Stereoselective synthesis of biologically active tetronic acids

doi:10.1016/S0957-4166(98)00040-8

Tetrahedron: Asymmetry

Volume 9, Issue 5, 13 March 1998, Pages 817-825

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Abstract

(4R)-3-Amino-4-trimethylsilyloxy-2-alkenoates (R)-3, obtained from O-trimethylsilyl protected optically active cyanohydrins (R)-1 via the Blaise reaction, are hydrolyzed under mildly acidic conditions to give optically active tetronic acids (R)-4 without racemization. From the follow-up reactions of (R)-4 investigated, only methylation with diazomethane afforded the biologically active tetronic acid derivative (R)-5a without racemization whereas acylation and reductive alkylation, respectively, resulted in partial racemization or failed on the whole.

Section snippets

Hydrolysis and cyclization of (R)-tert-butyl 3-amino-4-trimethylsilyloxyalkenoates (R)-3 to (R)-tetronic acids (R)-4

The (R)-enaminoesters (R)-3, derived from O-trimethylsilylated (R)-cyanohydrins (R)-1 by Blaise reaction with the Reformatsky reagents 2,[1]were lactonized under acid catalysis in tetrahydrofuran (THF) or methanol with removal of the O-protecting group via intermediates A to (R)-tetronic acids (R)-4 (Scheme. 1, Table 1).

The lactonization of the aliphatic enaminoesters (R)-3b–d proceeded without racemization. After recrystallization the (R)-tetronic acids (R)-4b–d were isolated with high ee

Follow-up reactions of tetronic acids 4 to compounds of known biological activity

O-Methylation, α-acylation and α-alkylation of (R)-tetronic acids (R)-4 should offer an approach to optically active derivatives which are of pharmacological interest and are known so far only as racemates. As starting compounds for the follow-up reactions we have applied (R)-4a and 4f. In Scheme. 3 both methylation and acylation of these derivatives are illustrated.

Methylation was examined first with racemic tetronic acid 4a. 4a was reacted with methanolic HCl solution (1%) according to

Materials and methods

AlCl₃ was purchased from Aldrich, p-chlorobenzaldehyde, TiCl₄ and CuBr·SMe₂ complex from Fluka, and Celite 503 from Roth. (4R)-tert-butyl 3-amino-4-trimethylsilyloxy-2-alkenoates 3 were prepared according to methods described elsewhere.[1]All solvents were purified and dried as described in the literature. Melting points were determined on a Büchi SMP-20 apparatus and are uncorrected. ¹H NMR spectra were recorded on a Bruker AC 250 F with TMS as an internal standard. Optical rotations were

Acknowledgements

This work was generously supported by the Bundesministerium für Bildung und Forschung (Zentrales Schwerpunktprogramm Bioverfahrenstechnik, Stuttgart).

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¹: Part of dissertation, Universität Stuttgart, 1997.

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