Solid-Phase Synthesis of Diversely Constrained Peptidomimetics

AGUSTINA LA VENIA; VIKTOR KRCHNAK

Praga

Congreso; 4th EuCheMS Chemistry Congress; 2012

ORAL PRESENTATIONAbstract:Methodology providing access to an array of diverse secondary structure peptidomimetics, with complete control of their stereochemistry, is an indispensable tool for investigation complex structure-function relationships of biologically significant peptides and proteins, and also to obtain highly active and selective compounds with enhanced proteolytic stability.1 In particular, tandem N-acyliminium ion cyclization ? nucleophilic addition, which represents a powerful strategy to generate fused-ring systems, has been useful to synthesize constrained peptidomimetics.2 The concept of these tandem cyclizations inherently enables sequential and independent synthesis of the lineal precursors for cyclic iminiums followed by incorporation of precursors for the nucleophilic addition, allowing the combination of the precursors of both rings to produce combinatorial libraries. The aim of this work has been to develop a general methodology for efficient and expeditious solid-phase synthesis of diversely constrained peptidomimetics, in which the constraints would be assembled from simple building blocks using the N-iminium chemistry during solid-phase synthesis, rather than typical incorporation of pre-formed scaffolds. Thus a library of varied heterocycles with functional as well as skeletal diversity was efficiently synthesized with full stereocontrol, achieving several ring sizes and including different internal nucleophiles (N, O, S, C). The analysis of these experiments allowed to recognize the internal nucleophile?s requirements to promote the second cyclization, concluding in the case of N nucleophiles that sulfonamides achieved the best results. In addition a strong influence of the different tested aminoacids in products? stereochemistry was observed, mainly of those aminoacids present in the first ring. All the fused-rings generated are available to be introduced in a larger peptide, but are also interesting per se, being their biological activity measurement in process.