Organotin reagents are routinely used to carry out radical reactions that create C-C bonds or effect the reduction of certain functional groups. They are valuable tools for the small-scale, laboratory synthesis of molecules for biochemical evaluation. Unfortunately, these tin reagents are unsuitable for use in manufacturing, because they are difficult to remove and quite toxic. An alternative way of generating radical intermediates is by the transfer of hydrogen atoms to unsaturated substrates from the hydride complexes of first-row transition metals. Such hydrides are non-toxic and their use is sustainable: they can be regenerated by hydrogen gas, so the generation of radicals by this method is catalytic. One H2 molecule produces two hydrogen atoms ? and two radicals ? with almost no waste. This proposal seeks to determine which hydride complexes can best do this chemistry and to identify new uses for radical reactions. First, the relative rates at which various alkenes and alkynes give radicals by this method will be measured, and the uses of such radicals in cyclizations will be investigated. These radicals should be particularly useful for cyclizations onto C=O, C=S, and C=N double bonds, and for the construction of three- and four-membered all-carbon rings that are not readily available by other methods. Second, the formation of radicals that do not cyclize can be followed by the transfer of another hydrogen atom in a separate step, enabling the anti addition of H2 across a C=C bond. This reaction should permit the synthesis of natural products that have been unavailable by traditional hydrogenation methods. Third, these new methods of radical generation will be tested on natural product targets that have already been prepared via radicals generated by established methods. The present syntheses have often been non-optimal; late-stage, polyfunctional, substrates will be emphasized, in order to provide as effective a benchmark as possible for the methods that have been developed. Successful catalytic reactions will then be applied to the synthesis of pharmaceutically promising natural products that have not yet been prepared in the laboratory. Finally, hydride complexes ? particularly anionic hydride complexes ? may also be able to generate radicals by electron transfer to appropriate halides R?X. It should be possible to regenerate these hydrides under hydrogen with base, so these reactions can also be made catalytic. We will also test this new method of radical generation on a natural product target that has been made with established methods.

Public Health Relevance

Radical-based reactions, both for constructing bonds and for effecting reductions, have been used innumerable times to fashion designed molecules and natural products of biomedical significance. These processes have relied upon tin hydride reagents that are both toxic and challenging to remove from the product. This proposal seeks to identify transition-metal hydride complexes that will ? with H2 as the only stoichiometric reagent ? catalyze such cyclizations and effect novel chemistry of broad value.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Yang, Jiong
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Columbia University (N.Y.)
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New York
United States
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Kuo, Jonathan L; Lorenc, Chris; Abuyuan, Janine M et al. (2018) Catalysis of Radical Cyclizations from Alkyl Iodides under H2: Evidence for Electron Transfer from [CpV(CO)3H]. J Am Chem Soc 140:4512-4516