New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

Abstract

The syntheses of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.

Cyclization of enaminones derived from N-phenacylpyrrolidin-2-ones to pyrrolizines under acidic conditions

“…The strategy we planned for preparing the key enaminones 4 is shown in disconnection form in Scheme 1. Eschenmoser sulfide contraction, 4,5 a method we have used with much success in our routes to alkaloids and related nitrogen heterocycles, [6][7][8][9][10] was envisaged between pyrrolidine-2-thiones 7 and appropriately substituted phenacyl halides 8. Intermediates 7 would themselves be made by thionation of the corresponding lactams 9, which would in turn be prepared by N-alkylation of pyrrolidin-2-one (10) with phenacyl halides 8'.…”

Biologically active indolizidine alkaloids

“…The toxicity of tashiromine is unknown 37 ; however, this indolizidine alkaloid is structurally related to toxic and teratogenic lupin (quinolizidine) alkaloids found in commercially important grain legume crops. Most studies on tashiromine have focused on its full synthesis 129‐132 …”

A de novo Stereocontrolled Synthetic Approach to a Functionalized Indolizidine Core

“…1 2 3 Among the large family of saturated azaheterocyles, 4,5 the indolizidine core may be found as a key element in the structure of some relevant bioactive natural compounds or alkaloids, such as (+) tashiromine, (–)-swainsonine, or (–)-steviamine (Figure 1 ). 6` b c…”