Synthesis of N-acyl thioimides. New direct, catalytic and asymmetric reactions of construction of C-C bonds

Abstract

A key step in the synthesis of natural and biologically active products is the stereoselective construction of carbon-carbon bonds. Hence, the reactions involving metal enolates occupy a preeminent position in organic synthesis. Metal enolates can react with a large variety of electrophiles to generate new C-C bonds and, in the last decades, stereoselective methodologies have been developed. In the beginning, stereochemical control was based on the use of substrate control or chiral auxiliaries. Despite the great synthetic capacities, stoichiometric amounts of the chiral auxiliary and the metal complex were needed. Also, in the synthetic path, two extra steps were needed to add and eliminate the chiral auxiliary. Given the need to develop more sustainable methodologies, direct and catalytic approaches have been studied. In recent years, our group has developed a new methodology based on the use of chiral Ni(II) complexes to catalyze direct and enantioselective alkylation of N-acyl-1,3-thiazinane-2-thiones with electrophiles. Initially, the formation of a single stereocenter was studied using electrophiles that were activated with TESOTf, generating oxocarbenium cations and stable carbocations. The asymmetric formation of two stereocenters is currently being studied by direct and catalytic reactions with acetals and aldehydes activated with silyl triflates in presence of chiral Ni(II) complexes. In this context, the aim of this project is to obtain large quantities of 1,3-thiazinane-2-thione and 1,3-oxazinane-2-thione to carry out acylation reactions with the mentioned scaffolds. The obtained N-acyl thioimides may be used in the previously mentioned studies. Finally, a first assay of a direct, catalytic and asymmetric alkylation reaction will be performed using a chiral nickel(II) catalyst and a commercially available acetal activated with TESOTf as an electrophile