α,α′‐Disubstituted Amino Acids with Silylated Side Chains as Lipophilic Building Blocks for the Synthesis of Peptaibol Analogues

Abstract

New alpha,alpha'-disubstituted amino acids with silylated side chains have been synthesized in racemic form. Starting from a Schiff base of glycine tert-butyl ester, a large variety of alpha,alpha'-dialkylated amino acids has been obtained, depending on the alkylating reagents. The application of a hydrosilylation methodology enabled the synthesis of the same unnatural amino acids in an enantiomerically pure form. The ability of these bulky amino acids to be incorporated into peptides by solution-phase methodology has also been demonstrated, since constrained silylated dipeptides have been synthesized. These new lipophilic building blocks could be useful and innovative in the design of peptaibol analogues.

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds

“…Unnatural amino acids are used to probe the bioactive conformation of peptides and find applications in peptidomimetics. , Amino acids with silicon incorporation have several attractive features that can be useful in drug discovery. , But only a few silicon amino acids are known and with limited structural variations. − Cavelier group has made significant contributions in this area. − Some of the known silicon containing amino acids are shown in Figure ( 145 – 148 ). Incorporation of a lipophilic silicon moiety can improve the cell penetration as well as stability of the peptide toward biodegradation.…”

Silicon-Containing Amino Acids: Synthetic Aspects, Conformational Studies, and Applications to Bioactive Peptides

“…By use of an imine of benzophenone, racemic α,α′-disubstituted amino acids were obtained (Scheme 23). 55 In this synthesis, the order of addition of the alkylating agent was important. The most bulky group had to be introduced first, yielding 85, which was then alkylated with methyl iodide to give 86a.…”

“…Diastereoselective Synthesis via the Schollkopf Method. To access enantiopure δ-silyl α,α′-disubstituted amino acids, Cavelier et al 55 developed an asymmetric synthesis by hydrosilylation of dialkylated amino acids bearing an unsaturated side chain. However, direct alkylation of a bulky silyl derivative was not possible (Scheme 32).…”

Hydrophobic α,α-Disubstituted Disilylated TESDpg Induces Incipient 310-Helix in Short Tripeptide Sequence

“…The stability of this structure 17,18 and its amphipaticity 19,20 were enhanced when silicon-containing amino acids were incorporated in peptide sequences. The pioneering combination of both characteristics, silicon and α,αdisubstitution, has been explored by our research group, 21 and recently, a constrained sila analogue of GABA (γ-amino butyric acid) was also reported by Ramesh et al 22 The synthesis of the first disubstituted disilylated amino acids has been recently reported (Figure 1). 23 These compounds are particularly attractive because they combine α,α-disubstituted conformational constraint and very interesting lipophilic characteristic thanks to the silicon atom present in both side chains.…”