Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 132, Issue 28, Pages 9591-9593Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja104250b
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Funding
- NIGMS [GM-65338]
- Amgen
- Eli Lilly
- Vertex Pharmaceuticals
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Reductive lithiation of N-Boc alpha-amino nitriles generated alpha-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A(1,3)-strain effect that biases the conformation of the radical. In cyclohexane rings with alpha-substituents the net effect is an inversion of configuration on reductive lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with alpha-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The alpha-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.
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