Concise Synthesis of (−)-Veratramine and (−)-20-iso-Veratramine via Aromative Diels–Alder Reaction

A concise and convergent synthesis of the isosteroidal alkaloids veratramine and 20-iso-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 N-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-iso-veratramine is not identical with a natural product proposed to have that structure. The single crystal X-ray structures of veratramine and 20-iso-veratramine are reported.