Enantiomer-selective ester synthesis

Table 3. Enantiomer-Selective Ester Synthesis from Acid Salts and Alkyl Bromides in the Presence of Optically Active Pol3oners at 80 C in Benzene... 

A method utilizing the Dess-Martin periodinane[12 for the conversion of a peptide a-hy-droxy ester into the corresponding a-oxo ester was reported by Burkhart et al.[8l The final product, peptide a-oxo ester, obtained in this process contains a mixture of enantiomers at C2 in PI of the peptide. The optical impurity arises not from the oxidation reaction but the synthesis of one of the intermediates, 2-hydroxy-3-nitro-4-phenylbutanoic acid, which generates four diastereomers at two adjacent chiral carbons. This procedure is limited to the synthesis of peptide a-oxo esters with the phenylalanine residue at the PI position. A more diversified approach is achieved by using a-hydroxy- 3-amino acids 14 as the key intermediate that permits selective introduction of an amino acid residue at PI of the peptide it can also be coupled to N-protected amino acids or N-protected peptides and further transformations give a-oxo esters 19, a-oxo acids 20, and a-oxoamides 22 (Scheme 4)J3 61... 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

In the hydrogenation of p keto esters (R, R) tartaric acid gives the (R) alcohols and the (S, S) tartaric acid gives the (S) enantiomers. Raney nickel is more effective than supported nickel catalysts. It appears that the active catalyst is nickel tartrate which is adsorbed on the catalyst surface and that the sodium bromide is adsorbed on the non-chiral active sites, thus, keeping them from promoting the non-selective hydrogenations. 2,84 -pj is procedure has been used to prepare the chiral intermediate in the synthesis of the Pine Sawfly sex pheromone. ... 

Since both (R,R)- and (5,5)-tartaric acid esters are readily available in optically pure form, this method allows the synthesis of both enantiomers of cyclopropanes from a,j8-unsaturated aldehydes in a predictable manner. The method has been successfully applied (see Table 1, entry 6) to the enantioselective synthesis of 5,6-methanoleukotriene A, a stable and selective inhibitor of leukotriene biosynthesis." ... 

Immobilized forms or reticulated crystals of Candida antarctica lipase are effective biocatalysts for the synthesis of pure enantiomers utilized as anti-inflammatory agents. For example, one route for produetion of the 5-isomers of 2-aryl propionic acids (ibuprofen, naproxen, ketoprofen, and flurbprofen) involves enantioselective hydrolysis of the corresponding raeemie esters. Arroyo has indicated that an immobilized form of C. antarctica lipase (fraetion B) is used to mediate the selective acetylation of a diol to form the 5-enantiomer of a monoaeetate (Fig. 5), which is further proeessed to obtain an antifungal agent. ... 

In this case, the first choice derivative is the poro-methoxy benzoate, but for some alcohols, the best selectivity was obtained with the paro-methyl or ortho-methoxy ester [95]. This kind of approach has been exploited to solve practical problems, as shown for the enantiomers of an intermediate used for the synthesis of the chiral anticancer agent edatrexate [2, 87]. 

A cost effective and easily scaled-up process has been developed for the synthesis of (S)-3-[2- (methylsulfonyl)oxy ethoxy]-4-(triphenylmethoxy)-1 -butanol methanesulfonate, a key intermediate used in the synthesis of a protein kinase C inhibitor drug through a combination of hetero-Diels-Alder and biocatalytic reactions. The Diels-Alder reaction between ethyl glyoxylate and butadiene was used to make racemic 2-ethoxycarbonyl-3,6-dihydro-2H-pyran. Treatment of the racemic ester with Bacillus lentus protease resulted in the selective hydrolysis of the (R)-enantiomer and yielded (S)-2-ethoxycarbonyl-3,6-dihydro-2H-pyran in excellent optical purity, which was reduced to (S)-3,6-dihydro-2H-pyran-2-yl methanol. Tritylation of this alcohol, followed by reductive ozonolysis and mesylation afforded the product in 10-15% overall yield with excellent optical and chemical purity. Details of the process development work done on each step are given. 

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

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