Synthesis of the Bicyclic Core of Pumiliotoxins

Abstract

Keywords: Medium rings / Ring contractions / Ring expansion / Sigmatropic rearrangements / ZwitterionsThe bicyclic core of the pumiliotoxins was synthesized in nine to eleven steps starting from L-(−)-proline. This chiral pool starting material was initially converted into an optically active 2-vinylpyrrolidine by standard operations. The first key step allowed the generation of a nine-membered ring lactam by means of a zwitterionic aza-Claisen rearrangement. The 1,4 chirality transfer was found to be low, but the double bond of the azoninone was generated with an exclusive trans configuration in a planar-S arrangement. The mixture of diastereomers thus obtained was immediately epoxid-

Asymmetric syntheses of (8R,8aS)- and (8R,8aR)-8-hydroxy-5-indolizidinones: Two promising oxygenated indolizidine building blocks

“…Following our previous reported protocol [19], without further separation, the mixture of 22 and 23 was directly treated with BF 3 OEt 2 /Et 3 SiH (CH 2 Cl 2 , 60 °C to rt) to give the reductive dehydroxylated, and concomitantly desilylated alcohols 24 and 25 as a separable diastereomeric Scheme 1 Synthesis of lactams 24 and 25 mixture (24:25 = 93:7, determined by 1 H NMR) in a combined yield of 52% (from 20). The major diastereomer 24 was tentatively assigned as trans based on our previous conclusion [16], which was confirmed by its conversion into the known bicyclic lactam 19a (vide infra) [42]. Deprotection of the N-allyl group in lactam 24 by treatment with RhCl 3 3H 2 O in propanol [43] [] D 20 37.7 (c 1.27, EtOH)}.…”

“…The spectroscopic data of (8R,8aS)-8-hydroxy-5-indolizidinone 19a is identical with those reported in ref. [42]. Thus, the stereochemical outcome of the trans-diastereoselective reductive dehydroxylation (22/23 to 24) is confirmed.…”

Total Synthesis of (+)-Pumiliotoxin 251D

“…Some suitable indolizidinone core compounds had been synthesized in nine to eleven steps, starting from L ‐(−)‐proline 11. In principle, that sequence should allow one to generate the 5‐indolizidinones and their corresponding enantiomers.…”

“…In the planning of a convergent total synthesis of (+)‐pumiliotoxin 251 D starting from a 5‐indolizidinone‐type material,11 the major challenge is the stereoselective generation of the exocyclic double bond (Figure 1). Two strategies seemed to be favorable.…”

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

“…[α] D 20 −35.3 ( c 0.89, CHCl 3 ) {lit. [27] [α] D 20 −35.1 ( c 1.08, CHCl 3 )}; IR (film) ν max : 2955, 2880, 1621, 1470, 1413, 1378, 1316, 1273, 1265, 1253, 1224, 1134, 1068, 1021 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 0.05 (s, 9H), 1.26 (s, 3H), 1.60–1.90 (m, 6H), 2.25–2.33 (m, 1H), 2.33–2.45 (m, 1H), 3.15–3.20 (dd, J = 10.0, 5.5 Hz, 1H), 3.38–3.48 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 2.1, 21.9, 26.2, 26.3 , 28.2, 35.2, 45.7, 67.3, 70.4, 168.9; HRMS ESI ( m / z ): [M + Na] + calcd for C 12 H 23 NO 2 SiNa , 264.1390; found, 264.1392.…”