Chapter 1: Biocatalytic Approaches to Chiral Heterocycles

1

Chapter 1 Biocatalytic Approaches to Chiral Heterocycles Steven J. Collier, Michael A. K. Vogel, Brian J. Wong and Naga K. Modukuru Codexis Laboratories Singapore [email protected]; [email protected]; [email protected]; [email protected]

1.1

INTRODUCTION

The use of biotransformations to synthesize chiral molecules has been building momentum steadily over the last 15 to 20 years, and biocatalysis is now considered an established approach to such compounds. An increasing number of applications are known, covering a wide array of targets and scales, from microbial oxidation of drug candidates for metabolite profiling studies, to the tonnes per annum commercial manufacture of agrochemical and pharmaceutical intermediates and APIs. Furthermore, with the advent of directed evolution technologies over the last few years, biocatalysis has emerged as a practical alternative for the large scale synthesis of a range of pharmaceutical intermediates including those for blockbuster drugs such as Atorvastatin <04WO015132; 05WO018579; 05WO017135; 08USP0248539; 08MI6>. Chiral heterocycles are of crucial importance to the development and manufacture of new pharmaceuticals and agrochemicals, as well as in countless smaller scale applications in synthetic, medicinal and natural product chemistry. The goal of this contribution is to review where these important but different areas intersect. A review of this limited size is not and cannot be comprehensive in any way, but is instead geared towards giving a flavor of what has been achieved so far, and to help develop ideas of what could be possible in the future. After a short discussion of some commonly used enzyme classes, the main discussion on synthetic application is subdivided into different heterocycle classes, much along the lines of Progress in Heterocyclic Chemistry as a whole. It should be noted that only examples in which the chirality is part of the heterocyclic ring itself are included; heterocycles with chirality in positions Į-to the ring, or further away are not considered. Sugars and other complex carbohydrates are also generally excluded. 1.2

ENZYME CLASSES DISCUSSED

By far the most familiar and widely used enzymes in biotransformations are lipases, proteases and lactamases, which perform hydrolytic or solvolytic reactions on carboxylic acid derivatives such as esters and amides. Biocatalysts are commonly used as isolated enzymes but in some cases the enzyme is immobilized on a solid support in order to confer greater stability and afford the opportunity for recycling. The reactions are typically easy to perform in either aqueous or organic media, and do not require cofactors to operate. c 2009 Elsevier Limited. All rights reserved. 

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S.J. Collier et al.

Synthetic applications include the hydrolysis or formation of esters, with the latter usually achieved via transesterification of vinyl esters; the vinyl alcohol released tautomerizes to an aldehyde, rendering the reaction essentially irreversible. However, many applications involve kinetic resolution (KR) of racemates, offering a maximum theoretical yield of 50% for a product or unreacted substrate. In instances where the unreacted enantiomer of the substrate can be racemized under the reaction conditions, i.e. dynamic kinetic resolution (DKR), quantitative yields of homochiral products are possible. The hydrolysis or acylation of compounds which bear a centre of symmetry (meso compounds) can also provide quantitative yields of chiral products through desymmetrization. Other useful enzyme classes are known, and can be employed using isolated enzymes or whole cell systems. These include: ketoreductase enzymes (alcohol dehydrogenases) which catalyze the reduction of carbonyl groups to alcohols, or the reverse reaction; amine oxidases and amino acid dehydrogenases which catalyze the oxidation of amines to imines or viceversa; monooxygenases which perform the hydroxylation of unactivated functions, the epoxidation of alkenes, or Baeyer–Villiger type oxidations; and dioxygenases which convert unsaturated carbon functions to syn-diols. Other less common enzyme classes are mentioned periodically in the text. Generic transformations for some of these are shown in the scheme below. An excellent text on the applications of enzymes in asymmetric organic synthesis has been published .

R1

R

X = OR 2, NR 22

X

O

O

Lipase, protease, lactamase

O

1

+

X

R

chiral

chiral

racemic

Kinetic Resolution OH (max yield: 50%)

1

In-situ Racemization

O

O

X

X

Dynamic Kinetic Resolution (max yield 100%)

Lipase, protease

O

O

X

OH chiral

Symmetrical O R racemic

R1

Epoxide hydrolase

O R chiral

X = O: Ketoreductase X = NH: Amine oxidase

X R2

Meso-desymmetrization (max yield 100%)

OH +

chiral

XH R1

Kinetic Resolution (max yield: 50%)

OH

R

R2

O

Baeyer-Villiger Monooxygenase

R n

O R O chiral

n

The development of directed evolution technologies has facilitated the application of isolated enzyme biocatalysis on a commercial scale, particularly in the field of chiral pharmaceutical intermediates. The technique involves the introduction of mutations into the enzyme protein structure, and the resulting mutants are screened against specific reaction criteria in high throughput format, resulting in the selection of improved (evolved) variants. Thus, the performance of a given wild-type enzyme can be vastly improved in terms of specific activity, substrate specificity, thermostability, enantioselectivity, substrate loading, pH and solvent tolerance, and other factors, ultimately providing a catalyst that can operate competitively on commercial manufacturing scale. Details and examples are referenced here <07MI338; 07MI717; 08MI132; B-08MI1>.

Biocatalytic Approaches to Chiral Heterocycles

3

1.3 THREE-MEMBERED RING SYSTEMS 1.3.1 Epoxides The enantioselective epoxidation of alkenes to give chiral epoxides is a well established technique in traditional organic chemistry, with reactions such as the Sharpless-Katzuki, Jacobsen-Katzuki and Shi epoxidations enjoying widespread application. However, it is also possible to epoxidize alkenes using enzymatic methods, often achieving very high enantioselectivity. Commonly, cytochrome P450 enzymes are employed in these reactions, either in whole cell biotransformations or as isolated enzymes, although other enzyme types have also proved useful and, in some cases, complementary. Styrenes are common substrates for enzymatic epoxidations <96C436; 01ASC732; 04AG(I)2163>, given the synthetic value of the products, and some examples employing whole cell biotransformation using a styrene monooxygenase expressed in recombinant E. coli are given below. The products were isolated on multigram scale and chemocatalytic routes to the same epoxides could not match the ee’s of the biocatalytic process <01ASC732>. The production of several of the examples below was improved by employing cell free isolated enzymes <04AG(I)2163>. Furthermore, the enantioselective epoxidation of styrene to (S)-styrene oxide using the styrene monooxygenase (from Pseudomonas sp. strain VLB120) expressed in recombinant E. coli cells has been demonstrated on pilot plant scale, utilizing a two-liquid phase fed batch bioconversion <02MI33>. Directed evolution techniques have been used to increase the performance of a cytochrome P450 BM-3 in reactions that give styrene oxide or substituted analogues <04T525; 01MI249> and, interestingly, mutations in the protein structure could lead to an inversion of enantioselectivity. Thus, the use of one mutant cytochrome P450BM3 enzyme (F87G mutant) gave (R)-styrene oxide in 92% ee, but a different mutant (A74G/F87V/P386S) gave (S)-styrene oxide in 58% ee. Only three amino acid residues differ in these two mutants; this is a simple but poignant demonstration of the power of directed evolution in enzyme development <06MI662>. recombinant E. coli JM101 (pSPZ10) containing styrene monooxygenase; aq. cell culture, dioctyl phthalate

R

R

<01ASC732> O

76.3% yield 99.5% ee

O

74.8% yield 96.7% ee

O

87.2% yield 99.8% ee

Cl

O

O

87.5% yield 99.4% ee

O

55% yield 98.5% ee

O

47.9% yield 98.0% ee

A wide range of other epoxides have been prepared enzymatically. For example, (R)propylene oxide can be obtained in up to 85% ee using an alkene monooxygenase from Nocardia coralina B-276 <97MI635>. The same enzyme was found to epoxidize alkylpropenes to give products useful in the synthesis of prostaglandin Ȧ-chains <89TL1583>, and also a range of C2 to C18 terminal alkenes, although production rates varied between substrates <86MI218>. The epoxidation of terminal alkenes is favored by Pseudomonas oleovorans <96C436; 00MI1957> whereas internal cis double bonds are epoxidized selectively by chloroperoxidase enzymes <03T4701; 99TL164> and, monoepoxidation of polyenes is readily achieved using xylene monooxygenase and chloroperoxidase <02TL6763>. Synthetic applications of such epoxidations include the synthesis of Mevalonolactone <96JOC3923> and ȕ-blockers such as Metaloprol <96C436; 00MI1957; 81T4789> and Atenolol <81T4789>. Enzymatic epoxidation has also been

4

S.J. Collier et al.

employed to target specific sites in complex substrates bearing more than one potentially reactive centre, a common application being metabolite synthesis. In the examples below, selective cytochrome mediated epoxidation of a single alkene in Carbomycin B gave Carbomycin A <95MI582>. Similarly, monoepoxides of Milbemycins A3, A4 and C were obtained (along with a monohydroxylated product) using whole cell fermentation <03MI583>. O R

