Concise Synthesis of (-)-Veratramine and (-)-20--Veratramine via Aromative Diels-Alder Reaction.

A concise and convergent synthesis of the isosteroidal alkaloids veratramine and 20--veratramine has been accomplished. A Horner-Wadsworth-Emmons olefination joins two chiral building blocks of approximately equal complexity and a transition-metal catalyzed intramolecular Diels-Alder cycloaddition-aromatization cascade constructs the tetrasubstituted arene. Other key steps include a highly diastereoselective crotylation of an -sulfonyl iminium ion and an Eschenmoser fragmentation. The chiral building blocks developed for this synthesis could be used to access a range of additional isosteroidal alkaloids using our diversifiable strategy. Our work shows that 20--veratramine is not identical with a natural product proposed to have that structure. The single crystal X-ray structures of veratramine and 20--veratramine are reported.