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

The formal synthesis of (-)-PHTX is described. Our approach was based on the anodic cyanation of (S)-1-(1-phenylethyl)-piperidine (-)-1 to afford alpha-aminonitrile 2 in 85 % yield in a 53:47 dr. The presence of the alpha-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.