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.