Total Synthesis of (−)‐Alstofolinine A through a Furan Oxidation/Rearrangement and Indole Nucleophilic Cyclization Cascade

Abstract

A reaction cascade of aza‐Achmatowicz rearrangement followed by indole nucleophilic cyclization was developed to generate the common indole‐fused azabicyclo[3.3.1]nonane core of the macroline family alkaloids. The key to the success of the strategy relies on the careful manipulation of protecting groups and judicious selection of chemoselective furan oxidation conditions. The synthetic utility was further demonstrated on the asymmetric total synthesis of (−)‐alstofolinine A.

Asymmetric synthesis of N-bridged [3.3.1] ring systems by phosphonium salt/Lewis acid relay catalysis

“…Moreover, only sporadic examples that disclosed the synthesis of chiral azabicyclo [3.3.1]nonane compounds have been available so far (Fig. 1b), which utterly relied on utilizing chiral auxiliary 24 or employing chiral starting materials [14][15][16][17][18][19][20][21][22][23] , respectively. To the best of our knowledge, the catalytic asymmetric protocol for constructing such ring systems has never been reported to date, which remains a tremendous challenge and long-standing assignment in modern synthetic chemistry.…”

Fenton Chemistry for Achmatowicz Rearrangement

“…A chmatowicz rearrangement (AchR) is a very important reaction for the construction of six-membered heterocyclic scaffolds (dihydropyranones and dihydropyridinones), which are frequently found in bioactive molecules and natural products. 1 The synthetic utility of AchR has been illustrated by various transformations of AchR products, 2 including Oglycosylation, 3 [5 + 2] cycloaddition, 4 Kishi reduction, 5 Ferrier allylation, 6 ketalization, 7 redox isomerization, 8 and Tsuji− Trost arylation 9 (Figure 1a). The importance of AchR in organic synthesis aroused great interest in developing new and more efficient oxidation protocols, which can be classified into chemical 10 and enzymatic strategies 11 (Figure 1b).…”

Natural product total synthesis using rearrangement reactions

“…Overman's aza-Cope rearrangement followed by Mannich cyclization is a powerful tool in generating complex architectures from easily synthesized precursors. The method has been applied to the total synthesis of a variety of natural products, including actinophyllic acid (24) discussed here (Scheme 5). 10 Iminium formation between 25 and formaldehyde triggered the aza-Cope rearrangement to afford an enol intermediate, which underwent an intramolecular Mannich cyclization to generate the pyrrolidinyl ring.…”

“…The use of furan derivatives as synthons to simplify bond disconnection was also adopted recently by the groups of Qi 24 and Beaudry 25 (Scheme 9). In Qi's work, an aza-Achmatowicz rearrangement of 78 furnished the hemiaminol intermediate, which was further engaged in a Pictet-Spengler type cyclization to generate the bridged [3.3.1] bicycle 79.…”