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.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) A highly productive strategy involving a crossed vinylogous Mukaiyama aldol reaction (VMAR) and an intramolecular silylative Mukaiyama aldol reaction (ISMAR)has been developed by using 1‐(tert‐butoxycarbonyl)‐2‐(tert‐butyldimethylsilyloxy)pyrrole and suitable ketones as the donor andacceptor species, respectively. Densely functionalized 2‐azabicyclo[2.2.1]heptanes and 6‐azabicyclo[3.2.1]octanes have been accessed in useful overall yields and with good‐to‐excellent margins of regio‐ anddiastereoselectivity.