Grant: Discovery Grants Program - Individual

Intro. This proposal concerns the invention and development of new organic transformations, and their application in the construction of complex targets of biological interest. A common thread throughout is harnessing the unique reactivity of transient species to permit the development of novel, non-intuitive bond-forming processes. To accomplish these goals, HQP will focus on mechanistic studies to understand the fate of reactive intermediates, molecular design and systematic study of conditions to optimize the desired pathways, and synthetic design to develop routes to complex targets that take advantage of the capabilities of new methodology.Metallocarbene Chemistry. We have developed a green route to reactive C-acylimines from diazo-azides via copper catalysis. The only by-products are two molecules of nitrogen gas. The resulting imine electrophiles are subject to efficient capture by pi-nucleophiles. Trapping with indole serves to activate the copper(II) triflate precatalyst, forming catalytically competent copper(I) and Brønsted acid to promote indole addition to the acylimine. We plan to exploit the intervention of Brønsted acid catalysis to achieve asymmetric catalysis using external chiral acids. In a related project, we seek to develop a general route to medium-sized azacycles via metallocarbene-derived sulfonium ylides.Cyclic Allenes. Imposition of an allene moiety within a small ring (8 members or less) places sufficient bond angle strain on the molecule that it cannot be isolated. The high reactivity of these distorted allenes permits their participation in a variety of extremely facile pericyclic or radical-based processes. We wish to optimize new routes to the reactive allenes, including methods that allow for enantioselective allene generation. In addition, intramolecular trapping processes that permit the use of ordinarily unreactive moieties will be explored, and the application of trapping products to natural product targets will be investigated.Lewis Acid Catalysis. We have recently discovered a process for indole derivatization employing simple aldehydes and ketones in the presence of silane. The reaction requires both catalytic ferric chloride and blue lightomission of either results in little or no conversion. We wish to generalize this process, while exploring other earth-abundant metal salts. At the same time, we will also examine other Lewis acid-mediated bond-forming processes, including higher-order cationic electrocyclizations, such as the “vinylogous Nazarov reaction” and a 6pi variant of the Nazarov reaction employing trienones to generate cycloheptanoid products.This research entails a strong training environment, exposing HQP to important laboratory techniques and characterization skills that are in high demand in the chemical and pharmaceutical industries.