An Expeditious Synthesis of the Dendrobatid Indolizidine Alkaloid 167B

Abstract

The synthesis of the racemic title alkaloid 1 has been accomplished in eight steps and 7.2% overall yield from pyrrolidine‐2‐thione (5) and ethyl hex‐2‐enoate (6). Key steps include a ring closure that takes advantage of the nucleophilicity of a vinylogous urethane 8, and stereoselective reduction of the C=C double bond of a bicyclic vinylogous amide 12.

Studies towards the enantioselective synthesis of 5,6,8-trisubstituted amphibian indolizidine alkaloids via enaminone intermediates

“…The reason for our optimism lay in our reported synthesis of the simple alkaloid indolizidine 167B 24, among others, one step of which entailed acid-or base-induced hydrolysis of ethyl, tertbutyl or (−)-menthyl esters 25 and cyclisation of the carboxylic acid intermediate via a mixed anhydride to yield the product 26 in overall yields of up to 89%. 18,22 In the event, when solutions of 20a and 20b in trifluoroacetic acid were maintained at ambient temperature for 3 h before neutralisation and work-up, (2R,3R)-3-[(2E)-(2ethoxycarbonylmethylene)pyrrolidin-1-yl]-2-ethylhexanoic acid 27a and its (2S,3R)-isomer 27b could be isolated and characterised (Scheme 4), although attempts at purification Scheme 4 Reagents and conditions: i, CF 3 CO 2 H, rt, 3 h; ii, Ac 2 O, K 2 CO 3 , MeCN, rt, 18 h, then reflux, 3 h. [Yields from (2R,3R)-precursors: 28a, 85% over 2 steps; 29a, 80% over 2 steps; 30, 83% over 2 steps. Yields from (2S,3R)-precursors: 28a + 28b, 52%, ca.…”

“…t and quintet, J ca. (5), 178 (7), 165 (12), 164 (53), 140 (9), 137 (10), 136 (100), 110 (22) and 55 (10) (found: M + , 207.1630. C 13 H 21 NO requires 207.1623).…”

A Simple Entry to the 5,8-Disubstituted Indolizidine Skeleton via Hetero Diels-Alder Reaction

“…In the literature, there are several examples of this transformation in similar compounds, and we tried some of them. The transformation of the ketone into a dithioketal and reduction with Ni-Raney/H2 [35], or treatment with TCDI and radical reduction of the thioester formed [36] gave complex mixtures. The structures and relative stereochemistry of both cycloadducts were studied using NMR experiments, which confirmed that the major compound was the endo cycloadduct.…”

“…In the literature, there are several examples of this transformation in similar compounds, and we tried some of them. The transformation of the ketone into a dithioketal and reduction with Ni-Raney/H2 [35], or treatment with TCDI and radical reduction of the thioester formed [36] gave complex mixtures. Scheme 7.…”

Recent advances in the synthesis of naturally occurring pyrrolidines, pyrrolizidines and indolizidine alkaloids using proline as a unique chiral synthon

“…The indolizidine moieties even with alkyl substitution at various positions exhibit unique characteristics especially in blocking neuromuscular transmission. 90 The polyhydroxy substituted indolizidines like swainsonine, castanospermine alkaloids have attracted special interest for their anti HIV and anticancer properties and are also known for being the best mimics of sugars to act as potential glycosidase inhibitors. 91 The formulation of indolizidine alkaloids can be achieved either by starting with a six member heterocycle and then annulating a ve member on to it or vice versa.…”