Recent advances in the generation of chiral intermediates using enzymes.

Biotechnology

Recent Advances in the Generation of ChiraI Intermediates Using Enzymes

There are a number of ways of producing homochiral intermediates apart from the employment of the classical, often wasteful, resolution procedures. First, readily available optically pure natural products, e.g., glucose, can be modified with careful control of the stereochemistry of asymmetric centers that are to be retained in the final product. Many elegant syntheses using compounds from the “chiral pool” are documented.’ Second, optically active agents and reagents can be employed. Thus, an optically active alcohol can be used to form a chiral ester; induction of asymmetry into reactions taking place in the acid portion of the ester can often be achieved before the ester is hydrolyzed and (if necessary) the chiral alcohol recycled (Figure 1). Thus, the required acid is formed by temporary attachment of a chiral ligand to the main body of the molecule. Important developments of this basic strategy have resulted from the work of Evans2and M e y e r ~Reagents .~ involving ( )- or ( - )-tartaric acid esters have been developed by Sharpless et aL4 for the formation of optically active epoxides from allylic alcohols. Similarly, Noyori et al. have developed reducing agents that convert unsymmetrical ketones into secondary alcohols often of very high optical p ~ r i t yThe .~ use of chiral catalysts is the most attractive method for the production of chiral intermediates. For example, optically active amines have been used to catalyze the Michael reaction (Figure 2).6 Reactions catalyzed by enzymes are under the control of a chiral macromolecule and, not surprisingly, enantiomers often react at different rates with enzymes; similarly, prochiral or meso- compounds are generally transformed in stereoselective or stereospecific fashion to produce chiral end products. Thus, enzyme-catalyzed reactions provide just one of a number of methods for producing chiral intermediates en route to optically active fine chemicals. The use of enzymes to promote desired transformations has a number of advantages. For instance, reactions can be performed that are difficult to emulate using conventional chemistry. Also, reactions can be conducted under mild con-

H. Geoff Davies, Richard H. Green, David R. Kelly, and Stanley M. Roberts

Critical Reviews in Biotechnology Downloaded from informahealthcare.com by University of California Irvine on 11/07/14 For personal use only.

ABSTRACT Different types of enzyme-catalyzed processes are reviewed, with particular regard to those procedures leading to the generation of chiral compounds of high optical purity. The main body of the review deals with hydrolyses and esterification as well as the reduction and oxidation of organic substrates. Other biotransformations of current and/or future importance in the synthesis of homochiral fine chemicals (such as the formation of carbon-carbon bonds using aldolases) are also discussed in some detail. Attention is drawn to current trends in the area and, to this end, a majority of the references are taken from journals published during the period April 1987 to September 1988.

+

1. INTRODUCTION There is currently much attention focused on the interaction of small molecules with biological macromolecules. For example, the search for selective enzyme inhibitors and receptor agonists or antagonists is one of the major focal points for target-oriented research within the pharmaceutical industry. In the agrichemical industry, there is an increased awareness that selective interference with a specific enzyme-catalyzedprocess in a key metabolic pathway in pests or weeds can produce highly desirable products for the marketplace. The fragrance and flavors industries are primarily concerned with the interaction of small molecules with the olfactory system and the receptors involved in producing the sensation of taste. In all of these areas of research, the biological macromolecules that are involved in the key process of molecular recognition are chiral. Therefore, not surprisingly, if the small molecule acting as the partner is also chiral, the interaction between the macromolecule and the small molecule will depend on the absolute configuration of the latter substance. For example, one enantiomer of a chiral material may be a potent enzyme inhibitor while the mirror image may well be essentially inactive. This difference in activity and reactivity of stereoisomers in vivo is well known and the drug authorities are increasingly aware that, where appropriate, new substances for the clinic should be homochiral to avoid the possibility of engendering unnecessary side effects. The pharmaceutical industry is thus particularly aware of the need to produce optically pure compounds from chiral intermediates.

H. G. Davies received a B.Sc. (Hons) from the University of Swansea, Swansea, U.K. Mr. Davies is a Research Chemist, Department of Medicinal Chemistry, Glaxo Group Research, Greenford, Middlesex, U.K. R. H. Green received a B.Sc. from the University of Sheffield, Sheffield, U.K.; a Ph.D. was earned at the University of Leicester, Leicester, U.K. Dr. Green is a Research Chemist, Department of Medicinal Chemistry, Glaxo Group Research, Greenford, Middlesex, U.K. D. R. Kelly received a B.Sc. and Ph.D. from University of Salford, Salford, U.K. Dr. Kelly is a Lecturer, School of Chemistry and Applied Chemistry, University of Wales College of Cardiff, Cardiff, U.K. s. M. Roberts received a B.Sc., Ph.D., and D.Sc. from University of Salford, Salford, U.K. Dr. Roberts is a Professor, Department of Chemistrv. Universitv of Exeter. Exeter, Devon, U.K.

1990

129

Critical Reviews In R ’cH ~ C O ~ H

R2’OH c

reaction at C(2)

EiamA

hydrolysis

R’&HCQH

7-


I

Fe

R”OH

0 cat. amine

EiuuLz *.*

ditions of temperature, pressure, and pH. In addition, products are often obtained with good chemical yield and high optical purity. There are also disadvantages. For example, some enzymes can only operate as part of a whole cell system. Sometimes high concentrations of substrate and/or product will deactivate the enzyme such that relatively large volumes of solvent are required for the conversion to proceed in a satisfactory manner. Both of the disadvantages cited do not provide insurmountable problems to the intended user. Most whole cell biotransformations are based on fungal or bacterial cell systems that are safe, easy to grow, and simple to use. The work-up procedure involves centrifugation and decantation to remove the supernatant liquid from the spent cells or simply filtration of the medium through a suitable adsorbant. Sometimes a particular biotransformation can be accomplished using either a whole cell system or an isolated, partially purified enzyme. The “pros and cons” of using one or the other system have been discussed elsewhere.’ The transfer of the appropriate technology from academic laboratories that are accustomed to performing biotransformations to many industrial research and development laboratories has been slow and in some cases nonexistent. However, the “activation energy” required before an experienced chemist will begin to use an enzyme as a catalyst is definitely getting lower (as evidenced by the volume of papers emerging in the chemical literature) and one can expect more and more important syntheses to contain a key step involving an enzymecatalyzed reaction. Some of these new syntheses will be transferred to scale-up laboratories and, if the enzyme step is a

130

. Nu H

crucial feature in the pathway, the biocatalytic process may survive any revamping of the route that may be perceived to be needed on transfer to the large-scale laboratories, pilot plant, and full-scale production unit. The thesis that enzyme-catalyzed reactions are gaining popularity is expounded in the following sections of this review. The survey is based on reaction types and, whenever possible, reference is made to recently reported reactions. It is impossible to be comprehensive in a review of this length and the transformations described hereunder are just a sample of the massive amount of information available in the primary journals. Other texts carry a more thorough survey of practical and theoretical aspects of enzyme-catalyzed reactions. Other reviewsi0 should be consulted for more details of biotransformations published before 1987. The reaction types under review here are as follows *sy

Hydrolysis of esters Hydrolysis of amides Other hydrolysis reactions Esterification reactions and formation of amide bonds 5 . Reduction of carbonyl compounds 6. Reduction of alkenes 7. Oxidation of alcohols 8. Oxidation of alkenes 9. Other oxidation reactions 10. Hydroxylation reactions involving aliphatic compounds 1 1 . Hydroxylation reactions involving aromatic compounds 12. Other biotransformation reactions 1.

2. 3. 4.

Volume 10, issue 2

Biotechnolog y have been converted into important p-lactam antibiotics. l 6 The controlled enzymic hydrolyses of 3-alkyl-glutarates (6) are


II. SELECTED BIOTRANSFORMATIONS A. Hydrolysis of Esters Much of the early work on the hydrolysis of enzymes involved the use of a-chymotrypsin. I ’ In recent years, pig liver esterase (ple), porcine pancreatic lipase (ppl), and other lipases have gained in popularity. An example of the continuing use of a-chymotrypsin involves the conversion of the rneso-diester (1) into the 2(S),4(R) enantiomer of methyl 2,4-dimethylglutamic acid (2) in 50% yield (77% enantiomeric excess [e.e.]).” This optically active compound was used in a synthesis of

R

h

bt

Me

W2Me

t,:

Me

Me

‘HC02H

n 11.2 (7)R = Me (8) R = H

(+)-conglobatin. The enzyme obviously hydrolyzes one of the pair of ester groups selectively; the useful model of the enzyme active site proposed by Cohen13 can be used to predict the outcome of an a-chymotrypsin-catalyzedhydrolysis. Much attention has been given to the hydrolysis of diesters of the type (3) and (4) using enzymes such as a-chymotrypsin and ple. For the compounds (3), it was shown that by changing the size and polarity of R the stereochemical outcome of the hydrolysis can be changed and good enantio-selectively

(10) R

\Me

H

equally important in synthesis: hydrolysis of compound [(6), R = R’ = Me] gave a useful synthon for ( +)-faranal,” the active component of the trail pheromone of the Pharaoh’s ant. Ple hydrolysis of glutarate [(6) R = CH,CH=CHPh, R’ = Et] gave the corresponding (S)-monoester which was converted over several steps into part of the rhizoxin skeleton.ls The structure-stereoselectivity relationships revealed by biotransformation studies of this sort gave information about the topography of the active site of ple, thus allowing an “active site model” to be con~tructed,’~ bearing in mind that ple, as obtained from most sources, is a mixture of isozymes.20 The enzyme-catalyzed hydrolysis of rneso-diesters, such as (3)-(6), is a particularly attractive strategy in synthesis since, in theory, it is possible to obtain a quantitative yield of optically pure material. Prochiral diesters derived from malonate are also hydrolyzed stereoselectively by ple .,’ Ple-catalyzed hydrolyses of dialkyl cycloalkyl- 1,Zdicarboxylates (7) afford good yields of the corresponding acids (8).22 The norbornene system (9) has also been subjected to ple hydrolysis whereupon the half-ester (10) was obtained in quantitative yield and in ca. 80% e.e. The chiral half-ester (10) was converted into the antibiotics ( - )-aristeromycin and (-)-neplanocin A by conventional chemical Other bioactive nucleoside analogs have been prepared by the hydrolysis of dimethyl cyclopentane 1,3-dicarboxylic acid derivatives.24 Up to this point, the utility of hydrolase-catalyzed reactions has been illustrated using, as examples, compounds in which the chiral center(s) is (are) present in the acid portion of the

n OR

Me02C

-

(9) R = Me

W2Me

(3)

achieved.l4 The enzyme-catalyzed hydrolysis of compounds (4) has been particularly well studied. When the amine-protecting group (Z) is large, high chemical and optical yields of the (S)-half-ester ( 5 ) can be obtained.I5Compounds of this type 1990

131

Critical Reviews In ester. An equal body of work has been done on the hydrolysis of esters in which chirality is present in the alcohol moiety. For these substrates, lipases are often the catalysts of choice. The prochiral diesters (1 1) are hydrolyzed by ppl to give the corresponding alcohols (12) in excellent chemical and optical yields."

