title: Rhodium-phosphoramidite catalyzed alkene hydroacylation: mechanism and octaketide natural product synthesis.
abstract: We describe a method that allows salicylaldehyde derivatives to be coupled with a wide range of unactivated alkenes at catalyst loadings as low as 2 mol %. A chiral phosphoramidite ligand and the precise stoichiometry of heterogeneous base are key for high catalytic activity and linear regioselectivity. This protocol was applied in the atom- and step-economical synthesis of eight biologically active octaketide natural products, including anticancer drug candidate cytosporone B. Mechanistic studies provide insight on parameters affecting decarbonylation, a side reaction that limits the turnover number for catalytic hydroacylation. Deuterium labeling studies show that branched hydride insertion is fully reversible, whereas linear hydride insertion is largely irreversible and turnover-limiting. We propose that ligand (R(a),R,R)-SIPHOS-PE effectively suppresses decarbonylation, and helps favor a turnover-limiting insertion, by lowering the barrier for reductive elimination in the linear-selective pathway. Together, these factors enable high reactivity and regioselectivity.
authors.affiliation: Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
authors.forename: Max
authors.initials: M
authors.lastname: von Delius
authors.forename: Christine M
authors.initials: CM
authors.lastname: Le
authors.forename: Vy M
authors.initials: VM
authors.lastname: Dong
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D012238:Rhodium / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D001688:Biological Products; D018942:Macrolides; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; C434331:phosphoramidite; D012238:Rhodium