Novel C-H Activation Methods: Synthesis of 3-oxo Rhazinilam

Rhazinilam and its related congeners are potent cytotoxic monoterpenoid ring-opened indole alkaloids which have been isolated from a hybrid cell culture RxR17 from Rauvolfia serpentina Benth. ex Kurz and Rhazya stricita Decaisne and have demonstrated high in vitro activity against a variety of cancer cells as well as to interfere with tubulin polymerization dynamics. Despite the interesting biological profile of the Rhazinilam family, the synthesis of 3-oxo-Rhazinilam has not yet been reported. 3-oxo-Rhazinilam has a complex tetracyclic carbon skeleton containing an embedded pyrrole moiety as part of its indolizinone core (C-D rings). Connection of its aromatic A- ring with its D-ring is facilitated by an amide bridge in the form of a nine membered lactam (B-ring). (-)-3-oxo- rhazinilam incorporates two points of chirality: a biaryl axis with absolute (aR) configuration (A-C rings) and a C20 quaternary stereocenter. Novel C-H functionalisation technology will be developed to incorporate both regioselective and controllable C-H arylation and C-H alkenylation reactions of heteroaromatic compounds, with particular focus on the pyrrole nucleus. This methodology will be implemented in the synthesis of 3-oxo-rhazinilam and selected analogues. Two separate strategies will be investigated: a) a controlled transannular C-H alkenylation approach; and b) a cascade approach where an intramolecular C-H alkenylation reaction is followed by a Pd(0) catalysed Buchwald-type amidation reaction. Novel chiral bis-sulfoxide Pd(II) complexes will be implemented to make the synthesis enantioselective. A further cascade sequence where 3-oxo-rhazinilam will be converted, via a "retro-biomimetic" skeletal rearrangement; to its "parent" indole alkaloid aspidospermidine will be investigated. 3-oxo-Rhazinilam is not only a challenging and inspirational target from a structural perspective but also presents the possibility of studying the mode of action of the potent antitumor agent, through the synthesis of analogues using innovative synthetic methods; and represents a fundamentally important contribution for both the chemical synthesis and chemical biology disciplines.