Formal Synthesis of (–)‐Perhydrohistrionicotoxin Using a Thorpe‐Ziegler Cyclization Approach. Synthesis of Functionalized Aza‐Spirocycles

Abstract

The formal synthesis of (–)‐PHTX is described. Our approach was based on the anodic cyanation of (S)‐1‐(1‐phenylethyl)‐piperidine (–)‐1 to afford α‐aminonitrile 2 in 85 % yield in a 53:47 dr. The presence of the α‐phenylethyl group as the chiral auxiliary ensured the control of the absolute configuration of the future C6 spiro‐center during the alkylation step of 2, which was carried out with 1‐bromo‐4‐chlorobutane. Next, elaboration of the 1‐azaspiro[5,5]undecane‐7‐one ring system was achieved in a two‐step sequence, involving (a) a Thorpe‐Ziegler annulation, and (b) the hydrolysis–decarboxylation of enaminonitrile (–)‐5 to afford spiroketone (+)‐6 in >99:1 dr. Finally, the incorporation of the future C7 butyl chain was carried out stereoselectively through a new reaction sequence which involved the synthesis of tricyclic oxazolidinone (–)‐11 and alkylation of the intermediary syn‐fluorohydrin (+)‐13 with nBuMgCl to form oxazolidinone (+)‐15 in an overall 19 % yield from (–)‐1.

(1R/S,7aS/R)-1-Benzyl-1-[2,8-bis(trifluoromethyl)quinolin-4-yl]-hexahydro-oxazolo[3,4-a]pyridin-3-one

“…Finally, the reaction with an electrophile such as benzyl bromide gives the C-alkylated product. Alkylation of oxazolidinone at this position has only been reported once, involving coupling with transition metal organometallics [12]. On the other hand, coupling reactions of lithiated 4-picoline are better known and proceed more efficiently at a more substituted center with benzyl bromide than with methyl iodide [13].…”

Total Synthesis of (−)-Lepadiformine A via Radical Translocation–Cyclization Reaction

“…Azaspirocyclic alkaloids have attracted considerable attention as promising drug candidates and synthetic targets due to their fascinating biological activities . Among them, (−)-lepadiformine A ( 1 ), which was isolated from the marine tunicate Clavelina lepadiformis in 1994 by Biard and co-workers, exhibits various biological activities such as cytotoxicity, acting as a cardiac K + -channel blocker, and antiarrhythmic properties (Figure ).…”