Asymmetric Synthesis via Heterocyclic Intermediates, XLVIII. Asymmetric Synthesis of Diastereomerically and Enantiomerically Pure, 3-Substituted (2S,3R)-N-Methylserine Esters

Abstract

N-Methyl amino acids deserve special attention as biologically active species[*] and for the preparation of peptide analogues[31. These peptide analogues are of increasing interest for obtaining information about the backbone conformation of pep tide^[^! Only a few satisfactory methods are currently available for the N-methylation of amidesr5’, Nacyl amino acidsL6] and their imine-type derivatives[’], but no general method has been reported for the N-methylation of serine esters until now. In 1976 Weinreb and co-workers[’] showed that simple amides can be N-methylated by reduction of their methylol derivatives with triethylsilane/trifluoroacetic acid. In 1983 this method was employed by Freidinger and co-workers[6b1 for the N-alkylation of Fmoc-protected amino acids via their oxazolidinone derivatives. In 1987 Grieco and Bahsas[*’ reported on a two-step sequence for the N-methylation of amino acids and peptides compatible with unprotected phenols and hydroxy compounds. The iminium ion generated in situ from the amino acid and aqueous formaldehyde solution undergoes an aza Diels-Alder reaction with cyclopentadiene to give the corresponding 2-azanorbornene derivative. The iminium-ion species, generated during an acid-catalyzed retro aza Diels-Alder reaction, can be reduced with triethylsilane to provide the Nmethyl amino acid in a total yield of 54-86%.