R = Pr: 32% yield, 76% ee R = Bu: 55% yield, 90% ee R = Pentyl, 56% yield, 88% ee

Nocar dia coralina whole cell suspension <89TL1583> O

Me O

CH O N M e2 O

Me O O

HO

O

O O

O

Me O OH

O

OC OM e C a rb am yc in A CY P1 0 7C 1 <9 5 MI5 82 >

H

R Me

O H

O O H

Me HO

O

OH

O

Me O

R : e po xi d e:a lc oh o l M e : 4 0 :60 E t: 3 0 :70 M e i -P r: 2 9:7 1

OH

S tre p to my ce s v i o la sc e ns A TC C 3 1 56 0 <0 3 MI 58 3 >

The kinetic resolution of racemic epoxides with epoxide hydrolases is an effective and well studied approach to chiral oxiranes, giving chiral 1,2-diols as by-products <01MI112; 06ASC1948; 06TA402; 99JOC5029; 01T695; 99TA3167 00TA3041; 01JOC538; 98S1259; 04T601; 98TA1839>. This reaction clearly has parallels with chemical techniques such as Jacobsen’s hydrolytic kinetic resolution <00ACR421>, but in some cases the performance of the enzymatic process far exceeds that of the more traditional synthetic approaches. Interestingly, there are examples in which the diol byproduct is chemically converted to the desired chiral epoxide (or the unreacted epoxide cleaved to the same diol), giving high overall yields and high ee’s for the two step process <04T601; 98S1259>. Typical examples of epoxides obtained via epoxide hydrolase enzymes are shown below, with the first example being used to prepare (S)-Ibuprofen <99JOC5029>. Analogues with the following 4substituents: H, F, Cl, Br, CN, NO2, could also be resolved with a range of hydrolytic enzymes.

Biocatalytic Approaches to Chiral Heterocycles O

i-Bu

5

O

O

O O

Asper gillus niger 35% yield; 95% ee <99JOC5029>

Cl

Cl

Asper gillus niger 51% yield; 98% ee <01T695>

O

Solanum t uber osum L. Rhodotor ula glutinis SC 16293 51% yield; 97% ee 45% yield, 99.9% ee <01T695> Asperigillus niger 16311 45% yield, 97% ee <99TA3167> Cl O

O

N Asper gillus niger GBCF 79 43% yield; 99% ee <00TA3041> <01JOC538>

F F Aspergillus niger 41.5% yield; 99.9% ee <04T601>

Br Asper gillus niger LCP 521 39% yield; 99.7% ee <98TA1839>

The activity and enantioselectivity of epoxide hydrolases has been improved using directed evolution techniques <06AG(I)1236; 03MI357; 04OL177; 04MI981>. Enantio- and stereocomplementary hydrolysis has been achieved using different epoxide hydrolases. Different pairings of epoxide and diol could be obtained with different enzymes, resulting from either inversion or retention of configuration during the ring opening <93JOC5533; 01T695>. In a related reaction, a racemic epoxide 1 was hydrolyzed in an enantioconvergent reaction (i.e. one enantiomer was hydrolyzed with retention and the other with inversion of configuration), providing an intermediate chlorodiol 2 which cyclized to a single enantiomer of epoxide 3. This was later used in the total synthesis of (+)-pestalotin and a Jamaican rum constituent <02TA523>. My cobacterium paraf f inicum NCIMB 10420

O n-Bu 1 racemic

Cl

OH Cl

HO n-Bu

HO

O

n-Bu 2

3 81% yield 93% ee, >99% de

Epoxide resolution can also be achieved using enzymatic hydrolysis of pendant functionality. For example, lipases perform kinetic resolutions of pendant esters to provide chiral epoxides such as glycidyl butyrate, although the reaction needs to be run beyond 50% to ensure the chiral purity of the desired (R)-glycidyl butyrate is sufficiently high; this approach has been operated on multi-ton scale <91T4789; 84JA7250>. A range of alkyl substituted racemic epoxides has been studied in the reaction, and the effect of ester chain length was investigated. Lipase mediated resolution of trans-phenylglycidates 4 (X = CO2Me) was used as an approach to the drug diltiazem. Interestingly, the undesired glycidic acid by-product 5 decomposed spontaneously to an aldehyde and CO2, the former of which was sequestered using bisulfate to prevent it negatively impacting enzyme activity <93USP5274300>. Following a similar approach, racemic trans-1-aryl-2-cyano epoxides 4 (X = CN) have been resolved using Rhodococcus sp. whole cells, which contain both nitrile hydratase and amidase enzymes. Thus the nitrile hydratase (which typically give poor enantiodiscrimination) hydrates the nitrile of the racemic substrate (giving 4, X = CONH2), and the amidase then performs a kinetic resolution on the amide, producing the unstable acid 5 and the desired chiral amide <03JOC4570>. Lipase mediated acetylative resolution of

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S.J. Collier et al.

racemic epoxides, or desymmetrization of meso epoxides has been used in approaches to the natural products epoxydon <04TL7683> and cycloepoxydon <04OL807> (proceeding via chiral epoxides 6 and 7, respectively). O

O Ar

4 ra ce m ic

Ar

X

O Y

+

Ar

A rC H 2C H O + CO 2

CO 2 H 5

X = C O 2 Me , Y = CO 2M e ; A r = 4-M e OC 6H 4 ,: 43 .6% y ie ld , 98 % ee (C a nd i d a cy l in d r a ce a l ip a se ) X = C N , Y = C ON H 2 ; A r = Ph , 4 -M e C6 H 4 ,4 -FC 6 H 4 , 4 -C lC 6 H 4 : 4 2 -4 9% yi el d , 9 9 .5% e e (R h o d oc oc cu s s p. AJ 27 0 ce ll s) X = C N , Y = C ON H 2 ; A r = 2-M e C 6H 4, 3 C lC 6 H4 : 6 0-6 1 % yie l d, 3 1.3 -3 9.9 % ee (R h od o c oc cu s sp . AJ 27 0 c el ls )

O

OT BS

TB SO

O

O

O O

H OAc 6 46 % yi el d ~9 9 % ee

H

OH

45 % yi el d ~9 9 % ee Ac yla tiv e K R L i pa se PS <0 4OL 8 0 7>

Ac O HO

O

O 7 A cyl a ti ve De s ymm e tr iz ati on L ip as e P S <0 4 OL 80 7 >

1.3.2 Aziridines The formation of chiral aziridines via biocatalysis is not widely employed, although a number of examples are known. Lipase mediated kinetic resolution or meso desymmetrization via hydrolysis of esters <93TA2295; 95MI37> or acylation of alcohols <05JOC1369; 02JCS(P1)1948> can provide products in good ee. Another interesting kinetic resolution involves cleavage of an amide bond of a racemic N-acylaziridine, leaving one enantiomer of the amide unreacted <93JCS(P1)3041>. The enantioselective N-acylation of aziridines has also been achieved using dialkyl carbonates and lipase enzymes, with diallyl carbonate giving the best results <96JA712; 99USP5981267>. Typical products are given below.

Biocatalytic Approaches to Chiral Heterocycles H N

H N HO

OM e

HO

OMe

O

O O O P ig liv e r es ter as e h yd ro ly ti c K R 9 2% e e 2 7% e e <9 3TA 22 9 5 > <9 3TA 22 9 5 > <9 5 MI3 7>

Ph

H N O

Me

Ph OH

H N O

Me

O i mm ob i li ze d P se u d om o na s c ep a ci a l ip a se PS- CII O ac yl ati ve K R 4 9 % y ie ld , 90 % e e 5 1 % y ie ld , 87 % e e 36 % yi el d , 9 5 % e e <0 5 JOC 1 3 69 >

O

O OMe

O

Me O

N

A cO

Pr

H N

Me

Ph N

Ph

7

OM e

H

OMe

O

O

N

N

OH

H

O

O

Am an o li pa se PS C an d i d a cy li n d r ac e a l ip as e C an d i d a cy li n d r ac e a l ip as e C an d i d a cy li n d r ac e a l ip as e a cy la tive N -a cy la tive KR Am id e h yd r ol ytic K R Am id e h yd r ol ytic K R d e sym me tri za ti o n 4 9 % y ie ld , 84 % e e 3 0 % y ie ld , 95 % e e 3 5 % y ie ld , 90 % e e 9 6% yi el d <96 JA 71 2 > <93 JC S (P1 )3 04 2 > <9 3J C S(P 1) 30 4 2> >9 7% e e <9 9 US P5 9 81 2 6 7> <02 JC S (P1 )1 94 8 >