H


(1 6) n =1,2

(1 1) n

1 - 4, R = Me or Pr

(12)

. I

In addition, the lipase from Candidu cylindracea converted the diester (13) into the (+)-(lR,4S)-alcohol (as did electric eel acetylcholinesterase26),while ple gave the ( - )-(1S,4R)-isomer.27 Both isomers of this alcohol can be converted into

OCOMe

0

(17)

optically pure alcohols (17) and recovered optically active ester in excellent yield. Both series of alcohols are useful chiral intermediates in organic synthesis.32 Perusal of the recent literature indicates that enzyme-catalyzed hydrolysis of esters derived from racemic alcohols has been taken up by numerous laboratories. The strategy has been used to make, inter ulia, optically active 2-arninoalkan-l-ol~,~~ 2,3-epoxyalkan- l - ~ l s 2-nitroalkanol~,~~ ,~~ 2-phenylalkanol~,~~ 2-piperidinomethylalkan-l - o l ~ , ~7-0xanorbomenes,~~ ' and bicyclic alcohols as chiral subunits for crown ethers.39 Enzyme-catalyzed hydrolysis of phosphate esters has also proved useful in synthesis, particularly in cases where the substrate contains sensitive functional groups. Thus, acid-catalyzed hydrolysis of polyprenyl pyrophosphates is unsuccessful due to the acid lability of the resulting alcohols. In contrast, commercially available potato acid phosphatase hydrolyzes these phosphates readily (in the presence of a simple alcohol) to afford the corresponding alchols.40 The nucleoside analog (18) is a potent inhibitor of herpes viruses in vitro and in vivo. The chiral material was obtained by enantioselective hydrolysis of racemic 5'-monophosphate using snake venom nu~leotidase.~'

6. Hydrolysls of Amides Carboxypeptidases hydrolyze amide bonds of the type illustrated by formula (19), particularly when R' is an aromatic or large aliphatic moiety.

0 enones (14) which are compounds of importance as synthons of prostaglandins of type E.2R While the elegant use of enzyme-controlled hydrolysis of meso-esters in the synthesis of various types of chiral synthons is noteworthy, the partial hydrolysis of racemic esters to give optically active ester and optically active alcohol can be equally valuable. For example, the hydrolysis of the simple ester (15) with either Mucor miehei lipase (mml)29or lyophilized yeast3' gave the (3S)-alcohol in good/excellent optical purity. 3(S)Oct-1-yn-3-01 has been used in the synthesis of coriolic acid29 and prostaglandin^.^' The acetates (16) are converted into the

132

Volume 10, Issue 2

Biotechnology

MeOCNH R'CHC02H

1


NHCOR~

Me

x

CF3 C02H

H2N?cF3 C02H

The susceptible substrates must have the (t)-configuration, hence carboxypeptidases have been used for the resolution of a wide variety of amino acids." Hog renal acylase I has been used for the same purpose; e.g., the racemic amido acid (20) was hydrolyzed to give the amino acid (21) in 53% yield (99% e. e. ) .42 A mold aminoacylase (produced from wheat bran and rice after challenge with Aspergillus oryzue) has been used for the production of (L)-amino acids such as alanine, methionine, tryptophan, and valine from the corresponding racemic N-acetyl precursors. The process can be operated on a very large scale.43Papain is the catalyst of choice for the resolution of N-carbobenzoxy-y-methyl glutamic acid, a starting material for the preparation of ( +)-mam~elolactones.~ An acylase from Aspergillus sp. was used for the hydrolysis of the racemic N-chloroacetyl amino acid (22). The hydrolysis was carried out in the presence of Co(I1) salt: both the amino acid (23) and recovered starting material could be obtained in a highly optically pure state.45The optically active compounds obtained were converted into rhreo-4-methylheptan-3-01~, pheromone components of the destructive elm-bark beetle Amidases have been shown to be extremely useful catalysts in the synthesis of semisynthetic penicillins and cephalosponns. This commercially important process has been the subject of investigation for over 30 years and the transformation has been optimized: immobilization of the penicillin acylase enzyme on Sephadex is a key feature in the conversion of potassium penicillin G into 6-aminopenicillanic acid (6-APA) in 90% yield on a 3-kg scale.46While 6-APA has been used to make semisynthetic penicillins and other p-lactams, it is a cheap, remarkably underused chiral synthon for general use in synthetic organic chemistry. Interestingly, the penicillin acylase from Escherichia coli is able to hydrolyze totally different types of esters of phenylacetic acid, e.g., compounds of formula (24).47

Me

C. Other Hydrolysis Reactions Enzymes have been used to hydrolyze a number of types of functional groups besides esters and amides.48 However, only a small number of these processes have been developed to give reliable access to chiral intermediates. The use of liver microsomes for the regio- and enantiospecific hydrolysis of epoxides has been studied. Monosubstituted and 1,l-disubstituted epoxides having at least one large lipophilic substituent are among the best substrates, while highly substituted epoxides are not h y d r ~ l y z e d .(Labeling ~~ studies show that the susceptible epoxides undergo hydrolysis by hydroxide attack at the least hindered carbon atom.)50In another example, cyclohexene oxide is converted into ( - )-trans(lR,ZR)-dihydroxycyclohexane(e.e. cu. 70%).51 Hydrolyses of the cis- and trans-isomers of 4-and 3-tertbutyl- 1,Zepoxycyclohexanes have been studied to gain insight into the detailed stereochemical features of the ring-opening process.52 The stereochemical studies were extended to provide a synthesis of a deoxy sugar;53thus, reaction of the racemic lyxo-epoxide ( 2 5 ) with epoxide hydrolase gave, after 50% conversion, samples of the (L)-diol (26) and the (D)-epoxide in a reasonably pure state.

Me

Me I

Me OH (26)

NHCOCH2Cl

As well as the microsomal epoxide hydrolases described above, a cytosolic epoxide hydrolase, with a proclivity for the

1990

133


Critical Reviews In hydrolysis of truns-epoxides, has been isolated.54Epoxide hydrolases from microorganisms have been used to prepare optically active compounds. cis-Epoxysuccinic acid gives (D)tartaric acid on incubation with several strains of Achromohactrr and Alcaligenes. ” The enzyme-controlled hydrolysis of epoxides is not yet at a stage where it can be routinely used in the preparation of useful chiral vicinal diols. The important paper by Sharpless defining an alternative, complementary chemical method for the production of such diols should be noted.56 The enzyme-catalyzed hydrolysis of nitriles is an area of increasing interest.s7 A nitrilase possessing a broad substrate specificity is commercially available, and this biocatalyst has been shown to convert methyl cyanoacetate into methyl malonate and adiponitrile into the corresponding half-amide in good yield. 5R The microorganism Brevibacterium sp. R3 12 appears to possess a nitrile hydratase and an amidase with wide substrate selectivities: highly functionalized acids such as y-alkoxy-aaminoacids are obtained from the corresponding nitrile in good yield.” Finally, the selective conversion of 1,3-dicyanobenzene into 3-cyanobenzoic acid (95% yield) using the bacterium Rhodococcus rhodochrous has been reported.60

D. Esterification Reactions and Formation of Amide Bonds The concept of forcing enzymes to catalyze reactions “in reverse” has recently captured the imaginations of many scientists. The concept itself is not new, and explorations into the use of lipases for the esterification and transesterification of fats have been on-going for many years: interesting results on large-scale conversions in this area are now being published.61 However, credit must go to Klibanov for popularizing the concept and bringing the immense potential of the strategy to the attention of a wide audience. Klibanov’s early work showed that one enantiomer of a racemic carboxylic acid such as 2-bromopropanoic acid was esterified with high selectivity using a lipase to catalyze the reaction between the acid and an appropriate alcohol in an inert solvent (e.g.. hexane) containing only a trace of water. The optically active ester and optically active acid were readily separated.62 The possibilities offered by working with enzymes in near nonaqueous conditions include the esterification of other chiral acids, e.g., amino and alcohols (sugars).62 Transesterification studies using dimethyl 2-alkyls~ccinate,~~ a-amino acids,“ and various have been featured recently. In transesterification reactions, the use of an enol acylate such as (27) has been advocated since release of the enol is immediately

134

MeCO--O< I

Me

followed by a rearrangement of this moiety to give acetone, thus making the reverse reaction (viz., acylation of the enol) a very unlikely event.68 The formation of lactones using enzymes has been studied. Sih has recently investigated the synthesis of macrocyclic dilactones [e.g., (28)] by lipase-catalyzed condensation of long chain alkanedioic acids and a l k a n e d i ~ l sA . ~method ~ has been developed for the intramolecular lactonization of w-hydroxy esters to furnish lactones such as the &lactone (29) using ppl in ether; oligomerization of the hydroxester can be a problem.70 The enzyme-catalyzed synthesis of peptides has been the focus of attention of a number of groups. The protease from Streptomyces cellulosae has been shown to be effective in coupling glycine to Pro-Leu to give melanocyte stimulating hormone (30).7’The complex of chitin and a-chymotryp~in~~

MeYoYo

Pro-LeuGty-NH2

U

and polyethylene glycol-modified papain and thermolysin7’ have recently been recommended for use in peptide synthesis. The synthesis of aspartyl-containing dipeptides has assumed considerable importance following the commercial success of Aspartame. Both thermolysin and a-chymotrypsin can be used to couple Z-Asp and, e.g., Phe-OMe and Phe-NH,.74 The former catalyst has been employed in super-critical CO, as the nonaqueous solvent.75 Wong and Klibanov have pioneered the use of lipase (as opposed to proteases) for the synthesis of di- and tripeptides. The lipase catalysts could prove to be advantageous in that they have less of a tendency to promote the undesirable hydrolysis of the amide bond.76 The synthesis of naturally occurring triphosphates, e.g., cytidine 5’-triphosphate, using enzymes such as adenylate kinase has been mastered by the Whitesides’ group.77Research into the in situ regeneration of adenosine triphosphate (ATP) has led to establishment of efficient systems for this process78

Volume 10, Issue 2


Biotechnology and, in turn, the ATP so produced has been used to prepare compounds such as glucose-6-phosphate (31) (Figure 3) using the enzyme hexokinase to control the regioselectivity of the pho~phorylation.’~ Simple monophosphates (32) have been prepared as chiral intermediates using ATP as the phosphate donor and glycerol kinase as the catalyst. The ATP was regenerated in situ using phosphoenolpyruvate (PEP) and pyruvate kinase (Figure 4). 8o Note that racemic glycerol analogs are often phosphorylated in an enantioselective fashion.

HO HO A

H

O

E. Reduction of Carbonyl Compounds The production of optically active secondary alcohols from unsymmetrical ketones has been the subject of investigation of numerous laboratories. The dehydrogenase enzymes generally used for this purpose utilize the reduced form of nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] as the cofactor in the reduction process (Figure 5 ) . In such a process, the NAD(P)H must be effectively regenerated since it is impractical to use stoicheiometric amounts of the cofactor in the reduction process. There are two approaches. First, a whole cell

hexokinase

n-

”

HO & H

OH

HO

ATP

ADP

acetate

(31)

acetyl phosphate

glycerol kinase z

R’ = CI.SH,0Me,CH20H,Br,C2H~

pyrivate

R’COR~

dehydrogenase c

R’-* HO

NAD(P)H

PEP

R2

JiUKGi

H

NAD(P)+

+ H+

1990

135


Critical Reviews In system (usually a fungus or bacterium) can be used; in this case, the regeneration of the cofactor is controlled by complementary metabolic processes in the cell. Second, isolated partially purified dehydrogenase enzymes can be employed and artificial cofactor regeneration systems set up. Such regeneration systems are well documented in the literature. The advantages and disadvantages of using whole cell systems or commercially available enzymes for reduction reactions has been discussed elsewhere.' Suffice is to say that both strategies are currently employed. The reduction of ketones with yeasts was described in the pioneering work of Prelog. Using yeast cells, the reduction of ketones having large (L) and small (S) groups around the carbony1 group takes place as shown in Figure 6.8' Yeast is still usefully employed in the reduction of ketones. For instance, bakers' yeast reduction of the compounds (33), (34) gave the corresponding secondary alcohols (50 to 70% yield), with the majority of the product having the expected (S)-stereochemistry at the reduction site (>95% e.e.).8zSimilarly, using fermenting bakers' yeast, the ketone (35) was converted into the corresponding (S)-alcohol (76% yield, 90% e.e.).*3The reduction

0

cohols. The ketone (37) was reduced by Curvularia lunata to give the alcohols (38) and (39) in the ratio 7.5:1.86 Racemic ketones are often reduced in enantioselective fashion to give optically active alcohol and optically active recovered ketone. Reduction of the racemic ketone (40) is a case in point in that

Me

(37)

