Enantioselective ketoester reduction

Many enantioselective catalysts have been developed for reduction of functional groups, particularly ketones. BINAP complexes of Ru(II)C12 or Ru(II)Br2 give good enantioselectivity in reduction of (3-ketoesters.49 This catalyst system has been shown to be subject to acid catalysis.50 Thus in the presence of 0.1 mol % HC1, reduction proceeds smoothly at 40 psi of H2 at 40° C. 

In an alternate approach, the enantioselective microbial reduction of methyl-4-(2 -acetyl-5 -fluorophenyl) butanoates 80 (Figure 16.19B) was demonstrated using strains of Candida and Pichia. Reaction yields of 40%-53% and EEs of 90%-99% were obtained for the corresponding (5)-hydroxy esters 77. The reductase that catalyzed the enantioselective reduction of ketoesters was purified to homogeneity from cell extracts of Pichia methanolica SC 13825. It was cloned and expressed in E. coli, and recombinant cultures were used for the enantioselective reduction of the keto-methyl ester 80 to the corresponding (5)-hydroxy methyl ester 77. On a preparative scale, a reaction yield of 98% with an EE of 99% was obtained [99]. 

The enantioselective reduction of a-ketoester was carried out using the cell suspension of Aureobasidium pullulans SC 13 849 to produce the corresponding (R)-alcohol in 94% isolated... 

Two interesting yeast carbonyl reductases, one from Candida magnoliae (CMCR) [33,54] and the other from Sporobolomyces salmonicolor (SSCR) [55], were found to catalyze the reduction of ethyl 4-chloro-3-oxobutanoate to give ethyl (5)-4-chloro-3-hydroxybutanoate, a useful chiral building block. In an effort to search for carbonyl reductases with anti-Prelog enantioselectivity, the activity and enantioselectivity of CMCR and SSCR have been evaluated toward the reduction of various ketones, including a- and /3-ketoesters, and their application potential in the synthesis of pharmaceutically important chiral alcohol intermediates have been explored [56-58]. 

The carbonyl reductase from Candida magnoliae catalyzed the enantioselective reduction of a diversity of ketones, including aliphatic and aromatic ketones and a- and /3-ketoesters (Figure 7.17), to anti-Prelog configurated alcohols in excellent optical purity (99% ee or higher) [56]. 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

Quallich and Woodall described the first asymmetric synthesis utilizing a catalytic enantioselective reduction of the ketoester 35 with (S)-terahydro-l-methyl-3,3-diphenyl-lH,3W-pyrrolo[l,2-c][l,3.2]oxazaborole (CBS) to give the desired hydroxyester 36 (90% ee). After mesylation, Sn2 displacement with a higher-order cuprate derived from copper cyanide gave the diaryl r-butyl ester 37 with good chirality transfer. Intramolecular Friedel-Crafts cyclization gave the tetralone 31 in 90% ee (Scheme 7). ... 

Baker s yeast reduction of organic compounds, especially carbonyl compounds, is an extremely useful method of obtaining chiral products255-257. Recently, much effort has been expended to improve the ee obtained in this process. In one very useful example, l-acetoxy-2-alkanones have been reduced enantioselectively into (5 )-l-acetoxy-2-alkanols in 60-90% yields and with 95-99% ee258. The reaction readily occurs in a variety of solvents, both aqueous and nonaqueous. The reduction is fairly selective and so may be brought about in the presence of a-amide, ether, ester and other acid functional groups, in reasonable yields and with excellent ee (equation 65)259 -261. Thus, in the synthesis of the C-13 side chain of taxol, the key step was the reduction of a w-ketoester to the corresponding alcohol in 72% overall yield (equation 66)262. 

CJ Sih, BN Zhou, AS Gopalan, WR Shieh, CS Chen, G Girdaukas, F vanMiddles-worth. Enantioselective reduction of P-ketoesters by Baker s yeast. Ann NY Acad Sci 434 186-193, 1984. 

S R ratio = 5 1) [22]. Yanada and Yoneda constructed the deazaflavinophane 26, which exhibits complete facial selectivity in its oxidation and reduction reactions, e.g. the reduction with NaBD to afford 27 [23], Belokon and Rozen-berg used scalemic 4-formyl-5-hydroxy[2.2]para-cyclophane (FHPC) 28 in the synthesis of a-ami-no acids (ee 45-98 %) [24], An alternative approach to FHPC was more recently reported by Hopf [25]. Other interesting advances in the area of chiral cyclophanes include the homochir-al [2.2]paracyclophane-derived amino acids 29 and 30 [26], as well as (5)-PHANEPHOS (31) [27], which has been shown to be an effective ligand for highly enantioselective Ru-catalyzed asymmetric hydrogenations of -ketoesters and... 

Asymmetric reduction of prochiral a-ketoesters as well as a-and -alkoxy ketones using the above reagent including chiral diamine 1 affords the corresponding functionalized secondary alcohols in good yields with high enantioselectivities (eqs 12-14). ... 

Orlistat (32 tetrahydrolipstatin, Xenical ) is a potent inhibitor of pancreatic lipase [23] which has been launched for the treatment of obesity in 1998. Large amounts of 32 required for clinical development were obtained using a route based on the enantioselective reduction of P-ketoester 29 to provide P-hydroxyester R)-30 followed by diastereoselective elaboration strategies (via (S,S,i )-31, Scheme 6)... 

Asymmetrical reduction of ketones to alcohols66 can be done in a number of ways. Reductions with microorganisms67 were described in Chap. 9. By choosing appropriate microbes both R and S isomers were obtained. The inclusion of dimethylsulfide in a reduction of /3-ketoesters with Baker s yeast raised the enantioselectivity from 94 to 98%.68... 

The reduction of ketones into alcohols can be achieved using biocatalytic methods. Amongst the most popular of the available methods is the use of Baker s yeast, BY (Saccharomyces cerevisiae). The use of P-ketoesters as substrates leads to the corresponding p-hydroxy esters, often with high enantioselectivity. In the particular case of a-substituted P-ketoesters, the substrates spontaneously racemize, and this provides the basis for many reports of dynamic resolution reactions, some of which are described in the following discussion. In 1976, Deol and co-workers showed that cycloalkyl p-ketoesters could be reduced under dynamic resolution conditions (Fig. 9-26) >58l... 

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