Building C(sp3)-rich complexity by combining cycloaddition and C–C cross-coupling reactions

Abstract

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres, cycloaddition reactions have featured in numerous total syntheses and are a key component in the education of chemistry students. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp manner. Despite the ability of cycloadditions to introduce multiple carbon sp centres in a single step, they are less used. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

Enantio‐ and Diastereoselective Suzuki–Miyaura Coupling with Racemic Bicycles

“…In this context, complex bicyclic and polycyclic structures with multiple C(sp 3 ) chiral centers are attractive molecular targets. Baran and co‐workers have recently reported on a modular cycloaddition/desymmetrization/cross‐coupling approach towards bridged bicyclic structures (Figure ), and Lautens and co‐workers have developed a rhodium‐catalyzed hydroarylation of strained bicyclic alkenes (Figure ) . Both methods desymmetrize prochiral meso starting materials and produce multiple stereogenic centers in a single reaction step.…”

Solar Photochemistry in Flow

“…Interesting, an apparent zero-order kinetic profile was observed, with the conversion correlating nicely with the integrated incident photon flux. Notably, given the recent advances in decarboxylative cross-coupling reactions, the succinic anhydride moieties resulting from the radical additions to maleic anhydride can be further functionalized, even in enantioselective ways [27].…”

Boron-Enabled Geometric Isomerization of Small Alkene Fragments via Selective Energy Transfer Catalysis

“…Despite these advances, the intractable challenges associated with inverting the geometry of small alkene fragments to enable stereodivergence from common precursors offer the opportunity for creative endeavor (8). In a broader sense, this strategic deficiency in alkene isomerization technology has been prominently highlighted by Baran and co-workers in the context of accessing dienophiles for cycloaddition chemistry (9). Terpene biosynthesis predicated on the sequential elongation of small (C5) alkene-containing linchpins such as DMAPP and IPP are conceptually attractive blueprints in reconciling this disparity ( Figure 1A) (10)(11)(12).…”