1.3.3 Other Three-Membered Heterocycles Chiral thiiranes have rarely been prepared through biotransformations, although examples do exist. Hydrolytic kinetic resolution with procine pancreatic lipase gave the chiral ester 8 in resonable ee <93CHIR250>. Chiral thiirane oxide 9 was obtained in good de, using a chloroperoxidase (from Caldariomyces fumago) mediated sulfoxidation, although the ee was poor <98CHIR246>. (R)-1-Isothiocyanatobutan-2-ol, available through the resolution of racemic 1,2-epoxybutane with thiocyanate, mediated by a halohydrin dehalogenase enzyme from Agrobacterium radiobacter, undergoes a slow rearrangement to the corresponding chiral thiirane <08CBC1048>. Chiral oxaziridines 10 and 11 have been prepared via kinetic resolution of a pendant ester unit <98CC1614>. O O

OS+

S

MeO 2C

8 9 Porcine pancreatic lipase Chloroperoxidase hydrolytic KR 99% yield 71% yield, 80% ee 100% de, 12% ee <93CHIR250> <98CHIR246>

N O +

HO2 C

N O

MeO 2C

MeO2 C 10 11 Porcine pancreatic lipase 62% yield 20% yield 36% ee 87% ee <98CC1614>

1.4 FOUR-MEMBERED RING SYSTEMS 1.4.1 Azetidines A number of enzymatic approaches to chiral azetidines have been reported, mostly focussing on azetidinones, given their importance in biologically active compounds and as precursors to unnatural amino acids. A wide range of chiral azetidinones have been prepared by the enzymatic resolution of racemates, through cleavage of one enantiomer of the ȕ-

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S.J. Collier et al.

lactam ring. As one may expect, this transformation has been achieved using lactamases, but lipases have also proved effective <03OL1209; 04T717; 00JOC4919; 06CEJ2587; 06ASC917; 04TA2875; 03ASC986; 91JCS(P1)2276; 92WO9218477; 04TA573; 06TA3193>. In some cases, the protracted reaction times were required to achieve high conversions. Typical reactions and products are given below. O

R

R

NH R

R

NH

O

O n

O

NH 2 NH

NH

49 % co n ve rsi on 94% ee <00 JO C4 9 19 >

50 % co nv er si on 9 9% e e <00 JOC 4 9 19 > O

O

H N O

R

NH

n

(-) iso m er

L ac tam a se f ro m R h od o co cc u s g lo b e ru l u s (w h ol e c el ls ) 3 1% yi el d >9 5% e e <0 4T7 1 7 >

n

Li po l as e (i mm o b C AL -B ) n = 1, 2 47 -4 8 % y ie ld 9 9 % ee <0 4 TA2 8 75 >

NH

NH

NH

O

n

Et C hi ra zy me L- 2 fr om Ca n d i d a a n tar ti c a, ca rr ie r fi xe d

O

NH

R

n

L ip o la se n = 1 -4 3 6 -4 5% yi e ld 93 -9 9 % e e <0 3O L1 2 09 >

O

C O 2H

O

NH

NH

H

R +

38 % yie l d >98 % ee <04 T7 17 >

n = 1 -3 L ip o la se (C AL -B) 4 4% yi el d >9 9% e e <0 6C E J2 58 7 >

O R = H , 4 -Me , 2- , 3 -, 4 -C l, 4- Br, 4 -F C AL -B >=4 1% y ie ld >=9 5 % e e <06 AS C 91 7 ; 0 3 AS C9 8 6 >

O

O HN

HN

NH

NH

H O O R h o d oc o ccu s e q u i Li po l as e (C A L- B) L ip o la se (C AL -B) L ip o la se (im mo b CA L -B) L ip o la se (im mo b CA L -B) 40 % yie l d 4 7% yi e ld (re stin g ce ll s) 4 7% yi el d 4 7% yi el d 99 % ee 99% ee 4 0% yi e ld >9 9% e e >9 8% e e <0 4 TA5 7 3> <0 4TA 5 73 > 99% ee <0 6TA 31 9 3 > <0 6TA 31 9 3 > <91 J CS (P1 )2 2 76 > <9 2W O9 21 8 47 7 >

Hydrolytic resolution of ester functions of hydroxyazetidinones has also proved to be a successful strategy to chiral azetidinones <94MI23; 93EP552041; 96MI1363; 95EP634492; 03WO016543; 03TA3673>. The resolved esters 12 were used to to install sidechains on taxol based drugs. Resolution of more remote ester functions has also proved to be a successful strategy, giving the interesting ethynyl azetidonone 13 <89TL2555> and gemdiethylazetidinone 14 <96JOC6575; 96USP5523233>. In the latter case, the unreacted ester byproduct could be recycled efficiently. Racemic 3-amino-ȕ-lactams have been resolved using carboxylic esters in the presence of penicillin acylase enzymes, providing the corresponding amides, useful intermediates for antibiotics, in excellent ee <91TL1621>.

Biocatalytic Approaches to Chiral Heterocycles

O

OH H

R

9 Et

O

O

NH

OH

Et

O O 12

NH

NH

O

O

14 13 Lipase PS30 Bacillus subt ilisis SANK 76759 Lipase PS-800 Hydrolytic KR Hydrolytic KR of benzoate Hydrolytic KR of ester 48-49% yield, 99% ee 60% overall yield 95% ee R = Ph: (af ter 3 cycles) <89TL2555> <94MI23; 93EP552041; 96MI1363> 93% ee R = 2-Furyl: <95EP634492> <96JOC6575> R = tBu: <03WO016543; 03TA3673> <96USP5523233>

Chiral hydroxyazetidinones (eg 15 and 16) have also been prepared via enzymatic reduction of the corresponding ketones <05TA4004>. Different product distributions (including trans-isomers) could be achieved using different enzymes. Other transformations of azetidines are also known. The lipase mediated ammoniolysis of a racemic azetidine ester gave the resolved ester 17 in very high ee, along with the corresponding amide 18 <98TA429>. Also, the diastereoselective 3-hydroxylation of contracted proline analogue 19 was achieved using a Streptomyces species TH1 proline 3-hydroxylase enzyme (the natural reaction for which is the hydroxylation of proline) <99TL5227; 00MI1967>. HO O

Ph

Yeast gene Ybr149w

O

NH O

15 Major product 90% ee

Yeast gene Yjr096w

HO

NH

Ph NH

O

16 Major product

CO2 Me N

Ph

Novozyme 435 (immob CALB) NH3 , tBuOH 35 oC 50-56% conversion

R

N

CO2 H NH

+ R

17 >99% ee

R = CH 2 Ph, PMB, allyl

Proline 3-hydroxylase

HO

CONH 2

CO2 Me N

R

18 80-97% ee

CO2 H NH

19 28% yield

1.4.2 Oxetanes Chiral ȕ-lactones can be prepared via the enzymatic alcoholysis of a racemic substrate, giving a mixture of the desired chiral oxetane, along with the solvolyzed byproduct. A range of chiral oxetanes have been prepared this way using various alcohol nucleophiles and lipase enzymes. One series of these is shown below <00JOC1227> and a selection of other typical chiral oxetanes prepared using this general approach is also given and others are referenced here <95JCS(P1)1645; 05TA3892; 97TA833; 00JCS(P1)71; <98T5523>; 96MM4582; 96MM3587; 00JOC7800>. Protracted reaction times were required to achieve high conversions.

10

S.J. Collier et al. Lipase PS Amano iPr 2 O, 35 oC

R O

+ BnOH

R

+

O

OBn

OH O O R = c-C 6H 11, PhCH 2CH 2, Me(CH 2)3 , Me(CH2 )2 , Me 2CHCH 2, CH 2=CH(CH 2) 8, BnOCH2 26-44% yield; 84-99% ee <00JOC1227>

O

Me

R

Me

O

O

O Lipase PS 38% yield 70% ee

Pr

R

O

O

O

Me Pr O

O

O

Me

PPL R = n-Pr, i-Pr, n-Bu. n-C 11 H23 Lipase PS 36% yield 50% yield Lipase PS; 27-46% yield; 96% ee 92% ee 70-96% ee

O

Lipase PS 13% yield 85% ee

<00JCS(P1)71> O

O Ph

O

Me

(S) Tropic acid lactone CAL-B 46% yield >98% ee <05TA3892>

O

CAL-B 99% ee <97TA833>

O

O

O O i-Pr ClF2C Lipase PS CAL-B 39% yield 37% yield 99.9% ee >99% ee <98T5523> <97TA833>

The hydrolysis of remote ester units has also proved a useful approach to chiral oxetanes, 20 and 21, which were used in the preparation of thromboxane agonists <89JA4510; 93JOC1882>. F F

F O

OH OAc

F

OH OAc

O

21 20 Pig liver esterase, hydrolytic KR 24% yield, 100% ee <89JA4510>

20% yield, 100% ee <93JOC1882>

1.4.3 Thietanes There are very few reports of the enzymatic preparation of chiral thietanes and these involve the hydrolytic resolution of ȕ-thiolactones. Very high yields and ee’s were achieved and examples are shown below <99WO45134; 00MI973; 00JMOC597; 06JMOC125>. R S

