Total Synthesis of Poison Dart‐Frog Alkaloids (−)‐209D, (−)‐209B, (−)‐223V, 3‐epi‐(−)‐223AB

Abstract

AbstractSynthesis of poison dart frog indolizidine alkaloids (−)‐209D, (−)‐209B and (−)‐223V were accomplished, with a common tricyclic lactone skeleton as the starting compound, in overall yields of 8.8 %, 5.5 %, and 5.2 %, respectively. The construction of the C7−C8 bond in the synthesis of 209D involves simple ring closure metathesis and hydrogenation reactions. However, in the synthesis of 209B and 223V, the C7−C8 bond and the stereochemistry of C8, is achieved through radical cyclization reactions controlled by allylic 1,3‐strain. Cleavage of the excess carbon on the C5 for all the related intermediates were done by Barton decarboxylation protocol. Reduction of the corresponding indolizidin‐3‐ones by LAH completed the total synthesis of these three target molecules. The quantum mechanics calculations were performed on α‐amidyl carbon radical intermediates to account for the observed diastereomeric ratio (~9 : 1) of the key Barton decarboxylation step. Ultimately, the synthesis of 3‐epi‐(−)‐223AB was accomplished in 51.6 % through the cuprate addition to the activated lactam of a late intermediate in the synthesis of (−)‐167B.