Enantioselective reduction 3-ketoesters

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... 

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]. 

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). ... 

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. 

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)... 

Reduction of carbonyl groups. Aldehydes and ketones are subjected to enantioselective reduction. Hydrogenation of benzaldehyde-a-d, a-alkoxyketones " or )3-ketoesters can be accomplished using either the Ru dihalide complexes or some modified forms. a-Ketoesters are also similarly reduced. 

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]. 

Reduction with hydrosilanes. Ketones undergo enantioselective reduction by PhjSiHj in the presence of [Rh(cod)Cl]2 and Ir(cod)Cl2. Ligands such as 11, " 73, 2-i 3 and 74 (for ketoesters) are effective. Note that it is possible to use isopropanol instead of... 

The influence of additives present in an enzymatic enantioselective reduction is illustrated in the next example [51]. In general, the use of microbial reducing systems provides efficient access to optically pure hydroxy compounds. One such system is the reduction of P-ketoesters to P-hydroxyesters with baker s yeast, which serve as versatile building blocks in organic synthesis. However, control of the configuration of the product can often not be accomphshed sufficiently (Scheme 3.29). 

The biocatalytic reduction of the keto group to the alcohol group proceeds with a great tolerance of other functional groups in the substrate, for example, the enantioselective reductions of ketoesters to chiral hydroxyesters [70-73] or of... 

A mixture of ethyl 3-keto-5-hydroxy 75 (major) and 5-keto-3-hydroxy 76 (minor) was obtained from partial microbial reduction of ketoester 73. Another mixture of ethyl 3-keto-5-hydroxy 75 (minor) and 5-keto-3-hydroxy 76 (major) was obtained from chemical reduction of ketoester 73. These two mixtures were subjected to microbial reduction by Aeinetobacter sp SCI3874 cells for 6 h. The results indicated that the second reduction of the mono-hydroxy compound by SCI3874 cells was quite enantioselective. Reduction of the 3-keto-5-hydroxy 75 provided predominantly the (3R)-hydroxy, while reduction of the 3-hydroxy-5-keto ester 76 provided predominantly the (5S)-hydroxy compound [136]. 

In the laboratoiy, baker s yeast is a commonly used microorganism for the enantioselective reduction of ketones. It is readily available and can be handled using standard, non-sterile laboratory equipment. Furthermore, it displays large substrate scope that includes /l-ketoesters and aliphatic, aromatic, cyclic, and acyclic ketones [150, 151, 154, 155). Its applicability and usefulness were recognized very early this is underscored by the fact that the first comprehensive review covering yeast reductions dates back to 1949 [156] A few examples of reductions that provide alcohols with high selectivity are shown in Scheme 2.31 methyl isopropyl ketone (246) [157], hy-... 

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. 

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]. 

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],... 

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. 

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... 

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