Carbanions, asymmetric protonation

ASYMMETRIC PROTONATION OF CARBANIONS AND POLAR DOUBLE BONDS APPLICATION TO TOTAL SYNTHESES... 

In this chapter, the enantioselective protonation of preformed and a-stabilized carbanions is disclosed. A second part is devoted to the asymmetric protonation of enolate species obtained in situ through a first chemical transformation with activated double bonds (i.e., ketenes or Michael acceptors). Herein, among all the advances made using these two main approaches, methodologies that have been used in total synthesis of natural and pharmacologically active products are emphasized. 

Asymmetric protonation of unstabilized carbanions and preformed carbanions or equivalents remained rare in the literature. To the best of our knowledge, three main approaches have been described so far, leading to the formation of highly valuable products. 

A second approach dealing with the asymmetric proto-nation of preformed carbanions was reported by Levacher and co-workers. ° The authors took advantage of the acidity of the diarylmethane position to perform a deproto-nation/asymmetric protonation sequence by the use of BuLi complexed with sparteine (Scheme 31.3). The use of... 

Asymmetric protonation of a-stabilized carbanions and equivalents is to date the most developed way to access tertiary chiral stereogenic centers. Since its introduction as a relevant synthetic method in the 1970s by Duhamel and Plaquevent (Scheme 31.1), " the asymmetric protonation of a-stabilized carbanions has been studied by a number of research groups during the last four decades. 

D-Methylmalonyl-CoA, the product of this reaction, is converted to the L-isomer by methylmalonyl-CoA epunerase (Figure 24.19). (This enzyme has often and incorrectly been called methylmalonyl-CoA racemase. It is not a racemase because the CoA moiety contains five other asymmetric centers.) The epimerase reaction also appears to involve a carbanion at the a-position (Figure 24.20). The reaction is readily reversible and involves a reversible dissociation of the acidic a-proton. The L-isomer is the substrate for methylmalonyl-CoA mutase. Methylmalonyl-CoA epimerase is an impressive catalyst. The for the proton that must dissociate to initiate this reaction is approximately 21 If binding of a proton to the a-anion is diffusion-limited, with = 10 M sec then the initial proton dissociation must be rate-limiting, and the rate constant must be... 

Biocatalytk decarboxylation is a imique reaction, in the sense that it can be considered to be a protonation reaction to a carbanion equivalent intermediate in aqueous medimn. Thus, if optically active compoimds can be prepared via this type of reaction, it would be a very characteristic biotransformation, as compared to ordinary organic reactions. An enzyme isolated from a specific strain of Alcaligenes bronchisepticus catalyzes the asymmetric decarboxylation of a-aryl-a-methyhnalonic acid to give optically active a-arylpropionic acids. The effect of additives revealed that this enzyme requires no biotin, no co-enzyme A, and no ATP, as ordinary decarboxylases and transcarboxylases do. Studies on inhibitors of this enzyme and spectroscopic analysis made it clear that the Cys residue plays an essential role in the present reaction. The imique reaction mechanism based on these results and kinetic data in its support are presented. 

The asymmetric (—)-sparteine-mediated deprotonation of alkyl carbamates was unprecedented until discovered in 1990 °. For the first time, protected 1-alkanols could be transformed generally to the corresponding carbanionic species by a simple deprotonation protocol. Moreover, an efficient differentiation between enantiotopic protons in the substrate took place and the extent of stereoselection could be stored in a chiral ion pair, bearing the chiral information at the carbanionic centre. 

The sulfone (18) (see Section VI,P) has been resolved.214,215 Unlike open-chain a-sulfonyl carbanions, whose generation and proton capture proceeds with high retention of configuration, Corey et Z.214, 216 found that the carbanion generated by base-catalyzed decarboxylation of (+ )-18 gave a completely racemic sulfone (19). It was concluded that the lack of stereospecificity of the reaction is evidence for a planar cyclic a-sulfonyl carbanion intermediate. Cram and Whitney216,218 have studied this reaction in some detail their results indicate that symmetrical (planar) a-sulfonyl carbanions in asymmetric environments are involved as discrete reaction intermediates in the decarboxylation reaction. 

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