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NIH grant 1R35GM161791-01: Chemical Methods for the Synthesis of Complex Molecules
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Donald Allen Watson. Award: $479532.
Start: 2026-08-26T00:00:00.
SUMMARY
Nitrogen-rich small molecules are essential components of modern medicines, and therefore critical to human
health. As medical science has evolved, there has been a drive to develop more selective and potent
pharmaceuticals that impart fewer side-effects while simultaneously tackling more complex diseases. At a
molecular level, this has resulted in the need to rapidly access more structurally and topologically complex
molecules that are able to differentiate between similar biological targets to effect the desired phycological
response without unwanted side effects. These challenges continue to drive the need for more efficient synthetic
methods to prepare complex nitrogen-containing small molecules.
Historically, due to the high electronegativity of the nitrogen atom, small molecule nitrogen chemistry has
largely focused on nucleophilic nitrogen centers. However, in recent years, there has been a growing realization
that electrophilic nitrogen centers can be easily accessed, and that the reactivity of electrophilic nitrogen provides
unique opportunities in the synthesis of complex nitrogen-containing molecules. Our group has contributed
significantly to this shifting paradigm, particularly in the areas of aza-Heck cyclization to build complex,
stereogenic nitrogen heterocycles and in developing chemistry to effect the C-alkylation of nitroalkanes to access
complex nitroalkanes as advanced precursors to nitrogen-rich molecules. Manipulation of high-valent,
electrophilic nitrogen centers is at the core of both of these research areas.
In this program, we will continue to build on our significant track-record in electrophilic nitrogen chemistry to
develop new methods to rapidly prepare complex organic molecules. Specifically, we will develop new Heck-like
reactions of electrophilic nitrogen centers to access sterically congested, stereogenic nitrogen heterocycles,
which are in high demand in modern medicinal chemistry but are challenging to prepare by other means. We will
further investigate the mechanism of aza-Heck cyclization to discover how these reactions proceed, and use that
understanding to further expand the synthetic horizons of this chemistry. Additionally, we will learn to control
absolute stereochemistry in these cyclizations to selectively prepare single enantiomers of these complex
molecules. To demonstrate the importance of aza-Heck cyclizations, we will also rapidly prepare several highly
complex natural products with significant reported biological activity. Through collaboration, our synthetic efforts
will enable biological follow-up studies to probe the modes of action of those compounds. Finally, using our
recent discoveries in alkylation chemistry, we will pursue new synthetic methods to prepare and utilize complex
nitroalkanes in the synthesis of medically relevant compounds.
Overall, we expect that the development of this chemistry will positively impact human health by providing
synthetic, medicinal, and process chemists valuable new tools for the construction of nitrogen-rich bioactive
small molecules.document fetched 2026-09-06 02:47