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Home , Diastereomer, Kinetic resolution

Dynamic Kinetic Resolutions

A MacMillan Group Meeting

Presented by Jake Wiener

On the sixth day of June, two thousand and two, at eight o!clock in the evening.

I. Overview of concept. Contrast to other types of resolutions.

II. Chemical methods.

III. Combined chemical/biocatalytic methods.

Relevant reviews:

Huerta, F.; Minidis, A. B. E.; Backvall, J-E. Chem. Soc. Rev., 2001, 30, 321.

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

Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn., 1995, 68, 36. Caddick, S.; Jenkins, K. Chem. Soc. Rev., 1996, 25, 447.

Cook, G. R. Curr. Org. Chem., 2000, 4, 869. (Transition metal mediated kinetic resolutions only)

Stecher, H.; Faber, K. Syntheses, 1997, 1. (Biocatalytic dynamic kinetic resolutions only)

Dynamic vs. Other Types of Resolutions

! Kinetic Resolution: One reacts much faster than the other

OH OH OH Ti(O-i-Pr)4 Me Me Me (L)-+-DIPT O

55% conversion > 96% ee 98 : 2 dr > 96% ee

Sharpless, JACS, 1981, 103, 6237. ! Parallel Kinetic Resolution: Each enantiomer undergoes a different reaction

O O O Me (DHQD) AQN Me Me 2 OCH2CF3 OH O OH OCH2CF3 CF3CH2OH O O O

93% ee 80% ee

36% yield 41% yield

Deng, JACS, 2001, 123, 11302.

! In dynamic kinetic resolutions, 100% of racemic SM can be converted to enantiopure product Dynamic Kinetic Resolution: Overview

! Kinetic Resolution ! Dynamic Kinetic Resolution

OH kF X OH kF X

R2 R1 R2 R1 fast R2 R1 fast R2 R1 A A + krac

OH k X OH S kS X

R2 R1 R2 R1 R2 R1 slow slow R2 R1 B B

50% theoretical yield of A If krac > kF >> kS 100% theoretical yield of A

! In a DKR, as with a classical KR, one enantiomer reacts slowly under the reaction conditions

! In a DKR, the rate of of SM is fast relative the rate of the asymmetric transformation

! Thus, using DKR, possible to convert 100% of racemic SM to enantiopure product due to equilibrating racemization of SM

! How can we control the two processes: racemization and asymmetric transformation?

First Reported Chemical Dynamic Kinetic Resolution: !-Keto Reduction

! Tai observes DKR phenomenon in 1979

O O O OH cat. (R,R)-Tartaric Acid—MHNi 2 71% yield MeO Me MeO 3 Me H 80% ee Et 2 Et (2S, 3R)

! (2S) attributed to influence of catalyst on epimerization of SM after complexation but prior to reduction

Ni* O O O O O OH O OH H 2 Ni* 2 2 2 MeO Me MeO Me MeO Me MeO Me Et Et Et Et (2S, 3R) (2S, 3S)

krac kinv

Ni* O O O O O OH O OH 2 2 Ni* 2 H2 MeO Me MeO Me MeO Me MeO Me Et Et Et Et (2R, 3R) (2R, 3S)

Tai, A. Bull. Chem. Soc. Jpn., 1979, 52, 1468. Chemical Dynamic Kinetic Resolution: Noyori Reductions

! Noyori !-keto ester reductions describe relative rates

O O O OH 0.4 mol% (R)-BINAP-Ru(II) 2 2 MeO 3 Me MeO 3 Me 94% de (93% ee) H2, CH2Cl2 NHCOPh NHCOPh kfast

k inv kfast/kslow = 15

kinv/kfast = 6.1 O O O OH 0.4 mol% (R)-BINAP-Ru(II) MeO Me 2 kinv/kslow = 92 MeO 3 Me H , CH Cl NHCOPh 2 2 2 NHCOPh kslow Noyori, Bull. Chem. Soc. Jpn., 1995, 68, 36.

!"The absolute configuration at C-3 is governed by the handedness of the BINAP ligand while the C-2 configuration is dependent on substrate structures." Noyori, JACS, 1989, 111, 9135.

