Unified Synthesis of Polycyclic Alkaloids by Complementary Carbonyl Activation*.

Guoli He,Benjamin List,Mathias Christmann

doi:10.1002/anie.202102518

Abstract

A complementary dual carbonyl activation strategy for the synthesis of polycyclic alkaloids has been developed. Successful applications include the synthesis of tetracyclic alkaloids harmalanine and harmalacinine, pentacyclic indoloquinolizidine alkaloid nortetoyobyrine, and octacyclic β‐carboline alkaloid peganumine A. The latter synthesis features a protecting‐group‐free assembly and an asymmetric disulfonimide‐catalyzed cyclization. Furthermore, formal syntheses of hirsutine, deplancheine, 10‐desbromoarborescidine A, and oxindole alkaloids rhynchophylline and isorhynchophylline have been achieved. Finally, a concise synthesis of berberine alkaloid ilicifoline B was completed.

Highlights

A complementary dual carbonyl activation strategy for the synthesis of polycyclic alkaloids has been developed
Intermediate III[4] was considered the central linchpin for a divergent synthesis[5] of polycyclic alkaloids
Toward this goal we identified two major challenges: 1) selective activation of the amide carbonyl group to participate in the electrophilic cyclization;[6] 2) subsequent selective activation of the second carbonyl group to achieve lactamization

Summary

Introduction

A complementary dual carbonyl activation strategy for the synthesis of polycyclic alkaloids has been developed. With POCl3, 10 was isolated in 6 % yield along with 84 % of imine 9 a (Table 1, entry 1). We hypothesized that imine–enamine tautomerization during second cyclization and the leaving ability of the alkoxyl group could be the critical prerequisites for the second cyclization.[11] After a screening of bases (see the Supporting Information), we achieved a slight improvement to 10 % yield of 10 using K2CO3 (Table 1, entry 8).

Results

Conclusion