Synthesis of enantiopure, axially chiral, Cα-tetrasubstituted α-amino acids with binaphthyl-based crowned side chains and 3D-structural analysis of their peptides

The syntheses of the terminally protected, crowned, C-alpha-tetrasubstituted alpha-amino acids with only axial chirality, the two diastereomers Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe and Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, and their respective enantiomers Boc-(R)-Bip[(S)-Binol-22-C-6]OMe and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe, all derived from 2',1':1,2; 1 '',2 '':3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bip), were performed by bis-alkylation with cyclization of racemic (R+S)-Boc-[HO](2)-Bip-OMe, possessing two phenolic OH groups at the 6,6'-positions of the biphenyl frame of Bip, using (+)-(R)- and (-)-(S)-Binol[(OCH2CH2)(2)OTs](2) (2,2'-bis[5-tosyloxy-3-oxa-l-pentyloxy]-1,1'-binaphthyl), respectively, as the alkylating agent followed by chromatographic separation. Two series of terminally protected model peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and i+3 positions of the sequence, combined with either L-Ala or L-Ala/Aib, were synthesized by solution methods. Their 3D-structural analyses by FTIR absorption and NMR suggest that these peptides preferentially adopt folded secondary structures. (C) 2008 Elsevier Ltd. All rights reserved.