide, 241,3-dipolar cycloaddition, 40–46DMAP. See 4-(N,N′-dimethylamino)

pyridine (DMAP)domino 1,5-hydride transfer/

cyclisation reaction, 65domino aldol/cyclisation

reaction, 69domino hydroboration/cyclisation

reactionof 1,6-enynes with

pinacolborane, 70domino Michael/cyclisation

reaction, 67domino reductive cyclisation

reactionof γ-azido-α,β-unsaturated

esters, 64of γ-cyano-α,β-unsaturated

ester, 64

epibromohydrin, 136epoxidations, 26–27

α-haloamides with aromatic aldehydes, 81

hetero-Diels–Alder cycloadditions, 36–40

hydrovinylation reactions1,3-siloxydienes with ethene, 201acyclic 1,3-dienes with ethene,

199β-alkyl-styrenes with ethene,

2021,4-hydrovinylation of

1-vinylcycloalkenes with ethene, 199

Subject Index 223

1,4-hydrovinylation of substituted 1,3-dienes with ethene, 198

vinylarenes, 202

intramolecular hydroacylation, 86iodolactonisation reaction, 80

β-ketoesters, 205Kumada cross-coupling reaction

α-bromo esters with aryl Grignard reagents, 191, 193

1-methoxy-[3-(tert-butyldimethyl-silyl) oxy]-1,3-butadiene with aldehydes, 39

α-methoxycarbonyl- α-diazosulfones, 87

methyleneindolinones, 44N-methylimidazole (NMI), 2methyllycaconitine analogues, 38Michael reactions

(nitro)-aldol reactions, 167–174

nitroolefins, 160–167α,β-unsaturated carbonyl

compounds and derivatives, 155–160

Nazarov reaction, 89

oxetanes, intramolecular opening of, 78

polymer-supported hydrolytic dynamic kinetic resolution, 136

porphyrin cobalt(ii) complex, 23porphyrin ligands, 86–88

Povarov reactionof 2-azadienes with

2,3-dihydrofuran, 91of 2-azadienes with ethyl vinyl

ether, 92of 2-azadienes with

N-Cbz-2,3-dihydropyrrole, 91

ring–opening of epoxides, chiral acyclic compounds

alcoholytic, 129–140by amines and carbamates,

140–143(co)polymerisation, 143–146hydrolytic, 129–140

salen cobalt(ii) complex, 21salen ligands, 75–835-substituted-4-pentenoic acid

derivatives, 80

tetrahydrofuran (THF), 211three-component domino

Diels–Alder/allylboration reaction, 63

three-component domino hydrosilylation/hydrogenation reaction

of terminal aryl alkynes with Ar2SiH2 and H2, 70

trichloroethoxysulfonyl azide, 26bis(2,2,2-trichloroethyl)phosphoryl

azide, 25trisubstituted alkenes, 86

α,β-unsaturated aldehydes, 36

vinylarenes, 202

Documents

Enantioselective cobalt-catalysed transformations