LSPN 04.12.2012

Jean-Baptiste Gualtierotti

Micro-topic: Desymmetrization

(Part 1?)

Last Group Metting of the Year

ConceptStructure A

Topicity?

enantio homo diastereo

Enantiopic differientiation monofunctionalisation Diastereotopic

differientiation

Structure B

A Lower state of chirality

R1 R1

R2 R3R1 R1

R2 R2

R3 R4R1 R1

R2 R2

R1 R1

R2 R2

R3 R4

achiral meso Chiral C2 Pseuo chiral C2

B Higher state of chiralityDesymmetrization

Magnuson, Tettrahedron 1995, 2167.Note: facial differentiation could be considered desymmetrization

Superior to kinetic resolution

R1 R1'R2 R3

R1 R1

R2 R3

R1' R1

R2 R3

R1 R1

R2 R3

Fast

Slow

Desymmetrisation

In theory may have 100% yield

R1 R1'R2 R3

R4 R1R2 R3

R1' R1R2 R3

R1 R4R2 R3

Fast

Slow

Kinetic resolution

In theory may have 50% yield

Concept

May be higher if starting compound can racemise during the process

What?

Anhydrides Epoxides Aziridine

DiolsDienes Ketones

EthersEnes

With what?

alkylation

Ring openings

methathesis

Asymetic deprotonationoxydationsreductions

hydrolysis transesterifications

Scope

Willis J. Chem. Soc., Perkin Trans 1, 1999, 1765

New frontiers in Asymmetric catalysis, Wiley, 2007, edited Leutens chapter 10 by Rovis (on server)

EnzymesTraditionally «feared» by chemists despite being often

highly selective

- Sensitive to contamination- Work in water- Require bio-knowledge to handle- Optimized by controlled mutagenis- Requires specific equipment

Modern advances made them «chemist-friendly»

Gotor, Chem. Rev. 2005, 105, 313

Classical optimisation possibilities

Commercial sources for broader substrate scope

Enzymes

Gotor, Chem. Rev. 2005, 105, 313Most enzymes from review are availible from sigma-aldritch

Basic prediciton rules through models and empiricla rules

Carrea, G.; Riva, S. Angew. Chem. Int Ed. 2000, 39, 2226-2254

Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem 1991, 56, 2656-2665.

Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumont, A.-C.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2003, 14, 3081-3093.

3D models availibe rcsb.PDB; following simple substituant size analysis

Organic media methods

Ionic liquids/additives

Small, convenient reactors

Cao, L.; Langen, L. v.; Sheldon, R. A. Curr. Opin. Biotechnol. 2003, 14, 387-394

Immobilized enzymes

Enzymes: desymmetrization of diols

Takabe Tetrahedron: Asymmetry 2000, 11, 4825

Few general enzymes: try and see method

Sacrificial group R3 controls ratio

Yields 77%, ee >95%

Many diols can de desymetrized

Chênevert, J. Org. Chem 2000, 1707

Synthesis of Rifamycin S fragment

Oku, J. Org. Chem 1992, 1637.

OH OHOOH OHTBDMS

O OHOOH OHTBDMS

Ac

O OOO OAc

2 steps

PPL, vinyl acetate r.t

76% 98% ee

Original synthesis: 9 steps from start to final intermediate

With 4.5:1 desym ratios

Large range of diols can be desymmetrized in relatively mild conditions

Enzymes: desymmetrization of diols

Enzymes Carboxilic acid derivates

O

O OH O

O HO

O O O

O

O O

O

O

N

O

NH

F

Atorvastatin

1) protection alcohol2) alpha CHY

94% 98% ee

R

Intermediate for several analogues

O

O O

O

Cl

Cl

HO

O O

O

Cl

Cl

up to 200kg scale for medical purposes with 100g enzyme

NK1/Nk2

Candida antarctica lipase B

80%, 99% ee

Zaks, Adv. Synth. Catal., 2001, 343

Ohrlein, Adv. Synth. Catal., 2003, 713

Pig liver esterase main family

Enzymes Carboxilic acid derivates

O

R

O O

O R O

O OH

Amano Pether r.t

>70%, >79% ee

R = aromatic, aliphatic, higly dependant on solvent and R, Strong vs H-bond donor/acceptors

weak vs aromatic

Oda, Tetrahedron Letters, 1988, 1717

O

RO O

O NH

RO O

OR2

CALB dioxane 30°C

60-98%, 70-99% eeGotor, Tetrahedron asymmetry, 2003, 603

Work best on R = H-bond donor or acceptor,Weak vs aromatic

Enzymes Carboxilic Baeyer-Villiger oxidationsDevelloped yet require more equipment

