A versatile annulation protocol toward novel constrained phosphinic peptidomimetics.

The development of a novel 3-center 2-component annulation reaction between alpha,omega-carbamoylaldehydes and suitably monoalkylated phosphinic acids is reported. Depending on the starting alpha,omega-carbamoylaldehyde, diverse phosphinic scaffolds varying in the size of their rigidity element, the nature and stereochemistry of substituents, and the participation of heteroatoms in the azacyclic ring system can be obtained in one synthetic step and in high yield. In addition, this methodology allows the synthesis of Fmoc-protected constrained aminophosphinic acids that can be easily converted to suitable pseudodipeptide building blocks compatible with the requirements of peptide synthesis on the solid phase.

Chemoselective protection of solid-phase compatible Fmoc-phosphinic building blocks.

An efficient four-step synthetic strategy able to fully discriminate hydroxyphosphinyl and carboxylic groups of Fmoc-phosphinic building blocks and related analogues has been developed. The proposed method applies selective acidic removal of the phenacyl (Pac) group from the hydroxyphosphinyl functionality and protection by the 1-adamantyl (Ad) group. Reductive removal of the Pac group from the carboxylic functionality leads to Fmoc-protected phosphinic pseudodipeptidic units suitable for phosphinic peptide and library development using solid-phase peptide synthesis (SPPS).

Active methylene phosphinic peptides: a new diversification approach.

[reaction: see text] Simple, rapid, and efficient methods for P(1)' diversification of phosphinic peptides have been developed, employing alkylation and Knoevenagel-type condensation reactions with active methylene phosphinic scaffolds, thus leading to a wide variety of diversified phosphinic and dehydrophosphinic peptides.