New synthetic applications of organozincs: Chemoselective methylene insertions and enantioselective preparation of functionalized secondary alcohols.

Abstract

Organozinc and copper derivatives are useful reagents in organic synthesis. Because of the high functional group tolerance of the carbon-zinc bond, many protection and deprotection steps can be avoided. Dialkylzincs can be used in the catalytic asymmetric addition to aldehydes; however, this chemistry has been limited by the unavailability of dialkylzincs. Thus, new methods for the preparation of zinc and copper organometallics, that are not easily obtainable by conventional methods, were investigated. The insertion of a methylene into a carbon-metal bond was realized by the reaction of iodomethylzinc iodide and a copper nucleophile. This process allowed the preparation of benzylic copper reagents by the methylene homologation of aryl copper compounds. Zinc homoenolates were prepared by the reaction of iodomethylzinc iodide and lithium enolates. The in situ trapping of methylene homologated copper acetylides by carbonyl compounds provided homopropargylic alcohols. Multiple methylene insertions were possible using an excess of iodomethylzinc iodide with copper acetylides. Two methods for the preparation of functionalized dialkylzincs have been developed: (1) the transmetalation of diorganomercurials, which were prepared by the reaction of bis-iodomethylmercury and functionalized zinc and copper reagents, and (2) a zinc-iodine exchange reaction using diethylzinc and functionalized alkyl iodides. The functionalized dialkylzincs can then be used in catalytic asymmetric addition to aldehydes in order to synthesize optically active secondary alcohols, using a trans-(1R,2R)-bis trifluorosulfinamidocyclohexane-titanium complex as the catalyst. The methylene homologation reaction proved to be useful in the preparation of benzylic and propargylic organometallics not easily obtainable by conventional methods. It also allowed the preparation of some interesting 2,3-disubstituted-1,3-butadienes through the multiple insertions of copper acetylides. Of the two methods for the preparation of dialkylzinc derivatives, the zinc-iodine exchange proved to be the most general and allowed the enantioselective synthesis of secondary alcohols.