The discovery and development of a Rh-catalyzed carbyne transfer platform for the skeletal modification of C(sp2)–C(sp2) bonds

Identifier:  TDX:3862

Handle: https://hdl.handle.net/20.500.11797/TDX3862

Authors:  Sarró Grané, Pau

Abstract:
The main objective of this thesis was the discovery and development of a new transition-metal-catalyzed carbyne transfer platform for the discovery of new carbon reactivity rules, applied in the skeletal editing of unsaturated molecules. Key on this thesis was the use of stable carbyne sources decorated with a hypervalent iodine moiety [I(III)(Ar)(X)] and a diazo functionality (=N2). Dirhodium carboxylate complexes enabled the catalytic diazo activation and generation of Rh-carbynoids as I(III)-substituted Rh-carbenes that emulated the carbene/carbocation behavior of a monovalent cationic carbyne (:+C–R). The Rh-carbynoids provoked the scission of C(sp2)–C(sp2) bonds of alkenes and dienes by inserting a monovalent carbon unit between both sp2-hybridized carbons, through the formation of cyclopropyl-I(III) intermediates able to undergo electrocyclic ring-opening, following the Woodward−Hoffmann−DePuy rules. Such process generated synthetically useful allyl cations that could be intercepted by a broad range of nucleophiles, leading to valuable allylic building blocks. Secondly, we exploited our catalytic carbyne transfer for the synthesis of fluorinated tertiary stereocenters. This process relied on the generation of tertiary allyl cations from 1,1-disubstituted alkenes that underwent nucleophilic fluorination with excellent branched/linear selectivity. Notable features of this process were the broad scope of 1,1-disubstituted alkenes, including natural products and drug molecule derivatives, applications in the late-stage fluorination of drug molecule and natural product derivatives, synthesis of a fluorinated drug molecule – (±)-F-flurbiprofen–and its translation to radiofluorination with [18F]TEAF. Finally, we developed an alkene-to-diene conversion by a desaturative C(sp2)–C(sp2) insertion, a distinct and alternative process to the classic catalytic alkene desaturation approaches. Overall, we believe that the insertion of a monovalent carbon unit in C(sp2)–C(sp2) bonds underscores an opportunity as a tool in skeletal editing that will be relevant to reach previously unattainable chemical space in drug discovery and development and to streamline the synthesis of complex natural products.