ja7b01718_si_008.cif (511.47 kB)
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
datasetposted on 2017-03-08, 00:00 authored by Zhongyin Zhang, Jinxin Wang, Jian Li, Fan Yang, Guodu Liu, Wenjun Tang, Weiwei He, Jian-Jun Fu, Yun-Heng Shen, Ang Li, Wei-Dong Zhang
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.
substrate scopeRh-Catalyzed Asymmetric HydrogenationStereochemical AssignmentDelavatineTotal Synthesisunfunctionalized olefinstetralin-based triflamidesenantioIncarvillea delavayisynthesisisoquinoline construction strategyselectivity factorindene-type tetrasubstituted olefinscancer cell linesisoquinoline alkaloidKinetic ResolutionIndene-Type Tetrasubstituted Olefinsquaternary chiral centers13 steps