Dynamic Kinetic Resolution: A Powerful Approach toAsymmetric Synthesis

OCO2EtMeO

Ru(II)(R)-BINAPOH

CO2EtMeOH2

OHCO2EtMeORu(II)(S)-BINAP

H2

Rhizopus arrhizus

Baker's yeast

100% yield97% de, 96% ee

93% yield93% de, 86% ee

OHCO2EtMeO

OHCO2EtMeO

98% yield98% de, 99% ee

70% yield98% de, 95% ee

Erik AlexanianSupergroup Meeting

March 30, 2005

For leading references, see: Pellissier, H. Tetrahedron 2003, 59, 8291Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247

Methods for Asymmetric Synthesis

Catalytic enantioselective organic reactions

- Chemocatalysis - metal-mediated, Lewis acid-mediated, organocatalysis- Biocatalysis - enzymes (hydrolases)

Resolution

Synthesis utilizing existing stereogenic centers (chiral substrates or auxiliaries)

- Conventional separation procedures- Kinetic resolution

SRkR PR

kSSS PS

Problems associated with standard kinetic resolutions:

- Theoretical yield = 50%

- Separation of product from remaining substrate required

- In the majority of processes, only one stereoisomer is desired

- Drop in enantiomeric purity as process nears 50% conversion

100

50

00 50 100

% ee

% conversion

E = kfast/kslow = 10

ee P

ee S

Dynamic Kinetic Resolution

SRkR PR

kSSS PS

100

50

00 50 100

% ee

% conversion

E = kfast/kslow = 10

ee Pee S

SRkR PR

kSSS PS

Classic Resolution Dynamic Resolution

ee P DKR

kinv

PRPS

SR

SS

kinv

kS

kR ∆∆G

If racemization can occur concurrently with kinetic resolution, then theoretically 100% of the racemic mixture can be converted to one enantiomer. This process is known as dynamic kinetic resolution (DKR).

DKR is an example of a Curtin-Hammett system in which the composition of products is controlled by the free energies of the transition states and not the composition of the starting materials.

Guidelines for Dynamic Kinetic Resolution

SRkR PR

kSSS PS

Dynamic Resolution

kinv

In order to design a successful DKR, both the inversion and resolution steps have to be carefully tuned. Here are a few established general guidelines for an efficient DKR:

(1) The kinetic resolution should be irreversible in order to ensure high enantioselectivity.

(2) The enantiomeric ratio (E = kR/kS) should be at least greater than ~20.

(3) To avoid depletion of SR, racemization (kinv) should be at least equal or greater than the reaction rate of the fast enantiomer (kR).

(4) In case the selectivities are only moderate, kinv should be greater than kR by a factor of ~10.

(5) Obviously, any spontaneous reaction involving the substrate enantiomers as well as racemization of the product should be absent.

Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry 1999, 10, 107

Examples of Racemization

1) Acid or base catalyzed racemization

2) Enzyme catalyzed racemization

The racemization/inversion step is key to a successful DKR. Following are a number of common techniques used for this step.

NO

R

O

Ph

CALBNEt3, R'OH

HN

OPh

R

COOR'

up to 96% yieldup to 98% ee

R1 R2

OHDehydrogenase

(reversible)

NAD(P)+ NAD(P)H

R1 R2

ORedox-Enzyme

(irreversible)

R1 R2

OH

Examples of Racemization (Cont'd)3) Schiff base-mediated racemization

4) Racemization via sp2 intermediates (redox, addition/elimination)

