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Structure-directed reversion in the pi-facial stereoselective alkylation of chiral bicyclic lactams

Posted June 8th, 2010 by pschmidtke
TitleStructure-directed reversion in the pi-facial stereoselective alkylation of chiral bicyclic lactams
Publication TypeJournal Article
Year of Publication2008
AuthorsSoteras, I, Lozano O, Escolano C, Orozco M, Amat M, Bosch J, Luque FJ
JournalThe Journal of organic chemistry
Volume73
Issue19
Pagination7756 - 7763
Date Published2008/10/03/
KeywordsAlkylation; Electrons; Lactams/chemistry; Models, Chemical; Molecular Structure; Pyrrolidinones/chemistry; Stereoisomerism
AbstractThe reversal of the pi-facial diastereoselectivity observed in the benzyl bromide alkylation of the enolate of phenylglycinol-derived oxazolopiperidone is examined by means of theoretical calculations and experimental assays. When the angular carbon adopts an R configuration, the endo addition is intrinsically favored due to the lower torsional strain induced in the TS, but for the reaction with benzyl bromide, which affords the exo product. This reversal is attributed to the formation of a C-H...pi hydrogen bond between the C-H unit of the C8a angular position and the benzene ring of the alkylating reagent. A similar secondary interaction explains the stereochemical reversion observed in the benzyl alkylation of the enolate of oxazolopyrrolidinone. These findings point out that the delicate balance between factors that dictate the diastereoselectivity in the alkylation of chiral byciclic lactams can be unexpectedly altered by weak secondary interactions. The results presented here provide valuable guidelines to tune the selective preparation of enantiopure bioorganic and pharmaceutical compounds.