Dynamic Kinetic Resolution:Practical Applications in

Synthesis

Valerie Keller

November 1, 2001

Outline

• Types of resolution reactions– Kinetic Resolution (KR)– Dynamic Kinetic Resolution (DKR)– Dynamic Thermodynamic Resolution

• Types of DKR

• Case study of KR vs. DKR

Kinetic Resolution

• Assume R is fast reacting enantiomer

Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330.

S R

PSPR

kSR=kRS=0

ΔΔG++

kSkR

energy diagramS

R PR

PS

kR

kS

Kinetic Resolution• ee of SM increases as time

increases, ee of product decreases as time increases

• Only when kR>>kS does the yield approach 50% and ee approach 100%

• In practice, one cannot maximize both high yield and high ee

Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330.Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5-27.

%eeremainingstarting material

% conversion

∞

1002510

5

2

relative rateln[(1-C)(1+ee)]

ΔΔG /RT++

= =[(1- )(1- )]ln C ee kR= e

kS

Kinetic Resolution by Sharpless Asymmetric Epoxidation

Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ideda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981,103, 6237-6240.

OH Ti(OiPr)4, L-(+)-DIPT,tBuOOH

OH

OH

+

O

(fast)

Ti(OiPr)4, L-(+)-DIPT,tBuOOH

(slow)

OHO

= kR/kS = 13855% conversion>96% ee

ln[(1-C)(1-ee)]ln[1-C)(1+ee)]

%eeunreacted

alcohol

60% conv.

Dynamic Kinetic Resolution

• Assume R is fast reacting enantiomer

• Rates are pseudo 1st order

• S and R racemize at the same rate

• Reaction is irreversible

• Products do not racemize under reaction conditions

Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36-56.Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.

R

S

PR

PS

kR

kS

kinv kinv

r. d. s.

ΔΔG++

PS

S R

PR

kSkR

kinv

energy diagram

Dynamic Kinetic Resolution

Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.

SEL(t) = PRR(t)

PRR(t) + PRS(t) + PSR(t) + PSS(t)

SEL100

kinv/kR kR/kS

R

S

PRR

PSR

kR

kS

kinv kinv

+

+

PRS

PSS

favoredfast

slow

Dynamic Kinetic Resolution

Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.

SEL(t) = PRR(t)

PRR(t) + PRS(t) + PSR(t) + PSS(t)

SEL100

R

S

PRR

PSR

kR

kS

kinv kinv

+

+

PRS

PSS

favoredfast

slow

kinv/kR kR/kS

SEL100

Dynamic Kinetic Resolution

Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.

SEL(t) = PRR(t)

PRR(t) + PRS(t) + PSR(t) + PSS(t)kR/kSkinv/kR

SEL100

R

S

PRR

PSR

kR

kS

kinv kinv

+

+

PRS

PSS

favoredfast

slow

kinv and kR

• kR/kS = 6.14 (relative rate)

• If kinv>>kR, the S/R ratio remains steady

• If kinv < kR, R is consumed faster than it is replaced

Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.

% conversion

%eeofproduct

100 10

1

0.1

0.01kinv/kR

Hoffmann Test

Hirsch, R.; Hoffmann, R. W. Chem. Ber. 1992, 125, 975-982.

ΔΔG++

PS

S R

PR

kSkR

kinv

energy diagram

R R'

X

R R'

X

kinv kinv

kR

kS

ER + EP

ER + EP

R R'

ER

R R'

ER

PRR

PSR

R R'

ES

R R'

ES

PRS

+

+

PSS

PRR + PRS

PSR + PSS

ΔΔG /RT++

=kR ekS

=

First Published Example of Chemical DKR

Noyori, R.; Ideda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Sayo, N. Saito, T.; Taketomi, T.;Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134-9135.