X P X OH O P Me P Ru O OH O OMe P Ru O O H O 2 Me OMe H H 3 OMe O N H Me HN Me Me O H anti syn O

Chemical Dynamic Kinetic Resolution: Noyori Reductions computations predict relative rates of reactions of

! Chiral Ru(II) complex catalyzes benzil reduction

Ts Ph N O Ru OH 100% yield Cl Ph Ph N Ph Ph H2 Ph >99% ee O OH chiral : meso = 9: 1 HCOOH, Et3N

OH OH kfast Ph Ph Ph Ph O OH O Ph Computational modelling indicates that Ph kinv O kfast/kslow = 55

OH OH kslow Ph Ph Ph Ph O OH

Noyori, Org. Lett., 1999, 1, 1119. Chemical Dynamic Kinetic Resolution: Ru(II) Reductions in Synthesis

! Formal synthesis of (—)-Balanol 1 proceeds through (2S,3R)-3-hydroxysilane 2.

HO

O HO

COOH OH OH H2N COOH O NH2 O O 2 N HN H OH 1

! Ru(II) catalyzed DKR provides key step in synthesis of 2.

H O 2 OH 100% yield PhthN COOMe PhthN COOMe Ru-[(R)-MeO-BIPHEP] > 99% ee (0.5 mol% catalyst) NHAc NHAc > 98% de CH2Cl2

Genet, Tet. Lett., 1998, 39, 6467.

Chemical Dynamic Kinetic Resolution: Conjugate Reduction racemization of starting material induced by added base

O 1. 10 mol% CuCl/(S)-p-tol-BINAP O 89% yield Me NaOt-Bu (1.7 eq) Me 91 : 9 syn : anti t-BuOH (5.0 eq) 91% ee Ph PMHS (2.2 eq) Ph , 26 h 2. TBAF ! A variety of alkyl, aryl kfast/kslow = 25-52 substituents at positions 3 and 5 are tolerated Buchwald, JACS, 2002, 124, 2892. ! Product trapped as silane to prevent epimerization

O OSiR3 O — R [H] R F R

kfast "fast" R1 R1 R1 k rac NaOtBu/ "very fast" tBuOH

O OSiR3 O R [H] R F— R

kslow "slow" R1 R1 R1

Without base, a classical KR is observed; choice of base is crucial for DKR. Chemical Dynamic Kinetic Resolution: Epoxide Opening Co-salen complexes catalyze DKR in phenolic epoxide opening

! LiBr is required for racemization and subsequent DKR

OH N N 4 mol% cat. Co O O Br OH Br Ph But O O tBu 4 mol% LiBr 74% yield CH CN, MS 3A tBu But 3 > 99% ee

catalyst

! Exceptionally high ee attributed to further resolution of minor product

OH OH O cat cat Br O Br O O PhOH Ph PhOH Ph Ph fast slow Br— Br—

OH O cat cat OH Br Br O Ph O O PhOH PhOH Ph Ph slow fast

Jacobsen, JACS, 1999, 121, 6086. Chemical Dynamic Kinetic Resolution: Azlactone and Dioxolanedione Opening

! Azlactones (pKa ~ 9) have good propensity for racemization; DMAP known to catalyze alcoholysis

O Me2N O 5% catalyst OiPr 61% ee O iPrOH N HN Ph 94% yield Fe Me N 10% PhCOOH Me Me Ph toluene, RT O Me Fu, JOC, 1998, 63, 3154. catalyst For other azlactone openings: Seebach, Tetrahedron, 1997, 53, 7539.

! Modifies Cinchona alkaloid: Bifunctional organic catalyst O O Et EtOH NR3* R = aryl: 91 - 95% ee N R O R OEt 68 - 85% yield H O O O fast OH O R = alkyl: No DKR H H MeO (due to decreased NR3* (10 mol%) acidity) N —78 °C

O Chiral amine catalyzes O catalyst EtOH NR * both racemization R O 3 R OEt and alcoholysis of O slow OH O dioxolanediones Deng, JACS, 2002, 124, 2870.

Lactone opening: Bringmann, Acc. Chem. Res., 2001, 34, 615. Chemical Dynamic Kinetic Resolution: !-allyl Pd Catalysis

! Equilibration between is not a trivial problem

k k OH rac OH OH inv OH k = —k k = —k rac rac R2 R inv inv R R R 2 1 2 R1 R2 1 R1 —krac —kinv Me Me enantiomers diastereomers

The rates of epimerization of two diastereomers are not necessarily equal

! Enhanced diastereomeric ratio after internal trapping suggests rapid equilibration of Pd complexes

Ph O O O O Pd0 Ph N O Ph N Ph N N O Ligand PdLn PdLn

Bn —CO2 Bn Bn Bn

Low DR Higher DR

Product oxazolines are also ionized by the catalyst, giving rise to thermodynamic product mixtures

Can the epimerizing intermediates be irreversibly trapped with nitrogen nucleophiles in a DKR?

