Stereoselective Synthesis of Heterocyclic Zinc Reagents via a Nickel-Catalyzed Radical Cyclization

Abstract

Unsaturated iodo or bromo acetals of type 2 undergo a smooth cyclization mediated by diethylzinc (2 equiv) and Ni(acac)2 as catalyst (2−5 mol %). These cyclizations proceed via a radical mechanism affording a (tetrahydrofuranylmethyl)zinc halide of type 1, which can be reacted with various electrophiles after a transmetalation with CuCN·2LiCl. High stereoselectivities are usually observed in the ring closures, especially if monocyclic cyclization precursors are used. In these cases, bicyclic products of the endo-configuration are obtained with over 94% diastereoselectivity. The synthetic method has been extended to the preparation of a nitrogen heterocycle and over 98% pure trans-4,5-disubstituted γ-butyrolactones. A short enantioselective synthesis of (−)-methylenolactocine (3) using the radical cyclization and a novel oxidation of α-silyl zinc peroxide as a key step is also described.