R1, R3 = Me, R2 = CH2NHCOMe, (R)-BINAP-Ru major product is synSR 98% de and ee

R1 OR3

O O

R2

R1 OR3

O O

R2

R1 OR3

OH O

R2R1 OR3

OH O

R2

R1 OR3

OH O

R2R1 OR3

OH O

R2

+

+

H2BINAP-Ru

H2BINAP-Ru

R

S

antiRR synRS

synSR antiSS

Labeling Experiment

Noyori, R.; Ideda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Sayo, N. Saito, T.; Taketomi, T.;Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134-9135.

O

O

O

OMe

O

D NHCOMe

O

O

OH

OMe

O

D NHCOMe

O

O

O

OMe

O

NHCOMe

1.3% conversion

H2, 100 atm(R)-BINAP-Ru

80% deuterium

0% deuterium

70% deuteriumin recoveredstarting material

D

Solvent Effects• Hydrogenation in

CH2Cl2 is much slower than in MeOH

• In MeOH, kinv/kR = 0.04

• In CH2Cl2, kinv/kR = 0.44

Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.

O

OMe

O

OMe

OOHH2, 100 atm

(R)-BINAP-Ru

solvent

major product

SEL100

% conversion

CH2Cl2

MeOH

Stereochemical Rationale

Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36-56.

enantiomerpreference

diastereomerpreference

O

O

R1 H

NO

Ru

X

PP

HR2

O

HO

O

HOMeRu

X

PP

H

nn = 1,2,3

Dynamic Thermodynamic Resolution

• First equilibrate to thermodynamically favored enantiomer

• Second rely on kinetic differences to enhance selectivity

• Rates of equilibration are not equal

• kR>>kS>>kSR, kRS

Beak, P.; Anderson, D. R; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715-727.

kSR,kRS > 0

kS

kR

SR

PS PR

energy diagram

R

S

PR

PS

kR

kS

kRS kSR

Dynamic Thermodynamic Resolution

Li*sparteine complex stable at -78oC, but equilibrates at -25oC

Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718-5719.

1. -25oC, 45 min

2. -78oC, 30 min, 0.45 eq. TMSCl

3. -25oC, 45 min

4. -78oC, 30 min, 0.45 eq. TMSCl

PivNH TMS72% yield94% ee

PivNLi Li.1

PivNLi Li.1

N N

1

Summary of Resolution Reactions

Kinetic Resolution

DynamicKinetic Resolution

DynamicThermodynamicResolution

kSR,kRS > 0

kS

kR

S

R

PS PR

S R

PSPR

kSR=kRS=0

kSkR

PS

S R

PR

kSkR

kinv

no equilibration equilibration rate fastcompared to reaction

equilibration rate slowcompared to reaction

Outline

• Types of resolution reactions

• Types of DKR– Enzymatic DKR– Substrate controlled DKR– Reagent controlled DKR– Catalyst controlled DKR

• Case study of KR vs. DKR

Enzymatic DKR

Huerta, F. F.; Bäckvall, J.-E. Org. Lett. 2001, 3, 1209-1212.

O

NCO2Et

O

NCO2H

protease fromStreptomycesgriseus

pH 9.7

92% yield85% ee

Fülling, G.; Sih, C. J. J. Am. Chem. Soc. 1987, 109, 2845-2846.

RuRu

R H

O

OR'

OLi+

R OR'

OOH

R OR'

OOH

R OR'

OOAc

R OR'

OOAc

Ru(II)

EnzymeAcyl donor

EnzymeAcyl donor

fast

slow

O OHPh

Ph

Ph

PhPhPh Ph

PhH

OC COCO OC

69% yield99% ee Ru(II) =

Nunami Chiral AuxiliarySubstrate Controlled DKR

O’Meara, J. A.; Jung, M.; Durst, T. Tetrahedron Lett. 1995, 36, 2559-2562.O’Meara, J. A.; Jung, M.; Durst, T. Tetrahedron Lett. 1995, 36, 5096

• Chiral auxiliary must be removed• Starting material takes several steps to synthesize

BnNH2

Et3NTHF

87% yield>98% deN NMe

OBr O

BrCO2

tBu

N NMe

OBr O

BrCO2

tBu

N NMe

OO

NBnCO2

tBu

Bu4NI

BnNH2

Et3NTHF

N NMe

OO

NBnCO2

tBu

(fast)

(slow)

Reagent Controlled DKR

DAGOH = diacetone-D-glucose

Stereochemistry controlled by base used

Khiar, N.; Alcudia, F.; Espartero, J.-L.; Rodríguez, L.; Fernández, I. J. Am. Chem. Soc. 2000, 122, 7598-7599.