Cook, ACIEE, 1999, 38, 110. Chemical Dynamic Kinetic Resolution: !-allyl Pd Catalysis

! Phthalamide is able to trap intermediates in a dynamic kinetic resolution

O O O O 1 mol% Pd0 - dppe NHCOPh P N O Ph N PdLn Ph N PdLn h phthalamide Me Nphth Me 20 h, RT, THF Me Me 97% yield 97 : 3 dr

As size of substituent increases, so does diastereoselectivity

! Chiral ligands on Pd afford matched/mismatched cases

O O NHCOPh O O NHCOPh 1 mol% Pd0 Pd0 P N O Me Ph N O Me h (S) - BINAP Nphth (R) - BINAP Nphth Me Me 96 : 4 dr 88 : 12 dr

Cook, ACIEE, 1999, 38, 110. Chemical Dynamic Kinetic Resolution: !-allyl Pd Catalysis

! Chiral catalyst effectively opens diene monoepoxides - Trost

2.5% Pd0Ln* OH 99 % yield O phthalamide Nphth 98% ee 5% Na2CO3

RT, CH2Cl2 O O NH HN

0 2.5% Pd Ln* PPh2 Ph2P OH 72 % yield O phthalamide Me Nphth Me 87% ee 5% Na2CO3 Ln*

RT, CH2Cl2

! Epoxide opening facilitates synthesis of anti-epileptic drug Vigabatrin

MeO Tf O 2 O THF, 0 °C CO2CH3 OH OTf Na Nphth Nphth Nphth CO CH 97% yield O 64% yield 2 3 MeO

O i. 6N HCl O Trost, JACS, 2000, 122, 5968. ii. Ion exchange resin NH3 96% yield Trapping of phenol nucleophiles with (R) - Vigabratin butenolides: Trost and Toste, JACS, 1999, 121, 3543. Chemical Dynamic Kinetic Resolution: Silylated "-Amino Acid Synthesis

! Racemic zirconaaziridines are readily available

1. 2 eq. BuLi O Ph Cp2ZrCl2 N Cp Zr N Ph 2 2. TMS

THF, —78 °C to RT, 6h, 60% TMS

! DKR of zirconaaziridines affords unnantural "-amino acids

O Ph O O N Ar Cp2Zr O O Ph Ph O NaOH/MeOH Ph NHPh MeO N O Ph Cp Zr 2 2-3 hour syringe pump addition Ar Ph Ar 83% de

!!Syringe pump addition required to achieve high selectivity due

to slow racemization of SM relative to insertion Norton, JOC, ASAP Norton, JACS, 1999, 121, 4520. Chemical Dynamic Kinetic Resolution: Displacements via Chiral Auxiliaries

! Chiral sultam facilitates highly selective SN2 DKR

Me Me

O

N Me Me Me Me Me S Br O O2 O CH3CN BnNH2 N Me N Me 100% de reflux quantitative S Br Me Me S NBn2 O2 O2 O enantiopure N Me Ward, Tet. Asymm., 1995, 6, 1475. SM epimerizes under reaction Br conditions; one S O2 see also: Nunami, JOC, 1995, 60, 6776. much more reactive than the Durst, JOC, 1998, 63, 3117. other Caddick, Tet., 2001, 57, 6589. epimerizing

! Hydrazones amenable to moderately selective alkylation

i. BF3OEt2 OMe OMe OMe OMe 90% yield TMSO Me N N N N 69% de N N BF3OEt2 N N Me Me OAc OAc OAc ii. MeO Me OMe epimerization O iii. Na2CO3 Me Me Me Me Me Me Me Me

Enders, Tet. Asymm., 1998, 9, 2155.

Biocatalytic Dynamic Kinetic Resolution: Enzymatic Reduction

! Relatively simple substrates are reduced in biocatalytic DKR

O O O OH Recombinant E. coli 81% yield EtO Me EtO Me > 98% ee Me expressing Gre3p Me > 98% de kfast

O O O OH Recombinant E. coli EtO Me EtO Me ! Me expressing Gre3p Me Recombinant E. coli express kslow enzymes from Baker's yeast which catalyze DKR.

O O O OH Recombinant E. coli 87% yield EtO Me EtO Me > 98% ee expressing Gre3p > 98% de

Stewart, JOC, 2000, 65, 2586. Biocatalytic Dynamic Kinetic Resolution: Pd0 in Allylic Acetate Hydrolysis

! Can organometallic and biological reagents be used in tandem?

