Direct synthesis of N-protected chiral amino acids from imidodicarbonates employing either Mitsunobu or triflate alkylation. Feasibility study using lactate with particular reference to 15N-labelling

Abstract

Two novel approaches to N,N-diprotected chiral α-amino acid esters, based on selected imidodi-carbonates as amine synthons, have been explored. Thus, N-alkylation of these substrates was smoothly accomplished by the Gabriel or Mitsunobu methods as well as by the use of triflates. Ethyl (R,S)-2-bromopropionate underwent nucleophilic substitution when treated with the potassium salt of selected imidodicarbonates in dry dimethylformamide to furnish the corresponding fully blocked (R,S)-alanines in high yield. The chirality of ethyl (S)-lactate was largely conserved when it was condensed with free imidodicarbonates and tosylcarbamates under conventional Mitsunobu conditions. The yield of the corresponding N,N-di-protected ethyl (R)-alaninate was strongly dependent on the electron-withdrawing properties of the imidodicarbonate alkyl groups. Thus, Boc₂NH gave < 5% of the product whereas Troc-NH-Z afforded the corresponding analogue in 83% yield under comparable conditions. On the other hand, triflates of various lactic acid esters reacted smoothly with the lithium salt of Boc₂NH, also with clean inversion, as a result of which, after selective removal of two blocking groups, the N-protected alanine of opposite configuration could be isolated in high yield and excellent stereochemical purity. Both methods have been used for the synthesis of ¹⁵N-labelled N-protected (R)- and (S)-alanines, suitable for direct application to peptide synthesis.