Stereoconvergent, Intramolecular Transfer Reactions to β-Titanoxy Radicals

Abstract

This thesis describes a number of reactions that exploit intramolecular, radical group transfer to β-titanoxy radicals. It is mostly aimed at advancing the field of titanium-catalyzed epoxide hydrosilylation reactions, which feature intramolecular hydrogen atom transfer reactions, but is also going to investigate more complex transferrable motifs. <br /> Epoxides are valued for their high ring strain and their highly regio- and chemoselective fragmentation upon encountering Ti(III) catalysts under the formation of β-titanoxy radicals. Since these radicals are typically conformationally labile, this opens up the possibility for stereoconvergent processes. By pairing the epoxide hydrosilylation with the enantioselective Shi epoxidation, it was possible to develop a two-step, regio- and stereoselective, formal addition of water to diastereomeric mixtures of olefins to yield optically enriched anti-Markovnikov alcohols (d.r. up to 99:1; e.r. up to 98:2). <br /> Aside from intramolecular hydrogen atom transfer, an intramolecular allyl group transfer reaction to β-titanoxy radicals was successfully developed that is suitable to obtain acyclic all-carbon quaternary stereocenters. It employs a combination of a Ti(IV) and an allylic Grignard reagent to yield the active titanocene(III) allyl species. This is then able to induce regioselective fragmentation of the epoxide before the resulting, conformationally labile β-titanoxy radical is saturated in a conjugate homolytic substitution. By combining it with the enantioselective Shi epoxidation, it was once again possible to yield the desired alcohols in high d.r. (up to 95:5) and excellent e.r. (up to 98:2) without the need for diastereomerically pure precursors. This method was then successfully employed in a protecting-group-free total synthesis of (–)-crinane, which is a member of the family of Amaryllidaceae alkaloids. <br /> Furthermore, contributions to the field of epoxide deuterosilylation are briefly discussed. This reaction could become a highly attractive method for deuterium labelling since it allows for deuterium introduction into metabolic soft spots, which can cause prolonged lifetimes of drugs. <br /> Also, contributions to the development of more sustainable, silicon-based, terminal hydrogen atom transfer reagents are presented. It was found that the industrial waste-product polymethylhydrosiloxane (PMHS) may be used instead of rather expensive arylsilanes in epoxide hydrosilylation reactions. Comparable stereoselectivities are induced while employing a sterically less demanding, commercially available precatalyst. <br /> Moreover, novel, silyl-substituted titanocene dichloride catalysts are introduced with the goal to frustrate the competing nucleophilicity of catalytically active titanocene(III) hydrides. Through suitable modification of the ligand sphere, it was possible to improve the regioselectivity of the hydrosilylation of long-chain, terminal epoxides to a synthetically attractive value of approx. 93:7