O

HOO

O

O

O

ClS

SCl

O

O

DAGOH

DAGOH

iPr2NEt

toluene, -78o

pyridine

THF, -78oDAGO

SS

ODAG

DAGOS

SODAG

O

O

O

O

tBuO2CCH2Li

tBuO2CCH2Li

toluene

toluene RS

SR

O

O

RS

SR

O

O

60% yield>98% de>98% ee

70% yield>98% de>98% ee

(S,S)

(R,R)

(R,R)

(S,S)

Effect of Base on Stereochemistry

Fernández, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem. 1992, 57, 6789-6796.Khiar, N.; Alcudia, F.; Espartero, J.-L.; Rodríguez, L.; Fernández, I. J. Am. Chem. Soc. 2000, 122, 7598-7599.

ClS

SCl

O

ON+ S

SN+

O

O

+ +N+ S

SN+

O

ON+ S

SN+

O

O

SS

N+

OH

OH

N+DAGOODAG

SS

N+

ODAG

ODAG

N+HOOH

- N

- N

DAGOS

SODAG

O

O

DAGOS

SODAG

O

O

+ N

- N

N = pyridine

N = iPr2NEt

(R,R)

(S,S)

DAGOH

DAGOH

Reagent Controlled DKR

Tunge, J. A.; Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1999, 121, 4520-4521.

Cp2ZrN R'

R

Cp2ZrN R'

R

kinvkinv

kR

(fast)

kS(slow)

OO

O

Ph Ph

Carbonate =

carbonate

carbonate

Cp2ZrO

R'N

O

O

R

Ph

Ph

Cp2ZrO

R'N

O

O

R

Ph

Ph

HClHO O

NHR'

O

RPhPh

MeONHR'

O

HO OH

R

PhPh

+

cat. NaOH, MeOH

Kinetic Studies

Tunge, J. A.; Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1999, 121, 4520-4521.

Cp2ZrN R'

R

Cp2ZrN R'

R

RSSSRR

RRRSSS

O O

O

PhPh

O O

O

PhPh

O O

O

PhPh

O O

O

PhPh

kslowkslow

kfastkfast

(S,S)

(R,R)(S,S)

(R,R)

kfast

kslow=

SSS + RRRSRR + RSS

complexcalculated

de (%)relative

rate

1a

1b

1c

1d

76

90

7.3

19

1a R' = R = Ph1b R' = TMS, R = Ph1c R' = TMS, R = iPr1d R' = R = CH2Ph1e R' = TMS, R = CH2

iPr

21 1.5

(R)-1 (S)-1

observedde (%)

76

90

18

relative rate =

74 6.7 71

1e 82 10.1 77

Catalyst Controlled DKR

Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195-2198.

Ph

MgClH

Ph

HClMg

Br

Br

Ph

H

Me2N PPh2

R HNiCl2, L*0oC(fast)

NiCl2, L*0oC(slow)

L* =

>95% yield>80% ee

R=iPr, sBu, tBu

H

Ph

Catalytic Cycle

Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195-2198.

NiBrN

Me2

Ph2P Ni

Br

Ph2P

Me2N

MgCl

NiNMe2

Ph2P

PhHMgBrCl

Ph

>95% yield81% ee

BrH

NiCl2L*

+

Br

HPh

Catalyst Control of DKR

Schaus, S. E.; Jacobsen, E. N. Tetrahedron Lett. 1996, 37, 7937-7940.

