title: Preparation of alpha-phosphono lactams via electrophilic phosphorus reagents: an application in the synthesis of lactam-based farnesyl transferase Inhibitors.
abstract: Conversion of N-alkyl lactams to the corresponding alpha-phosphono lactams has been investigated through procedures that involve formation of the lactam enolate and reaction with a phosphorus electrophile. With N-octylpyrrolidinone, the enolate could be trapped efficiently on oxygen by reaction with diethyl phosphorochloridate, and the resulting vinyl phosphate rearranges smoothly to the desired phosphonate upon treatment with additional LDA. Attempts to apply the same protocol to N-farnesyl lactams met with limited success. Studies with an isolated alpha-phosphono N-farnesyl lactam have shown that the farnesyl group is not stable to the excess of strong base required for rearrangement of a vinyl phosphate. However, a series of N-farnesyl lactams and imides was converted to the desired phosphonates through formation of the lactam enolate, reaction with diethyl phosphorochloridite, and subsequent oxidation of the phosphorus intermediate to the P(V) state.
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, USA.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Du
authors.forename: David F
authors.initials: DF
authors.lastname: Wiemer
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D051231:Farnesyltranstransferase; D007202:Indicators and Reagents; D007769:Lactams; D008958:Models, Molecular; D008968:Molecular Conformation; D063065:Organophosphonates; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007769:Lactams; D063065:Organophosphonates; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase