Development of catalytic asymmetric P(III)-C bond formations in ferrocenyl, heterobicyclic & exocyclic olefins

Abstract

This thesis aims to provide a holistic account of the synthetic methods applied and the solutions found towards achieving asymmetric P(III)-C bond constructions with ferrocenyl enones, heterobicyclic alkenes and exocyclic olefins. Chapter 1 presents the general field of metal-mediated P(III)-H additions and describes the motivation towards developing convenient protocols. In Chapter 2, asymmetric hydrophosphination (AHP) was employed in a kinetic resolution, as means to generate a series of enantioenriched ferrocenyl monophosphines imbued with both central and planar stereogenicity, in only one step, from ferrocenyl enone racemates. These enantioenriched ferrocenylphosphines could be protected with BH3 and further recrystallized to obtain mother liquors with e.e.s up to 99%. The modularity of the phosphine obtained were demonstrated via derivatization of its functional handles to yield chiral bisphosphines. In Chapter 3, asymmetric addition of diarylphosphines to oxa- and azabicyclic alkenes was performed in the presence of a chiral phosphapalladacycle catalyst and a mild acid at room temperature to give exclusively bicyclic core-retained enantioenriched products in excellent yields and good selectivities. In Chapter 4, the feasibility of current AHP protocols conducted on challenging electrophilic exocyclic olefins was investigated. The study led to intriguing mechanistic insights of AHP in general, and inspired modifications to the current protocols to achieve successful asymmetric P-H addition to such substrates. The method provided the first instance in literature of catalytic enantioselective P(III)-H addition on electrophilic exocyclic olefins, albeit with modest yields and selectivities. Finally, in Chapter 5, a library of ferrocenyl phosphine derivatives, generated from the hydrophosphination protocol, was investigated as potential metallopharmaceuticals in cancer and malarial studies. Structure-activity comparisons showed that the phosphines were more active than their parent chalcones, and both studies identified a gold-based ferrocenyl phosphine as a strong candidate for future developments in medicinal research.