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Enantioselective Addition of Ketene Silyl Acetals to Nitrones Catalyzed by Chiral Titanium Complexes. Synthesis of Optically Active B-Amino Acids

 



 

Abstract

The first catalytic, enantioselective synthesis of optically active ß-amino acids and their N-hydroxyl derivatives was developed. A chiral titanium complex, prepared from Ti(Oi-Pr)4, BINOL, and tert-butylcatechol, catalyzes enantioselective addition reaction of ketene silyl acetals to nitrones to give optically active N-hydroxyl-ß-amino acid derivatives. This is the rare case of a catalytic, enantioselective carbon—carbon bond formation reaction. The combined processes of catalytic oxidation of secondary amines and the titanium-catalyzed enantioselective addition of ketene silyl acetals to nitrones provide a useful two-step method for the synthesis of optically active ß-amino acid derivatives and related nitrogen compounds from secondary amines.

Introduction
Asymmetric synthesis of ß-amino acids and their derivatives is of importance in view of their pharmacological activities, structural properties, and usefulness as precursors for synthesis of nitrogen-containing biologically active compounds such as ß-lactam antibiotics. Various methods for synthesis of optically active ß-amino acids have been explored [1]; however, the number of catalytic and enantioselective methods is small and limited to hydrogenation of aminoacrylates [2], aminohydroxylation of olefins [3], addition of aminonucleophiles to acrylates [4,5], and Mannic-type reaction of aldimines with silyl enolates [6].

 

We have reported convenient and very useful methods for asymmetric synthesis of ß-amino acids by diastereoselective 1,3-dipolar cycloaddition of nitrones to alkenes bearing chiral auxiliaries [7] and diastereoselective addition of enolates to nitrones using either chiral enolates [8-11] or chiral nitrones [12,13]. Nitrones 2 are highly valuable intermediates for synthesis of nitrogen-containing biologically active compounds because of their easy preparation by catalytic oxidation of secondary amines 1 using hydrogen peroxide [14-18], configurational stability, and ease of handling. Therefore, to develop a method based on metal-catalyzed enantioselective addition of ketene silyl acetals 3 to nitrones 2 is appealing for synthesis of ß-amino acid derivatives 4 and 5 from secondary amines 1 (Scheme 1).

 

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