title: Development of an asymmetric trimethylenemethane cycloaddition reaction: application in the enantioselective synthesis of highly substituted carbocycles.
abstract: A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane (TMM) with electron-deficient olefins has been developed. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic pyrrolidine and azetidine structures, is discussed. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes with high levels of enantioselectivity. The donor scope was also explored, and substituted systems were tolerated, including one bearing a nitrile moiety. These donors were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA. bmtrost@stanford.edu
authors.forename: Barry M
authors.initials: BM
authors.lastname: Trost
authors.forename: Steven M
authors.initials: SM
authors.lastname: Silverman
authors.forename: James P
authors.initials: JP
authors.lastname: Stambuli
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D003500:Cyclization; D008024:Ligands; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D008024:Ligands; D009943:Organophosphorus Compounds; D011759:Pyrrolidines; C434331:phosphoramidite; C522820:trimethylenemethane; C032519:pyrrolidine; D008697:Methane