Navigating Excess Complexity: Total Synthesis of Daphenylline.

Retrosynthetic analysis is a framework for designing synthetic routes to complex molecules that generally prioritizes disconnections which reduce molecular complexity. However, strict adherence to this principle can overlook pathways involving highly complex intermediates that can be easily prepared through powerful bond-forming transformations. Herein, we demonstrate this tactic of generating excess complexity, followed by strategic bond-cleavage, as a highly effective approach for the 11-step total synthesis of the Daphniphyllum alkaloid daphenylline. To implement this strategy, we accessed a bicyclo[4.1.0]heptane core through a dearomative Buchner cycloaddition, which enabled construction of the seven-membered ring after C-C bond cleavage. Installation of the synthetically challenging quaternary stereocenter methyl group was achieved through a thia-Paternò-Büchi [2 + 2] photocycloaddition followed by stereospecific thietane reduction, further illustrating how building excess complexity can enable desired synthetic outcomes after strategic bond-breaking events. This strategy leveraging bond cleavage transformations should serve as a complement to traditional bond-forming, complexity-generating synthetic strategies.

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine.

An unusual photoredox-catalyzed radical decarboxylative cyclization cascade reaction of γ,γ-dimethylallyltryptophan (DMAT) derivatives containing unactivated alkene moieties has been developed, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This type of cyclization, which was hitherto very difficult to comprehend in ergot biosynthesis and to accomplish by more conventional procedures, enables the synthesis of ergot alkaloid precursors. In addition, this work describes a mild, environmentally friendly method to activate, reductively and oxidatively, natural carboxylic acids for decarboxylative C-C bond formation by exploiting the same photocatalyst.

Concise catalytic asymmetric synthesis of (R)-4-amino Uhle's ketone.

A practical and asymmetric synthesis of (R)-4-amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole, an enantiopure framework shared by most ergot alkaloids, was accomplished. Our method involves a Rh(i)-catalyzed 6-exo-trig intramolecular cyclization of an appropriate 4-pinacolboronic ester d-tryptophan aldehyde followed by the oxidation of the resulting secondary benzylic alcohol with a Cu(i)-ABNO catalyst and final deprotection under acidic conditions. This new procedure offers significant advantages over previous synthetic approaches, including brevity, mild reaction conditions, preservation of chiral integrity, and high overall yield and avoids the use of stoichiometric amounts of strongly basic and pyrophoric organometallic reagents.

Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides.

Organic halides are important building blocks in synthesis, but their use in (photo)redox chemistry is limited by their low reduction potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.