Covering: up to 2022Tricyclic bridgehead carbon centers (TBCCs) are a synthetically challenging substructure found in many complex natural products. Here we review the syntheses of ten representative families of TBCC-containing isolates, with the goal of outlining the strategies and tactics used to install these centers, including a discussion of the evolution of the successful synthetic design. We provide a summary of common strategies to inform future synthetic endeavors.

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Natural product synthesis remains a field in which new synthetic methods and reagents are continually being evaluated. Due to the demanding structures and complex functionality of many natural products, only powerful and selective methods and reagents will be highlighted in this proceeding. Since its introduction by Henri Kagan, samarium(ii) iodide (SmI 2 , Kagan's reagent) has found increasing use in chemical synthesis. Over the years, many reviews have been published on the application of SmI 2 in numerous reductive coupling procedures as well as in natural product total synthesis. This review highlights recent advances in SmI 2 -mediated synthetic strategies, as applied in the total synthesis of natural products since 2004.

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A summary of the investigation and applications of the inverse electron demand Diels-Alder reaction is provided that have been conducted in our laboratory over a period that now spans more than 35 years. The work, which continues to provide solutions to complex synthetic challenges, is presented in the context of more than 70 natural product total syntheses in which the reactions served as a key strategic step in the approach. The studies include the development and use of the cycloaddition reactions of heterocyclic azadienes (1,2,4,5-tetrazines; 1,2,4-, 1,3,5-, and 1,2,3-triazines; 1,2-diazines; and 1,3,4-oxadiazoles), 1-aza-1,3-butadienes, α-pyrones, and cyclopropenone ketals. Their applications illustrate the power of the methodology, often provided concise and nonobvious total syntheses of the targeted natural products, typically were extended to the synthesis of analogues that contain deep-seated structural changes in more comprehensive studies to explore or optimize their biological properties, and highlight a wealth of opportunities not yet tapped.

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The total synthesis of (-)-kopsinine and its unnatural enantiomer is detailed, enlisting a late-stage SmI 2 -mediated transannular free radical conjugate addition reaction for construction of the core bicyclo[2.2.2]octane ring system with strategic C21-C2 bond formation. Key to the approach is assemblage of the underlying skeleton by an intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the precursor C21 functionalized pentacyclic ring system 1 in a single step in which the C3 methyl ester found in the natural product served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels-Alder reaction and stabilizing the intermediate 1,3-dipole.

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The use of a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of an 1,3,4-oxadiazole in the divergent total synthesis of kopsinine (1), featuring an additional unique SmI(2)-promoted transannular cyclization reaction for formation of the bicyclo[2.2.2]octane central to its hexacyclic ring system, is detailed.

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