Chiral enzymatic inhibitors

Chiral 4-chloro-3-hydroxybutanoate esters are important chiral C4-building blocks [43-53]. For example, (i )- and (S)-isomers can be converted to L-car-nitine and the hydroxymethyl glutaryl-CoA reductase inhibitor. Since these compounds are used as pharmaceuticals, a high optical purity is required. A practical enzymatic method for the production of chiral 4-chloro-3-hydroxy-butanoate esters from prochiral carbonyl compounds, i.e.,4-chloroacetoacetate esters, or racemic 4-chloro-3-hydroxybutanoate esters is described. 

Rare or unnatural monosaccharides have many useful applications as nonnutritive sweeteners, glycosidase inhibitors and so on. For example, L-glucose and L-fructose are known to be low-calorie sweeteners. In addition, rare or unnatural monosaccharides are potentially useful as chiral building blocks for the synthesis of biologically active compounds. Therefore, these compounds have been important targets for the development of enzymatic synthesis based in the use of DHAP-dependent aldolases alone or in combination with isomerases. Fessner et al. showed that rare ketose-1-phosphates could be reached not only by aldol addition catalyzed by DHAP-dependent aldolases, but by enzymatic isomerization/ phosphorylation of aldoses [35]. Thus, for example, L-fructose can be prepared... 

Non-proteinogenic, chiral a.a-dialkyl-a-amino acids possessing stereochemically stable quaternary carbon centers have been significant synthetic targets, not only because they are often effective enzyme inhibitors but also because they are indispensable for the elucidation of enzymatic mechanisms. Accordingly, numerous studies have been conducted to develop truly efficient methods for their preparation [26], and in this respect phase-transfer catalysis has made unique contributions. 

L. W. Parker, and J. J. Venit, Biocatalytic preparation of a chiral synthon for a vasopeptidase inhibitor enzymatic conversion of N2-[N-phenylmethoxy)carbo-nyl] L-homocysteinyl]- l-lysine (1,1 J-disulfide to 4S-(4/,71,10aJ)]-l-octahydro-5-oxo-4-[phenylmethoxy)carbonyl]amino]-7H-pyrido-[2,l-b][l,3]thiazepine-7-carboxylic add methyl ester by a novel l -lysine e-aminotransferase, Enzyme Microb. Technd. 2000, 27, 376-389. 

Figure 1 Preparation of chiral synthon for vasopeptidase inhibitor enzymatic synthesis of L-6-hydroxynorleucine (1) using glutamate dehydrogenase.

Figure 9 Preparation of chiral synthon for neutral endopeptidase inhibitor stereoselective enzymatic hydrolysis of racemic ot-[(acetylthio)methyl]phenylpropionic acid (21).

Figure 17 Enzymatic synthesis of chiral synthon for BMS-188494, a squalene synthase inhibitor stereoselective acetylation of racemic (52).

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

By retro synthetic analysis collagenase inhibitor RO0319790 (1) can be assembled from two chiral building blocks, (R) -succinate 2 and (S)-tert-leucine N-methyla-mide 13. As the latter can be prepared from commercially available (S)-tert-leucine 8 our work concentrated in particular on the construction of the first building block 2. In order to assemble the carbon skeleton of 2 in the most efficient way, extremely cheap maleic anhydride 4 was converted in a known ene reaction with isobutylene to provide the cyclic anhydride 6. Hydrogenation of the double bond followed by the addition of EtOH/p-TsOH yielded the racemic diethyl ester substrate 9 for the enzyme reaction. The enzymatic monohydrolysis of 9 afforded the monoacid (R)-2a. (R)-2 a was coupled via its acid chloride with leucine amide 13 to ester 14, which finally was converted into the hydroxamic acid 1. 

Atazanavir 11 (Figure 16.4A) is an acyclic aza-peptidomimetic, a potent HIV protease inhibitor [43,44] approved recently by the U.S. Food and Drug Adminstration for treatment of autoimmune diseases (e.g., AIDS). An enzymatic process has been developed for the preparation of (lS,2/ )-[3-chloro-2-hydroxy-l-(phenylmethyl)pro-pyljcarbamic acid, 1,1-dimethylethyl ester 13 (Figure 16.4B), akey chiral intermediate... 

Patel RN, Banerjee A, Pendri YR, et al. Preparation of a chiral synthon for an HBV inhibitor enzymatic asymmetric hydrolysis of (la,2p,3a)-2-(benzyloxymethyl)cyclo-pent-4-ene-l,3-diol diacetate and enzymatic asymmetric acetylation of (la,2p,3a)-2-(benzyloxymethyl)cyclopent-4-ene-l,3-diol. Tetrahedron Asymmetry 17(2), 175, 2006. 

Patel. R.N.. Banerjee.A., Nanduri, V., Goldberg. S.. Johnston. R.. Hanson, R., McNamee, C., Brzozowski. D.. Tully. T.. Ko. R.. LaPorte. T.. Cazzulino, D., Swaminathan, S.. Parker. L.. and Venit. J. (2000) Biocatalytic Preparation of a Chiral Synthon for a Vasopeptidase Inhibitor Enzymatic Conversion of bP- N-[(Phenylmethoxy)carbonyl]L-homocysteinyl]-L-lysine (1>1 )-disulfide to [4B-(4a.7a,10ab)]l-Octahydro-5-oxo-4-[(phenyl-methoxy) carbonyl]amino]-7H-pyrido-[2.1-b][l 3]thiazepin-7-carboxylic Acid Methyl Ester by a Novel S-Lysine a-Amino-transferase. Enzyme Microb. Technol. 27,376-389. 

Various optically active compoimds have been synthesized by enzymatic hydrolysis of esters. - Some examples are shown in Fig. 10.21. The kinetic resolution of racemic esters afforded an intermediate in the synthesis of a j8-blocker (Fig. 10.21(a)) and phosphodiesterase inhibitor (Fig. 10.21(b)).Useful chiral acids can be obtained through the resolution of meso esters by pig liver esterase-catalyzed hydrolysis (Fig. 10.21(c)). 

An enzymatic process has been developed for preparing the chiral intermediate (-i-)-42a (Figure 11.11) needed for the synthesis of compound SCH66336 43, a selective farnesyl transferase inhibitor involved in binding Ras which moderates cell proliferation [96]. Ras proteins have been observed in 30% of all human... 

---