New methodologies in enantioselective catalysed C-C bond formation

The proposed research focuses on the development of novel catalytic approaches for asymmetric C-C bond formation, a key transformation in the synthesis of pharmaceuticals, agrochemicals and novel materials. In particular, we will develop new and robust catalytic methods for the enantioselective addition of readily available nucleophiles to carbonyls under mild conditions that allow their implementation in industrial processes.

This project will develop new and robust catalytic methods for the enantioselective addition of readily available nucleophiles to carbonyl compounds under mild conditions that allow their implementation in industrial processes.

Background – The enantioselective addition of organometallic reagents to prochiral electrophiles is a widely used synthetic method to generate chiral building blocks for natural product synthesis and pharmaceutical or agricultural compounds. We have recently developed a very successful catalytic system for the addition of accessible and economically viable nucleophiles (i.e. Grignard, organolithium, organoaluminum and organotitanium reagents) to aldehydes, based on readily available Ar-BINMOL chiral ligands and a titanium source (see, for example: B Macia et al. ACS Catal. 2016, 6, 1952). This method represents the first catalytic methodology applicable to such a wide variety of nucleophiles, including alkyllithium reagents, whose asymmetric addition to carbonyls was not possible in a catalytic way before this work.

Project objectives – Part A: Expand the use of Ar-BINMOLs as ligands in asymmetric catalysis addressing remaining challenges such us: (i) use of ketones as substrates: the asymmetric addition of organometallic reagents to ketones is a straightforward way to build chiral quaternary alcohols, which are interesting and useful scaffolds from a pharmaceutical point of view. (ii) expansion of organometallic scope: We will develop a novel methodology for the formal use of alkenes as nucleophiles in enantioselective 1,2-additions to carbonyls. The in situ hydrometallation of alkenes will provide organometallic reagents such as organzirconium, organoboron and organosilicon reagents, whose enantioselective addition to different carbonyl compounds will be explored under the catalysis of Ar-BINMOL ligands. (iii) Mechanistic studies on the developed processes will be undertaken in collaboration with Dr M. A. Fernández-Ibañez (University of Amsterdam).

Part B: In collaboration with Dr V. Caprio (MMU), the synthesis of novel hydroxylamine derived ligands will be carried out and these novel ligands will be evaluated in the enantioselective addition of organometallic reagents to carbonyl compounds.