Practical enhancement and applications of dirhodium catalyzed reactions of donor/acceptor carbenes

Dirhodium(II) complexes are versatile catalysts for the reactions of diazo compounds, catalyzing a wide array of synthetic transformations such as cyclopropanation, dipolar additions, aromatic cycloadditions, ylide reactions, and C-H, N-H, O-H, and Si-H insertion reactions. Rh2( S-DOSP)4 is the most generally effective chiral dirhodium(II) catalyst for highly enantioselective transformations involving donor/acceptor carbenoid intermediates. Several Rh2(S-DOSP) 4--catalyzed transformations have been used as key steps in the syntheses of natural products.;The metal-catalyzed decomposition of diazo compounds in the presence of alkenes is a general method for the stereoselective synthesis of cyclopropanes. Rhodium-catalyzed cyclopropanation of donor/acceptor carbenoids is an effective means for the enantioselective synthesis of cyclopropanes with one or more quaternary stereogenic centers. As many cyclopropyl amines are known to have significant CNS activity, we initiated a program to use the cyclopropanation methodology to access novel diarylcyclopropylamines. For the methodology to be broadly useful in drug discovery, access to a range of diarylcyclopropyl derivatives with high levels of enantioenrichment is required. In Chapter 2, a guide to choosing the optimal chiral dirhodium(II) catalyst for asymmetric cyclopropanation with various types of methyl aryldiazoacetates is presented.;Although dirhodium catalysts can be extremely effective, often giving rise to a broad range of synthetically useful products in high yields with excellent regio-, diastereo- and enantioselectively, their cost is prohibitive and impedes to their use in pharmaceutical processes. Although considerable advances have been made in the immobilization of various dirhodium(II) catalysts, efforts to alleviate the cost associated with Rh2(S-DOSP) 4 by synthesis of re-usable heterogeneous derivatives have been met with limited success. Chapter 3 describes how this complication could be alleviated with the development of a broadly-applicable and highly enantioselective immobilized variant of Rh2(S-DOSP)4. This Rh 2(S-DOSP)4-derivative was immobilized by covalent attachment of a carboxylate ligand to a solid support. Chapter 4 describes the advances made toward increasing the efficiency of Rh2(S-DOSP)4 by application of the immobilized Rh2(S-DOSP) 4-derivative in continuous flow chemistry.;Finally, the application of dirhodium-stabilized donor/acceptor carbenoids the syntheses of natural products was explored in Chapter 5. As Rh2( S-TCPTAD)4 has been shown to be an effective chiral catalyst for different types of C--H functionalization reactions, this catalyst was applied towards the syntheses of marine alkaloids dictyodendrins A and F which are known to possess inhibitory activity against telomerase and BACE-1 respectively, making them of interest for use as potential targets for cancer chemotherapy and treatment Alzheimer's disease respectively. Syntheses of dictyodendrin A and F were achieved by sequential C--H functionalization reactions utilizing a combination of different C--H coupling methodologies.