Azine Dearomatization in Natural Product Total Synthesis

Abstract

Since antiquity, alkaloid natural products have served as medicinal ingredients that still contribute as an inspiration for the development of novel therapeutics. For the synthetic chemist, much of the importance of natural products lies in their acting as a forcing-function for the invention of new synthetic strategies and tactics for molecular assembly. With this rich history in mind, it remains an important goal for chemists to build nitrogenous structures with greater efficiency, abiding by economies of synthesis. Nitrogenous aromatic feedstocks have been an intriguing starting point for the functionalization and construction of alkaloids for several decades, but recent advances in reaction design have opened new doors for leveraging their abundance in concise synthesis. Herein, advances in this area of synthetic ingenuity will be summarized with the aim of instructing chemists towards considering dearomatization as a strategic avenue for both target-oriented and diversity-oriented synthetic campaigns. Overall, syntheses are evaluated, compared, and contrasted to give a systematic overview of this continued area of research.

Keywords: Alkaloids; Dearomatization; Heterocycles; Pyridines; Total synthesis.

Figure 1.

(A) A depiction of the death of Socrates by the neoclassical painter Jacques-Louis David. The cup in the center of the image depicts the poisonous hemlock mixture. (B) The first synthesis of coniine (3) by Ladenburg in the late 19^th century.

Figure 2.

(A) Important heterocyclic co-factors found in biochemically important processes. (B) Various pharmaceuticals and agrochemicals that contain azines or azinium motifs. (C) Various ligand scaffolds and catalysts bearing aromatic nitrogenous heterocycles. ADP=adenosine diphosphate.

Figure 3.

(A) The two paths of nucleophile addition into pyridiniums and the reactivity of the resulting dihydropyridine; (B) An illustration of pyridinium reactivity through the retrosynthetic analysis of (±)-ervitisine.

Figure 4.

Retrosynthetic analysis of (±)-isomatrine by (A) Sherburn and co-workers, and (B) Reisman and co-workers.

Figure 5.

Mechanistic options for pyridinium reduction.

Figure 6.

Retrosynthetic analyses of GB13 by (A) Mander, (B) Sarpong, and (C) Shenvi.

Figure 7.

Mechanistic possibilities for pyridinium photoisomerizations.

Figure 8.

Zincke rearrangement overview.

Figure 9.

Synthetic strategies to of (+)-porothramycin by Fukuyama and Vanderwal.Retrosynthetic analysis of (+)-porothramycin B by (A) Fukuyama and co-workers, and (B) Vanderwal and co-workers.

Figure 10.

Dearomative cycloadditions strategic overview.

Figure 11.

Retrosynthetic analysis of (+)-nominine by (A) Natsume and (B) Gin.

Scheme 1.

Total synthesis of (±)-ervitisine by Bosch and co-workers.

Scheme 2.

Total synthesis of (±)-lemonomycinone and (±)-renieramycin by Magnus and co-workers.

Scheme 3.

Total synthesis of (−)-lasubine I by Comins and co-workers.

Scheme 4.

Total synthesis of (+)-lepadin B by Charette and co-workers.

Scheme 5.

Total synthesis of (+)-N-Me-aspidospermidine by Smith and Grigolo.

Scheme 6.

Total synthesis of (−)-nuphar indolizidine by Karimov and co-workers.

Scheme 7.

Total synthesis of (±)-cocculidine B by Sarpong and co-workers.

Scheme 8.

Comparative synthetic approaches to the matrine alkaloids by (A) Sherburn and (B) Reisman.

Scheme 9.

Total synthesis of (±)-LSD by Vollhardt and co-workers.

Scheme 10.

Total synthesis of (±)-dihydrolysergic acid by Boger and co-workers.

Scheme 11.

Total synthesis of (±)-lysergic acid by Smith and co-workers.

Scheme 12.

Total synthesis of (±)-corynoxine by Xia and co-workers.

Scheme 13.

Total synthesis of (−)-securinine by Horii and co-workers.

Scheme 14.

Total synthesis of (±)-cytisine by Arnold and co-workers.

Scheme 15.

Total synthesis of (±)-lasubine II by Unsworth and co-workers.

Scheme 16.

Total synthesis of (−)-quinocarcin by Stoltz and co-workers.

Scheme 17.

Total synthesis of (−)-juromycin by Stoltz and co-workers.

Scheme 18.

Comparative synthetic approaches to the GB13 by (A) Mander, (B) Sarpong, and (B) Shenvi.

Scheme 19.

Total synthesis of ()-dihydrofumariline by Hanaoka and co-workers.

Scheme 20.

Total synthesis of (±)-mannostatin A and derivatives by Mariano and co-workers.

Scheme 21.

Total synthesis of (±)-strychnine by Vanderwal and Martin.

Scheme 22.

Total syntheses of of (+)-porothramycin B by (A) Fukuyama and (B) Vanderwal.

Scheme 23.

Total Synthesis of (±)-norsecurinine by Magnus and co-workers.

Scheme 24.

Total Synthesis of (±)-keramaphidin B by Baldwin and co-workers.

Scheme 25.

Total synthesis of (±)-altemicidin B by Maimone and Magnani.

Scheme 26.

Total synthesis of (±)-Bao Gong Teng A by Jung and co-workers.

Scheme 27.

Total synthesis of (+)-affinisine by Gaich and co-workers.

Scheme 28.

Comparative total syntheses of (+)-nominine by (A) Natsume and co-workers, and (B) Gin and Peese.