O

Pseudomonas cepacia lipase phosphate buffer, cyclohexane R = Me: 48% yield, 98% ee R = Et: 46% yield, 99% ee

R

R S

+ O

HS

OH O

Biocatalytic Approaches to Chiral Heterocycles

11

1.5 FIVE-MEMBERED RING SYSTEMS 1.5.1 Tetrahydrothiophene Derivatives A number of chiral tetrahydrothiophenes have been prepared using biotransformations. As one would expect, resolutions can be utilized. For example, tetrahydrothiophenones (thiolactones), e.g. 22, can be resolved using lipase enzymes, giving mercaptobutyric acids as byproducts <06JMOC125>. Simple resolution of pendant esters has also been reported for both tetrahydrothiophenes <93TL6517> and their sulfone analogues <06TL5273>. Me

Me

O

Candida antarctica lipase O

S 22

+

HS

O S 76% conversion >99% ee O

O

PhS S O O

OH Me

O

OH PhS

O S O O

Novozym e 435 Hydrolytic KR 98% ee (ester and alcohol) <06TL5273>

S Lipase PS-800 Triton X-100 Hydrolytic KR 98-99% ee <93TL6517>

Enzymatic reductions have also proved useful, and chiral 3-hydroxytetrahydrothiophenes can be obtained via enzymatic reduction of tetrahydrothiophen-3-ones using ketoreductase enzymes <81CJC1574> or baker’s yeast <99JMOC324; 99SL1328; 83CB1631; 82TL3479>. Furthermore, (R)-3-hydroxytetrahydrothiophene has been manufactured on a commercial scale from the corresponding ketone using an evolved ketoreductase enzyme derived from Lactobacillus species. The process operated efficiently under mild conditions, using high substrate loadings, and gave high yields of product in very high ee <09WO029554>. Dynamic kinetic resolutions have also been employed, giving products with reasonable yield and very high de and ee <99JMOC324; 99SL1328>. O

OH Bakers Yeast

S

CO 2Me

S

CO2Me

64% yield >99% ee >99% de

Aromatic thiophenes and benzothiophenes <96CC2361; 93CC49> give interesting cisdihydroxylated products in very high ee upon exposure to the toluene dioxygenase enzymes from Pseudomonas putida UV4. However, the 2-hydroxy group could be racemized via equilibration through a ring open aldehyde.

12

S.J. Collier et al.

P . putida UV4 oxygen

OH

X

OH

OH

Me

OH

OH S 11% yield 3:2 cis:trans 48% ee <96CC2361>

X

S

Me

OH

OH

15% yield 4:1 cis:trans >98% ee <96CC2361> <93CC49>

OH

S

79% yield 4:1 cis:trans >98% ee <96CC2361>

Some more complex transformations have also been reported. For example, a series of thiosugars (eg. 23 and 24) have been prepared from 2-mercaptoacetaldehyde and either glycerol <94BMC639> or glycerol phosphate <92LA1297> using aldolase enzymes. In the former case, glycerol is converted to glycerol phosphate and then to dihydroxy acetone phosphate. After an aldol reaction, the product was dephosphorylated using an acid phosphatase. In the latter case the mercaptoacetaldehyde was formed in situ by the dissociation of its dimer. The synthesis of 5-thio-D-xylulofuranose 25 was accomplished using a transketolase; the racemic aldehyde was used as a substrate, but only the Denantiomer is accepted by the enzyme <06EJO5526>.

OH HO OH O P O

S HO

23

OH

OH Aldolase

O racemic

+

77% R = PO3 H2

SH O

HS O

O +

HO

OH O

OH

HO

i. Kinase/Dehydrokinase ii. Aldolase

OR Transketolase TPP Tris buffer pH 7.5/30 o C 48%

S

70% R =H

HO

P OH O

OH HO

S

O

24

OH

OH OH

OH 25

1.5.2 Tetrahydrofuran Derivatives Chiral tetrahydrofurans are readily accessible using resolutions <94BMC387; 93JCS(P1)313> and desymmetrizations <01ASC527; 01MI355; 00JOC847> with example products of each given below. Intermediate 26 was used to prepare (-) podophyllotoxin and picrodophyllin <00JOC847>. Bicyclic hydroxyfurans have been prepared via lipase mediated acylative desymmetrization of meso diols <03TL2225>. Chiral furanones have been prepared by lipase mediated lactonisations. For example, meso-hydroxydiester 27 can undergo a porcine pancreatic lipase catalyzed desymmetrization via lactonization giving (S)-furanone 28 in high optical yield. The (R)-isomer could be obtained using Pseudomonas fluorescens lipase, although ee’s were lower <89JOC4263; 95MI87>. Treatment of 3,4epoxytetrahydrofuran with an epoxide hydrolase can give the corresponding (3R,4R)-diol <04JA11156>. Epoxide hydrolases have also been employed in an elegant enzyme-triggered enantioconvergent cascade reaction. Thus racemic 2,3-disubstituted cis-2-chloroalkyl epoxides 29 can be hydrolyzed enantioconvergently using resting cells of Rhodococcus sp. or Rhodococcus ruber. One enantiomer is cleaved with retention of stereochemistry, the other with inversion, providing a single, stereo-defined chlorodiol intermediate 30, which

Biocatalytic Approaches to Chiral Heterocycles

13

spontaneously cyclizes to yield chiral 3-hydroxytetrahydrofurans 31 as sole products in good yields and reasonable ee’s <01TA41; 01EJO4537>. HO

H

O

O O

O H

Lipase from Pseudomonas f luorescens Hydrolytic KR 22% yield, 92% ee <93JCS(P1)313> <94BMC387>

O

O

O OH

O

Immobilized lipase from P seudomonas cepacia Hydrolytic meso desymmetrization 90% yield, >98% ee; <01ASC527> <01MI355> Porcine pancreatic lipase

26 Porcine pancreatic lipase hydrolytic meso desymmetrization 66% yield, 95% ee; <00JOC847>

O

Cl

O

O

100%

O

O 28

27 epoxide hydrolase

O

OH OAc

O

OH OAc

R 29 Racemic R = Et, n-butyl

OH

OH

-HCl

R

Cl

O

OH (3R,4R) 30

R

(2R,3R) 31 R = Et: 42% conversion, 61% ee R = n-Bu: 79% yield, 86% ee

Enzymatic ketone reductions have also been shown to provide chiral dihydro- and tetrahydrofuran-3-ols in high ee from the corresponding ketones, with either enantiomer accessible through selection of an appropriate variant <07ACR1412>. Enzymatic reductions of ketones bearing pendant ester groups to chiral alcohols can result in cyclization of the intermediate hydroxyester to give chiral butyrolactones. Enzymes from the yeasts Mucor rouxii <04TA3763> or Pichia etchellsi <01TA1039> gave excellent yields and ee’s. O

O

RO

OR

M ucor r ouxii hexane/water

O

OR

O O

O

R = Me, Et, n-Pr, i-Pr: 98-100% yield; 94-99% ee O P. etchellsi

O

O

99% ee 90%

O

O

Oxidations have also proved to be valuable and efficient approaches to chiral tetrahydrofuran derivatives. For example, HLADH (horse liver alcohol dehydrogenase) catalyzes the oxidation of meso 1,4-diols 32 to give enantiomerically pure furanones 33 bearing fused rings of varying sizes on multigram scale <82JA4659>. Cyclobutene-fused furanones have been prepared using the same approach <99TA403>. Chiral

14

S.J. Collier et al.

dihydrobenzofuran diol 34 was synthesized from benzofuran using toluene dioxygenase <96CC2361>.