H2N CO2R

R1 Alcalase

t-BuOH/H2O (19:1) H2N CO2H

R1

90-98% ee, 87-95% yield

pyridoxal 5-phosphate

NCO2R

R1

CH

NCO2R

R1

CH2NH+

OH

O H

OPO

OO

pyridoxal 5-phosphate

R

OH

X

High pH

R

O

X

Lipase

Acyl donorR

OAc

XX = SR', OR', NHR', CN

R1 R2 R1 R2

XH

[M]R1 R2

X

[M]HH

+X

H[M]H

H

Examples of Racemization (Cont'd)5) Anionic interconversion

6) Racemization via π-allyl intermediates

O N

Ets-BuLi

(-)-sparteine

ONLi L

ONLi L E

ONE

R2R1

Nu

[ M ] R2R1

MNu R2R1

Nu

7) Racemization via SN2 processes

CO2Me

BrC. rugosa

PPh3 BrCO2H

Br

79% ee, 78% yield

The "Catalytic Triad" - Reaction Mechanism of CALB

N N

His224

H

Asp187

O O

Ser105OHO

O

R2R1

N N

His224

H

Asp187

O O

Ser105OH

OO

R2

R1

O

O

R2

R3

R4

N N

His224

H

Asp187

O O

Ser105OH

OO

R2

R3

R4

R3 R4

OHR1OHN N

His224

H

Asp187

O O

Ser105OH

O

R2O

R1

Pamies, O; Backvall, J-E. Chem. Rev. 2003, 103, 3247

Enzymatic Methods - Reductions of β-Ketoesters

Pellissier, H. Tetrahedron 2003, 59, 8291

H3C

OH O

OEt H3C

OH O

OEt

OHCO2Et

OHCO2Et

OHCO2Et

OMe

OHCO2Et

O

OH

O OO

OHCO2EtBocN

OHO

MeOS

OH O

OMe

1 2 3 4 5

6 7 8 9 10Product Microorganism Yield (%) de (%) ee (%)

1

2

3

4

5

6

7

8

9

10

G. candidum

Baker's yeast

M. racemosus

Saccharomyces sp.

Baker's yeast

K. magna

Y. lipolytica

Dipodascus sp.

Baker's yeast

Baker's yeast

80

94

75

95

72-85

80

95

80

74

71

Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475

98

92

98

98

99

100

-

-

98

-

98

99

99

98

99

94

95

99

98

85

Enzymatic Methods - Other Selected Reductions

Pellissier, H. Tetrahedron 2003, 59, 8291

1 2 3 4

5

Product Microorganism Yield (%) de (%) ee (%)

1

2

3

4

5

6

7

8

Baker's yeast

Baker's yeast

Baker's yeast

S. montanus

Baker's yeast

R. arrhizus

M. isabellina

M. isabellina

88

82

76

89

95

97

92

100

100

76

-

-

96

98

72:28 dr

92

96

99

80

97

98

99

99

99

OH O

SEt

OHCN

OHSO2Ph

S

OH OH

C5H11

OHCO2Et

OH

OH O

NH2

OH O

NHBn

OH

CN

6 7 8

MeO

Enzymatic Methods - Hydrolysis

H2N CO2R

R1 Alcalase

t-BuOH/H2O (19:1)H2N CO2H

R1

90-98% ee, 87-95% yield

pyridoxal 5-phosphate

NH+

OH

O H

OPO

OO

pyridoxal 5-phosphate

Amino acid synthesis

S N

NH2

CO2HP. thiasolinophilum CO2HHS

NH2

100% ee, 100% yield

N O

Ph

OLipozyme

Et3N/BuOHToluene N

HCO2Bu

O

Ph H2N CO2HL-(S)-tert leucine99.5% ee, 94% yield

Many other useful hydrolysis systems

ON

CO2Et S. griseusbuffer pH 9.7

ON

CO2H

(S) - keterolac85% ee, 92% yield

Stecher, H.; Faber, K. Synthesis 1997, 1

Enzymatic Methods - EsterificationsDKR of Hemiacetals, cyanohydrins, and derivatives

Many other esterifications

Taniguchi, T.; Ogasawara, K. Chem. Commun. 1997, 1399

R

OH

X

High pH

R

O

H

Lipase

Acyl donorR

OAc

XX = SR', OR', NHR', CN

OH

SBuO

MeO P. cepacia

OAc TBME,

SiO2

OAc

SBuO

MeO

> 95% ee, 63% yield

OH

OH O

OHH

O

OAcH

97% ee, 75% yield

fastslow

O

HO H

O

AcO H

Conditions: Lipase, vinyl acetate, Et3N

Other Enzymatic Methods via DKRDKR applied to microbiological Baeyer-Villiger oxidation

O

OBn O

O

OBn

O

OBnO

O

OBn

fastslow

recombinantE.coli, pH 9

96% ee, 85% yield

Chemoenzymatic DKR of Phenylglycine Methyl Ester

O

OMeNH2 CALB (Candida antarctica lipase B)

NH3, tert-butanolN

HOOH

OOH

O or

O

NH2

NH2

88% ee, 85% yield

DKR combining enzyme and racemization via SN2 displacement

O

OEtCl

C. cylindracea lipaseR'NH2, PPh3 Cl

O

NHR'Cl

up to 86% ee, up to 92% yield

Berezina, N.; Alphand, V.; Furstoss, R. Tetrahedron: Asymmetry 2002, 13, 1953Wegman, M. A.; Hacking, A. P. J.; Rops, J.; Pereira, P.; van Rantwijk, F.; Sheldon, R. A. Tetrahedron: Asymmetry 1999, 10, 1739Badjic, J. D.; Kadnikova, E. N.; Kostic, N. M. Org. Lett. 2001, 3, 2025.

