Collective Total Synthesis of Aspidofractinine Alkaloids through the Development of a Bischler–Napieralski/Semipinacol Rearrangement Reaction

Abstract

A tandem Bischler-Napieralski/semipinacol rearrangement reaction has been developed for the purpose of assembling a bis(spirocyclic) indole framework, a privileged structural unit of aspidofractinine-type monoterpenoid indole alkaloids, and was used in combination with a subsequent Mannich reaction to expeditiously construct the central bridged bicyclo[2.2.1]heptane ring system of these molecules with contiguous quaternary centers. The development of this novel strategy culminated in the collective total synthesis of four aspidofractinine alkaloids.

Two Green Protocols for Halogenative Semipinacol Rearrangement

“…It has been strategically used for natural product synthesis and construction of highly congested and synthetically challenging quaternary carbons . For examples, semipinacol rearrangement was designed as a key step in the recent total syntheses of lycojaponicumin A, aspidofractinines, gardmultimine A, brevianamide A, illisimonin A, and kopsinitarine E (Scheme a, the quaternary carbon center from semipinacol rearrangement was highlighted in red). Halogenative semipinacol rearrangement (HSPR) of allylic alcohols produces β-halocarbonyls with an α-quaternary center and the β-halo functional group that allows for a vast number of well-established reactions including nucleophilic substitution, cyclization, cross-coupling, and radical reactions .…”

Recent development and applications of semipinacol rearrangement reactions

“…Aiming at assembling a bis(spirocyclic) indole framework with continuous quaternary carbon centers, Tu's group established a Bischler–Napieralski/semipinacol rearrangement that enables the transformation of tryptamine-derived allylic alcohols 70 to tetracyclic indoles 71 in a highly diastereoselective fashion ( Scheme 15 ). 65 Upon treatment of bis(spirocyclic) indole 74 under acidic conditions, the following intramolecular Mannich reaction would produce bridge[2.2.1]cyclic ketone 75 . This advanced pentacyclic intermediate could be applied in the collective total synthesis of four aspidofractinine alkaloids, further showcasing the synthetic utility of this methodology.…”

Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine A

“…[15] In 2017, Qin's group provided a new procedure using an α-ketol rearrangement to get access to the F-ring in the synthesis of kopsine and kopsanone. [16] Ma's group reported their synthesis of kopia alkaloids in 2018 through SmI 2 -mediated reductive coupling of keto and nitrile groups followed by an α-ketol rearrangement, [17a] and in 2020, a Mannich type cyclization to establish the ring system of complex kopsinitarine E. [17b] Three other methods have been reported for the construction of the bicyclo [2.2.2] octane ring system along the way towards kopsia alkaloids in 2020, including a Fischer indole/ Mannich cascade reaction by Soós's group, [18] an aldol cyclization by Tu's group, [19] and an intramolecular alkylation by Ye's group. [20] Most recently, in 2022, Jia's group reported an asymmetric Diels-Alder reaction to assemble the bicyclo [2.2.2] octane moiety.…”