NN

tBu tBuO O

tBu tBu

H H

Cr

N3

ClO

0.5 eq. TMSN3, 16 hr.

(S,S)-11. 0.2 eq.

2. 0.5 eq. TMSN3 slow addition, 16 hr.

(+)

Cl N3 Cl Cl N3 N3

OTMS OTMSOTMS

+

76% yield97% ee

12% yield 12% yield

+

Salen Catalytic Cycle

Schaus, S. E.; Jacobsen, E. N. Tetrahedron Lett. 1996, 37, 7937-7940.

ClO Cr

Cr

CrCr

N3

Cl N3

O

Cl N3

OTMS

Cl Cl

O

Cl

TMSN3

N3O

ClO

(S,S)-1

reaction cycle racemization cycle

DKR in Small Library Synthesis

Peukert, S.; Jacobsen, E. N. Org. Lett. 1999, 1, 1245-1248.

BrO

Br O

OH

R1

OR1

O

N O

OH

R1

O O

OH

R1 R2

R3

R1'

OH

R1

(R,R)1, F9-tBuOH,CH2Cl2, 4o-25o KOH, ether

R2R3NH

Yb(OTf)3

(or Cu(OTf)2)

CH2Cl2

(S,S)1, F9-tBuOH,CH2Cl2, 4o-25o

OH

R1'

83 - 96% yield>99% ee

81-87% yield98% ee

85-99% ee

NN

tBu OO O

tBu tBu

H H

Co

OAc

=polystyrene resin

(R,R)1

O

O

KR vs. DKR

OMe

OMeMe

OO

OMe O

O

OMe

OMeOMe

OMe

OH

OHOH

OH

Mastigophorene B

DynamicKinetic Resolution

KineticResolution

Mastigophorene B: Kinetic Resolution

Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P,; Peters, K.; Peters, E.-M. Synthesis 2001, 155-167.

OO

OMeOMe

OMeOMe

OO

OMeOMe

OMeOMe

HO

OMeOMe

OMeOMe

OH

OHOH

OHOH

NB

O

Me

H PhPh

Mastigophorene B

unreacted isomer96% de

BH3.THF

(M) (P)58:42

recycle

(P)46% yield30% de

slow reacting fast reacting

(M)

Mastigophorene B: Dynamic Kinetic Resolution

Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J.; Peters, K.; Peters, E.-M.; Rycroft, D. S.; Connolly, J. D. J. Am. Chem. Soc. 2000, 122, 9127-9133.

OMeOMe

Me

OMeOMe

Me

OO OO

OMe OMe

rapidN

BO

Me

H PhPh

OHOH

OHOH

Mastigophorene B

OMeOMe

OHOMe

HO

61% yield94% de

(M) (P)

BH3.THF

slow reactingfast reacting

(M)

Kinetic vs. Dynamic Kinetic Resolution

Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J.; Peters, K.; Peters, E.-M.; Rycroft, D. S.; Connolly, J. D. J. Am. Chem. Soc. 2000, 122, 9127-9133.

Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P.; Peters, K.; Peters, E.-M. Synthesis 2001, 155-167.

Kineticresolution

DynamicKinetic resolution

OO

OMeOMe

OMeOMe

OMeOMe

Me

OOOMe

1% yield24 steps

4% yield17 steps

OHOH

OHOH

Mastigophorene B

CHO

IOH

OMe

50% yield2 steps62% de(no recycles)

52% yield5 steps84% de

(M) (M)

Conclusions

• In situ racemization of dynamic kinetic resolution can compensate for limitations of kinetic resolution

• Ratios of kinv, kR, and kS important for ee of products

• Wide variety of reactions possible

Thank youLei Jiang John Herbert

Bill Lambert Jen Slaughter

John Campbell Whitney Erwin

Eric Voight Margaret Biddle

Greg Hanson Jason Adasiewicz

Melissa Feenstra Belshaw Group

Joe Martinelli Tolga Gulmen

Susie Martins Lisa Jungbauer

Jason Pontrello