Synthesis of novel d-secoestrone isoquinuclidines by an unpredicted iminium ion-induced 1,5-hydride shift

Unique 9,13-bridged D-secoestrone alkaloids have been synthesized and structurally characterized. Treatment of 3-methoxy-16,17-secoestra-1,3,5(10)-trien-17-al (6a) with aniline (7) or substituted aniline derivatives 8-28 in the presence of different Lewis and Bronsted acids produces the bridged azaestrone derivatives 51-67 and the alkenes 68-73 in high yields in a domino-type process. The imines 29-50 are proposed as intermediates, undergoing 1,5-hydride shifts via the iminium. ion salts 75 to give the cations 77, which, depending on the substitution pattern on the aniline moiety, either afford the bridged compounds through a nucleophilic addition of the formed secondary amine to the benzylic carbocation or give the alkenes through the abstraction of a proton at C-8. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004).