Silaproline, a Silicon-Containing Proline Surrogate

Silaproline (Sip) is a proline analogue that exhibits similar conformational properties as the natural amino acid in peptides. Moreover, the presence of a dimethylsilyl group confers to silaproline higher lipophilicity as well as improved resistance to biodegradation. The stereoselective synthesis of protected silaproline and two routes to obtain Fmoc-(L)Sip-OH on gram scale using chiral HPLC resolution are reported. Silaproline was introduced into the sequences of various natural peptides, and the influence of the silylated proline analogues on bioactivity was studied. In particular, considering the importance of polyproline II helices (PPII) in protein–protein molecular interactions and biology, a series of silaproline oligomers from dimer to pentamer were studied and shown to preferentially populate the polyproline type II secondary structure in both chloroform-d and methanol-d4 as shown by circular dichroism (CD), NMR spectroscopy, and molecular modeling.