Fully substituted carbon centers by diastereoselective spirocyclization: stereoselective synthesis of (+)-lepadiformine C.
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.
Perry
Matthew A
MA
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, USA.
Morin
Matthew D
MD
Slafer
Brian W
BW
Wolckenhauer
Scott A
SA
Rychnovsky
Scott D
SD
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D003500:Cyclization; D013237:Stereoisomerism
D000470:Alkaloids; C431548:lepadiformine; D002244:Carbon