OH n 32

OH HLADH

O

n

O

O

OH

33 n = 1-4: 68-90% yield; 100% ee

OH

34 Toluene dioxygenase from Pseudomonas putida UV4 17% yield, 55% ee 3:2 cis:trans <96CC2361>

There are many examples of the synthesis of stereochemically defined Ȗ-butyrolactones, using the enzymatic Baeyer–Villiger oxidation of substituted cyclobutanones with a range of isolated enzymes or whole cell processes. The products of such reactions play a key role in the synthesis of many types of natural products and therapeutic agents (particularly those bearing substituents at the 3-position) <93JOC2725>. High stereoselectivities and good yields can be obtained using the fungus Cunninghamella echinulata in whole cell processes <00JMOC209; 98JMOC219> and the same or similar substrates can be also prepared from isolated Baeyer–Villiger monooxygenases (BVMO), such as cyclohexanone monooxygenases (CHMO), cyclopentanone monooxygenases (CPMO), or 4hydroxyacetophenone monooxygenases (HAPMO) <07ASC1436>. Bacteria expressing a mutant CHMO (F432S) were tested against a range of ketones in a 24-well microplate, in some cases giving products with high conversion and good ee <06OL1221>. An interesting variant of this approach involves the Baeyer–Villiger oxidation of 4-hydroxycyclohexanone, to give (S)-4-hydroxycaprolactone 34 which spontaneously rearranges to give an (S)butyrolactone derivative 35 <04AG(I)4075>. The product could be obtained in high yield and good stereoselectivity after screening and directed evolution. R BVMO

O

R

R

BVMO O

O (S)-lactone-derivative Acinetobact er calcoaceticus R = 4-ClC 6H 4, 4-MeC6 H 4, 3,4-(OCH2 O)C6 H3 , 3-MeOC6H4 CH2 : 70-94% yield, 85-100% ee <98JMOC219>

HO O

CHMO r.t. 24 h

O O

(R)-lactone derivative Cunninghamella echinulata NRLL 3655 R = Ph, 4-ClC6 H 4,4-FC6H4, PhCH 2OCH 2: 65-80% yield, 98% ee R = CH2Ot -Bu: 25% yield, >98% ee <00JMOC209; 98JMOC219>

HO

O

O O 34

O

HO 35 95% yield, 79% ee <04AG(I)4075>

Biocatalytic Approaches to Chiral Heterocycles

15

1.5.3 Pyrrolidine Derivatives Enzymatic approaches to chiral pyrrolidine derivatives are widespread, with various biotransformation strategies being employed to prepare a wide range of products. A small selection of the many tranformations, including some of the more elegant examples, is given here. Chiral pyrrolidine derivatives are readily accessed via resolution. In the example shown below, a lipase was used to cleave the carbonate function of the undesired enantiomer of a racemic substrate, leaving the chiral carbonate 36, an intermediate to (S)-zoplicone <97TA995>. Protease enzymes have been used to cleave ethyl esters of racemic alkyl and aryl oxalamic pyrrolidines leaving chiral esters in high ee <05OL4329>. Lactam 37, an intermediate to the drug Abacavir, was prepared via lactamase mediated resolution of its racemate (R = H) <92JCS(P1)589; 00MI105; 90CC1120; 99BMC2163>. Protected analogues could be resolved using enzymes such as savinase <99TA1201>. Chiral indol-2ones (e.g. 38 and 39) bearing a quaternary stereogenic carbon at the 3-position have been prepared via lipase mediated hydrolytic or acylative meso desymmetrization of diesters or diols respectively <01TA897; 01TL7315; 04JOC2478>. Desymmetrization of meso Ncarboxybenzoyl-3,4-epoxypyrrolidine with an epoxide hydrolase can give the corresponding (3R,4R)- <03CC960; 04JA11156> or (3S,4S)-diols <04JA11156>. OH

O N

O N

R

O O

N

Cl N

N O

O

O 36 Can di da a ntar cti ca li p as e- B 5 0% c on vers io n 98% e e <97 TA99 5>

O

O

O

O

O OH O

N R

N R 37 38 39 L ac ta m as e (R = H ) Li p as e OF L ipa se OF or Acy la tiv e d esym me tri zati o n Hyd ro lyti c des ym metriz ati on S a vin a se (R = B oc , A c) R = Bo c, C bz, Ac R = M e, Bo c, Cb z, Ac, M OM, Bn u pto 50 % yi el d 71 -9 3 % yie ld 29 -5 7% yi e ld at l east 9 8% e e 9 7- 99 % ee 98 -9 9% ee <9 2J CS(P 1) 589 > <0 4JOC2 47 8> <04 JO C24 7 8> <9 9 TA1 201>

3-Hydroxy-2,3-dihydroisoindolidin-1-ones (hemiaminals) are the core unit of a wide range of naturally occurring substances and bioactive compounds. Racemic N-acylhemiaminals are readily synthesized, and acylative DKR is a straightforward approach to the corresponding enantiopure esters. For example, the acetylation of racemic N-acylhemiaminals 40 mediated by lipase PS (Pseudomonas cepacia), lipase AK (Pseudomonas fluorescens) and lipase QL (Alcaligenes species) exclusively produced the (R)-acetates 41 in high enantiomeric purity and quantitative yields, using isopropenyl acetate as the acyl donor <03TA1581>. OH N O

Lipase PS, AK or QL Isopropenyl acetate O Hexane, 60-70 o C R

quant

OAc O N O

41 40 R = CH3 : 63% ee; R = Et, Pr, i-Pr, t-Bu, Ph: 95 - >99% ee

R

16

S.J. Collier et al.

Candida antarctica lipase A is described to catalyze the highly enantioselective DKR of the methyl esters of racemic proline 42 (n = 1) and pipecolic acid 42 (n = 2) (Scheme 1). Vinyl butenoate or 2,2,2-trifluoroethyl butanoate proved to be the best achiral acyl donors <04T671>. n N H 42

CO2 Me

Candida ant ar ct ica lipase-A PrCO2R, MTBE

n

CH 3CHO, Racemization

N H

n CO 2Me

CO 2Me

+ N O

Pr

n = 1, R = CH=CH2 : 88% yield, 97% ee; R = CH 2CF3: 97% yield, 99% ee n = 2, R = CH=CH2 : 69% yield, 97% ee

Scheme 1 Enzymatic reduction has also proved to be fruitful. For example, ketoreductase enzymes provide chiral pyrrolin-3-ols and pyrrolidin-3-ols in high ee from the corresponding ketones, with either enantiomer accessible through selection of an appropriate variant <07ACR1412>. In a more interesting example, the asymmetric reduction of the alkene moiety of Nsubstituted maleimides can be conducted by whole cell processes or isolated enzymes. Thus the highly stereo- and diastereoselective reduction of 3-methyl and 3,4-dimethylmaleimides 43 was effected using a cell culture of Marchantia polymorpha <06TA1859>. Several reductions of N-substituted maleimides are also described using a plant cell culture of Nicotiana tabacum <04TA15; 04JMOC245>. The reaction has also been effectively performed using the 12-oxophytodienoate reductase isoenzymes (OPR-1 and OPR-3) from Tomato <07AG(I)3934>. The employed system exhibits broad substrate specificity and affords the product in high yields and enantiomeric purity. R2

R1 O

O

N R3 43

Enzymatic reduction

R2

R1 O

O

N R3

R1 = H, R2 = Me, R3 = 4-MeOC6 H4 : 90% conversion, CH 2Ph: 99% conversion; 99% ee: M. polymorpha; <06TA1859> R 1 = H, R2 = Me, R3 = Ph: 99% conversion; 99% ee: N. t abacum; <04TA15> R 1 = Me, R 2 = Me, R 3 = 4-MeOC 6H 4: 77% conversion, Ph: 99% conversion; 99% ee: M. poly mor pha; <06TA1859> R1 = Me, R2 = H, R3 = Ph: 100% conversion; 99% ee: N. tabacum; <04JMOC245>

Enzymatic oxidations are also known. For example, the direct hydroxylation of Nprotected pyrrolidines, 44 (X = CH2) <01JOC8424> and pyrrolidinones 44 (X = CO) <00OL3949> has been achieved using Sphingomonas sp. HXN-200 (using resting cells or a cell free extract), giving 3-hydroxypyrrolidines, or 4-hydroxypyrrolidinones respectively, in moderate yield and ee on gram scale. Crystallization of the products dramatically increased the chiral purity, and with pyrrolidines, a simple change in the nitrogen substituent resulted in a reversal of stereochemistry <01JOC8424>.

Biocatalytic Approaches to Chiral Heterocycles

OH

N R (S)-isomer O

Sphingomonas sp. HXN-200 X = CO

X N R 44

Sphingomonas sp. HXN-200 phosphate buffer glucose

17

OH

OH

or N N R R (S)-isomer (R)-isomer

X = CH 2

X R Conversion Enantiomer % ee % ee After Crystallization CH2 COPh 43 (R) 52 95 CH2 CO2CH2Ph 91 (R) 75 98 CH2 CO2Ph 73 (S) 39 96 C=O Bn 68 (S) >99.9 -C=O CO2tBu 46 (S) 92 99.9 Monoamine oxidase (MAO) enzymes convert amines to imines with chiral discrimination. Thus, treating racemic amines with monoamine oxidase enzymes, in the presence of achiral reducing agents can provide chirally pure products. For example, in aqueous buffer solution, the aminoketone 45 cyclises to an achiral iminium ion 46, which is subsequently reduced to racemic amine by NH3-BH3 complex <06JA2224>. The (S)-enantiomer 47 is selectively oxidized back to the iminium ion by the monoamine oxidase (from Aspergillus niger). As the cycle repeats, the (R)-amine 48 accumulates, and the product, nicotine, can be obtained in quantitative yield with 99% ee. A similar approach was used to deracemize racemic proline to give L-proline in high yield and ee <01JMOC149; 02CC246; 02TL707>.