B

0

0 (36)n = 0,2

of cyclic ketones with yeast has also been the subject of SCNtiny: the configuration at the newly formed secondary alcohol is usually (S).84 Other microorganisms can be employed to reduce simple ketones; for instance, Corynebacterium equi transforms the ketones (36) into the (S)-alcohols (95%e.e.).85 Ketones containing a preexisting chiral center or centers can be reduced to give optically active diastereoisomeric al-

0

U

136

HO

reduction with Thermoanaerobium brockii alcohol dehydrogenase gives the 1(S), 5(R), 6(S)-bicycloheptenol (41) and recovered ketone. Isopropanol was used to recycle NAD(P)H.*' Various enantiomerically pure hydroxydecalones have been prepared by horse liver alcohol dehydrogenase (HLAD) catalyzed reductions of decalindiones. All the reductions took place to give the (S)-alcohol in enantiomeric excess >98% as expected from the cubic-space model for HLAD reductions proposed by Jones and Jakavoc.88Ethanol was used as the coupled substrate for recycling NADH. P-Diketones and P-keto-esters have been reduced by whole cell systems and isolated enzymes. From the former category, the dione (42) was reduced with baker's yeast to give, mainly, the 2(R),3(S)-hydroxyketone (43) (99% e.e.) while another organism, Pichia terricola, gave almost exclusively the enantiomerically pure 2(S),3(S)-diastereomer (44).The latter compound was used to prepare the naturally occurring

0

yeast

Me

CHMe2

0

(35)

Me

c

U

Volume 10, Issue 2

Biotechnology ester (51). Reduction of (51) using dried bakers’ yeast gave the 3-hydroxyproline derivative (52) (e.e. 80%) which was used in an enantioselective synthesis of ( - ) retr~necine.’~ The reduction of P-ketoesters (53) with immobilized cells of


0

0

n0

0

BOC

Me

Me

0

enantiomers of juvenile hormones I and ILa9 The acyclic dione (45) is transformed by bakers’ yeast into the (S)-ketol (46) en route to an interesting bicyclic compound.w A careful examination of the bioreduction of the ketone (47) using Geotrichium cundidum cells led to fermentation conditions from which optically pure sitophilure (48) (a pheromone) was i~olated.~’

I

Me

Boc

I

Me

Succharomyces spp. and other organisms gave various amounts of the 2(S),3(S)- and the 2(R),3(S)-3-hydroxy-2-methylesters showing fair to good enantiomeric excess.96Reduction of the P-ketoester (54) with Hunsonulu unomala gave the ester (55) in a 90% yield and 92% diastereoisomeric excess.97

H

OMe

(49)

OMe

The work involving the study of P-ketoesters possessing substituents in the (2)- and (4)-positions is exemplified by studies on the reduction of alkyl 2-methyl-4-benzyloxybutanoates using various microorganism^.^^ In an interesting paper by Christen and CroWWthe iterative reduction of P-ketoesters was investigated. The ester (56) was reduced by Succharomyces cerevisiue to give the (R)-hydroxyester which was then homologated by chemical methods to give the hydroxyketoester (57). Bioreduction of the latter

Methods for the production of 3(S)-9’ and 3(R)-hydroxybutanoate esters93have been reported. The reductions of pketobutanoatespossessing various substituents in the 4-position have been studied and for yeast reductions the “rule of thumb” is that esters of type (49) are reduced to give the 3(R)-hydroxyesters while ketoesters of type (50) are reduced to give the 3(S)-hydroxye~ters.~~ The studies in this area of research have progressed so as to encompass compounds such as the

1990

137

Critical Reviews In

u

Uo Critical Reviews in Biotechnology Downloaded from informahealthcare.com by University of California Irvine on 11/07/14 For personal use only.

(611

OMe (57)

compound gave the diastereoisomeric diols (58) and (59). In

OH

(62)

synthesis of homochiral 2-hydroxyacids has been investigated in some depth. The enzyme, obtained from rabbit muscle, can be immobilized on polyacrylamide gel and for a range of aketoacids of type (63) [R = alkyl] furnished the (S)-hydroxy acid. Io3 Both (R)- and (S)-selective lactate dehydrogenases are available.

0 R

C02H

-

(58) R' = H; R2 OH (59) R' = OH; R2 = H

R

(64)

CO2Et

complementary fashion reduction of the ketoester (56) with Candida guilliermondii gave the (S)-hydroxyester ent - (57) which was subsequently converted into ent- (58) and ent(59). While historically P-ketoesters have been studied more extensively than a-ketoesters, the usefulness of optically active a-hydroxyesters in synthesis has prompted a good deal of recent work in the preparation of these materials by biological methods. For example, esters of type (60) [R = alkyl] have been reduced by bakers' yeast to give the (S)-a-hydroxyester as the major enantiomeP and by glycerol dehydrogenasefrom Geotricum candidum to afford the (R)-a-hydroxyester in high optical purity. lo' The more highly substituted a-ketoester (61) gave the hydroxyester (62) (93% e.e.) on reduction using Torufopsis sp.lo2 The use of t-lactate dehydrogenase for the

138

C02H

Ph

0

Ph'

0 (65)

The reduction of y- and 6-ketoacids with bakers' yeast is also being explored. Reduction of the y-ketoacid (64)with bakers' yeast gave the lactone (65),'04while the 6-ketoacid (66) provided the (R)-hydroxyacidin 32% yield and 95%e.e.Io5 Immobilized bakers' yeast converted 9-oxodecanoic acid into 9(S)-hydroxydecanoic acid in 12 to 43% yield (96% e.e.)*06

F. Reduction of Alkenes The most common bioreduction of an alkene unit involves the saturation of the carbon-carbon double bond of qp-unsaturated aldehydes, ketones, esters, or lactones. The possibilities offered by this bioreduction process have been known

Volume 10, Issue 2

Biotechnology for some time; the large-scale reduction of the unsaturated dione (67) using bakers’ yeast to give the ketone (68) is a classic example. lo’

tained in good yield but the substrate is toxic to the organism at concentrations (>0.6%).”* Et

Ph.


H

C02H

‘i.. .“

Ph

0

Ls

H

Me

2

H.

Ph

.

(“ C02H

H

H

G. Oxidation of Alcohols

(69)

Recent results have demonstrated that the same organism reduces a,P-unsaturated aldehydes such as (69) to give the 2(S)-methyl compound. Io8 Allylic alcohols can also be reduced through the intermediacy of the corresponding aldehydes or ketones to give useful optically active synthons. For example, bakers’ yeast reduction of the alcohol (70) gave the reduced compound (71) in 22% yield and 68% e.e.’08 The organism Beauveria sulfurescens has been recommended for the reduction of substituted cyclohex-2-enones. The use of enoate reductases from Clostridia sp. for the reduction of alkene units has been investigated. The reduction of chiral allenes is a particularly elegant transformation performed by these enzymes. The enantiomers (72) and (73) gave the P,y-unsaturated acids (74) and (75) in quantitative yield,It0 respectively. A preliminary study of the reduction of a-allenyl alcohols by bakers’ yeast has been reported . I t 1 A recent paper has described the reduction of various nitropropenes by R. rhodochrous. The reduced products are ob-

1990

The oxidation of alcohols to carbonyl compounds by enzymatic methods is not as popular as the reverse process described in subsection E. There are several reasons for this situation. First, the oxidation process converts an sp’ hybridized carbon center into an sp2 center, often losing a useful stereochemical feature at the position of oxidation. Second, the methods for using isolated enzymes in the process are limited by the absence of a “user friendly” method for recycling the cofactors that often need to be added in oxidation processes of this type. For example, the use of HLAD requires the use of NAD+ as cofactor. In early work, Jones and Taylortt3 used flavin mononucleotide (FMN) to oxidize NADH back to the required cofactor, but the amount of FMN required for this process was rather large, making work-up of the reaction and purification of the product somewhat difficult. Gunther and Simon have invented an electrochemical method for regeneration of NAD(P)+,’l4 but the method has not been taken up in nonspecialist laboratories. Undoubtedly, a “user-friendly” recycling system is required for the ubiquitous cofactor NAD(P) before such oxidative biotransformations become widely employed.It5 The very attractive feature of many biocatalyzed oxidation processes is that prochiral substrates can be converted in high yield into chiral intermediates of excellent optical purity. For example, the diol (76) is transformed into the lactol (77) and then into the lactone (78) using HLAD and NAD+.’l6 The lactone (78) was converted into grandisol, a pheromone of the boll weevil. +

139

Critical Reviews In H

CH20H

CH20H

I

I

HErf.

H

H


H

OH

0

OH

CH20H

CH20H

H

H

The oxidation of xylitol (79) into L-xylose (80) using the enzyme (D)-galactose oxidase is another typical example of this elegant strategy. 117

H; R2 OH (85) R' L OH; R2 = H (84) R'

L

I

The oxidation of the diastereoisomeric diols (84) and (85) using Corynebacterium equi gave (R)- and (S)-hydroxypropiophenone, respectively, in ca. 30% yield and in high optical purity.'20

H. Oxidation of Alkenes The production of chiral epoxides of predictable stereochemistry and high optical purity from alkenes using a simple organism or an easily used enzyme could be a major step forward in the field concerned with the production of chiral intermediates. The literature does contain evidence that alkenes can be converted into optically active epoxides. For example, cis-propenyl-phosphonatecan be oxidized by Penicillium spinulosum to give fosfomycin (86) enantiospecifically in 90% yield. 12'

Me

@OH

In view of the difficulties that can be faced in conducting oxidations catalyzed by partially purified enzymes, it is not surprising to find that recourse is made to the use of whole cell systems. For example, the enantioselectivity in the oxidation of alcohols such as carvomenthol (8 1) using Nicotiana tahacum has been studied. ' I 8 Immobilized cells of Gluconobacter uxydans have been used in the regioselective oxidation of 2-deoxy-(~)-arabinohexitol(82) to 5-deoxy-(~)-threo-hexdose (83), a potential artificial sweetener.IL9 140

The most intensively studied microbiological epoxidizing agents are the Pseudomonas organisms. It has been demonstrated that Pseudomonas oleovarans epoxidizes terminal acyclic olefins to produce (R)-1,2-epoxides together with alken- 1-01s. The amount of methyl group hydroxylation is minimal with long chain alkenes such as dec-l-ene as substrate.122I ,7-0ctadiene is converted into (R)-7,8-epoxyoct-l-ene (>80% e.e.) and then into the 1,2-7,8-diepoxide using this organism."'

