title: Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade.
abstract: The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh(I) -catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox-neutral acid-catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel-Crafts alkylation.
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA).
authors.forename: Eric M
authors.initials: EM
authors.lastname: Phillips
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA).
authors.forename: Tehetena
authors.initials: T
authors.lastname: Mesganaw
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569 (USA).
authors.forename: Ashay
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA).
authors.forename: Simon
authors.initials: S
authors.lastname: Duttwyler
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA).
authors.forename: Brandon Q
authors.initials: BQ
authors.lastname: Mercado
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569 (USA). houk@chem.ucla.edu.
authors.forename: Kendall N
authors.initials: KN
authors.lastname: Houk
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA). jonathan.ellman@yale.edu.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000701:Analgesics, Opioid / Q000138:chemical synthesis*; D002384:Catalysis; D003500:Cyclization; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D010084:Oxidation-Reduction; D012238:Rhodium / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D000701:Analgesics, Opioid; D004095:Dihydropyridines; C000609208:ent-ketorfanol; C038806:1,4-dihydropyridine; D012238:Rhodium
keywords: CH activation; alkaloids; asymmetric synthesis; heterocycles; torquoselectivity