O N

45

HN

N N

NH3 .BH3 phosphate buffer 20 C / 24 h H N

46

N

47

Air, MAO-N-5 (resting cells)

+

H N

N

48 quant yield 99% ee

1.5.4 Five-Membered Ring Systems with More Than One Heteroatom A number of chiral five-membered heterocycles bearing two heteroatoms have been prepared using biotransformations. A small selection is given here, and as one would expect, numerous examples involve lipase mediated resolutions or desymmetrizations. Chiral dioxolanes, e.g. 49 and 50, have been prepared through enzymatic desymmetrization reactions, with both configurations available depending on the approach taken (acylative versus hydrolytic) <95TL853>. Chiral isoxazolines such as 51 have been prepared using a lipase mediated DKR, with the racemization step occurring via a reversible Michael reaction <01JA11075>. The drug Emtricitabine, 52, a chiral oxathiole, was prepared in excellent ee on multi-kilo scale using a lipase resolution of the corresponding racemic butyrate ester <06OPRD670>. The opposite (+) enantiomer could be obtained using pig liver esterase <92JOC5563>. Chiral dithiolane 1-oxide 53, thioxolane-S-oxides and benzo dithiolane 1oxides have been prepared via whole cell asymmetric enzymatic sulfoxidation, with the former being obtained in good ee <96TA565; 97T9695>. Typical products are given below.

18

S.J. Collier et al. O O

HO

O O

O

OH

OAc 49 Lipase from Pseudomonas f luor escens or P seudomonas cepacia Acylative desymmetrization 90% yield, 99% ee <95TL853>

NC

O

O N O

OH 50 Pseudomonas cepacia lipase Hydrolytic desymmetrization 86% yield, 99% ee <95TL853>

51 Pseudomonas cepacia lipase Hydrolytic DKR of ethyl thioester >99% conversion, 97.6% ee 89% yield, 99.7% ee af ter recryst <01JA11075>

O N

O

HO

NH2

S

S

N

F Emtricitabine, 52 Immobilized cholesterol esterase from Candida cy clindicacea hydrolytic KR 31% yield, 98% ee <06OPRD670>

S O

53 A cinetobact er TD63 whole cells chiral sulfoxidation 87% yield, >95% ee <97T9695>

Chiral oxazolidinones 54 have been prepared from racemic epoxides using an interesting enzymatic transformation. The enzyme halohydrin dehalogenase catalyzes the attack of a range of nucleophiles upon epoxides, and when sodium cyanate is used, the ring opening of one epoxide enantiomer is favored, giving an intermediate isocyanate, which spontaneously cyclizes to give the chiral isoxazolidinone <08OL2417>.

R1

O

Halohydrin dehalogenase f rom Agr obacter ium radiobacter , NaOCN, buffer

R2 O O

O

O NH

O

O

NH

44% yield 97% ee

O R1 R2

O NH

Cl 47% yield 80% ee

O

O

54

NH

Br 46% yield 93% ee

NH

O O

NH

Cl 47% yield 98% ee

54% yield 69% ee

1.6 SIX-MEMBERED RING SYSTEMS 1.6.1 Piperidines Chiral piperidines have been prepared using a wide range of different biocatalysts. The use of lipase mediated desymmetrizations <99TA3117; 96TA345; 96JOC3332; 99JOC5485> and kinetic resolutions <01OPRD415; 02TA2375; 02TA2653> is widespread with a number of examples given below. Such approaches provided all four diastereomers of 4hydroxypipecolic acid <02OPRD762>; chiral piperidine intermediates to the drug paroxetine <01JOC8947>, and intermediates to the Kishi lactam <99JOC5485>. Protease enzymes have been used to cleave ethyl esters of racemic alkyl and aryl oxalamic piperidines leaving chiral

Biocatalytic Approaches to Chiral Heterocycles

19

esters (e.g. 55) in high ee <05OL4329>. Lipase mediated DKRs are have also been employed, providing chiral pipecolic acid derivatives <04T671>. O HO

R

R

O OMe

HO OAc AcO OH N N N Cbz Cbz Bn Lipase from Candida ant ar ct ica Candida cylindracea lipase Lipase from A. niger Acylative desymmetrization Hydrolytic desymmetrization Hydrolytic desymmetrization R = H: 80% yield, 95% ee 25% yield, 80% ee R = H: 82% yield, >98% ee <96TA345> R = OMOM: 76% yield, >98% ee R = OMOM: 83% yield, 96% ee <99TA3117; 96JOC3332> <99TA3117; 96JOC3332>

OH N Boc

Lipase PS/PP Hydrolytic KR 46% yield, 99% ee <01OPRD415>

OAc

OH N

O

Boc

N

N H HO

Et

O

O OEt Pig liver esterase 55 Lipase PS/PP Hydrolytic KR Hydrolytic desymmetrization Protease from Aspergillus sp. 87% yield, 93% ee Hydrolytic KR 43% yield, >90% ee <99JOC5485> 49% conversion, 99% ee <01OPRD415> <05OL4329> HOOC

HOOC F

N H

F

N H

O O Candida antar ctica lipase-B Candida antar ctica lipase-A Hydrolytic KR Hydrolytic KR 50% conversion, 99% ee 50% conversion, 99%ee <02TA2375> <02TA2653>

An interesting DKR approach to chiral tetrahydroisoquinolines is shown below. The amine substrate 56 undergoes racemization in the presence of an iridium catalyst, and a lipase selectively acylates a single enantiomer to give the corresponding carbamate 57 in high yield and good ee <07OPRD642>. 0.2 mol% [Cp*IrI2 ]2 Candida rugosa lipase Toluene, 40 oC

MeO NH

MeO 56

MeO

O

OPr O

MeO MeO

N

OPr

O 57 86% yield, 96% ee

Enzymatic reductions have also proved to be successful approaches to chiral piperidines. For example, hydroxylated derivatives of the antianxiety drug Buspirone have been accessed using enzymatic reduction of ketone derivative 58 <05TA2778; 06MI1441>, although other approaches including lipase mediated resolution of an acetoxylated derivative <05TA2711>,

20

S.J. Collier et al.

or direct microbial hydroxylation of Buspirone itself <05TA2711> were also demonstrated. (R)-Quinuclidinol 59 has been prepared via enzymatic reduction of the corresponding prochiral ketone <03EP1318200>. N O O

(R)-Reductase from H ansenula polym orpha SC13845 expressed in E. coli O

N

4 O 6-Ketobuspirone 58

>98% yield >99.9% ee

(S)-Reductase f rom Pseudomonas put ida SC16269 expressed in E . coli O

>98% yield >99.9% ee

N HO

N

N

N

N

O

HO

O

OH

Tropinone reductase-I from Datur a st ramonium 88.4% yield, 98.6% ee N <03EP1318200>

59

A range of enzymatic oxidations have been used to prepare chiral piperidines. Chiral hydroxylated L-pipecolic acids 60 and 61 can be prepared via highly diastereoselective hydroxylation using proline hydroxylase, cloned and purified from several bacterial sources including Streptomyces sp. <99TL5227>. Toluene dioxygenase can convert quinolin-2-one to chiral quinolone diol 62 in high ee <98CC683>. Racemic pipecolic acid has been deracemized using a combination of amine oxidase and reducing agent to give the L-isomer in high yield and ee <92MI2081 >. OH N H O 60 38% yield >99% ee

OH

Proline 3-Hydroxylase Aqueous, 35 C

N H

Proline 4-Hydroxylase OH Aqueous, 35 C O

<99TL5227> OH OH N H 62

O

HO N H

OH

O 61 40% yield >99% ee

Toluene dioxygenase from Pseudomonas put ida UV4 10% yield, >98% ee <98CC683>

A scalable route to synthesize chiral piperidines involves the use of both oxidizing and reducing enzymes – an amino acid oxidase and an amino acid dehydrogenase (AADH). For example, L-pipecolic acid, a chiral pharmaceutical intermediate and an important diagnostic marker for epilepsy, is produced in three steps starting from L-lysine (63, X = CH2CH2). Amino acid oxidation by L-lysine oxidase (from Trichoderma viride) affords the corresponding ketoacid 64, which spontaneously cyclizes to form a cyclic imino acid 65. The latter is a substrate for the dehydrogenase (from Pseudomonas putida), giving L-pipecolic acid (66, X = CH2CH2, Scheme 2) <06TA1775>. On lab scale, this reaction has reported to give 90% yield and 99.7% ee at 27 g/L lysine loading <06MI2296 >. It should be noted that

Biocatalytic Approaches to Chiral Heterocycles

21

this method can also be used to prepare other heterocyclic amino acids from the appropriate open chain amino acid analog. <06TA1775>. NH2 X