Volume 10, issue 2

Biotechnology


The biological epoxidation reaction is simple to perf01~1-1~~~ compound (87) gave a 4:6 ratio of compounds (88) and (89).130 and can be conducted on a multigram scale125but, as yet, it is Oxidation of the racemic ketol (90) gave the lactone (91) and only suitable for the production of very simple chirally enriched unchanged (R)-ketol (e.e. 97%), an interesting example of synthons. remote stereoselection. I 3 l The oxidation of cyclic ketones using

1. Other Oxidation Reactions One of the best known transformations under this category is the oxidation of sulfides into chiral sulfoxides. Early studies on the oxidation of unsymmetrical sulfides using A. niger and Mortierella isabellina showed that high enantiomeric excesses were possible, although the yield of sulfoxide often left much to be desired.’26The preparation of both enantiomers of ethyl p-tolyl sulfoxide using two different systems has been reported by Walsh et al. Purified monooxygenase from pig liver microsomes gave the (R)-sulfoxide (95% e.e.), while cyclohexanone oxygenase from Acinetobacter gave the (S)-enantiomer (82% e.e.).I2’ Oxidation of alkyl aryl sulfides and ally1 aryl sulfides by C. equi gave (R)-sulfoxides in high enantiomeric excess but in variable yield.’28Partially purified P. oleovoruns alkane monooxygenase has been shown to convert alkyl methyl sulfides into the (R)-sulfoxides(e.e. 50 to 90%in most cases).’29 The oxidation of a ketone to an ester (or cyclic ketone into a lactone) can be performed using a peracid. The same transformation can be accomplished using organisms and isolated enzymes; sometimes the ratio of products obtained from the biotransforrnation can be different from that observed using the chemical method. Thus, the monocyclic terpene fenchone (87) gave the lactones (88) and (89) in the ratio 9:l using a whole cell system; in contrast, peracetic acid oxidation of

OH (90)

OH (911

1 C02H

cyclohexanone oxygenase has been studied in detail. 132 At the present time, the opportunities offered by enzymes and whole cells to perform Baeyer-Villiger reactions, thus providing (at least potentially) useful chiral intermediates, has hardly been noticed by synthetic organic chemists. Recently, the use of a lipoxygenase to catalyze the oxygenation of unnatural substrates, such as the cyclopropyl compound (92), has been investigated. 133

6G Me

0

Me

J. Hydroxylation Reactions Involving Aliphatic Compounds The hydroxylation of “unactivated” centers in hydrocarbons is potentially one of the most useful of all biotransformations. This is because the process has few counterparts in traditional organic synthesis. The range of compounds subjected to microbiological hydroxylation is vast and general texts’34 and reviews’35have appeared. Many of the more detailed investigations have concentrated on the biohydroxylation of steroids,136~137 alkal o i d ~ , ’ ~t e~r*p ’e ~n e~~ , ’and ~ ~ hydrocarbons.I4O The major problems with using biocatalytic procedures for the ‘‘remote’’ hydroxylation of aliphatic and alicyclic compounds are as follows (1) the preferred site of hydroxylation is often difficult to predict; (2) the biohydroxylation is rarely

Me

Me

Me=

Me

Me (89)

1990

141


Critical Reviews In regioselective; and (3) the hydroxyl compound so formed can undergo further transformation if, as is often the case, whole cell systems are being utilized. The employment of whole cell systems for hydroxylation processes stems from the fact that only very few of the monooxygenase and dioxygenase enzymes exhibit good catalytic activity when extracted from the cell. The conversion of progresterone (93) into 1la-hydroxyprogesterone (94) by Rhizopus arrihius is a classic example of a microbiological hydroxylation of a steroid14' and is an example of the sort of oxidative biotransformation that has assumed commercial importance. Work on biotransformations

as well as into two aromatic compounds. L44 Desoxyforskolin has been hyclroxylated to give the interesting natural product forskolin (97) (albeit in low yield)I4' and 1,4-cineole (98) was

.\'\ OH OAc

Me

R

(98) R = H

(97)

(99)R = OH

0 (93)R = H (94) R = OH

q

0

3 OH

.@Ill 0

(100) R = H

(1 02)

(101) R =OH

(95) R = H (96) R = OH

of steroids still continues today; for example, the hydroxylation of progesterone using rat hepatic P-450 isozymes was shown to result in 2a-,6a-, 6p-, 7a-, 15a-, 16a-, and 21-hydroxy compounds. 142 Rat liver mitochondria have been used to hydroxylate 3P-hydroxy-5a-cholest-8( 14)-en-15-one in the 25position. 143 The microbiological hydroxylation of other natural products has been studied recently. A. niger converted (-)+ santonin (95) into the corresponding hydroxy compound (96)

142

I

OH

converted by Sfreptomyces griseus into the tertiary alcohol (99) in 18% yield.'& A similar regioselective hydroxylation of a remote carbon atom was noted in the conversion of cedrol (100) into the diol (101) (30%).147 The conversion of unnatural hydrocarbons into alcohols is of interest to a wide audience. The hydroxylation of 3-methylcyclohexene using methane monooxygenase gave the alcohol (102) as the major product.'48 On fermentation with Cunninghamella blakesleeana, the hydrocarbon cyclohexyl cyclohexane provides the 4,4'-diol in amounts useful for multistage synthetic work. 149 Finally, oxidation of indane using naphthalene dioxygenase from Pseudomonas putida gave 1-(R)-indanol (103) (92 to 100% e.e.).I5'

Volume 10. Issue 2

Biotechnology R

I

I


OH

0

R“ (106) R = H

(105) R =OH

(107) R = OH

(1 11) R = CF3

(1 10) R = H

(112) R = Me

derivatives using Pseudomonas sp. gives optically active materials (although the absolute configuration of the products has not always been determined). For instance, oxidation of trifluoromethylbenzene using P.purida has been reported to give the diol (111) by two groups.15’ The work of Hudlicky has demonstrated that the toluene derivative (1 12) is a useful compound for the production of chiral prostaglandinintermediates.158 The metabolism of quinoline, isoquinoline, quinazoline, and quinoxaline by a Pseudomonas mutant (once again lacking cis-glycol dehydrogenase) yielded optically active diols of the type (1 13), although the optical purity and the absolute configuration were not determined. 159 The work of Ribbons is also noteworthy. For example, in the Imperial College laboratories, 3,5-difluorobenzoicacid has been converted into thedienediol (1 14).160 In addition, p-bro-

R

(104)R=H

(109) R = Me

In the area concerning the formation of optically active alcohols from achiral or racemic substrates, the conversion of isobutyric acid into (S)-P-hydroxy-isobutyric acid using P. put id^'^' is noteworthy since the process is operated on a commercial scale in Japan. Oxidation of the cyclopentenone (104) with A. niger furnished the useful prostaglandin synthon (105) (67% yield).”* In a very interesting transformation, the norbornane (106) was hydroxylated with A. awamori to give the endo-alcohol (107) in 57% yield (85% e.e.).153

OH

I

K. Hydroxylatlon Reactions involving Aromatic Compounds Simple hydroxylation reactions involving aromatic compounds to produce phenols are well known.’54The production of cyclohexadienediolsfrom aromatic compoundshas also been known for some time but the whole area has been popularized by the work of Ley et al.’55 The production of chiral cyclohexanediol derivatives has been accomplished by extending this work in two ways. First the protected (achiral) cyclohexa3,5-diene-l,2-diol (108) has been reacted with dimethyl acetylene dicarboxylate to give the diester (109), and enantioselective hydrolysis has been carried out with ple to give the acid (1 Second, the oxidation of monosubstituted benzene +#\OH

1990

“‘OH

143

Critical Reviews In


mobenzoic acid furnished the 2(R),3(R)-cyclohexadiene carboxylic acid (1 15).Io1 Obviously, a mouthwatering array of chiral intermediates will be available to synthetic organic chemists by future extension of this work.

L. Other Biotransformations The formation of chiral intermediates by enzyme-catalyzed carbon-carbon bond formation is an area of real promise. The use of rabbit muscle aldolase to catalyze reactions between dihydroxyacetone monophosphate and various aldehydes is well known;162unfortunately, the enzyme is very selective for the former moiety and this restricts the range of materials that can be synthesized. Nevertheless, the related, independent works of Effenberger and Wong illustrate the power of the method. Dihydroxyacetone phosphate and ( 2 )-3-azido-2-hydroxypropanal were coupled using rabbit muscle aldolase or fructose1,6-diphosphate aldolase as catalyst to give the tetrahydrofuran derivatives (1 16) and (1 17) which were, in turn, converted into 1-deoxymannojirimycin(1 18) and 1-deoxynojirimycin(119)? OH

(116)R' =CH2N3;R2=H

(118) R'

(1 17) R' = H ; R2 = CHzN3

(119) R'

-

H°KH N H

0

0

reactions between hydroxypyruvate and various hydroxyaldehydes has been studied in connection with the preparation of selected ketoses. Acetolactate decarboxylase from Bacillus sp. has been shown to catalyze some remarkable conversions; for instance, the ketoacid (122) is converted into the hydroxyketone (123)? The formation of optically active cyanohydrins from aldehydes has received attention. The enzyme mandelonitrile lyase, immobilized on cellulose and used in ethyl acetate, gave good yields of materials possessing the (R)-configuration (124). Good optical yields were obtained for compounds

OH; R2 H

I

H ; R~ = OH I

OH

Me (125) R' = H or OMe = H or TBDMS /

In the Effenberger paper, the coupling of ( +)-3-azido-2hydroxypropanal and lithium hydroxypyruvate using transketolase was described. The product ( 1 20) was isolated and converted into 1,4-dideoxy-l,4-imino-(D)-arabinitol (121). The use of transketolase from S. cerevisiue or spinach to catalyze

144

Volume 10, Issue 2

OH


Biotechnology [(124) R = Ph, CH=CHMe, CH,CH,CH,Me (e.e. >96%)].166 The facile obtention of other chiral synthons from the cyanohydrins has been demonstrated; thus, chiral acyloins (125) (e.e. 92 to 99%) were obtained in three steps from the corresponding (R)-cyanohydrin.'67 The use of enzymes for the synthesis of sugar derivatives is becoming popular. Monoacyl galactoglycerides such as 1O-~-(~)-galactopyranosyl-2,3-epoxypropanol(l26) have been prepared by the action of p-galactosidase on lactose or unitrophenyl galactopyranoside in the presence of 2,3-epoxywere propanol. (~)-Acyl-3-O-~-(~)-galactopyranosylglyce~des prepared by opening the epoxide ring with a fatty acid.L68 Glycosidase-catalyzed formation of disaccharides is generally undertaken using the u- or p-nitrophenyl monosaccharide derivative as the glycosyl donor and either the a- or the pglycoside as the acceptor. The regioselectivity of disaccharide formation was found to depend on the nature of the aglycon of the glycosyl acceptor and its stereochemistry; a preponderance of one particular isomer could be obtained.169 A method for preparing fructosyl disaccharides has been described that utilizes a fructosyl transferase isolated from Bacillus subtilis. 170 A timely review of enzymatic syntheses of oligosaccharides has been published.17' The enzyme chloroperoxidase from Calderiomycesfumago has received attention in terms of its potential in organic synthesis. The chlorination of 1,3-dihydroxybenzene, uracil, pyrazole, and 2-aminopyridine using this enzyme has been described recently. 172 The use of fungal haloperoxidase enzymes for the synthesis of chiral compounds is illustrated by the conversion of ally1 alcohol into 2,3-dichloropropan-1-01,173 S. cerevisiae has been used to convert thia- and dithia analogs of stearic acid into the corresponding A9(Z)-compounds [e.g., (127)'74].

0

Two methods for the formation of amino acids have received further attention. First, p-methylaspartase has been used to convert 2-methylfumaric acid into 2(S) ,3(S)-3-methylaspartic acid (128).175Other 2-substituted fumaric acids (e.g., 2chlorofumaric acid) behave similarly.176 Second, the conversion of a-ketoisocaproate into @)-leucine (99% e.e.) can be accomplished using Corynebacterium glutamicum and (L)-glu~ aspartate transaminase has been tamate (91% ~ i e l d ) , "while shown to convert a wide range of a-keto acids into the (L)amino acids using aspartate or glutamate as the amine group donor.'78 Note that a-amino acids can also be prepared from a-hydroxy acids using an elegant coupled enzyme system; cofactor recycling is accommodated nicely within the scheme (Figure 7). 179 Many other enzyme-controlled transformations are being used to prepare unnatural compounds by allowing the enzyme to modify a foreign substrate. One such series of endeavors involves the conversion of tripeptides into new penicillins using isopenicillin-N-synthetase:the 3-methoxy penicillin (129) is just one of the many new products obtained from this intriguing work.