OAc OH enzyme R R R R kfast

A selective enzyme is crucial Pd-catalyzed Organometallic catalyst must racemize substrate racemization Catalyst must not influence selectivity/reactivity of enzyme

OAc enzyme OH

R R R R kslow

! !-allyl Pd complex results in facile epimerization

Ph 5 mol% [PdCl (MeCN) ] Ph 2 2 81% yield OAc 0.1 M phosphate buffer OH 96% ee lipase from Pseudomonas fluorescens 19 days

Sturmer, ACIEE, 1997, 36, 1173.

Biocatalytic Dynamic Kinetic Resolution: Esterification via Ru-Catalyzed Racemization how else can organometallic and biological reagents be used in tandem?

! Backvall Ru catalyst can function without interfering with enzymes

Requirements for metal catalyzed racemization: No Base OH Ru catalyst OH 1. No interference with enzyme in esterification Ph CO Me Ph CO Me 2. No direct base-catalyzed esterification 2 cyclohexane, 60 °C 2 racemic

! Ru complex functions by dissociative mechanism

Ph Ph O O Ph Ph Ph O H OH O Ph Ph Ph Ph + Ph Ph Ph Ph Ph H Ph Ph Ph Ph Ru Ru Ph Ph OC CO Ru Ru Ru CO CO OC H CO OC OC CO OC

acts as base for deprotonation/racemization

Backvall, Org. Lett., 2000, 2, 1037. For a related process see: Park, JOC, 2001, 66, 4736. Backvall, Chem. Soc. Rev., 2001, 30, 321. Biocatalytic Dynamic Kinetic Resolution: Esterification via Ru-Catalyzed Racemization organometallic catalyst functions in tandem with enzyme

! Ru catalyzed racemization plus enzymatic esterification: DKR

O O Ph Ph H OH 2 mol% Ru catalyst OAc Ph Ph P. cepacia lipase Ph Ph CO Me CO Me H 2 2 Ph Ph 4-Cl-C H OAc Ru Ru 6 4 OC CO CO CO cyclohexane, 60 °C 80% yield 98% ee catalyst

Backvall, Org. Lett., 2000, 2, 1037. ! Variation: One-pot — DKR. First DKR of !-hydroxy .

i. LDA, THF OAc O O O ii. NH Cl 4 73% yield OEt Ph H Me OEt 95% ee iii. 6 mol% Ru catalyst P. cepacia lipase

4-Cl-C6H4OAc TBME, 60 °C, 6d

Substrate must have two differently sized groups adjacent to These two groups cannot exceed the size of the active site in the enzyme

Backvall, Org. Lett., 2001, 3, 1209.

Biocatalytic Dynamic Kinetic Resolution: Ester Hydrolysis

! "-bromo esters racemized by Br—, resolved by enzymatic hydrolysis

Br + — Br CH2P Ph3Br OMe OH 78% yield Ph Ph Candida rugosa lipase O O 79% ee H2O—MeOH

! Enantioenriched carboxylate product cannot racemize

fast Br slow Br H Br H Br OMe OMe O O Ph Ph Ph Ph O O O O

Williams, Chem. Comm., 1998, 2519. Biocatalytic Dynamic Kinetic Resolution: Unique Racemization Protocols

! Racemization via Schiff base intermediate/enzymatic aminolysis

N Me O OMe NH2 NH2 NH3 OMe NH2 Ph HO Ph OH Candida antarctica lipase Ph N O O tBuOH, —20 °C O H Ar H

"catalytic" 85% yield readily epimerized 88% ee

amide racemizes 30 more slowly than ester

Sheldon, Tetrahedron: Asymmetry, 1999, 10, 1739.

! Racemic and readily epimerizing hemithioacetal generated and resolved by enzyme

O Pseudomonas fluorescens lipase O O H SH TESO S S MeO MeO OTES MeO OTES O OAc OH OAc

TBME, SiO2, RT 87% yield 90% ee

SiO2 promotes hemithioacetal epimerization via dissociation/recombination mechanism

Rayner, Tet. Lett., 1995, 36, 8493.

In Conclusion

OH kF X

R2 R1 fast R2 R1 A

krac

OH kS X

R2 R1 slow R2 R1 B

If krac > kF >> kS 100% theoretical yield of A

Dynamic kinetic resolutions have attracted increased attention in the last decade as the need for inexpensive chiral materials has increased and as the understanding of asymmetric catalytic processes has blossomed.

Crucial to a succesful DKR is simultaneous epimerization and resolution: What are ways to epimerize i. in the presence of asymetric catalysts (enzymes, metals)? ii. without epimerizing enantio- and diastereo- enriched products?