One-step stereospecific strategy for the construction of the core structure of the 5,11-methanomorphanthridine alkaloids in racemic as well as in optically pure form: synthesis of (±)-pancracine and (±)-brunsvigine

Abstract

The unique core structure of the complex pentacyclic 5,11-methanomorphanthridine has been constructed stereospecifically in one step by an intramolecular [3+2] cycloaddition of a non-stabilized azomethine ylide (AMY), generated by the sequential double desilylation of 14 using Ag^IF as a one-electron oxidant. The formation of the single diastereomer in the key step is explained by the preferred transition state produced by endo attack of the AMY on the "Re" face of the dipolarophile. An asymmetric version of the cycloaddition using a chiral dipolarophile was applied to construct the core structure 68 with 63% ee. This strategy was successfully applied to the formal synthesis of (±)-pancracine and the total synthesis of (±)-brunsvigine. An unprecedented and interesting skeletal rearrangement product 49 was observed during the attempted assembly of the E ring from 46 through Horner-Wadsworth-Emmons reactions. Mechanisms involving azetidinium salt formation or the Grob-type fragmentation are advanced to explain the observed rearrangement.