Enantioselective Synthesis of β²-Homotryptophan for a Somatostatin Mimetic

Abstract

There is no general method available for preparation of enantiomerically pure β²-amino acids. They can be prepared by stereoselective alkylation of chiral enolates which are synthetic equivalents of “β-alanine” (= H-β-HGly-OH) [1]. In another approach, the amino acid side chain is first attached to the auxiliary, followed by amino-methylation with synthetic equivalents of the [H₂NCH₂]⁺ cation [2]. Similarly, using bromoacetates as electrophiles, with reagents, which are synthetically equivalent to chiral enolates, followed by Curtius rearrangement also leads to the net attachment of the protected aminomethyl group [2a, 3]. To the present day only β²-HA1a [lb, 4], β²-HVal [4], β²-HLeu [lb, 4], β²-HPhe [lb, 2a, 4], β²-HThr [5], β²-HLys [6] and β²-HAsp [7] have been prepared. Also, syntheses of the precursors of β²-HTyr, β²-HSer and β²-HGlu have been published [2b], and β²-HPro (piperidine-3-carboxylic acid) is known from 1951 [8]. To the best of our knowledge, the preparation of other β²-homologs of proteinogenic amino acids has not been published yet.