Me2CHCH2CH(OH)C02H_

\

&) - and 1p)- hydroxyacid dehydrogenase

- leucine dehydrogenase

1990

145

Critical Reviews In 0

CHsCH(0Ac)

I

I

(CH2)n


I

111. CONCLUSIONS AND FUTURE DEVELOPMENTS The past 5 years have witnessed an exponential increase in the use of enzymes and whole cell systems for the production of chiral intermediates.18' This trend will continue, at least for the next few years. About 45% of the papers concerned with biotransformations and published in the primary journals in 1987 to 1988 relate to the use of lipases and esterases in enantioselective hydrolysis and esterification reactions. A similar number of papers describe reduction reactions involving dehydrogenase enzymes. In the latter area, isolated enzymes and whole cell systems are equally popular, while in the hydrolysis/ esterificationwork isolated enzymes are used almost invariably. The availability and ease of use of esterase and lipase enzymes means it is likely that many more examples involving their employment will be published in due course. The use of hydrolases for the production of chiral organometallic substances is in its infancy; the production of the acid (130) from the racemic ethyl ester using ple is one of the rare examples.182 The selective hydrolysis of prochrial diesters will remain popular. Thus, the preparation of the acid (131) from the diester using ple provided a building block for HMG-CoA reductase inhibitors.Ix3 The latter compounds are important as cholesterol-lowering agents and are being used in the clinic, and it is exciting to see a hydrolase enzyme being put to use to provide a modem chiral synthon for the pharmaceutical industry. It is also interesting to note that in those cases where chiral synthons can be made by enantioselective hydrolysis or stereocontrolled reduction processes, the hydrolysis pathway is preferred, particularly for large scale work.32For example, diesters of type

AT

(132) are deacetylated very selectively by lipases giving access to optically active rert-butyl hydroxyalkanoates which could also be obtained, in the alternative process, by reduction of the corresponding ketoesters. IB4 However, enzyme-catalyzed reduction processes are still proving to be very useful in organic synthesis. The reduction of methyl 3-oxohex-5-enoate using yeast gave the 3(R)-hydroxyester (133) which was used to prepare 6(R)-goniothalamin ( 134).Is5In this area, like the lipaselesterase area, the potential of using enzymes for the production of selected organometallic substances is becoming appreciated. The synthesis of the hydroxyaldehyde ( 1 35) from the dialdehyde,la6 and the preparation of the chiral chromium complex (136)lS7(66% e.e.) illustrate this trend.

(133)

QCHO

XO" I

H02C

146

In these areas of enzyme-catalyzed biotransformations that form the bulk of the current work (viz. hydrolysis/esterification and reduction processes), the use of immobilized systems is increasingly important. Both enzymes and whole cells can be immobilized. The lipase from Mucor miehei has been immobilized on ion-exchange resin for employment as a catalyst

Volume 10, Issue 2


Biotechnology for the esterification of various alcohols.’89Whole cells are less easy to immobilize satisfactorily, but the importance of being able to support large volumes of cells in such a state as to allow for the construction of continuous flow systems for selected biotransfonnations will ensure continued focus of attention on this area. The use of enzymes for the modification and construction of sugars will continue to be a very important topic in the future. Recent work has shown diastereoselective transfer of @)-galactose from phenyl P-galactopyranoside or p-(D)-lactose to mesodiols (such as cis- 1,2-~yclohexanediol)using pgalactoside from E. coli or A. oryzae.Iw Such a selective reaction would be difficult to emulate using conventional chemical catalysts and it is in fields of this sort that enzyme-controlled reactions score heavily. Similarly trans-P-deoxyribosylase from Lactobacillus helveticus has been used to transfer the ribose moieties from 2’ ,3 ’-dideoxynucleosides to a diverse range of purine and pyrimidine base acceptors. The new dideoxynucleosides were screened for anti-HIV activity.’” The use of enzymes as a “front-line’’ synthetic method is obviously increasing and this trend will continue. Probably no area of biotransformations is more ripe for development than the use of aldolases. The employment of aldolase to construct polyhydroxyketones with high defined stereochemical patterns is known’92and the use of enzymes such as N-acetyl neuraminic acid aldolase to convert the substrate (137) and pyruvic acid into the desired product (138) has been reported.’93A tremendous increase in the volume of work in this area can be expected. AC

1

also connected by the studies concerned with abzymes. Following the work by Lerner on the antibody-catalyzed enantioselective lactonization of &hydroxyesters, two groups in the U.S. have raised antibodies that catalyze an important Claisen reaction. 195 Hilvert and Nared, and independently Bartlett,I% raised antibodies to the diacid (139), a mimic of the transition state of the chorismate to prephenate transformation (Figure 8). The antibody/enzyme accelerated the [3,3]-rearrangment by a factor S1 x lo4 at 10°C, pH 7. This intriguing result will stimulate a lot more activity in this area. However, it must be remembered that a good transition state mimic must be made available before this strategy has a chance of success.

OH

One can anticipate rapid progress being made in many areas involving the synthesis of man-made chiral catalysts. The field concerned with the asymmetric hydrogenation using transition metal catalysts is at a particularly exciting phase. The Noyori catalyst [(S)-BINAP] Ru(I1) [CF,CO; J2 is recommended for the asymmetric hydrogenation of allylic alcohols,l’’ while the reduction of a,@-unsaturated acids (140) into the saturated counterparts (141) can be accomplished using a chiral rhodium catalyst. 19* Equally interesting is a cobalt (I) epoxidation system which is purported to act as an enzyme mimic.Iw

R H >CH2R’ (137)

The increase in the number of uses of enzymes for the production of optically active synthons will be matched by increased activity in the preparation of man-made chiral catalysts. Some of these man-made catalysts will evolve from enzyme-related work. For example, manipulations at the active site of an enzyme can open up methods of preparation of novel proteins; for example, the catalytic properties of a lactate dehydrogenase have been altered by site-directed mutagenesis. Highly reactive “semisynthetic” enzymes are formed by inccrporation of coenzyme analogs into the active site. The two areas of work (enzymes and man-made chiral catalysts) are

It has been suggested already that the controlled oxidation of organic molecules at points remote from preexisting functionality is a considerable challenge for the future. Control of the regioselectivity of hydroxylation of hydrocarbons using monooxygenases is not well understood as yet. Neither are chemical methods available for widespread use, although the “biomimetic” electrochemical system for the oxidation of hydrocarbons by dioxygen, catalyzed by manganese-porphyrins and imidazole, is noteworthy.200The Gif system (iron-based catalyst, oxygen, zinc, carboxylic acid) and the electrochemical

1990

147


Critical Reviews In chemicals, although it will not eliminate the necessity to resolve racemates on some nor will it eliminate the need for new asymmetric reagents203or chiral templates.2" It is probably fair to say that up to now many of the studies using enzymes have been involved in investigating processes that have a preexisting, workable chemical route. As confidence in the use of enzymes increases, using new biotransformations to create new chiral intermediates for the production of new, useful fine chemicals should become the norm. Finally, coupling two or more enzyme processes will be increasingly in evidence following the quite brilliant pioneering work of Whitesides in setting up complex multienzyme systems for the synthesis of high-value compounds. The strategy has been used by Frost et al. to provide 3-deoxy-(~)-arabinoheptulosonic acid (143) from (D)-fructose (142) (Figure 9),205and more examples of this elegant methodology in the area of carbohydrate synthesis can be anticipated.

equivalent system (the Gif-Orsay system) involving the oxidation of hydrocarbons such as trans-decalin and cyclohexane is a significant signpost for future work.2o1 The use of enzymes in synthetic organic chemistry will increase, as will the use of other novel catalysts. The range of synthetic methods available to the practicing organic chemist is constantly increasing and it would be imprudent to suggest that enzymes will always provide the best method for the preparation of chiral intermediates. At best, perhaps 10 to 20% of new chiral intermediates will be made in vitro by enzymic methods by the end of this millenium. The enzyme method will be particularly useful when there is no clear chemical alternative. Nevertheless, the range of enzymes that are available, and those that will become available shortly, will add to the synthetic methods at the disposal of the organic chemist. The enzymic methods will complement conventional chemical methods in producing an array of fine chemicals and some bulk

0

-

OH

L

OH

OH

0 II

pyruvate ahasr

HK

HK mhexokinase; PK = pyruvate kinase; TK

transketalase; DS = DAHP synthetase;

I

PEP = phosphoenol pyruvate

148

Volume 10, Issue 2

OH

1

OH

Biotechnology Helv. Chim. Acta, 70, 1250, 1987. 22. Sabbioni, G. and Jones, J. B., J. Org. Chem., 52, 4565, 1987. 23. Ohno, M., in Enzymes in Organic Synthesis. Ciba Foundation Symposium No. 111, Clark, S . and Porter, R., Fils., Pitman, London, 1985, 171. 24. Zemlicka, J. and Craine, L. E., J. Org. Chem., 53, 937, 1988; for ple catalyzed hydrolysis of heterocyclic 1,3-diesters see Morimoto, Y., Terao, Y., and Achiwa, K., Chem. Pharm. Bull. (Tokyo), 35, 2266, 1987. 25. Kasel, W., Hultin, P. G., and Jones, J. B., J . Chem. Soc., Chem. Commun., 1563, 1985; see also Lipases, Borgstrom, B. and Brockman, H. L., Elsevier, Amsterdam, 1984. 26. Deardorff, D. R., Matthews, A. J., McMeekm, D. S., and Craney, C. L., Tetrahedron Lett., 27, 1255, 1986. 27. Schneider, M. and Laumen, K., Tetrahedron Lett., 25, 5875, 1984. see also Sugai, T. and Mori, K., Synthesis, 19, 1988. 28. Baxter, A. D. and Roberts, S . M., Chem. fnd., 510, 1986. 29. Chan, C., Cox, P. B., and Roberts, S. M., J. Chem. Soc., Chem. Commun., 971, 1988. 30. Gliinzer, B. I., Faber, K.,and Griengl, H., Tetrahedron, 43, 5791, 1987. 31. Newton, R. F. and Roberts, S. M., Tetrahedron. 36, 2163, 1980. 32. Cotterill, I. C., Macfarlane, E. L. A., and Roberts, S. M., J. Chem. Soc., Perkin Trans. I . , 3387, 1988; Cotterill, I. C., Finch, H.,Reynolds, D. P., Roberts, S. M., Rzepa, H., Short, K. M., Slawin, A. M. Z., Wallis, C. J., and Williams, D. J., J. Chem. Soc., Chem. Commun., 470, 1988; see also Beres, J., Shgi, G., Thomoskozi, I., Gruber, L., Gulhcsi, E., and Otvos, L., Tetrahedron Lett., 29,268 1, 1988. 33. Faber, K., Honig, H.,and Seufer-Wasserthal,P., Tetrahedron Len., 29, 1903, 1988; Francalanci, F., Cesti, P., Cabri, W., Bianchi, D., Martinego, T., and Foa, M., J. Org. Chem., 52, 5079, 1987. 34. Bianchi, D., Cabri, W., Cesti, P., Francalanci, F., and Rama, F., Tetrahedron Lett., 29, 2455, 1988. 35. Eberle, M., Egli, M., and Seebach, D., Helv. Chim. Acta, 71, 1, 1988. 36. Lauman, K. and Schneider, M. P., J. Chem. Soc., Chem. Commun., 598, 1988; Whitesell, J. and Lawrence, R. M., Chimia, 40, 318, 1986; see also Hoshino, O., Itoh, K., Umezawa, B., Akita, H., and Oishi, T., Tetrahedron Lett., 29, 567, 1988. 37. Toone, E. J. and Jones, J. B., Can. J . Chem., 65, 2722, 1987. 38. Saf, R., Faber, K., Penn, G., and Griengl, H., Tetrahedron, 44, 389, 1988. 39. Naemura, K., Matsumura, T., Komatsu, M., Hirose, Y., and Chikamatsu, H., J . Chem. Soc., Chem. Commun., 239, 1988. 40.Fujii, H.,Koyama, T., and Ogura, K., Eiochim. Eiophys. Acta, 712, 716, 1982. 41. Borthwick, A. D., Butt, S., Biggadike, K., Exall, A. M., Roberts, S. M., Youds, P. M., Kirk, B. E., Booth, B. R., Cameron, J. M., Cox, S. W.,Marr, C. L. P., and Shill, M. D., J. Chem. Soc., Chem. Commun., 656, 1988. 42. Keller, J. W. and Hamilton, B. J., Tetrahedron Lett., 27, 1249, 1986. 43. Wandrey, C., in Enzymes as Catalysts in Organic Synthesis, Schneider, M., Ed., D. Reidel, Dordrecht, Holland, 1986, 263; for the resolution of a-alkylamino acid amides see Kruizinga, W. H.,Bolster, J., Kellogg, R. M., Kamphuis, J., Baesten, W. H. J., Meuer, E. M., and Schaemaker, H. E., J. Org. Chem., 53, 1826, 1988. 44. Nishida, Y., Ohrui, H., and Meguro., H.,Agric. Eiol. Chem., 47, 2123, 1983. 45. Mori, K. and Iwasawa, H., Tetrahedron, 36, 2209, 1980. 46. Lagerlof, E., Nathorst-Westfelt, L., Ekstrom, B., and Sjoberg, B., Methods Enzymol., 44, 759, 1976; see also Park, J. M., Choi, C. Y., Seong, B. L., and Han, M. H., Biotechnol. Eioeng., 24,


