Total synthesis of Cacospongionolide

Objective

Marine natural products have long served as a rich source of bioactive compounds, inspiring the discovery of anti-inflammatory and cytotoxic drugs. The pharmaceutical success of of different marine-derived metabolites such as ziconotide, trabectedin, and lurbinectedin, together with many others ongoing clinical trials, underscores the potential of marine scaffolds in drug development. Within this context, the Cacospongionolide family of marine sesterterpenoids is particularly attractive due to its unique molecular framework and promising cytotoxic and anti-inflammatory properties. However, sustainable access to these rare metabolites remains a major bottleneck, reinforcing the importance of innovative synthetic approaches. Pd-PHOTOMARINE addresses the total synthesis of this marine metabolite through two key innovations: (1) a novel Pd-catalyzed C–H activation strategy for the construction of the sterically congested decalin fragment, and (2) a photoredox-mediated Giese-type addition for the late-stage coupling of the eastern and western fragments. Together, these methodologies provide scalable and versatile solutions to long-standing synthetic hurdles, offering a platform applicable to other complex natural products. The complementary expertise of the host group, led by Prof. Olivier Baudoin in Pd-catalyzed C–H activation, and of Dr. Matteo Balletti in photocatalysis and visible-light radical chemistry, creates a highly synergistic framework for collaboration. This integration of skills not only secures the feasibility of the project and enhances its innovative potential, but also maximizes the reciprocal transfer of knowledge between both parties.