Synthesis and resolution of β2,2-HBin, the first enantiomerically stable β-amino acid with chirality only due to axial dissymmetry

The first gem-disubstituted beta (2.2)-amino acid possessing only axial chirality, was synthesized by bis-alkylation of methyl or ethyl cyanoacetate with both racemic and enantiomerically pure (R)-2,2'-bis-(bromomethyl)-1,1'-binaphthyl, followed by NaBH4/CoCl2 reduction of the cyano group, treatment of the resulting amino esters with Boc(2)O and finally saponification of thc ester function, to afford the C- and/or N-protected derivatives of 2',1':1,2,1.2:3,4-dinaphthcyclohepta-1,3-diene-6-aminomethyl-6-carboxylic acid: (RS)- and (R)-X-beta (2.2)-HBin-OR (X = Boc: H) (R = Me. Et or H). For the medium-scale resolution of beta (2.2)-HBin. the racemic amino esters (RS)-H-beta (2.2)-HBin-OR (R= Me. Et) were treated with benzoic anhydride and the resulting derivatives (RS)-Bz-beta (2.2)-HBin-OR were saponified, The obtained (RS)-Bz-beta (2.2)-HBin-OH was coupled with L-phenylalanine cyclohexylamide by the EDC/HOBt method to afford the dipeptide diastereoisomers Bz-(R)-Bin-L-Phe-NH-C6H11 and Bz-(S)-Bin-L-Phe-NH-C6H11, which were separated by chromatography. Complete hydrolysis under acidic conditions. followed by esterification of the resulting free amino acid enantiomers, N-protection and saponification, led to the enantiomerically pure derivatives (R)- and (S)-X-beta (2.2)-HBin-OR (X=Boc-H) (R=Me, H). (C) 2001 Elsevier Science Ltd. All rights reserved.