Palladium-catalyzed asymmetric formal [3+2]-cycloadditions with donor-acceptor cyclopropanes [electronic resource]

Abstract: The development of new methods for the synthesis of densely-functionalized enantioenriched five-membered hetero- and carbocycles is of importance in organic chemistry. Such functionalized five-membered ring are one of the motifs found in a wide array of biological targets. One atom- and step-economical method for the synthesis of these these five-membered ring systems is via a formal [3+2]-cycloaddition between a 1,3-dipole and a dipolarophile. Vicinally-substituted donor-acceptor cyclopropanes contain an electron-withdrawing group at the 1-position and an electron-donating group at the 2-position. This allows for their heterolytic cleavage to form a 1,3-dipoles under appropriate reaction conditions. Typically, Lewis acid-catalysis has been utilized to affect formal [3+2]-cycloadditions with donor-acceptor cyclopropanes. However, the use of palladium-catalysis to affect formal [3+2]-cycloadditions with donor-acceptor cyclopropanes has been relatively unexplored, and prior to this work had never been examined in an asymmetric fashion. The asymmetric allylic alkylation ligands developed by Trost and coworkers have been extensively used over the last 15 years in a variety of enantioselective reactions. However, the ability of these ligands to induce enantioselectivity in a bond-forming event two-bonds away from the [pi]-allyl-palladium center had never been demonstrated. The development of an asymmetric formal [3+2]-cycloaddition with donor-acceptor cyclopropanes and Meldrum's acid alkylidenes demonstrated the ability of this class of ligands to direct stereochemistry quite far away from the [pi]-allyl-palladium complex. A range of substituted cyclopentane derivatives were synthesized in this manner. An analysis of the relative stability of the donor-acceptor cyclopropanes in conjunction with the the palladium-ligand complex led to the development of a new class of donor-acceptor cyclopropane, the bis(2,2,2-trifluoroethyl)malonate-substituted vinyl cyclopropane. This new class of donor-acceptor cyclopropane was then utilized successfully in a formal [3+2]-cycloaddition with a variety of dipolarophiles, including the nitroolefins, isocyanates, and N-tosylimines. The azlactone alkylidenes, which represent protected amino acids, were further explored as dipolarophiles for this reaction, and a range of spirocyclic products were synthesized in high yield, enantiomeric excess and diastereomeric excess. Notably, three contiguous stereocenters were set in this reaction. In addition to this project, two approaches towards the synthesis of biyouyanagin A were explored. The initial approach, involving a proposed 11-endo-dig cyclization of an alcohol onto an alkyne ultimately proved to be unsuccessful. A secondary approach involved the use of a palladium-catalyzed dynamic kinetic asymmetric reaction between a hydroxyfuran and isoprene monoepoxide. Use of this strategy successfully synthesized hyperolactone C, which represented a formal synthesis of biyouyanagin A.

Keywords: Chemistry
Advisor: Trost Barry M. primary advisor. Thesis advisor
Chen James
Wender Paul A. advisor. Thesis advisor