Late-Stage Diversification of Phosphinic Dehydroalanine Pseudopeptides Based on a Giese-Type Radical C-Alkylation Strategy

Abstract

A straightforward, late-stage diversification strategy for the installation of side chains on readily accessible unsaturated phosphinopeptidic scaffolds based on a Giese-type addition of alkyl radicals has been investigated. Among different alternatives, the preferred methodology is operationally simple as it can be carried out in an open flask with no need for protection of acidic moieties. Direct application to the synthesis of SPPS-compatible building blocks or to longer peptides is also reported.

Phosphinic Peptides as Tool Compounds for the Study of Pharmacologically Relevant Zn-Metalloproteases

“…Another major concern that must be taken under consideration is that optimization opportunities strongly depend on synthetic advances in the field, ,,, as highlighted by the application of combinatorial chemistry principles in the discovery of selective inhibitors of several Zn-metalloproteases ,,, or the successful preparation of capricious sequences which allowed the synthesis of RXPA380 , or inhibitors of aminopeptidase A. , Finally, the transformation of phosphinic inhibitors of MMPs to molecular probes has set the basis for similar studies with other pharmacologically important Zn-metalloproteases, expanding the range of applications of this privileged class of tool compounds. Future development of novel, improved tool compounds or probes thereof will be largely accelerated by addressing unmet challenges such as stereoselective synthetic strategies, late-stage diversification approaches, or synthesis of unusual, conformationally constrained analogues. − …”