Development and application of lanthanide and group 3 metallocene catalyzed hydrosilylation and hydroamination reactions

Lanthanide metallocene complexes have been developed as powerful catalysts for olefin hydrogenation, hydrosilylation and hydroamination. When combined with the robust alkene insertion chemistry of these complexes, the synthetic utility of these methods was expanded by the formation of a variety of complex ring systems from simple substrates. One dominant limitation of this class of catalysts was their severe steric sensitivity. Although this allowed interesting steric selectivity, cyclization of substrates containing other than monosubstituted alkenes was precluded.;A primary goal of the current research was to relax the steric environment of the catalysts to allow the incorporation of more hindered alkenes into the catalytic cycle. An initial survey of the hydrosilylation of 1-decene with a variety of complexes was undertaken to identify several compounds that have vastly different steric properties while still showing excellent regioselectivity for olefin insertion.;With this knowledge in hand, conditions were developed for the cyclization/silylation of substrates containing 1,1-disubstituted alkenes. The reaction proved to be effective for the formation of cyclopentanes containing quaternary centers using complexes of the form [CpTMS2LnMe]2. Excellent diastereoselectivity in the ring-forming event was observed with the major product predictable by a simple steric model. A wide variety of ring systems was generated, bearing several diverse protected functional groups. Attempts to extend this reaction to the formation of six-membered rings failed.;The intramolecular hydroamination reaction was similarly extended to substrates bearing 1,1-disubstituted alkenes using the same series of catalysts. A large variety of mono- and bicyclic amines bearing quaternary centers was generated in excellent yield. The potent anticonvulsant MK-801 was synthesized by the transannular hydroamination of a 1,1-disubstituted alkene.;A final synthetic application of the intramolecular hydroamination reaction was realized in the preparation of (+)- and (--)-pinidinol. As the diastereomeric preference in the formation of 2,6-disubstituted piperidines was unknown at the outset of this project, a simple model system was cyclized to determine the conditions required to give excellent selectivity for the cis diastereomer. The preparation of both enantiomers of the natural product was then completed in asymmetric fashion using a selective baker's yeast reduction to generate the required stereocenters.