REFERENCES 1. Hanessian, S., Total Synthesis of Natural Products: The ‘Chiron’ Approach, Pergamon Press, Elmsford, NY, 1983. 2. Evans, D. A., Top. Stereochem., 13, 1, 1982; Evans, D. A. and Weber, A. E., J. Am. Chem. Soc., 109, 7151, 1987; Evans, D. A. and Britton, T. C., J. Am. Chem. Soc., 109, 6881, 1987. 3. Meyers, A. I., Ace. Chem. Res., 11, 375, 1978. 4. Carlier, P. R., Mungall, W. S., Schroder, G., and Sharpless, K. B., J . Am. Chem. SOC., 110, 2978, 1988; Pfenninger, A., Synthesis, 89, 1986; Finn, M. G. and Sharpless, K. B., Asymmetric Synthesis, Vol. 5 , Momson, J. D., Ed., Academic Press, New York, 1988, chap. 8. 5 . Noyori, R., Ohkuma, T., Kitamura, M., Takaya, H., Oayo, N., Kumobayashi, H., and Akutagawa, S., J. Am. Chern. Soc., 109, 5856, 1987; see also Pfau, M., Revial, T., Guingant, A., and d’Angelo, J., J. Am. Chem. Soc., 107, 273, 1985; Kitamura, M., Ohkuma, T., Inone, S., Sayo, N., Kumobayashi, H.,Akutagawa, S., Ohta, T., Takaya, H., and Noyori, R., J. Am. Chem. Soc., 110, 629, 1988. 6. Helder, R., Arends, R., Bolt, W., Hiemstra, H., and Wynberg, H., Tetrahedron Lett., 2181, 1977; for an example involving an intramolecular Michael reactionsee Trast, B. M., Shuey, C. D., Winno, F., and McElvain, S. S., J . Am. Chem. Soc., 101, 1284, 1979; for an example using crown ether complexes as catalysts see Cram, D. J. and Sogah, G. D. Y., J. Chem. Soc. Chem. Commun., 625, 1981. 7. Butt, S. and Roberts, S. M., Chem. E r . , p. 127, 1987. 8. Davies, H. G., Green, R. H.,Kelly, D. R., and Roberts, S. M., Biotransformations in Preparative Organic Chemistry: the Use of Isolated Enzymes and Whole Cell Systems in Synthesis, Academic Press, London, 1989. 9. Whitesides, G. M. and Wong, C.-H., Enzymes in Organic Synthesis, Pergamon Press, Oxford, 1990. 10. Butt, S. and Roberts, S. M., Natural Prod. Rep., 489, 1986; Jones, J. B., Tetrahedron, 42, 3351, 1986; Whitesides, G. M. and Wong, C.-H., Angew. Chem. Int. Ed. Engl., 24, 617, 1985. 11. Jones, J. B., Si,C. J., and Perlman, D., Tech. Chem., 10, 107, 1976; Dirlam, N. C., Moore, B. S., and Urban, F. J., J. Org. Chem., 52, 3587, 1987. 12. Schregenberger, C. and Seebach, D., Liebigs Ann. Chem., 2081, 1986. 13. Cohen, S. G., Trans N.Y. Acad. Sci., 31, 705, 1969. 14. Santaniello, E., Chiari, M., Ferraboschi, P., and Trave, S., J. Org. Chem., 53, 1567, 1988; Roy, R. and Rey, A. E., Tetrahedron Len., 28, 4935, 1987. 15. Adachi, K., Kohayashi, S., and Ohno, M., Chimia, 40, 311, 1986. 16. Yamashita, H., Mmami, N., Sakakibara, K., Kobayashi, S., and Ohno, M., Chem. Pharm. Bull. (Tokyo), 36, 469, 1988. 17. Poppe, L., NovBk, L., Kolonits, P., Bata, A., and Szhtay, C., Tetrahedron, 44, 1477, 1988. 18. NPkada, M., Kobayashi, S., Ohno, M., Iwasaki, S., and Okuda, S., Tetrahedron Lett., 29, 3951, 1988. 19. Mehr, P., Waespe-Sar?evi&,N., Tamm, C., Gawronska, K., and Gawronski, J. K., Heh. Chem. Acta, 66, 2501, 1983; Klunder, A. J. H., van Gastel, F. J. C., and Zwanenberg, B., Tetrahedron Lett., 29, 2697, 1988; Ohno, M., Kobayashi, S., and Adachi, K., in Enzymes as Catalysts in Organic Synthesis, Schneider, M. P., Ed., D. Reidel, Dordrecht, Holland, 1986, 122. 20. Lam, L., Brown, C., De Jew, B., Lym, L., Toone, E., and Jones, J. B., J . Am. Chem. Soc., 110, 4409, 1988. 21. Morimoto, Y. and Achiwa, K., Chem. Pharm. Bull (Tokyo), 35, 3845, 1987; Luyten, M., Miiller, S., Herzog, B., and Keese, R.,

1990

149


Critical Reviews In 1623, 1982. 47. Fuganti, C., Grasselli, P., Servi, S., Lazzarini, A., and Casati, P., Tefrahedron, 44, 2575. 1988; see also Baldaro, E., Faiardi, D., Fuganti, C., Grasselli, P., and Lazzarini, A., Tetrahedron, 44, 4623, 1988; Waldmann, H., Tetrahedron Lett., 29, 1131, 1988; and Baggaley, K. H., Nicholson, N. H.,and S h e , J. T., J. Chem. Soc., Chem. Commun , 567, 1988, for the resolution of proclavamic acid using immobilised E. coli acylase. 48. Norln, G., Chem. Scr., 27, 557, 1987. 49. Oesch, F., Zenobiotica. 3, 305, 1972; Oesch, F., Biochem. J., 139, 11,1974. 50. Hanzlik, R. P., Edelman, M., Michaely, W. J., and Scott, G., J. Am. Chem. Soc.. 98, 1952, 1976. 51. Posternak, T., Reymond, D., and Friedli, H., Helv. Chim. A m , 38, 205, 1955. 52. Bellucci, G., Berti, G., Ferretti, M., Mastrorilli, E., and Silvestri, L., J. Org. Chem., 50, 1471, 1985; see also Bellucci, G., Ferretti, M., Lippi, A., and Marioni, F., J. Chem. Soc. Perkin Trans. I . , 2715, 1988. 53. Barili, P., Berti, G., Catelani, G . , Colonna, F., and Mastrorilli, E., J . Chem. Soc., Chem. Commun., 7, 1986; J . Org. Chern.. 52, 2886, 1987. 54. Meijer, J. and Depierre, J. W., Chem. Biol. Interact., 64, 207, 1988. 55. Ohno, M., Ferment. Ind., 37, 836, 1979; Toray Industries Ltd., G. B. Patent 1,445,326, 1975. 56. Jacohsen, E. N., Marko, I., Mungall, W. S., Schriider, G., and Sharpless, K. B., J. Am. Chem. Soc., 110, 1968, 1988. 57. Thompson, L. A., Knowles, C. J., Linton, E. A,, and Wyatt, J. M., Chem. Britain, 24, 900, 1988. 58. Godfredsen, S. E., in World Biotech Report 1988, Blenheim Online Ltd., London, 1988. 59. Vo-Quang, Y., Marais, D., Vo-Quang, L., Le GoMc, F., Thibry, A., Maestracci, M., Arnaud, A., and Galzy, P., Tetrahedron Lett., 28, 4057, 1987. 60.Bengis-Garber, C. and Gutman, A. L., Tetrahedron Len., 29,2589, 1988. 61. Wisdom, R. A., Dunnill, P.,and Lilly, M. D., Biotechnol. Bioeng., 29, 1081. 1987; see also Ibrahim, C. O., Nishio, N., and Nagi, S., At@. Biol. Chem., 51, 2153, 1987. 62. Kircher, G., Scollar, M. P., and mibanov, A. M., J. Am. Chem. Soc.. 107, 7072, 1985. 63. Mori, T., Nilsson, K., Larsson, P.-O., and Moshach, K., Biotechnol. Lett., 9, 455, 1987; Cantaculne, D. and Guerreiro, C., Tetrahedron Len., 28. 5153, 1987. 64. Riva, S., Chopineau, J., Kieboom, A. P. G., and Klihanov, A. M., J . Am. Chem. Soc., 110, 584, 1988. 65. GuiM-Jampel, E. and Rousseau, G., Tetrahedron Lett., 28, 3563, 1987. 66. Tester, E., Baboulene, M., Speziale, V., and Lattes, A., J. Chem. Tech. Biotechnol., 41, 69, 1988. 67. Njar, V. C. 0. and Caspi, E., Tetrahedron Len., 28, 6549, 1987. 68. Wang, Y.-F., Lalonde, J. J., Momongan, M., Bergbreiker, D. E., and Wong, C.-H., J. Am. Chem. Soc., 110, 7200, 1988; Wang, Y.-F. and Wong, C.-H., J . Org. Chem.. 53, 3127, 1988; Hennen,

W. J., Sweers, H. M., Wang, Y.-F., and Wong, C.-H., J. Org. Chem.. 53, 4939, 1988. 69. Zhi-Wei, G. and Sih, C. J., J. Am. Chem. Soc., 110, 1999, 1988. 70. Gutman, A. L., Oren, D., Boltanski, A., and Bravdo, T., Terrahedron Lett., 28, 5367, 1987. 71. Muro, T., Tominaga, Y., and Okada, S., Agric. Biol. Chem., 51, 1207, 1987. 72. Kise, H., Hayakawa, A., and Noritomi, H., Biotechnol. Lett., 9, 543. 1987.

150

73. Ferjancic, A., Puigserver, A., and Gaertner, H., Biotechnol. Lett., 10, 101, 1988; Lee, H.,Takahashi, K., Kadera, Y., Ohwada, K., Tsuzuki, T., Matsushima, A., and Inada, Y., Biorechnol. Lett., 10, 403, 1988. 74. Adisson, L., Bolte, J., Demuynck, C., and Mani, J.-C., Tetrahedron, 44, 2185, 1988. 75. Kamihira, M., Taniguchi, M., and Kobayashi, T . , Agric. Biol. Chem., 51, 3427, 1987. 76. Barhas, C. F. and Wong, C.-H., Tetrahedron Lett., 29,2907, 1988. 77. Simon, E. S., Bednarski, M. D., and Whitesides, G. M., Tetrahedron Lett., 29, 1123, 1988. 78. Crans, D. C. and Whitesides, G. M., J. Org. Chem., 48, 3130, 1983; Bolte, J. and Whitesides, G. M., Bioorg. Chem., 12, 170, 1984. 79. Pollak, A., Baughn, R. L., and Whitesides, G . M., J. Am. Chem. Sac., 99, 2366, 1977; see also Wong, C.-H. and Whitesldes, G. M., J. Am. Chem. Sor., 105, 5012, 1983. 80. Crans, D. C. and Whitesides, G. M., J. Am. Chem. Soc., 107,7008, 1985. 81. Prelog, V., PureAppl. Chem., 9, 119, 1964. 82. Guanti, G., Banfl, L., and Narisano, E . , Tetrahedron Len., 27, 3547, 1986. 83. Manzochi, A., Fiecchi, A., and Santaniello, E., Synthesis, 1007, 1987. 84. Wimmer, Z., Budeskinsky, M., Macek, T., Svatos, A., Saman,

