Silane alkylation by transient introduction of a metalation-directing-group

ORGN 644

Cui Cao and Scott McN. Sieburth, Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, PA 19122
Silanediols 1 are effective inhibitors of aspartic and metallo protease enzymes, prepared by treatment of the corresponding diphenylsilane 2 with strong acid. As part of an effort to develop efficient and general methods for the preparation of 2, we have studied the alkylation of chloromethylsilane 3, which can be prepared in one step. In an approach inspired by the Comin's ortho metallation of benzaldehydes (J. Org. Chem. 1984,49,1078.), the fluoride in 3 is displaced with a nitrogen carrying a metal ligating group. This intermediate is then treated with a lithium reagent to effect deprotonation and then alkylated. Workup with aqueous HF reintroduces the fluoride, yielding 4. Introduction of the amine and elaboration to 2 will be discussed.