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.…”

“…9.6, CHCO 2 Bu t ), 1.99 (2H, quintet, J ca. 7.6, OCMe 3 ), 22.8, 20.1 and 19.0 (remaining CH 2 ), 14.1 and 11.6 (2 × Me); m/z (EI) 300 (14%), 299 (M + , 71), 266 (10), 243 (16), 242 (67), 226 (35), 214 (12), 210 (62), 198 (30), 157 (51), 156 (53), 125 (29), 124 (32), 115 (55), 102 (100), 101 (12), 85 (18), 57 (28)…”

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.…”

Indolizidine and quinolizidine alkaloids

“…24c), has been modified to yield the alkaloid's (Ϫ)enantiomer 129 (Scheme 13). 61 The desired absolute configuration at the site adjacent to nitrogen was assured by using the Davies protocol, which involves the highly diastereoselective conjugate addition of the anion of (R)-N-benzyl-1-phenylethylamine 130 to a conjugated ester, in this case (ϩ)-menthyl (E)-hex-2-enoate 131. The amino-ester product 132 was converted into the thiolactam 133 in four steps.…”