Facile and highly stereoselective synthesis of the C-2-symmetrical diaminodiol core-unit of HIV-1 protease inhibitors and of their symmetrical and unsymmetrical analogs from lithiated 2-(dibenzylamino)alkyl carbamates: Oxidative dimerization

The lithio derivatives of (S)- and (R)-2-(N,N-dibenzylamino)alkyl carbamate s 3 and ent-3, generated by substrate-directed deprotonation from the precu rsors 2 and ent-2, add with high diastereoselectivity to (S)-2-(N,N-dibenzy lamino)alkanals. The (S)aminoaldehyde 5a, derived from (S)-phenylalanine, i s produced in situ from the lithium compound 3a by the controlled addition of dioxygen to the reaction mixture affording the protected anti,syn,anti-a lpha,delta-diamino-beta,gamma-diol 6aa which is the core unit of anti-HIV 1 protease agents. Several symmetric and unsymmetric structure analogs, diff ering in the substitution pattern and the configurations, Rave been synthes ized. A further approach to the title compound is given by the acylation of lithium derivatives 3/4, followed by a hydride reduction. The reaction of the lithium derivatives 3a/4a with CuCl leads to an eliminative oxidative c oupling with formation of (3E/Z, 2S,5S)-2,5-dibenzylamino-1,6-diphenylhex-3 -enes (E)- and (Z)-26.