Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino Nitriles as Trianion Synthons

Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a reductive cyclization strategy. N-Boc alpha-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent reductive lithiation followed by intramolecular allcylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski-Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc alpha-amino nitriles as linchpins for alkaloid synthesis.