22 November 2007

Amino acids and peptides are widespread throughout nature, and their chemistry is under intensive study. Recently it has been shown that their unnatural analogs are key elements of drug design, and among such compounds sila-peptides are of increasing interest. Our goal is to replace α-carbon to silicon in peptide chain (Scheme 1), since it is probably one of the most interesting positions in peptides. This substitution may lead to a dramatic change in peptide reactivity and bioactivity.

The strategy we chose for the synthesis of the desired molecule, the model of α-silapeptide 1, was via α-amido silyl lithium 2 (Scheme 2, path a). Unfortunately during our research we found, that in contrast to its carbon analog, 2 is thermally unstable and could not be synthesized by conventional techniques, neither by exchange from 3 nor by transmetallation form 4 (Scheme 2, paths b and c).

In this report we show an elegant way for stabilization of 2 (Scheme 2, path d), and other unstable silyl lithiums by “ate”-complexation. Using this approach we were able to stabilize 2 in its “ate”- complex form 5, and use it for the synthesis of 1 (Scheme 2). We believe that even more exotic molecules can be prepared using the same method, and that it may be useful in many fields of organometallic chemistry.