| The major goal of this project was to develop a general method for catalytic asymmetric C-H activation. Rhodium-carbenoids derived from rhodium catalyzed decomposition of diazo compounds are capable of insertion into inactivated C-H bonds. This process is well developed for the intramolecular C-H insertion reaction. The intermolecular C-H insertion process is not generally considered to be a synthetically useful method.; The first area of investigation in this study was aimed at examining if the intermolecular C-H insertion reaction was an effective process, and if the reaction could be carried out in an asymmetric manner. It was discovered that dirhodium tetrakis (S-(N-dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4) catalyzed decomposition of methyl aryldiazoacetates in the presence cycloalkanes resulted in intermolecular C-H insertion in good yields and with high asymmetric induction.; The next area of investigation was to examine the scope of the intermolecular C-H insertion reaction. It was discovered that alkanes, tetrahydrofuran, N-Boc-pyrrolidine, N-Boc-piperidine, 1,4-cyclohexadiene and 1,3,5-cycloheptatriene yielded C-H insertion products with good control of regioselectivity, diastereoselectivity and enantioselectivity. The carbenoids derived from methyl aryldiazoacetates were considerably more chemoselective than carbenoids derived from alkyldiazoacetates. These Rh(II)-carbenoids strongly favored C-H insertion at sites that stabilize charge build-up in the transition state, although steric factors could alter this effect. Formation of side products due to carbene dimerization was not a major problem with rhodium-carbenoids derived from aryldiazoacetates.; To highlight the asymmetric C-H activation methodology, intermolecular C-H insertion reactions into N-Boc-pyrrolidine and N-Boc-piperidine were applied to the synthesis of methyl phenidate analogs. Bis C-H insertion into N-Boc-pyrrolidine was performed to make C2-symmetric bases, and the products from intermolecular C-H insertion into 1,4-cyclohexadiene were used to make 1,1-biarylacetic acid derivatives with high asymmetric induction. |
