Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2(S)-Cathafoline, and (−)-Aspidophylline A

Abstract

The akuammiline alkaloids are a family of natural products that have been widely studied for decades. Although notable synthetic achievements have been made recently, akuammilines that possess a methanoquinolizidine core have evaded synthetic efforts. We report an asymmetric approach to these alkaloids, which has culminated in the first total syntheses of (−)-2(S)-cathafoline and the long-standing target (+)-strictamine. Moreover, the first enantioselective total synthesis of aspidophylline A is described.

Pardon the Interruption: A Modification of Fischer’s Venerable ­Reaction for the Synthesis of Heterocycles and Natural Products

“…The target had not been synthesized previously and, more generally speaking, the akuammilines had not yet captured the full attention of the synthetic community. 28–30 This is especially noteworthy given that the akuammilines share a common biosynthetic precursor with the popular strychnos alkaloids. 31 Compound 42 also possessed interesting biological activity (i.e., promising anticancer activity against resistant cell lines) and its structure was suitably complex due to its five interconnected rings and five contiguous stereocenters.…”

“…30a We reasoned that 42 could be accessed from 51 via a straightforward functional group manipulation. Then, in the key step, the pentacyclic core of the natural product would arise from an interrupted Fischer indolization sequence involving phenylhydrazine ( 20 ) and ketoalcohol 52 .…”

“…By the introduction of three new rings, three new bonds, and two stereogenic centers (including the quaternary center formed in the Fischer indolization), this transformation enabled us to complete the first total synthesis of aspidophylline A ( 42 ). 30a …”

“…Although Ben Boal initiated our efforts toward picrinine ( 43 ), he would eventually pass the torch to graduate students Joel Smith and Jesus Moreno who took the reins and completed the total synthesis. 30b,c …”

“…This effort marked the first total synthesis of this natural product and remains the only total synthesis of 43 to date. 30b,c …”