The Development and Synthetic Application of Titanium - Mediated Carbon - Heteroatom Double Bond Hydrosilylation Methodologies

Polymethylhydrosiloxane, when combined with titanium(IV) isopropoxide, provided a convenient system for the conversion of esters to the corresponding primary alcohols in the presence of a wide range of functional groups. Reactions were carried out as mixtures of the neat reaction components; work-up with aqueous alkaline THF afforded primary alcohols in good to excellent yields. The system tolerated primary alkyl bromides and iodides, olefins, and to a lesser extent epoxides and alkynes. Steric differentiation of methyl and tert-butyl esters was also possible. The results observed in the parent and related reactions argued against pathways involving Lewis-acid catalysis and anionic hydridosilicate-mediated reductions, and instead supported a neutral titanium hydride complex or strongly associated titanium/silane complex as the active reducing agent. When a solution of (S,S)-ethylenebis(Tl 5-1,2,3,4-tetrahydroindenyl)titanium difluoride was treated with phenylsilane, heating the mixture yielded a solution which displayed catalytic activity for the asymmetric hydrosilylation of imines. A variety of Nmethyl and endocyclic imines were hydrosilylated with high enantioselectivity. Treatment of the silylamines thus produced with aqueous acid gave highly enantiomerically enriched amines. The initial development of this system for the hydrosilylation of imines was followed by an examination of the scope of the reaction with regard to chemoselectivity in the presence of 1,2-disubstituted olefins. Although these olefins were found to be reactive under a variety of reaction conditions, a method for obtaining the desired products with high enantioselectivity and reasonable chemoselectivity was achieved. Furthermore, several important parameters of the protocol were more precisely delineated. The diasteroselectivity of the transformation of imines bearing stereogenic centers was also explored. The first catalytic, asymmetric syntheses of the piperidine alkaloids (S)-coniine and (2R,6S)-trans-solenopsin A were carried out. The method for highly enantioselective imine hydrosilylation described above allowed for a direct and efficient route to these synthetically interesting chiral amines. Thesis Supervisor: Stephen L. Buchwald Title: Camille and Henry Dreyfus Professor of Chemistry