Combination of Enzymes and Transition Metals in DKR

Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247

Question: Why use anything other than simple enzymes and nonmetallic racemization methods?

Answer: These DKR approaches are mainly limited to substrates that possess a stereogenic centerwith an acidic proton.

R2R1

Nu

[ M ] R2R1

MNu R2R1

Nu

R1 R2 R1 R2

XH

[M]R1 R2

X

[M]HH

+X

H[M]H

H

A Possible Solution: Transition Metal-Catalyzed Racemizations

Shvo's Catalyst - Mechanism of Action

Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247

Ph

PhPh

Ph

O

Ru HOC

OC

Ph

PhPh

Ph

O

RuCO

CO

H

Shvo's Catalyst

OHPh

Ph Ph

Ph

RuOC

OCH

OPh

Ph Ph

Ph

RuOC

OC

+

OPh

Ph Ph

Ph

RuOC

OC

OH

R H*R'

OHPh

Ph Ph

Ph

RuOC

OCH*

R R'

OOPh

Ph Ph

Ph

RuOC

OC

OH

R R'H*

+ + +

Combination Enzyme-Metal Catalysis - DKR of Alcohols/Diols

Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247

R1

OH

R2

CALBp-Cl-C6H4-OAc (3 equiv)

Shvo's Ru Cat. (2 mol%)PhCH3

R1

OAc

R2

78-92% yield91- >99% ee

OAc OAc OAcOAcO

OAc OAcOAc

5

80%, >99% ee 80%, 98% ee 77%, >99% ee 88%, >99% ee 79%, >99% ee 65%, >99% ee 90%, >97% ee

OH

OH

CALBp-Cl-C6H4-OAc (3 equiv)

Shvo's Ru Cat. (4 mol%)PhCH3

OH

OH

OH

OH

+

(R,R)-product meso-product

86 14:

63%, >99% ee

OAc OAc

OAc OAc

OAc

OAc

OAcAcO

NOAcOAc

NBn OAcOAc

90%, >99% ee(R,R:meso)

(38:62)

63%, >97% ee(90:10)

43%, >99% ee(74:26)

78%, >99% ee(100:0)

77%, >99% ee(98:2)

64%, >96% ee(89:11)

Enzyme-Metal Catalysis - DKR of Hydroxy Acid Derivatives

Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247

3) P. cepacia lipase

p-Cl-C6H4-OAcShvo Cat. (6 mol%)

TBME, 60 oC, 6d

O

R H

O

OEt+

1) LDA/THF2) NH4Cl sat. 2 equiv.

R OEt

OAc O

up to 82% yieldup to 99% ee

O

R H

OLi

OEt

C-C bond

formation

R OEt

OH O

R OEt

OH O

R OEt

OAc O

R OEt

OAc O

EnzymeAcyl donor

Fast

EnzymeAcyl donor

Slow

+

Minor

MajorRu - catalyzedracemization

R

OH

CO2R'

P. cepacia lipaseShvo Cat. (2 mol%)

p-Cl-C6H4-OAc (3 equiv)Cyclohexane

R

OAc

CO2R'

R = alkyl, arylR' = Me, Et

60-80% yield30-98% ee

Tandem Aldol Reaction/DKR

DKR of Racemic α-Hydroxy Esters

Huerta, F. F.; Backvall, J.-E. Org. Lett. 2001, 3, 1209

Enzyme-Metal Catalysis - Other Alcohol DKRs

Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247

Azido Alcohols

Hydroxy Nitriles

Halo Alcohols

Allylic Alcohols

N3

OH CALBShvo's catalyst (4 mol%)

p-Cl-C6H4-OAc (3 equiv)PhCH3

N3

OAc

86%, >99% ee

CNOH

7

CALBShvo's catalyst (4 mol%)

p-Cl-C6H4-OAc (3 equiv)PhCH3

CNOAc

7

93%, 92% ee

ClOH

CALBShvo's catalyst (4 mol%)

p-Cl-C6H4-OAc (3 equiv)PhCH3

ClOAc

74%, 91% ee

Pr

OH

Pr

OAc

83%, 95% ee

P. cepacia lipaseRu catalyst (4 mol%)

p-Cl-C6H4-OAc, Et3NCH2Cl2

RuCl Cl

HRuCl

Enzyme-Metal Catalysis Utilizing Palladium

Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247

PhOAc

PF lipase37-40 oC, pH 7.0

0.1M phosphate bufferPdCl2(MeCN)2 (5 mol%)

