Formal Total Synthesis of (±)‐Strictamine by [2,3]‐Sigmatropic Stevens Rearrangements

Abstract

To date, more than 100 congeners of the akuammiline alkaloid family have been isolated. Their signature structural element is a methanoquinolizidine moiety, a cage-like scaffold structurally related to adamantane. The structural variations of the family members originate from oxidative processes that mostly trigger rearrangements of the methanoquinolizidine motif. The family of the akuammiline alkaloids is best represented by strictamine. It bears the least functionalized carbon skeleton of all family members without lacking the signature structural motifs. Herein, we report the formal synthesis of strictamine through a Stevens [2,3]-sigmatropic rearrangement as a key step and the synthetic pitfalls related with its synthesis.

α-Arylamino Diazoketones: Diazomethane-Loading Controlled Synthesis, Spectroscopic Investigations, and Structural X-ray Analysis

“…In fact, the addition of amines could trigger ketene formation events on acid halides featuring acidic α-protons, while realizing chemistry with big excesses of CH 2 N 2 (2–6 equiv, i.e., 200–600 mol %) poses serious questions on the real practicability of using such an hazardous reagent . The reliability of the method was further documented in the synthesis of enantiopure diazoketones, as reported in recent works by Deska and Gaich . Additionally, we also extended its use to the chemoselective acylation of different nucleophiles such as amines and alcohols in the biomass-derived solvent 2-methyltetrahydrofuran (2-MeTHF) …”

“…18a The reliability of the method was further documented in the synthesis of enantiopure diazoketones, as reported in recent works by Deska 32 and Gaich. 33 Additionally, we also extended its use to the chemoselective acylation of different nucleophiles such as amines and alcohols 34 in the biomass-derived solvent 2-methyltetrahydrofuran (2-MeTHF). 35 Cognizant of the substantial improvement introduced in acylation processes by running reaction in the presence of CaO, we deemed similar alkylation procedures could benefit as well.…”

Asymmetric Total Syntheses of the Akuammiline Alkaloids (−)‐Strictamine and (−)‐Rhazinoline

“…In 2016, Zhu's group reported a successful synthetic approach to (±)‐strictamine using a sequence of ring forming reactions; however, the final Ni‐mediated E‐ring formation suffered from low efficiency . Later, a few groups including Fujii/Ohno, Gaich,, and Snyder, as well as our group independently reported formal syntheses of strictamine by intercepting Zhu's intermediate. In 2017, Zu et al described the synthesis of (±)‐strictamine featuring a bioinspired late‐stage ring migration step .…”

Total Synthesis of (±)‐Corymine

“…Garg and co‐workers also introduced the elegant synthesis of picrinine ( 2 ) . The synthesis of strictamine ( 3 ) was achieved by the groups of Garg, Zhu, Ohno, Gaich,, and Snyder, and the synthesis of scholarisine A (not shown) was accomplished by the groups of Smith and Snyder …”