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

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.