D., Vasickova, S., and Romanuk, M., Coilect. Czech. Chen. Commun., 52, 2326, 1987. 85. Ohta, €Kato, I., Y., and Tsuchihashi, G., J. Org. Chem.. 52, 2735, 1987; see also Bernardi, R., Bravo, P., Cardillo, R., Ghiringhelli, D., and Resnati, G., J. Chem. Soc., Perkin Trans. I . , 2831, 1988. 86. Goswami, A,, Steffek, R. P., Liu, W. G., Rosazza, J. P. N., and Steffens, J. J., Enzyme Microb. Technol., 9, 521, 1987. 87. Drueckhammer, D. G., Sadozai, S. K., Wong, C.-H., and Roberts, S. M., Enzyme Microb. Technol., 6, 564, 1987; similar reductions can be accomplished using yeast, Kluge, A. F. and Kertesz, D. J., J. Org. Chem., 53, 4962, 1988. 88. Dodds, D. R. and Jones, J. B., J . Am. Chem. Soc.. 110,577, 1988; Jones, J. B. and Jakovac, I. J., Can. J. Chem., 60, 19. 1982; the stereochemistry of the product can be predicted using a diamond-lattice model of HLAD originally proposed by Prelog" see Lemierb, G. L., Van Osselaer, T. A., Lapoivre, J. A,, and Alderweireldt, F, C., J. Chem. Soc., Perkin Trans. II, 1123, 1982; see also Horjales, E. and Branden, C.-I., J. Biol. Chem., 260, 15445, 1985. 89. Mori, K. and Fujiwhara, M., Tetrahedron, 44, 343, 1988. 90. Ohta, H., Ozaki, K., and Tsuchlhashi, G., Chem. Lett., 2225, 1987. 91. Fauve, A. and Veschambre, H . , Tetrahedron Lett., 28, 5037, 1987. 92. Ehrler, J., Giovannini, F., Lamatsch, B., and Seebach, D., Chimia, 40, 172, 1986. 93. Bernardi, R., Cardillo, R., Ghiringhelli, D., and Vajna de Pava, O., J . Chem. SOC., Perkin Trans. I . , 1607, 1987. 94. Sih, C. J. and Chen, C. S., Angew. Chem. Int. Ed. Engl., 23, 570, 1984. 95. Cooper, J., Gallagher, P. T., and Knight, D. W., J. Chem. Soc.. Chem. Commun., 509, 1988. 96. Akita, H., Matsukura, H.,Sonomoto, K., Tanaka, A., and Oshi, T., Chem. Pharm. Bull. (Tokyo), 35, 4985, 1987. 97. Raddatz, P., Radunz, H. E., Schneider, G., and Schwartz, H., Angew. Chem. Int. Ed. Engl., 27, 426, 1988. 98. Buisson, D., Henrot, S., Larcheveque, M., and Azerad, R., Terrahedron Lett., 28, 5033, 1987. 99. Christen, M. and Crout, D. H.G., J . Chem. Soc., Chem. Commun., 264, 1988. 100. Nakamura, K., Inoue, K., Ushio, K., Oka, S., and Ohno, A., J . Org. Chem., 53, 2589, 1988.

Volume 10, Issue 2


Biotechnology 101. Nakamura, K., Yoneda, T., Miyai, T., Ushio, K., Oka, S., and Ohno, A., Tetrahedron Lett., 29, 2453, 1988. 102.Suemune, H., Mizuhara, Y.,Akita, H., Oishi, T., and Sakai, K., Chem. Pharm. Bull. (Tokyo), 35, 3112, 1987. 103.Kim, M. J. and Whitesides, G. M., J. Am. Chem. SOC., 110, 2959, 1988. 104. Manzocchi, A., Casati, R., Fiecchi, A,, and Santaniello, E., J. Chem. Soc., Perkin Trans. I . , 2753, 1987. 105. Naoshima, Y., Hasegawa, H., and Saeki, T., Agric. Biol. Chem., 51, 3417, 1987;for another interesting strategy to provide o-hydroxy esters see Scilimati, A., Ngooi, T. K., and Sih, C. J., Tetrahedron Lett., 29,4927, 1988. 106. Naoshima, Y. and Hasegawa, H., Chem. Lett., 2379, 1987. 107.Leoenberger, H. G., Boguth, W., Barner, R., Schmid, M., and all,R., Helv. Chim. Acta, 62,455, 1979. 108. Sato, T., Hanayama, K., and Fujisawa, T., Tetrahedron Lett., 29, 2197, 1988;see also Gramatica, P., Manitto, P., Monti, D., and Speranza, G., Tetrahedron, 44, 1299, 1988. 109. Fauve, A., Renard, M. F., and Veschambre, H., J . Org. Chem., 52,4893, 1987;Kergomard, A., Dauphin, G., and Veschambre, H., Agric. Biol. Chem., 51, 2117, 1987. 110. Simon, H., Bader, J., Gunther, H., Neumann, S., and Thanos, J., Angew. Chem. Int. Ed., 24,539, 1985. 111. Gil, G., Ferre, E., Barre, M., and Le Petit, J., Tetrahedron Lett., 28, 3797,1988. 112.Sakai, K., Nakazawa, A., Kondo, K., and Ohta, H., Agric. Biol. Chem., 49,2331, 1985. 1 13. Jones, J. 8. and Taylor, K. E., Can. J . Chem., 54, 2969, 1976. 114.Gunther, H. and Simon, H.,Appl. Microbiol. Biotech., 26,9,1987; Laval, J. M., BourdUlon, C., and Moiroux, J., Biotechnol. Bioeng., 30, 157, 1987. 115. For other literature and recent reviews on NAD+/NADP+ recycling see Komoschinski,J. and Steckhan, E., Tetrahedron Lett., 29,3299, 1988;Bednarski, M. D., Chenault, H. K., Simon, E. S., and Whitesides, G. M., J. Am. Chem. SOC., 109,1283,1987;Riva, s., Bovara, R., Zettn, L., Pasta, P., Ottolina, G., and Carrea, G., J . Org. Chem., 53, 88, 1988. 116. Irwin, A. J. and Jones, J. B., J . Am. Chem. Soc., 99,556, 1977. 117.Root, R. L., Durrwachter, J. P.,and Wong, C.-H., J . Am. Chem. Soc.,107. 2997, 1985. 118. Hamada, H., Bull. Chem. SOC. Japan, 61,869, 1988. 119. Tiwari, K., Dhawale, M., Szarek, W., Hay, G., and Kropinski, M., Carbohydrate Res., 156, 19, 1986. 120.Ohta, H., Yamada, H., and Tsuchihashi, G., Chem. Lett., 2325, 1987. 121. White, R. F., Birnbaum, J., Meyer, R. T., ten Broeke, J., Chemerda, J. M., and Demain, A. L., Appl. Microbiol., 22, 55, 1971. 122. May, S. W., Schwartz, R. D., Abbott, B. J., and Zaborsky, 0.R., Biochim. Biophys. Acta, 403,245, 1975. 123.May, S. W. and Schwartz, R. D., J. Am. Chem. Soc., 96,4031, 1974. 124. Kumler, P. L. and De Jong, P. J., J. Chem. Ed., 52,475, 1975. 125. de Smet, M.J., Kingma, J., Wynberg, H.,and Witholt, B., Enzyme Microb. Technol., 5, 352, 1983. 126. Dobson, R. M., Newman, N., and Tsuchiya, H. M., J . Org. Chem., 27,2707,1962;May, S. W. and Phillips, R. S., J. Am. Chem. Soc., 102,5981,1980;Holland, H.L., Popperl, H., Ninniss, R. W., and Chenchaiah, P. C., Can. J . Chem., 63, 11 18, 1985. 127. Light, D. R., Waxman, D. J., and Walsh, C., Biochemistry, 21, 2490, 1982;see also Branchaud, B. P. and Walsh, C. T., J. Am. Chem. Soc., 107,2153, 1985. 128. Ohta, H., Okamoto, Y., and Tsuchihashi, G. I., Chem. Lett., 205, 1984;Ohta, H., Okamoto, Y., and Tsuchihashi, G. I., Agric. Biol. Chem.. 49,671, 1985.

129. Katopodis, A., Smith, H.,and May, S . W., J. Am. Chem. Soc.. 110,897, 1988;the stereoselective oxidation of 1,3-dithianes using Aspergillus mortierella and Helminthosporium species has been investigated, Auret, B. J., Boyd, D. R., Dunlop, R., and Drake, A. F., J . Chem. SOC. Perkin Trans. I , 2827, 1988. 130. Chapman, P. J., Meerman, G., and Gunsalus, 1. C., Biochem. Biophys. Res. Commun., 20, 104, 1965. 131. d’AngeIo, J., Revial, G., Azerad, R., and Buisson, D., J. Org. Chem., 51, 40, 1986. 132. Walsh, C. T. and Chen, Y.-C., J . Angew. Chem. Int. Ed. Engl., 27, 333, 1988. 133. Corey, E. J. and Nagata, R., Tetrahedron Lett., 28, 5391, 1987; Funk, M.O.,Andre, J. C., and Otsuki, T., Biochemistry, 26,6880, 1987. 134.Johnson, R. A., Oxygenations with microorganisms, in Oxidation in Organic Synthesis, Part C , Trahanovsky, W. S., Ed., Academic Press, New York, 1978, 131; Kieslich, K., Biotransformations in Biotechand Reed, nology: A Comprehensive Treatise, Vol. 6a. Rehm, H.-J. G.,Ms., VCH Verlagsgesellschaft, Weinheim, 1984, 1. 135. KiesUch, K., Bull. SOC.Chim. France, 11, 9,1980. 136. Kieslich, K. Steroid conversions, in Economic Microbiology, Microbial Enzymes andlioconversions, Vol. 5 , Rose, A. H., Ed., Academic Press, London, 1980, 369; Vezina, C. and Rakhit, S., Microbial transformations of steroids, in CRC Handbook of Microbiology, Vol. 4,CRC Press, Boca Raton, FL, 1974, 117;Sedlaczek, L., Biotransformationsof steroids Crir. Rev. Biotechnol., 7,187,1988;a predictive model for steroid hydroxylation is described by Bell, R. A., Cherry, P. C., Clark, I. M., Denny, W. A., Jones, E. R. H., Meakins, G. D., and Woodgate, P. D., J . Chem. Soc., Perkin Trans. I . , 2081, 1972. 137. Iizuka, H. and Naito, A,, Microbial Transformations of Steroids and Alkaloids, University Park Press, State College, PA and University of Tokyo Press, 1967,1; Iuuka, H. and Naito, A., Microbial Conversion of Steroids and Alkaloids, University of Tokyo Press and SpringerVerlag. Berlin, 1981, 1. 138. Holland, H. L., The Alkaloids, VoI. 18, Rodrigo, R. G. A , , Ed., Academic Press, New York, 1981. 139. Ciegler, A., Microbial transformations of terpenes, in CRC Handbook on Microbiology, Vol. 4, CRC Press, Boca Raton, FL, 1974,449. 140. Dalton, H., Oxidation of hydrocarbons by methane monooxygenases from a variety of microbes, in Applied Microbiology, Vol. 26, Academic Press, London, 1980, 71; Antony, C., The Biochemistry of Methylotrophs, Academic Press, London, 1982;Ericson, A., Hedman, B., Hodgson, K. O., Green, J., Dalton, H., Bentsen, J. G., Beer, R. H., and Lippard, S. J., J. Am. Chem. Soc., 110,2330, 1988. 141. Peterson, D. H., Murray, H.C., Eppstein, S. H.,Reineke, L. M., Weintraub, A., Meister, P. D., and Leigh, H.M., J. Am. Chem. Soc., 74,5933, 1952. 142. Swinney, D. C., Ryan, D. E., Thomas, P. E., and Levin, W., Biochemistry, 26,7073, 1987. 143. Schroepfer, D. J., Kim, HA., Vermilion, J. L.,Stephens, T. W., Phkerton, F. D.,Needleman, D. H., Wilson, W. K., and St. Pyrek, J., Biochem. Biophys. Res. Commun.. 151, 130, 1988. 144.Iida, M., Mikami, A,, Yamakawa, K., Nishitani, K., J. Ferment. Technol., 66,51, 1988. 145. Nadkarni, S. R., Akut, P. M., Ganguli, B. N., Khandelwal, Y., de Souza, N. J., and Rupp, R. H., Tetrahedron Leu., 27, 5265, 1986. J. P. N., Steffens, J. J., Sariaslani, F. S., Goswami, A., 146. ROSBZZB, Beale, J. M.,Reeg, S., and Chapman, R., Appl. Environ. Microbiol.. 53,2482, 1987. 147. Lamare, V., Fourneron, J. D., and Furstass, R., Tetrahedron Lett., 28,6269, 1987.

