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Regio- and stereoselective SN2′ reaction of an allylic picolinate in the synthesis of LY426965

Author:
Kobayashi, Yuichi, Yamaguchi, Kai, Morita, Masao
Source:
Tetrahedron 2018 v.74 no.15 pp. 1826-1831
ISSN:
0040-4020
Subject:
aldehydes, amination, catalytic activity, chemical structure, copper, esterification, ozonolysis, palladium, picolinic acid, piperazine, stereoselectivity
Abstract:
Allylic substitution of secondary γ,γ-disubstituted allylic picolinates with ArMgBr-based copper reagents was applied to the synthesis of LY426965. Reduction of (R)-6-(PMB-oxy)-3-hexyn-2-ol of 93% ee (PMB = p-MeOC6H4CH2) using Red-Al gave (R,Z)-4-iodo-5-(PMB-oxy)hex-3-en-2-ol, which was later converted to the Me-substituted allylic picolinate by Pd-catalyzed coupling with MeZnI followed by esterification with picolinic acid. Allylic substitution with PhMgBr/Cu(acac)2 proceeded with high anti SN2′ selectivity (99%). Ozonolysis, addition of c-Hex-MgBr to the resulting aldehyde, and reductive amination with the piperazine derivative afforded LY426965.
Agid:
6289802