O

R1

O

O

R2 R2R2

R1 R2

H

H

O R

H

H

O

RO

CHMO Brevil I or II

CHMO Brevil I or II

R1 and R2 = H or Me>60%, >95% ee

5 or 6 membered rings> 60%. >95% ee

Mihovilovic, Bioorg. Med. Chem., 2003, 1479

Some recent examples function in ionic liquids with commercial enzymes

Arends, Green Chem, 2011, 2154

O

O

OCaLB, H2O2

NN

OH

NO3-

1-(3-hydroxypropyl)-3-methyl-1H-imidazol-3-ium [HOPMIm]+NO3-

Ring opening Desymmetrizations: Epoxides

R2

R2

O

R2

R2 OH

R

R = Thiols, >60%, 20-80%R = Amines > 40%, 30-60% eeR Azide > 50%, 20-30%

R2 cycle n = 5,6, Me

Zn d-tartrate

Yamashita, Bull. Chem. Soc. Jpn, 1988, 1213

Early examples

First high ee’s examples

R2

R2

O

R2

R2 OH

R

R = Nitriles >80%, >90% ee M = YbR = Azides >65%, >80% ee M = CrR = Thiols >70%, >90% ee M = CrR = Acids > 90%, > 55% ee M = Co

R2 cycle n = 5,6, Me, Ph

Salen/PyBoxComplexes

JacobsenNitriles: org lett, 2000, 1001

Azides: J. Am. Chem. Soc., 1995, 5897Thiols: J. Org. Chem., 1998, 5252

Acids: Tettrahedron Letters, 1997, 773

Jacobsen, J. Am. Chem. Soc. 1996, 10924

Ring opening Desymmetrizations: Epoxides

L = THF or ether

Catalyst plus TMSN3 generate pre-catalyst

Cr N3 Cr N3

O

isolated

Ar

ArO

Ar

Ar OH

R

Salen ligand, Ti(OiPr)4

anilines, r.t>90%, 96% eeee drops with non aromatic substituants

R = Phenols>67%, >66% ee

Shibasaki, J. Am. Chem. Soc., 2000, 2252

Kureshy, chirality 2011, 76.

R2

R2

O

R2

R2 OH

R

cat.

Ring opening Desymmetrizations: Epoxides

Cat.

RR

O

RR

ORR

HO RSiCl

ClCl

LBLBCl-

SiCl4

2 eq cat

R2

R2

O

R2

R2 OH

RR = Cl

NH

NHP

O

NSiCl4

HMPA

N

N O

OSiCl4

SiCl4> 94%, > 87%>88%, >90% ee

Denmark, J. Org. Chem., 1998, 2428 Fu, J. Am. Chrm. Soc., 2001, 353

Nakajima, Tetrahedron Letters, 2002, 8827

>95%, >90% ee

Ring opening Desymmetrizations: Epoxides

Mechanistic studies

Ar

ArO

Ar

Ar OH

R

Sc(OTf)3 ligand, 35°C>90%, >90% ee

N

HNR1

R2R1

NH

O

N N

OH

N

O O

Feng, Chem. Eur. J. 2012, 3473

Ring opening Desymmetrizations: Aziridines

R2

R2

N

R2

R2 NH

R3

R

RCatalyst

75-95%, 83-94% ee

Jacobsen, Org. Lett., 1999, 161194-99%, 87-96% ee

Shibasaki, J. Am. Chem. Soc., 2006, 6312

49-97%, 70-95% ee

Antilla, J. Am. Chem. Soc., 2007, 12084.

Ring opening Desymmetrizations: Aziridines

Salen complexes are too big, lowering of catalitic acitvity due to substituent on nitrogen

R = alkylR3 = TMSN3

O

NO2

NO2

R = R3 = TMSN3

O

CF3

CF3

R = R3 = TMSN3

NNH

R

Ts

TsCatalyst

89% yield 55% ee

R = Me, Pent, ipr, ph, 2,4,6-trimethyl-ph

Muller, Helvetica Chimica Acta, 2001, 662

With TMSCl

R = Cl

>80%, 95% ee

N

N

N

Ph

CF3

F3C

NHO

NO2

Cl

Cl

Cl

Ooi, J. Am. Chem. Soc., 2012, 8794

Ring opening Desymmetrizations: Aziridines

With RMgBr

O Cat.Ligand

NuOH

Nu

Nu = rich amines Cat = Rh(COD)l2 71-97%, 88-98%Indol (C-3 position reactive)

Nu = alcohol/poor amines Cat = Rh(COD)Cl2 53-96%, 93-99% ee

Lautens, Org. Lett., 2000, 1677.

Lautens, J. Org. Chem., 2004, 2194.Nu = thiols, 52-92%, 90-98% ee

Lautens, J. Am. Chem. Soc, 2001, 7170.

