Enantioselective synthesis and reactivity of bicyclobutanes: Strained molecular platforms for 4-, 5-, and 6-membered ring synthesis and rhodium(II)-catalyzed reactions of diazoesters with organozinc reagents

This dissertation is centered on reaction methodology and its application in the total synthesis of natural products. The results described herein include the development of a new method for enantioselective synthesis of cyclobutanes, the total synthesis of cyclobutane-containing natural products, the development of the first examples of transition-metal catalyzed vinylcyclobutane ring expansion reactions, and the rhodium-catalyzed organozincation of diazoesters.;The rich chemistry of diazocompounds rapidly builds complexity across many modes of reactivity. The propensity of Rh(II)-carbenes to undergo beta-hydride migration has been a long standing limitation to this chemistry. In Chapter 1, I will provide an overview of chemistries involving alpha-alkyl-beta-diazoesters that contain beta-hydrogens including the major contributions from our group. The ability to limit this undesired pathway by studying temperature and ligand effects has further extended the powerful chemistry of diazocompounds.;Rhodium(II)-catalyzed intermolecular cyclopropanation of diazoesters and alkenes has been widely studied and applied to complex synthesis; however, reports of intramolecular cyclopropanation had been quite limited. In Chapter 2, I will discuss the development of general conditions for the enantioselective intramolecular cyclopropanation or bicyclobutanation of alpha-diazoesters. Additionally, this chemistry has been coupled with a Cu(I)-catalyzed homoconjugate addition of Grignard reagents to bicyclobutanes in a one-pot procedure to provide rapid access to complex cyclobutanes in a highly stereocontrolled manner.;Cyclobutane-containing natural products exhibit diverse biological activity and have shown promise as therapeutic leads in areas including oncology, neurology, pain management, infectious diseases, and respiratory diseases. General and stereoselective methods to access unsymmetrical cyclobutane cores are still needed. In Chapter 3, I describe the application of the Rh(II)-catalyzed bicyclobutanation/Cu(I)-catalyzed homoconjugate addition of diazoesters for the synthesis of cyclobutane-containing natural products. I have completed the total synthesis of piperarborenine B in 0.4 g, 10 steps, and 8% overall yield in 1 week. I have also applied this methodology towards the synthesis of incarvillateine D and SB-FI-26 both of which have shown promise in pain management via adenosine receptor pathways.;In contrast to the well-known and widely-utilized vinylcyclopropane--cyclopentene rearrangement, the analogous vinylcyclobutane--cyclohexene rearrangement has found limited use due to the requirement of harsh conditions. In Chapter 4, I will discuss the development of the first examples of transition metal catalyzed ring expansions of vinylcyclobutanes. I have discovered the combination of Ni(0) and NHC ligands provides cyclohexenes while Rh(I)-catalysts provide exclusively cyclopentenes.;Organozinc reagents are widely used reagents in light of their excellent functional group tolerance; however, their use in Rh(II)-catalyzed reactions with diazoesters has not been reported. In Chapter 5, I describe the development of general conditions for the Rh(II)-catalyzed organozincation of diazoesters. The resulting hydrazone products have been elaborated to tertiary aminoesters and pyrazoles.