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.
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van Ha Vu, Christelle Bouvry, Thierry Roisnel, Stéphane Golhen, Jean-Pierre Hurvois. Formal Synthesis of (-)-Perhydrohistrionicotoxin Using a Thorpe-Ziegler Cyclization Approach. Synthesis of Functionalized Aza-Spirocycles. European Journal of Organic Chemistry, Wiley-VCH Verlag, 2018, 2019 (6), pp.1215-1224. ⟨10.1002/ejoc.201801604⟩. ⟨hal-01988911⟩

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