19 days

PhOH

81%, 96% ee

DKR of Allylic Acetates

DKR of Amines

NH2Pd/CCALB

Et3N, EtOAc

NHAc

64%, 99% ee

NH2

Ph+ Pd NH

Ph

HPdH

PdH2NH

Ph

Ph

NH2HN

PhN

Ph

PhNH

Ph

Ph+Pd

+

- NH3PdH2

Challenges w/Enzymatic DKR

Question: Why use anything other than enzymatic systems with DKR?

Answer: There are currently a number of serious drawbacks towards applications of this technology.

Since enzymes and chemical catalysts usually work in different environments, their combinationin a one-pot transformation in far from straightforward.

For instance, with lipase catalyzed DKRs with transition-metal catalysts, solvents, metal, acyl donor,and temperature all need to be optimized.

The necessary chiral recognition by enzymes can place significant constraints on substrate scope.

M L

OHH

Finally, the achilles' heel: in many cases only one enantiomer is accessible.

Potential Solution: Enzyme-free DKR!

Using Chiral Auxiliaries in DKR

SRkR PRR

kSSS PSR

kinv

PSS

+

+

PRS

R*

O

X

Nuslow R*

O

Nu

R*

O

X

addition-inducedepimerization

NuFast R*

O

Numajor

O

OHO

H3CN N

O

CO2tBu

NSO2

N

O

Me

O

H3CN N

O

PhMe

R* =Durst Nunami

Ward

Devine

Caddick & Jenkins

N N

O

PhMe

OMe

Br

MeN N

O

PhMe

OMeMe

CH(CO2Me)2

N N

O

PhMe

OMeMeNaCH(CO2Me)2

TBAITHF

BnNH2

TBAIEt3N / THF

100%, 74% de

NHBn

78%, 40-60% de

Caddick, S.; Afonso, C. A. M.; Candeias, S. X.; Hitchcock, P. B.; Jenkins, K.; Murtagh, L.; Pardoe, D.; Gil Santos, A.; Treweeke, N.; Weaving, R. Tetrahedron 2001, 57, 6589

DKR Utilizing Configurationally Labile Anions

Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J. Am. Chem. Soc. 1999, 121, 9522

Ph

NArBoc

n-BuLi / (-)-sparteine

PhCH2Br NBocArPh

HPh

84%, 96% ee

R

NArBoc

LiL*

R

NArBoc

LiL*

R

NArBoc

LiL*

R

NBocAr

HH

NBocAr

E

HRenantioenriched

E

E

asymmetricsubstitution

asymmetricdeprotonation

RLi / L*

RLi / L*

Ratio of products identical with racemic or enatiomerically pure electrophile

Ph Me

Li Ph

O

HNBn2

+ Ph

OH

NBn2

PhPh

OH

NBn2

PhPh

OH

NBn2

PhPh

OH

NBn2

Ph

60% 21% 13% 6%

Hoffmann, R. W.; Ruhl, T.; Chemla, F.; Zahneisen, T. Liebigs Ann. Chem. 1992, 719

DKR with Boron Electrophiles

Sturmer, R. Angew. Chem. Int. Ed. Engl. 1990, 29, 59Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475

ClMg OPrOB

O Cy

Cyi

B O

OCy

Cy PhCHOPh

OH

71%, 94% ee89%, 94% de

O N

O O

O N

O OLi

O N

O O BOOB

OO

BrLDANaI (cat), 18-Crown-6

100%, >97% de

Ruthenium-Catalyzed Hydrogenation of β-Ketoesters

Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995 68, 36

Ru-catalyzed DKR has been developed into a powerful transformation of very broad scope

O O

OMe

NHBz

[RuCl2((R)-BINAP)]2Et3N

H2 , 100 atm

syn:anti = 94:698% ee

OH O

OMe

NHBz100% conv.