Amino acid NH2 oxidase OH

NH2 O

X

X

O

OH

N

64 O

63

OH

Amino acid dehydrogenase

X

OH N H 66

O

65

O

X = (CH 2 )2, CH 2 , (CH2 )3 , CH2 S, (CH 2) 2S, CH 2O: 99% ee

Scheme 2 1.6.2 Pyrans Chiral pyran derivatives are readily prepared using kinetic resolutions. Two complimentary examples, 67 and 68, are given below, and for the latter of these, the DKR occurred via reversible opening of the hemiacetal to give a transient hydroxyaldehyde <97TL1655>. Other resolutions are also known <92MI56; 02OPRD471>. Bicyclic hydroxypyrans have been prepared via lipase mediated acylative resolution <03TL2225>. Mesodesymmetrization was used to prepare the chiral chroman monoacetate 69, an intermediate to (S)-Į-tocotrienol, from the corresponding diol in high ee <02TL7971>. Chiral acetamidochroman 70 was prepared using an interesting dynamic kinetic resolution. The corresponding ketoxime was reduced to a racemic amine, which is in constant palladium mediated equilibration. Lipase catalyzed acylation of one enantiomer of the amine gave the chiral acetamide shown in good yield and high ee <01OL4099>. F O

O O

OH O

OAc 67

O

OAc 68

F

Immobilized Lipase PS Immobilized Lipase PS Hydrolytic KR Acylative DKR 3:1 hexane:n-butanol Vinyl acetate 65% conversion >99% conversion >99% ee <97TL1655> 76% ee

N N N N Immobilized Lipase PS-30 Hydrolytic KR 48% yield, 98% ee <92MI56>

HO

CO 2Et

O

O Bacillus lent us protease Hydrolytic KR 38% yield, >99% ee <02OPRD471>

NHAc O

OAc

O HO 69 70 Candida antarctica lipase B Candida antarct ica lipase B Hydrolytic desymmetrization Acylative DKR 60% yield, 98% ee 89% yield, 99% ee <02TL7971> <01OL4099>

Enzymatic reduction and oxidation reactions have also proved to be versatile options. For example, the chiral hydroxytetrahydropyran 71 was prepared in high yield and ee on pilot

22

S.J. Collier et al.

plant scale using an isolated ketoreductase coupled with a glucose/GDH cofactor recycling system <08OPRD584>. Toluene monooxygenase enzymes can give chiral benzopyran diols 72 and 73 from the corresponding alkenes, in high ee <93CC49; 96JCS(P1)1757>. MeO HO

OMe

OH

OH

OH

OH O 71

Me O Me 73

O 72

Toluene dioxygenase from Pseudomonas put ida UV4 20% yield, >98% ee 18% yield, >98% ee <93CC49> <96JCS(P1)1757> <93CC49>

KRED 101/GDH 101 96-98% yield >99% ee <08OPRD584>

Chiral tetrahydropyranones are also readily accessible from cyclopentanones using Baeyer–Villigerase enzymes. For example, both wild-type and mutant CHMOs from Acinetobacter sp. catalyze the ring expansion of a range of bicyclic substrates to give the corresponding chiral lactones. Depending on the variant used, the conversion and enantioselectivity varied greatly, as shown <06OL1221>. A range of tetrahydropyranones have been prepared this way, some of which are shown below <02TA1953; 03BMCL1479; 05SL2751; 02SL700>. H

H

O Cl

O

O

O

O

O

H

H > 90% yield 17-94% ee, (-) only

> 90% yield 60-99% ee, (+/-)

O O

1-90% yield 12-92% ee, (+) only

50-90% yield 60-90% ee, (+/-)

CHMO from Acinet obacter sp. <06OL1221> H

O O OBn CHMO from Acinetobact er calcoaceticus >85% yield, 96% ee <02TA1953>

O

O H CHMO from Brevibacter ium >92% yield, 94% ee <03BMCL1479>

An interesting approach to chiral tetrahydropyrans uses 2-deoxyribose-5-phosphate aldolase (DERA). The native reaction catalyzed by this enzyme involves the condensation of acetaldehyde with D-glyceraldehyde-3-phosphate to form 2-deoxyribose-5-phosphate. DERA has been shown to have the unique ability to accept multiple aldehyde donors in a sequential and stereoselective manner. This feature has been exploited both in the laboratory and on a manufacturing scale to produce a variety of chiral hydroxytetrahydropyrans – several examples of which are shown below <95JA3333; 02AG(I)1404>. Of particular note is the synthesis of the chlorolactol (74, R1 = Cl) which is an important intermediate for statin drugs such as Atorvastatin (Lipitor) and Rosuvastatin (Crestor). Large-scale production of this compound utilizing the DERA process achieved a throughput of 30 g/L/h with a yield of 89% and an ee and de of 99.9% and 99.8%, respectively <04PNAS5788; 03WO006656>.

Biocatalytic Approaches to Chiral Heterocycles

O

DERA, 20 C O Aq. buffer

O R1

23

O

R1

OH

OH 74 R 1 = H, N3 : 22-23% yield; R 1 = OMe, CH 2CO2H, Cl: 65-80% yield; <95JA3333> O

O

DERA, 20 C Aq. buffer

O

HO

OH

R2

R2

R 2 = OH, N 3, trans-Me:47-60% yield <02AG(I)1404>

OH

1.6.3 Thiopyrans Chiral thiopyran derivatives can be produced following similar approaches to pyrans. For example, chiral hydroxytetrahydrothiopyrans can be accessed via enzymatic ketone reduction using alcohol dehydrogenases <83JOC791; 91TL7055; 92TL5567>. Thiopyran dioxide 75, an intermediate in the synthesis of the drug Trusopt, was obtained in high yield and de through alcohol dehydrogenase mediated diastereoselective reduction of the corresponding ketone <96MI17; 96USP5580764; 97MI513>. Toluene dioxygenase gives chiral benzothiopyran diol 76 in high ee from the corresponding alkene <93CC49>. OH

OH

OH Me

S

S

47% yield 78% ee

34% yield 38% yield 85% ee 65% ee Horse liver alcohol dehydrogenase <83JOC791>

OH

OH

OH OR

S

OH

O

S

Bakers yeast alcohol dehydrogenase R=H, CH 3 , C 2H 5, C8 H17 28-86% yield, >98% ee <91TL7055>

R S Bakers yeast alcohol dehydrogenase R=CH 3 , C2 H 5, C6 H5 32-66% yield, 93-97% ee <92TL5567> OH

OR O

O

Et

S

S

49% yield 90% ee

OH Me

Et

OH S

S O2 75 Alcohol dehydrogenase from Neurospor a cr assa >85% yield, >98% ee <96USP5580764>

S 76 Toluene dioxygenase f rom Pseudomonas putida UV4 40% yield >98% ee <93CC49>

Again, in direct analogy to tetrahydropyrans, DERA-catalyzed reactions can give chiral tetrahydrothiopyrans. In the case below, a single diastereomer of the thiosugar 77 is produced due to DERA’s exquisite selectivity for 2-hydroxyaldehydes <95CS3333>.

24

S.J. Collier et al.

O

DERA, aq. buffer 48 h, 20 C

O

HS

33% yield

OH

S

OH

HO OH 77

1.6.4 Six-Membered Heterocycles with More than one Heteroatom A range of chiral six-membered heterocycles which bear more than one heteroatom in the ring are accessible using enzymatic reactions. A small selection is given below, although one could envisage many viable approaches to such compounds. Hydrolase mediated resolutions of racemates are, again, readily employed to access heterocycles bearing chiral alcohol, amine or acid residues. For example, chiral dioxane 78, an intermediate to the natural product leustroducsin, was prepared via acylative desymmetrization of the corresponding meso-diol followed by silylation <03JA4048>. Lipases and esterases also act as racemases in that they can catalyze the interconversion between the two enantiomers of a single substrate. Thus, the (2R,3R)-enantiomer of the oxazinol 79 can be ring-opened by commercial Lipase P-800 to give the corresponding aminoketone. The Į-methyl group can be inverted via enolization and upon enzyme-catalyzed ring closure, the (2S,3S)-enantiomer can be obtained. Treatment of an equilibrated mixture with seeds of the desired (2S,3S)-enantiomer results in a crystallization driven transformation, providing the product in 97-98% ee <05WO044809>. O

O

78

Cl OTBS

O

OH

OAc

Lipase AK Acylative Desymmetrization then silylation 86% yield, 90% ee <03JA4048>

Cl

Lipase P-800 acetone, water 16 h, 20 C

O

N H

OH

N H 79

Deracemization of racemic amines using chemo-enzymatic synthesis is a powerful approach to chiral amines. For example, the piperazine amino acid 80 (an intermediate for the HIV-protease inhibitor Crixivan) can be prepared using a combination of an amino acid oxidase from porcine kidney (which selectively oxidizes the (S)-carboxylic acid to the corresponding imine) and sodium cyanoborohydride (which reduces the prochiral imine back to the racemate). The resulting (S)-amino acid is then reoxidized to the imine and the cycle continues. The desired L-piperazine-2-carboxylic acid is produced in 86% yield and 99% ee using this elegant one-pot synthesis <02CC246>. Either enantiomer of the same piperazine acid could also be prepared via resolution of the racemic amide using different hydrolase enzymes. Chiral morpholino and thiomorpholino carboxylic acids (66, X = CH2O, CH2S) have been prepared in direct analogy to the route used to prepare L-pipecolic acid (Scheme 2) using a sequence of L-amino acid oxidase then dehydrogenase reactions <06TA1775>. Amino acid oxidase f rom P seudomonas put ida aq. buffer, 37 o C, 3 eq NaCNBH 3

