title: Synthesis of (-)-(R)-pyrrolam a and studies on its stability: a caveat on computational methods.
abstract: The asymmetric synthesis of (-)-(R)-pyrrolam A was achieved in three operations from N-Boc pyrrolidine via an alpha-(N-carbamoyl)alkylcuprate vinylation reaction followed by N-Boc deprotection and cyclization. One-pot deprotection-cyclization procedures led to mixtures of pyrrolam A and its double bond isomers. These isomerization events could be circumvented by use of a two-step procedure. To guide aspects of the experiments, a series of computational energy evaluations and chemical shift predictions were performed with molecular mechanics, semiempirical, ab initio, and density functional methods. The relative stabilities of the double bond isomers, as estimated by experiment, challenged a number of computational methods, and only the MP2 model with its moderate degree of electron correlation came close to matching the experimental data. The MP2 method was further applied to an unusual aspect of the double bond migration between pyrrolam A and its isomer 9. The reaction (1 to 9) on neat samples is irreversible without racemization, and the alumina-mediated equilibration is accompanied by complete loss of enantiomeric excess. The source of the irreversibility was traced to asymmetric charge distribution in the intermediate dienolate anion. The analysis ultimately led to a semiquantitative sketch of the pyrrolam energy surface.
authors.affiliation: Department of Chemistry, Hunter Laboratory, Clemson University, Clemson, South Carolina 29634, USA.
authors.forename: Rhett T
authors.initials: RT
authors.lastname: Watson
authors.forename: Vinayak K
authors.initials: VK
authors.lastname: Gore
authors.forename: Kishan R
authors.initials: KR
authors.lastname: Chandupatla
authors.forename: R Karl
authors.initials: RK
authors.lastname: Dieter
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D008958:Models, Molecular; D015394:Molecular Structure; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism; D013302:Streptomyces / Q000737:chemistry
chemical_list: D011763:Pyrrolizidine Alkaloids; C419422:pyrrolam A