Given their wide availability, chiral oxazolidinones are potentially useful but ignored substrates for catalysis. Using transition metal catalysts, CO2 extrusion from oxazolidinones could be envisioned to afford reactive aza-metallacyclobutane intermediates that can be taken to a variety of complex nitrogenous products. The Ni-catalyzed transformation of chiral oxazolidinones to small chiral heterocycles, such as aziridines and ?-lactams, will be developed. Following Ni-mediated alkyl C-O insertion into a chiral oxazolidinone, decarboxylation will afford the aza-metallacyclobutane intermediate. Reductive elimination will afford chiral aziridines. Alternatively, under a carbon monoxide atmosphere, highly substituted chiral ?-lactams can be constructed. Many natural products containing chiral aziridine or ?-lactam functionality exhibit medicinally important properties, such as anticancer and antibiotic activity;however, due to the scarcity of methods toward the synthesis of these chiral heterocycles, they present formidable synthetic challenges. The Ni-catalyzed method outlined in this proposal would offer a convenient, facile, and divergent approach to these pharmacophores from readily available chiral precursors. Importantly, this method can be used combinatorially to construct libraries of potentially bioactive molecules. Reaction screening will be carried out on a simple, unsubstituted oxazolidinone model substrate to optimize reaction conditions, including ligands and solvent. Substrates of higher-substitution will then be evaluated in this transformation. Mechanistic and spectroscopic studies, including radical trap experiments, are proposed to determine whether a Ni0/NiII or NiI/NiIII cycle operates, and whether deleterious loss of stereochemical information occurs via a radical intermediate. In addition, hypothesized intermediates will be synthesized and subjected to reaction conditions to determine whether or not they lie along the catalytic cycle. By gaining insight into the mechanism of the proposed transformation, further optimization can be rationalized, and the method made general.

Public Health Relevance

Synthetically-challenging nitrogen-containing rings are found in countless medicinally-active molecules. In this proposal, a novel nickel-catalyzed reaction will be developed to allow the fast, convenient construction of these functionalities from readily available starting material. This approach uses cheap, abundant catalysts and precursor, and may potentially be amenable to the large-scale production of pharmaceuticals in industry.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F04-D (20))
Program Officer
Barski, Oleg
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Berkeley
Schools of Arts and Sciences
United States
Zip Code
Kawai, Hiroyuki; Wolf, William J; DiPasquale, Antonio G et al. (2016) Phosphonium Formation by Facile Carbon-Phosphorus Reductive Elimination from Gold(III). J Am Chem Soc 138:587-93
Winston, Matthew S; Wolf, William J; Toste, F Dean (2015) Halide-Dependent Mechanisms of Reductive Elimination from Gold(III). J Am Chem Soc 137:7921-8
Winston, Matthew S; Wolf, William J; Toste, F Dean (2014) Photoinitiated oxidative addition of CF3I to gold(I) and facile aryl-CF3 reductive elimination. J Am Chem Soc 136:7777-82
Wolf, William J; Winston, Matthew S; Toste, F Dean (2014) Exceptionally fast carbon-carbon bond reductive elimination from gold(III). Nat Chem 6:159-64