Asymmetric synthesis of heterocycles via nucleopaladation reactions: Development, rational design of chiral ligands and mechanistic studies

Abstract

The main objective of this project is the application of stereoselective oxo-palladation reactions aiming the synthesis of heterocycles of biological interest, where the formation of the sigma-Pd (II) intermediate should be used in subsequently variations. To do so, two approaches will be applied. The first focuses on the synthesis of ”2-isoxazolinic, which, despite a high occurrence, few methodologies point to its stereoselective synthesis involving the C-O bond. Thus, the general objective of the first part of the work will be the developement of enantioselective methodologies involving the intermediate Wacker sigma, aiming at a synthesis of this compounds from oximes. Considering the great potential of methodological application of Heck reactions, in the second part of this project we envisage a stereoselective Wacker / "Heck-type" tandem conditions for a formal C(sp3)-C(sp3) coupling employing alkenols. For this purpose, a Redox-Relay strategy, which has precedents only for sp2 and sp carbons, will be employed.For all the successfully developed reactions, we intend to study from the mechanistic point of view the processes that govern its stereochemistry. We will employ computational techniques, where each proposed reactive intermediate and its transition states will be calculated. In addition, traditional organic physics-chemistry tools (kinetic velocity laws, KIE, etc.) will bring us evidence of limiting steps. We will also employ the approach involving multidimensional predictive models developed by Prof. Sigman for rationalization and development of ligands in metal catalysis.