151


Critical Reviews In 148. Leak, D. J., Ellison, S. L. R., Murricane, C., and Baker, P. B., Biocatalysis, I , 197, 1987. 149. Davies, H.G., Dawson, M. J., Lawrence, G. C., Mayall, J., Noble, D., Roberts, S. M., Turner, M. K., and Wall, W. F., Tetrahedron Lett., 27, 1089, 1986. 150. Wackett, L. P., Kwart, L. D., and Gibson, D. T., Biochemistry, 27, 1360, 1988. 151. Goodhue, C.T. and Schaeffer, J. R., Eiotechnoi. Bioeng., 13,203, 1971. 152. Kurozumi, S., Toru, T., and Ishimoto, S., Tetrahedron Lett.. 4959, 1973. 153. Yamazaki, Y., and Maeda, H., Tetrahedron Lett., 26,4775,1985. 154. For example see Pasutto, F., Singh, N., Jamali, F., Coutts, R., and Abuzar, S., J. Pharm. Sci.. 76, 177, 1987;Martin, R., Baker, P., and Ribbons, D., Biocatalysis, 37, 1987. 155. Ley, S. V., Sternfeld, F., and Taylor, S., Tetrahedron Left., 28. 225, 1987;Ley, S. V. and Sternfeld, F., Tetrahedron Lett., 29,5305, 1988. 1.56.Cotterill, 1. C., Roberts, S. M., and Williams, J. O., J. Chem. Soc., Chem. Commun., 1628, 1988. 157. Taylor, S. C. and Turnball, M. D., European Patent, 0253485; Schoefield, J. A . , European Patent, 0,252,568. 158.Hudlicky, T.,Luna, H., Barbieri, G., and Kwart, L. D., 1.Am. Chem. Sac., 110, 4735, 1988. lS9. Boyd, D. R., McMordie, R. A. S., Porter, H. P., Dalton, H., Jenkins, R. O., and Howarth, 0. W., J. Chem. Soc., Chem. Comm u . , 1722, 1987. 160. Cass, A., Ribbons, D., Rossiter, J., and Williams, S., FEES Lett., 220, 353, 1987. 161. Taylor, S. J. C., Ribbons, D. W., Slawin, A. M. Z., Widdowson, D. A., and Williams, D. J., Tetrahedron Lett.. 28, 6391, 1987. 162. Wong, C.-H., in Enzymes as Catalysts in Organic Synthesis. Schneider, M. P . . Ed., Reidel, Dordrecht, 1986,199;see also Bischofberger, N., Waldmann, H., Saito, T., Simon, E. S., Lees, W., Bednarski, M. D., and Whitesides, G. M., J. Org. Chem., 53, 3457, 1988. 163. Ziegler, T.,Straub, A., and ETTenberger, F., Angew. Chem. fnt. Ed. Engl., 27,716, 1988;Pederson, R. L., Kim, M.-J., and Wong, C.-H., Tetrahedron Lett., 29,4645, 1988. 164. Bolte, J., Demuynck, C., and Samaki, H., Tetrahedron Lett., 28, 5525, 1987. 165. Crout, D. H. G. and Rathbone, D. J., J. Chem. Soc., Chem. Commun.. 98, 1988. 166.Effenberger, F., Ziegler, T., and Forster, S., Angew. Chem. fnt. Ed. Engl., 26, 458, 1987. 167. Brussee, J., R m , E. C., and van der Gen, A., Tetrahedron Lett., 29,4485, 1988. 168. Rjorkling, F. and Godtfredsen, S. E., Tetrahedron, 44,2957,1988. 169.Nilsson, K. G. I., Carbohydrate Res.. 167,95, 1987. 170. Rathbone, E. B., Hacking, A. J., and Cheetham, P. S. J., U.K. Patent GB2145080B. 171. Nilsson, K. G. I., Tibtechnology, 6,256, 1988. 172. Franssen, M. C. R., Weuen, J. G. J., Vincker, J. P., Laane, C., and van der Plas, H. C., Biocatalysis, 1, 205, 1988;Itahara, T. and Ide, N., Chem. Lett., 231 1, 1987; Franssen, M. C. R., van Boven, H. G., and van der Plas, H. C., 1. Heterocyrlic Chem.. 24, 1313, 1987. 173. Hunter, J. C., Belt, A,, Sotos, L. S., and Fonda, M. E., U.S. Parent 4,707,447;for a good review see Neidelman, S. L. and Geigert, J., Binhalogenation: Principles, Basic Roles, and Applications, Ell is-Honvood, Chichester, 1986.

152

174. Buist, P. H. and Dallmann, H. G., Tetrahedron Lett., 29,285,1988. 175. Akhtar, M. and Gani, D., Tetrahedron, 43, 5341, 1987. 176. Akhtar, M., Botting, N. P., Cohen, M. A., and Gani, D., Tetrahedron, 43, 5899, 1987. 177. Groeger, U. and Sahm, H., Appl. Microbial. Biotechnol., 25, 352, 1987. 178. Baldwin, J. E., Dyer, R. L., Ng, S. C., Pratt, A. J., and Russell, M. A., Tetrahedron Lett., 28, 3745, 1987. 179. Schmidt-Kastner, G. and Egerer, P., in Biorerhnology, Vol. 6a, Kieslich, K.,Ed., Verlag-Chemie, Weinheim, 1984,387. 180. Baldwin, J. E., in Recent Advances in the Chemistry of thep -Lactam Antibiotics. Roberts, S . M. and Brown, A. G., Eds., RSC, London, 1985, 62; Baldwin, J. E., Adlington, R. M., Moss, N., and Robinson, N. G., J. Chem. Soc., Chem. Commun., 1664, 1987;Baldwin, J. E., Norris, W. J., Freeman, R. T., Bradley, M., Adlington, R. M., Long-Fox, S., and Schofield, C. J., J. Chem. Soc., Chem. Commun., 1128, 1988. 181. Yamada, H. and Shlmizu, S., Angew. Chem. Int. Ed. EngI., 27, 622, 1988. 182. Alcock, N. W., Crout, D. H. G., Henderson, C. M., and Thomas, S. E., J. Chem. Soc., Chem. Commun., 746, 1988. 183. Baader, E., Bartmann, W., Beck, G., Bergmann, A., Fehlhaber, H.-W., Jendralla, H., Kesseler, K., Saric, R., Schiissler, H., Teetz, V., Weber, M., and Wess, G., Tetrahedron Lett., 29, 2563, 1988. 184. Scilmati, A., Ngooi, T. K., and Sih, C. J., Tetrahedron Lett., 29, 4927, 1988. 185. Bennett, F. and Knight, D. W., Tetrahedron Left., 29,4625,1988; Bennett, F., Knight, D. W., and Fenton, G., Tetruhedron Lett., 29, 4865, 1988; Mohr, P., Rosslein, L., and Tamm, C., Helv. Chim. Acta. 70, 142, 1987. 186. Yamazaki, Y. and Hosono, K., Tetrahedron Lett., 29, 5769, 1988. 187. Top, S., Jaomen, G., Gillois, J., Baldoli, C., and Maiorana, S., J . Chem. Soc., Chem. Commun., 1284, 1988. 188. M. D. Trevan, Ed., fmmobilized Enzymes. Wiley, Chichester, 1980. 189. Sonnet, P. E., J . Org. Chem., 52, 3477, 1987. 190. Gais, H.-J., Zeissler, A,, and Maidonis, P., Tetrahedron Lett., 29, 5743, 1988. 191. Carson, D. A. and Wasson, D. B., Biochem. Biophys. Res. Commun., 155, 129, 1988. 192. Durswachter, J. R. and Wong, C.-H., J . Org. Chem., 53, 4175, 1988. 193. Simon, E. S., Bednarski, M. D., and Whitesides, G. M., J. Am. Chem. SOC., 110,7159, 1988. 194. Clarke, A. R., Smith, C. J., Hart, K. W., Wilks, H. M., Chia, W. N., Lee, T. V., Birkofl, J. J., Banaszak, L. J., Barstow, D. A., Atkinson, T., and Holbrook, J. J., Eiochem. Eiophys. Res. Commun., 148, 15. 1987. 195. Napper, A. D., Benkovic, S. J., Tramontano, A., and Lerner, R. A., Science, 237, 1041, 1987. 196. Hilvert, D. and Nared, K. D., J. Am. Chem. Sac., 110,5593, 1988; Jackson, D. Y., Jacobs, J. W., Sugasawara, R., Reich, S. H., Bartlett, P. A., and Schultz, P. G., 1. Am. Chem. Soc., 110,4841, 1988. 197. Takaya, H., Ohta, T., Sayo, N., Kumobayashi, H., Akutagawa, S., Inoue, S., Kashara, I., and Noyori, R., J . Am. Chem. Soc., 109, 1596, 1987. 198. Brunner, H. and Leitner, W., Angew. Chem. int. Ed. Engt., 27, 1180, 1988. 199. Koola, J. D. and Kochi, J. K., J . Org. Chem., 5 2 , 4545, 1987. 200. Leduc, P.,Battioni, P., Bartoli, J. F., and Mansuy, D., Tetrahedron

Volume 10, Issue 2

Biotechnology


Lerr., 29, 205, 1988. 201. Balavoine, G., Barton, D. H. R., Boivin, J., Gref, A., Le Cornpanec, P., Ozbalik, N., Bestana, J. A. X., and Riviere, H., Tetrahedron, 44, 1091, 1988. 202. Newman, P., Ed., Oprical Resolution Procedures for Chemical Compounds, Vol. 3, Manhatten College, New York, 1984. 203. ApSimon, J. W. and Collier, T. L., Tetrahedron, 42, 5157, 1986. 204. Scott, J. W., Chiral templates, in Asymmetric Synthesis, Vol. 4, Morrison, J. D., Ed., Academic Press, New York, 1984. 205. Reimer, L. M., Conley, D. L., Pompliano, D. L., and Frost, J. W., J . Am. Chem. SOC., 108, 8010, 1986.

153

Recent advances in development of chiral fluorescent and colorimetric sensors.

Recent advances in chiral separation of amino acids using capillary electromigration techniques.

Molecular engineering of industrial enzymes: recent advances and future prospects.

Recent Advances in Lipase-Mediated Preparation of Pharmaceuticals and Their Intermediates.

Recent advances in the development of synthetic chemical probes for glycosidase enzymes.

Recent Advances in Chiral Nematic Structure and Iridescent Color of Cellulose Nanocrystal Films.

Recent advances in CE analysis of antibiotics and its use as chiral selectors.

Recent advances in the phakomatises.

Improving the stability and activity of oral therapeutic enzymes-recent advances and perspectives.

Recent advances in the chemical biology of nitroxyl (HNO) detection and generation.

Recent Advances in Voltammetry.

Recent advances in pancreatology.

Recent Advances in Surgery.

Recent advances in asthma.

Recent Advances in Supramolecular Analytical Chemistry Using Optical Sensing.

Recent advances in bone regeneration using adult stem cells.

Recent advances in capillary electrochromatography using molecularly imprinted polymers.

Recent Advances in Endoscopy.

Recent advances in epilepsy.

Recent advances in the genetics of dystonia.

Recent advances in the management of liposarcoma.

Recent advances in the understanding of acupuncture.

Recent advances in electrochemiluminescence.

Recent advances in epilepsy.