Biocatalytic synthesis of chiral alcohols and amino acids for development of pharmaceuticals

Abstract

Chirality is a key factor in the safety and efficacy of many drug products and thus the production of single enantiomers of drug intermediates and drugs has become increasingly important in the pharmaceutical industry. There has been an increasing awareness of the enormous potential of microorganisms and enzymes derived there from for the transformation of synthetic chemicals with high chemo-, regio- and enatioselectivities. In this article, biocatalytic processes are described for the synthesis of chiral alcohols and unntural aminoacids for pharmaceuticals.

Figure 1

Hydroxy buspirone (antianxiety drug): Enzymatic preparation of 6-hydroxybuspirone.

Figure 2

Cholesterol lowering agents: Enzymatic preparation of (3S,5R)-dihydroxy-6- (benzyloxy) hexanoic acid, ethyl ester.

Figure 3

Atorvastatin: Enzymatic preparation of (R)-4-cyano-3-hydroxybutyrate.

Figure 4

Chloesterol lowering agents: Preparation of (S)-4-chloro-3-hydroxybutanoic acid methyl ester.

Figure 5

Rhinovirus protease inhibitor: Enzymatic process for the preparation of (R)-3-(4-fluorophenyl)-2-hydroxy propionic acid.

Figure 6

Atazanavir (antiviral agent): Enzymatic reparation of (1S,2R)-[3-chloro-2-hydroxy-1-(phenylmethyl) propyl]-carbamic acid,1,1-dimethyl-ethyl ester.

Figure 7

Enzymatic reduction process for synthesis (S)-alcohol 27 for Montelukast intermediate.

Figure 8

Anticancer drug: Enzymatic preparation of C-13 paclitaxel side-chain synthon.

Figure 9

Antipsychotic drug: Enzymatic reduction of 1-(4-fluorophenyl)4-[4-(5-fluoro-2-pyrimidinyl)1-piperazinyl]-1-butanone.

Figure 10

Retinoic acid receptor agonist: Enzymatic preparation of 2-(R)-hydroxy-2-(1',2',3',4'-tetrahydro-1',1',4',4'-tetramethyl-6'-naphthalenyl)acetate.

Figure 11

Anti-Alzheimer’s drugs: Enzymatic reduction of 5-oxohexanoate and 5-oxohexanenitrile.

Figure 12

(A) Anti-Alzheimer’s drugs: Enantioselective microbial reduction of substituted acetophenone; (B) Enantioselective microbial reduction of methyl-4-(2'-acetyl-5'-fluorophenyl) butanoates.

Figure 13

Anticancer drug: Enzymatic preparation of (S)-2-chloro-1-(3-chlorophenyl)ethanol.

Figure 14

Thrombin inhibitor: Enzymatic preparation of (R)-2-Hydroxy-3,3-dimethylbutanoic acid.

Figure 15

Endothelin receptor antagonist: Enantioselective microbial reduction of keto ester and chloroketone.

Figure 16

Calcium channel blocker: Preparation of [(3R-cis)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluromethyl)-2H-1-benzazepin-2-one].

Figure 17

β3-Receptor agonist: Reduction of 4-benzyloxy-3-methanesulfonylamino-2-bromo-acetophenone.

Figure 18

Penem and carbapenem: Enzymatic preparation of (R)-1,3-butanediol and (R)-4-chloro-3-hydroxybutonoate.

Figure 19

Integrin receptor agonist: Enzymatic preparation of (R)-allylic alcohol.

Figure 20

NK1 receptor antagonists: Enzymatic synthesis of (S)-3,5-bistrifluoromethylphenyl ethanol.

Figure 21

Tigemonam: Enzymatic synthesis of (S)-β-hydroxyvaline.

Figure 22

Atazanavir (anti-viral agent): Enzymatic synthesis of (S)-tertiary-leucine.

Figure 23

Vanlev: Enzymatic synthesis of (S)-6-hydroxynorleucine by reductive amination.

Figure 24

Vanlev: Enzymatic conversion of racemic 6-hydroxy norleucine to (S)-6-hydroxymorleucine.

Figure 25

Vanlev: Enzymatic synthesis of allysine ethylene acetal.

Figure 26

Saxagliptin: Enzymatic reductive amination of 2-(3-hydroxy-1-adamantyl)-2-oxoethanoic acid.

Figure 27

Enzymatic synthesis of (S)-neopentylglycine.

Figure 28

Glucogen like peptide: The (S)-amino-3-[3-{6-(2-methylphenyl)}pyridyl]-propionic acid.

Figure 29

Thrombin inhibitor inogatran: Enzymatic synthesis of (R)-cyclohexylalanine.

Figure 30

Calcitonin gene-related peptide receptors (antimigraine drugs): Enzymatic preparation of (R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoic acid.

Figure 31

Corticotropin releasing factor (CRF)-1 receptor antagonist: Enzymatic synthesis of (R)-1-cyclopropylethylamine and (R)-sec-butylamine.