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Formal Synthesis of (–)‐Perhydrohistrionicotoxin Using a Thorpe‐Ziegler Cyclization Approach. Synthesis of Functionalized Aza‐Spirocycles
Author(s) -
Vu Van Ha,
Bouvry Christelle,
Roisnel Thierry,
Golhen Stéphane,
Hurvois JeanPierre
Publication year - 2019
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201801604
Subject(s) - yield (engineering) , alkylation , chemistry , piperidine , stereochemistry , combinatorial chemistry , organic chemistry , materials science , metallurgy , catalysis
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 .