title: Total Synthesis and Stereochemical Assignment of Delavatine A: Rh-Catalyzed Asymmetric Hydrogenation of Indene-Type Tetrasubstituted Olefins and Kinetic Resolution through Pd-Catalyzed Triflamide-Directed C-H Olefination.
abstract: Delavatine A (1) is a structurally unusual isoquinoline alkaloid isolated from Incarvillea delavayi. The first and gram-scale total synthesis of 1 was accomplished in 13 steps (the longest linear sequence) from commercially available starting materials. We exploited an isoquinoline construction strategy and developed two reactions, namely Rh-catalyzed asymmetric hydrogenation of indene-type tetrasubstituted olefins and kinetic resolution of β-alkyl phenylethylamine derivatives through Pd-catalyzed triflamide-directed C-H olefination. The substrate scope of the first reaction covered unfunctionalized olefins and those containing polar functionalities such as sulfonamides. The kinetic resolution provided a collection of enantioenriched indane- and tetralin-based triflamides, including those bearing quaternary chiral centers. The selectivity factor (s) exceeded 100 for a number of substrates. These reactions enabled two different yet related approaches to a key intermediate 28 in excellent enantiopurity. In the synthesis, the triflamide served as not only an effective directing group for C-H bond activation but also a versatile functional group for further elaborations. The relative and absolute configurations of delavatine A were unambiguously assigned by the syntheses of the natural product and its three stereoisomers. Their cytotoxicity against a series of cancer cell lines was evaluated.
authors.affiliation: School of Pharmacy, East China University of Science and Technology , 130 Meilong Road, Shanghai 200237, China.|Department of Phytochemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, China.|State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 345 Lingling Road, Shanghai 200032, China.
authors.forename: Zhongyin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, China.|State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 345 Lingling Road, Shanghai 200032, China.
authors.forename: Jinxin
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 345 Lingling Road, Shanghai 200032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, East China University of Science and Technology , 130 Meilong Road, Shanghai 200237, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 345 Lingling Road, Shanghai 200032, China.
authors.forename: Guodu
authors.initials: G
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 345 Lingling Road, Shanghai 200032, China.
authors.forename: Wenjun
authors.identifier: 0000-0002-8209-4156
authors.initials: W
authors.lastname: Tang
authors.affiliation: School of Pharmacy, East China University of Science and Technology , 130 Meilong Road, Shanghai 200237, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: He
authors.affiliation: School of Pharmacy, East China University of Science and Technology , 130 Meilong Road, Shanghai 200237, China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Fu
authors.affiliation: Department of Phytochemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, China.
authors.forename: Yun-Heng
authors.initials: YH
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 345 Lingling Road, Shanghai 200032, China.
authors.forename: Ang
authors.identifier: 0000-0002-8808-0636
authors.initials: A
authors.lastname: Li
authors.affiliation: School of Pharmacy, East China University of Science and Technology , 130 Meilong Road, Shanghai 200237, China.|Department of Phytochemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Zhang
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D029402:Bignoniaceae / Q000737:chemistry; D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006865:Hydrogenation; D007192:Indenes / Q000737:chemistry*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry*; D007700:Kinetics; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D012238:Rhodium / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D007192:Indenes; D007546:Isoquinolines; C000627245:delavatine A; D010165:Palladium; C093581:indene; D012238:Rhodium