N Cat.Ligand

Nu = HN(R)2 OH(R)2N

Boc

>80%, >89% ee

Lautens, Org. Lett, 2002, 3465.

Ring opening Desymmetrizations: Bridged compounds

Lautens, J. Am. Chem. Soc., 2000, 5650

Nu = phenol, 60-41%, 91-99% ee

Ring opening Desymmetrizations: Bridged compounds

X Pd(MeCN)2Cl2i-Pr-POX

R2ZnOH

R2

X = O, N-Ph

Lautens, J. Am. Chem. Soc., 2000, 180490%, 89% ee

X

Pd(t-Bu-POX)Cl2

(R3)2Zn

OHR3

X = O, N-Boc

R1

R2

R2R1

R1

R2

R2

R1

O

R1

R1

O R1

R1

OR2R2

R3

OH

O

OTIPS

OTIPS

TIPSO

OTIPSR3

HO

Pd(t-Bu-POX)Cl2

(R3)2Zn

Pd(t-Bu-POX)Cl2

(R3)2Zn

Fesulphos-Palladium(II) Complexes with secondary amines as nucleophiles:

Ring opening Desymmetrizations: Bridged compounds

Lautens, J. Am. Chem. Soc., 2004, 1437

O

N

P

i-Pr-POX: (4S)-2-(2-(diphenylphosphino)-phenyl)-4-isopropyl-1,3-oxazoline

O

N

P

Carretero J. Am. Chem. Soc. 2005, 17938

Ring opening Desymmetrizations: Bridged compounds

XIr[(COD)Cl]2

Binap

NuOH

R3

X = O, N-Boc

R1

R2

R2R1

R1

R2

R2

R1

With AgOTf, TBAI, TMEDA 80°C

Nu = Phenols >92%, 93%ee

Yang, J. Org. Chem. 2012, 9756

Mechanistically hypothesized that Ir functions as Rh

Ring opening Desymmetrizations: Bridged compounds

O Cu(OTf)2Ligand

(R2)2ZnZn(OTf)2

OHR2

R

R 58-90%, 80-99% ee

Zhou, Chem. Asian J. 2008, 2105

O Cu(OTf)2Ligand/ NaBArF

R2MgBrOH

R2

R

R>75%, 85% ee

Ring opening Desymmetrizations: Bridged compounds

Zhou J. Org. Chem, 2005, 3734

O

O

O

R1

R1

Cyclic n = 5 or 6 with Metyl substituentsBi cyclic 2:2:1, 2;2;2

OH

O

O

R1

R1OiPr

>75%, >70% ee

Ti(OiPr)4 TADDOL

-40°C Seebach, J. Org. Chem., 1998, 1190

Ring opening Desymmetrizations: Anyhdrides

O

O

O

R1

R1

Cyclic n = 5 or 6 with Metyl substituentsBi cyclic 2:2:1, 2;2;2

OH

O

O

R1

R1OMe

>80%, >90% ee

First report

Most popular method See Diaz de Villegas, Chem. Soc. Rev. 2011, 5564

Chinchona alkaloid catalysts

OTBS

O2N

N

HN S

NHF3C

CF3

NH

N

N

OSO

F3CCF3

O

HO

O

O

OH CH3

NH

R

N

O

R =

OH HN

O

HN

Ar

HN

S

HN

Ar S

O

O

Ar

Oba 1980Bolm 1999

Song 2009Nagao 2005

Chen 2008

NH

O

N

O

O

NH

N

O

OO

(DHQ)2AQN and derivates

N

F3C

CF3

CF3

CF3

OP

O S

NH

List 2010Deng 2000

Mode of action

Ring opening Desymmetrizations: Anyhdrides

Song 2009

O

R1

R2

R1

OO R1

R2

R1

OO

R3 OH

Metal catLigandM-R3

Ni(COD)2, i-Pr-POX Et2Zn 85%, 79% ee Rovis, J. Am. Chem. Soc, 2002, 174.

Pd(OAc)2 (5 mol%), JOSIPHOS, Ph2Zn 61-83%, 89-97% ee Rovis, J. Am. Chem. Soc, 2004, 10248.

Rh(COD)2Cl2 (4 mol%), Taddol-PNMe2, Li-Aryl, Zn(OTf)2 56-88%%, 76-88% ee Rovis, Angew. Chem. Int. Ed, 2007, 4514.

Rh(COD)2Cl2 (5 mol%), t-Bu-POX, (Alkyl)2Zn 62-87%%, 88-95% ee Rovis, J. Am. Chem. Soc, 2007, 9302.

Ring opening Desymmetrizations: Anyhdrides

Ring opening Desymmetrizations: Anyhdrides

Summerized: Rovis, Acc. Chem. res., 2008, 327

The end?