N

OH

O

SR

CO2Hcarbapenems

O

OO[RuCl((R)-BINAP)(C6H6)]Cl

H2 , 100 atm O

O

H

OH

96% de, 94% ee

OO

H

O

H3C

Ru

X

H

[(R)-binap]

Cl

CO2H

BnO

ClBnO

O

CO2MeAcHN

ClBnO

OH

CO2MeAcHN

(R)-MeO-BIPHEPRuBr2H2 , 140 bar

100% yield, 95% de, 80% ee(enantiomerically pure after

two recrystallizations)

Ph

O O

OEtCl

[(R)-BINAP]Ru(II)

H2 , 80 bar Ph

OH O

OEtCl

90% de, 88% ee

diltiazem (a potent channel blocker)

Ruthenium-Catalyzed Hydrogenations (Cont'd)

Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995 68, 36

[(S)-BINAP]Ru(II)O

P(OCH3)2

O

Br

H2

MeOH

OHP(OCH3)2

O

Br O

PH3CO

OHOH

HH

fosfomycin80% de, 98% ee

O

PhO

Ph

Ph

Ph

TsN

NTs

RuCl

H2, HCO2H, Et3N

OH

PhOH

Ph

100%, 97% de, >99% ee

O O

NOMe

Ru(S-C3-Tunephos)

MeOH, 50oC100 bar

OH O

NOMe

>99% ee, anti:syn >97:3

PPh2

PPh2

O

On

(S)-Tunephos

Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004 126, 1626

DKR via Cross-Coupling

Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475

Ph

MgClBr

cat. NiCl2 / L* PhL* =

PPh2Me2N

R

(R = iPr, sBu, tBu)

H

>95%, >80% ee

MgCl

Ph CH3H

MgCl

Ph HCH3

NiLL

Ph HCH3

Ni(L2)(Br)NiLL

Ph CH3H

Ph CH3H Ph H

CH3

BrBr

MgBrCl MgBrCl

Pd

DKR via Pd-Catalyzed Allylic Substitution

Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543

OBocO O

O

OEtO O

I

H3CO OH

O OROH

OO

O

O O

H3CO

H

H

6 steps

Aflatoxin B

+ R OH

2.5 mol% Pd2dba37.5 mol% L*

30 mol% Bu4NCl

R = HNNHOO

PPh2 Ph2P

L* =

O OOR

O

O O

LLPd

O O

LL

O OPdL2 O ONuNu

racemization via η3-η1 complexes

Pd

L*

89%, >95% ee

DKR via Asymmetric Conjugate Reduction

Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 2892

OR

R'

10 mol% CuCl/(S)-p-tol-BINAPNaOt-Bu (1.7 equiv)

tBuOH (5.0 equiv), PMHS (2.2 equiv)PhCH3, 26 h, then TBAF

OR

R'R = alkylR' = alkyl, aryl de = 82-93%, ee=91-94%

OR

R'

OR

R'

OTMSR

R'

OTMSR

R'

OR

R'

OR

R'

very fastNaOR, ROH

[H]fast

F

F[H]slow

DKR Utilizing Organocatalysts

Berkessel, A.; Cleemann, F.; Mukherjee, S.; Muller, T. N.; Lex, J. Angew. Chem. Int. Ed. Engl. 2005, 44, 807

DKR of azlactones using urea-based bifunctional organocatalysts

RNH

O

NH

NR2

NO

O

R1

H

R2

H-bond donor

* chiral spacer

Bronsted base

RNH

O

NH

NR2

NO

O

R1

H

R2

H-bond donor

* chiral spacer

Bronsted base

OR3

H

NO

O

Ph

R catalyst (5 mol%)allyl alcohol (1.5 equiv)

PhCH3, RT, 48 h Ph NH

Oallyl

O

O

R H

R = PhCH2, Me, iPr, iBu, tBu, Ph 43-96% conversion, 72-87% ee

NMe2

NH

O

NH

CF3

F3C

urea-based catalyst

DKR Utilizing Organocatalysts

Tang, L.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2870

Asymmetric Synthesis of α-Hydroxy Carboxylic Acids

OO

O

O

RO

OEtOH

R (DHQD)2AQN (10 mol%)

EtOH (1.5 equiv), Et2O

R = aryl61-85% yield60-96% ee

HNR3* OO

O

O

R+

OO

O

O

HR

OO

O

O

HR

O

OR'OH

R

O

OR'OH

R

R'OH, NR3*

R'OH, NR3*

fast

slow

Racemization rate with R=alkyl was too slow to allow for efficient DKR