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
posted on 2017-03-08, 00:00authored byZhongyin 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.