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The chiral intermediate (2R,3S)-(−)-N-benzoyl-3-phenyl isoserine ethyl ester 2a , a potential taxol 5 side-chain synthon, was prepared by microbial and enzymatic processes. Taxol 5 is an anticancer compound recently approved by FDA for the treatment of ovarian cancer. The stereoselective reduction of racemic 2-keto-3-(N-benzoylamino)-3-phenylpropionic acid ethyl ester 1 to the corresponding alcohol 2 was carried out using microbial cultures. Among microorganisms evaluated, Hansenula polymorpha SC 13865 and Hansenula fabianii SC 13894 effectively reduced compound 1 to the desired syn diastereomer 2a . Reaction yields of >80% and enantiomeric excesses of >98% were observed for these bioreduction process. About 10–20% of anti diastereomers ( 2c,2d ) were produced during bioreduction.

The chiral intermediates (S)-3,4-dihydro-1,2(2H)-pyridinedicarboxylic acid, 1-(phenylmethyl)ester [BMS 202665-01] and (S)-3,4-dihydro-1,2(2H)-pyridinedicarboxylic acid, 1,1-dimethylethyl ester [BMS 264406-01] were prepared by oxidation of Nα-carbobenzoxy- l -lysine (Nα-CBZ- l -lysine) and Nα-t-butoxycarbonyl- l -lysine (Nα-t-BOC- l -lysine), respectively, by cell suspensions of Rhodotorula graminis SC 16005.

Chirality is a key factor in the efficacy of many drug products and thus the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Biocatalysis is now accepted as a one of key methodologies for the preparation of chiral drug intermediates and fine chemicals. The biocatalytic production of several key intermediates in the synthesis of antihypertensive, anticholesterol, anti-Alzheimer’s, β3-receptor agonist, HIV-protease inhibitor, and other pharmaceuticals is described. These includes (1) the synthesis of L-6-hydroxynorleucine from racemic 6-hydroxynorleucine, (2) the enzymatic synthesis of (S)-allysine ethylene acetal by reductive deamination using phenylalanine dehydrogenase, (3) the synthesis of [4S-(4a,7a,10ab)]-1-octahydro-5-oxo-4-{[(phenylmethoxy)carbonyl]-amino}-7H-pyrido-[2,1-b][1,3]thiazepine-7-carboxylic acid (BMS-199541–01) by enzymatic oxidation process using L-lysine-ϵ-aminotransferase, (4) the enzymatic synthesis of the lactol [3aS-(3aα,4α,7α,7aα)]-hexahydro-4,7-epoxyisobenzofuran-1(3H)-ol and corresponding lactone, (5) the microbial synthesis of (3R-cis)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one, (6) the microbial oxygenation of 6-cyano-2,2-dimethyl-2H-1-benzopyran to the corresponding chiral epoxide and (+)-trans diol, (7) the enantioselective microbial reductions of N-[4-(2-chloroacetyl)phenyl]methanesulfonamide and (4-benzyloxy-3-methanesulfonylamino)-2'-bromoacetophenone to the corresponding (R)-alcohols, (8) the enzymatic resolution of racemic α-methyl phenylalanine amides by amidase, (9) the enantioselective hydrolysis of diethyl methyl-(4-methoxyphenyl)-propanedioate by lipase PS-30, (10) the enantioselective microbial reduction of methyl 4-chloro-3-oxobutanoate, (11) the enzymatic synthesis of ethyl (3S,5R)-dihydroxy-6-(benzyloxy)hexanoate, (12) the enantioselective hydrolysis of racemic epoxide 1-{2',3'-dihydrobenzo[b]furan-4'-yl}-1,2-oxirane by epoxide hydrolase, (13) the biocatalytic dynamic kinetic resolution of R,S-1-{2',3'-dihydrobenzo[b]furan-4'-yl}-ethane-1,2-diol, and (13) the diastereoselective microbial reduction of (1S)-[3-chloro-2-oxo-1-(phenylmethyl)propyl]carbamic acid 1,1-dimethylethyl ester. 1 Introduction 2 Antihypertensive Drugs 3 Thromboxane A2 Antagonists 4 Calcium Channel Blocking Drugs 5 Potassium Channel Openers 6 Antiarrhythmic Agents 7 β3-Receptor Agonists 8 Anticholesterol Drugs 9 Microbial Resolution10 Anti-Alzheimer Drugs11 HIV Protease Inhibitors12 Conclusion

The production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Chiral intermediates and fine chemicals are in high demand from both the pharmaceutical and agrochemical industries for the preparation of bulk drug substances and agricultural products. The enormous potential of microorganisms and enzymes for the transformation of synthetic chemicals with high chemo-, regio- and enantioselectivities has been demonstrated. In this article, biocatalytic processes are described for the synthesis of chiral pharmaceutical intermediates.

Reaction of the sodium carboxylates (I) with the Grignard reagent (II) in THF (III) leads to the formation of the new phenylmagnesium carboxylates (IV).

Reactions of dichlorobis(cyclopentadienyl)zirconium(IV) and dichlorobis(cyclopentadienyl)titanium- (IV) with 2-thiophenecarboxylic acid (2-TCH), 2- thiopheneacetic acid (2-TAH) and nicotinic acid (HNicA) were carried out in different stoichiometric ratios. The complexes of the type Cp 2 M(2-TA)Cl, Cp 2 M(2-TA) 2 , Cp 2 M(2-TC)Cl, Cp 2 M(2-TC) 2 , Cp 2 - M(NicA)Cl and Cp 2 M(NicA) 2 (where M = Ti or Zr) were obtained. These were characterized by their elemental analysis, 1 H NMR, IR, mass spectra and electronic spectral data. Magnetic susceptibility data reveals their diamagnetic nature.

The complexes of the type Cp2M(3-TC)Cl, Cp2M(3-TC)2, Cp2M(3-TA)Cl, Cp2M(3-TA)2, Cp2M(2-TB)Cl, Cp2M(2-TB)2 [where Cp = cyclopentadienyl, M = Zr or Ti] were synthesized by the reactions of dichlorobis(cyclopentadienyl)zirconium(IV) and dichlorobis(cyclopentadienyl)titanium(IV) with 3-thiophenecarboxylic acid (3-TCH), 3-thiopheneacetic acid (3-TAH) and 2-thiophenebutyric acid (2-TBH) respectively in different stoichiometric ratios. The new complexes were characterized by their elemental analysis, 1H NMR, IR, and electronic spectral data.