title: Asymmetric [C + NC + CC] coupling entry to the naphthyridinomycin natural product family: formal total synthesis of cyanocycline A and bioxalomycin β2.
abstract: A full account of our [C + NC + CC] coupling approach to the naphthyridinomycin family of natural products is presented, culminating in formal total syntheses of cyanocycline A and bioxalomycin β2. The key complexity-building reaction in the synthesis involves the Ag(I)-catalyzed endo-selective [C + NC + CC] coupling of aldehyde 7, (S)-glycyl sultam 8, and methyl acrylate (9) to provide the highly functionalized pyrrolidine 6, which was carried forward to an advanced intermediate (compound 33) in Fukuyama's synthesis of cyanocycline A. Since cyanocycline A has been converted to bioxalomycin β2, this constitutes a formal synthesis of the latter natural product as well. The multicomponent reaction-based strategy reduces the number of steps previously needed to assemble these complex molecular targets by one-third. This work highlights the utility of the asymmetric [C + NC + CC] coupling reaction in the context of a complex pyrrolidine-containing target and provides an illustrative guide for its application to other synthesis problems. The synthesis also fueled collaborative biological and biochemical research that identified a unique small molecule inhibitor of cell migration (compound 30).
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078, United States. ppg@wsu.edu
authors.forename: Philip
authors.initials: P
authors.lastname: Garner
authors.forename: H Ümit
authors.initials: HÜ
authors.lastname: Kaniskan
authors.forename: Charles M
authors.initials: CM
authors.lastname: Keyari
authors.forename: Laksiri
authors.initials: L
authors.lastname: Weerasinghe
mesh_terms: D001685:Biological Factors / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D001685:Biological Factors; D009287:Naphthyridines; D010080:Oxazoles; C525935:bioxalomycin beta2; C010752:naphthyridinomycin; C035070:cyanonaphthyridinomycin