Further Uses of Pyrrole-Based Dienoxysilane Synthons: A Full Aldol Approach to Azabicyclo[x.2.1]alkane Systems

Two racemic 2-azabicyclo[2.2.1]heptane structures, 15 and 21, and two chiral non-racemic 6-azabicyclo[3.2.1]octane representatives, 28 and 36, have been synthesized starting from 1-(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyloxy)pyrrole (TBSOP, 5) and suitable ketones, 9, 16, 22 and 29. 2-Azabicycle 15 was then elaborated to racemic cyclopentane amino acid 38, while 6-azabicycle 36 served to access the enantiomerically pure normorphan-type structure 40. For all substrates, a uniform synthetic scheme was implemented based on the combination of two diastereoselective aldol-type carbon–carbon bond-forming reactions, the efficiencies of which were secured by appropriate aldol-stabilizing steps. A mechanistic rationale accounting for the markedly diastereoselective character of the key Mukaiyama aldol reactions between TBSOP and the ketone acceptors has been postulated that involves hetero-Diels–Alder transition-state structures in which the preference for endo versus exo addition is governed by the electronic nature of the substituents in the ketone substrates.