Kay M. Brummond

Reaction Discovery, Synthesis of Natural Products and Biologically Relevant Compounds, Reaction Mechanisms and Molecular Sensors.

Reaction Discovery. Research in our lab focuses on the discovery and development of transformations to facilitate and overcome the synthetic challenges posed by molecularly complex bioactive compounds. One example of our approach involves using one allene-containing compound and by using different conditions skeletally unique products are afforded. We were amongst the first to validate this DOS strategy and efforts along these lines continue in our lab.

Synthesis of Natural Products and Other Biologically Relevant Compounds. The allenic-Pauson–Khand reaction (APKR) developed in our group provides rapid access to a bicyclo[5.3.0]decane ring system of the guaianolide family of natural products. Guaianolides are a subclass of sesquiterpene lactones with a rich diversity of bioactivity but remain underrepresented in the drug discovery process. One compound from this class that is particularly exciting is Thapsigargin (Tg), a subnanomolar inhibitor of SERCA and one in which a PMSA-activated prodrug has been developed and is currently in Phase II clinical trials because it successfully kills cancer cells independent of proliferation. Despite Tg’s extraordinary chemotherapeutic promise, access to analogs for SAR studies remains challenging. Using the APKR, our group is preparing analogs of Tg and other densely oxygenated guaianolides and/or analogs in an enantio- and stereoselective way.

Intramolecular Didehydro-Diels–Alder Reaction (IMDDA) and Molecular Sensors. The IMDDA reaction offers a rarely used approach to the synthesis of a variety of naphthalene derivatives and benzofused heterocycles. We have showcased the utility of this method by preparing a series of solvatochromic fluorophores that are structurally related to a state of the art sensor. An understanding of the structure-function relationships was made possible by the de novo construction of the aromatic portion of these sensors. Future studies are directed towards expanding this chemistry-driven approach to the rational preparation of sensors with enhanced photophysical and chemical properties for application in biological systems.

Reaction Mechanism. The reaction discovery thrust of our research program has inspired mechanistic studies both experiment and calculation. Success stories include: explaining the selective reaction of the proximal and distal double bond of an allene when using Mo(0)- or Rh(I)-catalysis for the APKR; establishing the existence of a biradical intermediate in the thermally-induced intramolecular [2 + 2] cycloaddition reaction between an allene and an alkyne to afford alkylidene cyclobutenes; and the formation of aromatic compounds by a unimolecular elimination of hydrogen gas. We continue to work closely with our computational collaborators to understand reaction mechanisms. 

Complete Listing of Published Work in MyBibliography:

http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/50348838/?sort=date...