H N N H

COOH

H N N COOH H 80

Biocatalytic Approaches to Chiral Heterocycles

25

In an interesting and unusual reaction, 1,3-dithianes 81 can be oxidized using CHMO enzymes to give the corresponding chiral monosulfoxides 82. Such chiral sulfoxides have proven to be excellent chiral auxiliaries for use in asymmetric syntheses. Selected products are given below, and in all cases, no evidence of bis-sulfoxide formation was noted, although sulfone formation (<20%) was observed in some cases <96TA565; 97T9695>. R1 S

R2 S

A cinetobact er sp. CHMO, 30 C

R1

R2

S

S

O

82 81 R = R = H: 74% yield, 93% ee (R); Me: 66% yield, 60% ee (R) <97T9695> R 1 = H, R2 = Me, COPh: 90-100% yield, 90-95% ee (1R,2R) <96TA565> 1

2

1.7 SEVEN-MEMBERED AND LARGER RING SYSTEMS Biotransformations have proved to be useful approaches to a range of 7-membered and larger heterocyclic rings containing one or more heteroatoms. Again, lipase mediated reactions are widespread. For example, chiral macrolactones 83–86 have been prepared through lipase mediated intramolecular cyclization of racemic hydroxyesters (a kinetic resolution) <89CL1775; 92LA1011>.

O OH

O

Lipase P Iso-octane, 4A Mol.sieves 65 C, 24 h 14% yield, 99% ee

O

20% yield 98% e.e

83

O

O

O 84 O

O

O

O 85 16% yield 96% e.e

86 17% yield 99% e.e

Chiral benzazepanes have been prepared by lipase catalyzed esterification, giving a mixture of the resolved chiral benzazepane along with the solvolyzed product. Typical products of such resolutions are shown below <01H(54)131; 02H(58)635; 04H(63)17; 06H(69)333>. Similar approaches have been used to prepare chiral benzodioxepines,<99IJC(B)397> benzodiazepines <98WO9829561; 04GC475; 98HCA85; 98HCA1567; 00CCA743; 02OPRD488; 02TL4915; 98HCA1567>, and benzothiazepinones <00TA4447; 96JAP0800277>. Chiral hydroxyoxepanes 87, and 8- and 9-membered

26

S.J. Collier et al.

analogues 88 and 89 have been prepared through lipase mediated acetylation of meso-diols, and have been used to make rings of the marine polyether ciguatoxin <99T7471>. Examples are given below. O

Ts

Ts

N

N Cl

O

O

O O

N

O

Cl

OH

O O

O

O

O

Me N

O

H N O

O

H N

O

H N

OH

O

N

Cl

O Pig li ve r e ste ra se H yd ro ly ti c K R <99 IJC (B )39 7 >

N o vo zym e 43 5 Acy la tiv e K R 4 6 % y ie ld , 97 .8 % e e 04 H (6 3 )17

O

NH N ov oz ym e 4 3 5 H yd ro ly ti c KR 56 % yie l d, 9 9% e e <98 WO 98 2 95 6 1>

O O

Li p as e QL Ac yl ati ve K R 3 5 % y ie ld , 93 % e e <0 1 H( 54 )1 3 1>

Li p as e QL Ac yl ati ve K R 9 0 % y ie ld , 9 7% e e <0 6 H (69 )3 3 3>

Ph

Ph

HO

O

Ph

O

O O

O N

Cl

N Me

Ph N ov oz ym e 4 35 A cyl ati ve KR 4 9 % yie l d, 8 3% e e <9 8H C A1 5 67 >

O

Ph Li p oz yme IM Acy la tiv e K R 4 3% yi e ld , 9 8 % ee <9 8H C A8 5 >

N ov oz ym e 4 35 H yd ro lyti c KR 4 7 % yie l d, 9 9% e e <04 GC 4 7 5>

O H N Cl

O

OO

HN

H N

H

N

O

N

Ph Ph N ov oz ym e 4 3 5 A cyl a ti ve KR 54 % yi el d, 3 0 % e e <0 0C C A7 4 3>

OH

N

OO

N

O

OH N

Cl Ph

O C h ir az ym e L 2 A cyl ati ve KR 42 % yie l d, >9 5% e e <0 2 OPR D 48 8 >

N o vo zym e 4 3 5 A cyl ati ve de sy mm etr iza tio n 8 6% yi el d , 9 0 % e e <9 8 HC A 15 6 7>

Cl A cO S N O

OH O L ip as e FA P-1 5 Hy dr ol yti c KR 4 5 % yie ld , 9 9% e .e <0 0 TA4 4 47 >

B nO

OH O

OBn

87 Li pa se AK A cyl a ti ve d es ymm e tr iz ati on 8 1 % y ie ld , >99 % ee <99 T7 47 1 >

OB n

Bn O A cO

O

OH

M PM O Ac O

O MP M O

OH

88

89

L ip a se A K Ac yla tiv e d e sym me tri za tio n 92 % yi el d, 9 2 % e e <9 9T 74 7 1>

Li pa se AK A cyl a ti ve d es ymm e tr iz ati on 7 6 % y ie ld , 94 % ee <99 T7 47 1 >

Enzymatic reductions have also proved valuable. For example, chiral benzazepinone 90 was prepared by enzymatic ketone reduction with enzymes such as Nocardia salmonicolor <92IJC(B)817> and Rhodococcus fascians <93EUP486727>, although other reductase enzymes may be used for such transformations <96USP5559017>. Either enantiomer of a range of hydroxyazepanes and oxepanes have been prepared using ketoreductase enzymes <07ACR1412>. Optically active benzothiazepinones, e.g. 91, have also been prepared by reduction of the corresponding ketones under dynamic conditions <93JAP05244992; 95MI28; 96MI534; 97MI195>. Chiral thiazepino carboxylic acid 66 (X = CH2CH2S) has

Biocatalytic Approaches to Chiral Heterocycles

27

been prepared in direct analogy to L-pipecolic acid (Scheme 2, above) using a sequence of Lamino acid oxidase then dehydrogenase reactions <06TA1775>. H N

O

H N

O

N. salmonicolor phosphate buffer, pH 8

O CF3

OH

85% yield

CF3 90

OMe O

Baker's yeast

S

S

O N H

OMe O

OH N O H 91 85% yield, 99% ee

O

The synthesis of 7-membered chiral lactones or oxepan-2-ones and derivatives thereof, via the enzymatic Baeyer–Villiger oxidation of cyclohexanones is a widely studied reaction. <05AG(I)3609; 05CRV313; 04CRV4105; 04JOC12; 03BMCL1479; 01JMOC349; 01JOC733; 01S947; 97TA2523; 88JA6892; 05ASC1035>. A classical example of cyclohexanone monooxygenase catalyzed oxidation is shown below, as are other chiral lactones synthesized similarly. Chiral dioxepines, e.g. 92, can also be prepared via the Baeyer–Villiger oxidation of prochiral pyranones utilizing recombinant whole cells of Escherichia coli overexpressing Acinetobacter sp. NCIMB 9871 CHMO <03SL1973>, with a typical reaction shown below. O

CHMO from Acinet obacter sp. NCIMB 9871

O O

>99% e.e

O

O O

O

O

O

O

O O

Et

O

O O OMe H CHMO from Acinetobacter sp. NCIMB 9871 65% yield >99% ee <05AG(I)3609>

76% yield 79% yield 75% ee 95% ee <88JA6892> <04CRV4105>

35% yield >99% ee <05ASC1035>

22% yield >99% ee <05ASC1035>

O O

O

O

26% yield >99% ee <05ASC1035>

28

S.J. Collier et al. R

O

R

CHMO f rom Acinetobacter sp. air, aq. buffer, 20 C

O R

O

O

O

R 92 R = Me: 80% yield, >99% ee; Et: 90% yield, >99% ee; Pr: 19% yield 98% ee; i-Pr/n-Bu: no reaction

1.8 CONCLUSION The preparation of chiral heterocycles using biotransformations is an effective synthetic strategy which can provide high value products with exquisite control of chirality, typically under mild and environmentally benign conditions. Although this review is limited in coverage, the potential of biocatalytic chiral heterocycle synthesis is clear. Furthermore, the development of directed evolution technologies allows rapid optimization of inefficient wild type enzymes, providing superior catalysts that are highly active, selective and robust, and that are commercially attractive alternatives to traditional chiral chemical technologies. Given the increasing access to such evolved catalysts, and the growing acceptance of biocatalysis in the synthetic community, the stage is set for continued growth in this field, with many new and exciting applications waiting to be discovered.

1.9 REFERENCES B-08MI1

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