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 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 n BuMgCl to form oxazolidinone (+)‐ 15 in an overall 19 % yield from (–)‐ 1 .