title: Crystallographic/experimental electron density characterizations and reactions with nucleophiles of beta-enaminonitriles possessing a pyrrolobenzazepine core.
abstract: In connection with a total synthesis of cephalotaxine (1a), we have examined the addition of various nucleophilic reagents to [ABC] subunits 2 and 7 possessing a pyrrolobenzazepine core. In fact, this reaction implicates invariably the carbonyl group of 2. Regarding the reaction of 7 with nucleophiles, the most striking aspect is the complete lack of reactivity of the enaminonitrile moiety. For instance, the condensation of 7 with methylmagnesium bromide involves exclusively the cleavage of the dioxole ring, yielding regioisomers 9 and 10. With the aim of understanding the unexpected reactivity of 2 and 7 toward nucleophiles, crystallographic studies of 2 and 7 and an experimental electron density determination of 7 were carried out. The marked reactivity of the carbonyl group of 2 was interpreted by invoking the weakness of the amide resonance, due to a pronounced delocalization of the N(9) lone pair over the enaminonitrile moiety. The electron density study of 7 reveals this electron delocalization along the enaminonitrile fragment, highlighted and quantified through the bond geometries, topological indicators, and atomic charges, a phenomenon that is responsible for the failure of the addition of nucleophilic species.
authors.affiliation: Laboratoires BIOCIS (UMR 8076), PPB (UMR 8612), and Cristallographie Bio-inorganique, Faculté de Pharmacie, Université Paris-Sud, 5, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Pizzonero
authors.forename: Laurent
authors.initials: L
authors.lastname: Keller
authors.forename: Françoise
authors.initials: F
authors.lastname: Dumas
authors.forename: Michèle
authors.initials: M
authors.lastname: Ourevitch
authors.forename: Georges
authors.initials: G
authors.lastname: Morgant
authors.forename: Anne
authors.initials: A
authors.lastname: Spasojević-de Biré
authors.forename: Goran
authors.initials: G
authors.lastname: Bogdanović
authors.forename: Nour Eddine
authors.initials: NE
authors.lastname: Ghermani
authors.forename: Jean
authors.initials: J
authors.lastname: D'Angelo
mesh_terms: D001552:Benzazepines / Q000737:chemistry*; D003461:Crystallography; D004583:Electrons; D006248:Harringtonines / Q000138:chemical synthesis; D000077863:Homoharringtonine; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D001552:Benzazepines; D006248:Harringtonines; D009570:Nitriles; D000077863:Homoharringtonine