The pool of abundant chiral terpene building blocks (i.e. “chiral pool terpenes”) has long served as a starting point for the chemical synthesis of complex natural products, including many terpenes themselves. As inexpensive and versatile starting materials, such compounds continue to influence modern synthetic chemistry. This review highlights 21st century terpene total syntheses which themselves use small, terpene-derived materials as building blocks. An outlook to the future of research in this area is highlighted as well.

Cyclase enzymes weave simple polyprenyl chains into the elaborate polycyclic ring systems of terpenes, a sequence that is often difficult to emulate under abiotic conditions. Herein we report a disparate synthetic approach to complex terpenes whereby simple prenyl-derived chains are cyclized using radical, rather than cationic, reaction pathways. This strategy efficiently forges challenging 5/8/5-fused ring systems found in numerous complex natural product classes and enabled a nine-step total synthesis of (−)-6-epi-ophiobolin N, a member of the large family of cytotoxic ophiobolin sesterterpenes. A small-molecule thiol catalyst was found to override the inherent diastereoselectivity observed during a reductive radical cascade cyclization process. This work lays the foundation for efficiently accessing historically challenging terpenoid ring systems of interest in medicinal research.

Chemical syntheses of two stereochemically unique resveratrol dimers, caraphenols B and C, have shown that their structures are misassigned. Thoughts on their potential chemical etiology led to an alternate structural proposal that has been confirmed through synthesis, one indicating that the substituents on their respective indane systems exist in a relative trans,trans orientation rather than the originally postulated all-cis arrangement.

Continuous flow has been used widely in process chemistry and academic settings for various applications. However, initial reaction discovery has generally remained “batch-exclusive” despite the existence of efficient, reproducible flow systems. We hereby disclose a workflow to bridge the gap between early medicinal chemistry efforts and process-scale development, showcased by the discovery and optimization of a metallaphotoredox-catalyzed cross-coupling between benzylic chlorides and aryl bromides, followed by two library syntheses of complex drug-like compounds.

The ophiobolin sesterterpenes are notable plant pathogens which have recently elicited significant chemical and biological attention because of their intriguing carbogenic frameworks, reactive functionalities, and emerging anticancer profiles. Reported herein is a total synthesis of (+)‐6‐epi‐ophiobolin A in 14 steps, a task which addresses construction of the synthetically challenging spirocyclic tetrahydrofuran motif as well as several other key stereochemical problems. This work demonstrates a streamlined synthetic platform to complex ophiobolins leveraging disparate termination modes of a radical polycyclization cascade for divergent elaboration and functionalization.

Several dozen spirocyclic sesquiterpenoids known as the bromo-chamigrenes have been isolated to date. Yet, despite their unique structures, synthetic efforts toward this collection have been modest. Herein, we outline two strategies to generate their skeletons based on (1) a biomimetic bromonium-induced polyene cyclization using BDSB (EtSBr·SbClBr) and (2) a Diels-Alder reaction which ultimately delivered four members of the class. In addition, X-ray crystallography reveals that one member has a structure in need of revision.

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The ophiobolin sesterterpenes are notable plant pathogens which have recently elicited significant chemical and biological attention because of their intriguing carbogenic frameworks,r eactive functionalities,a nd emerging anticancer profiles.R eported herein is at otal synthesis of (+ +)-6-epiophiobolin Ai n1 4s teps,atask which addresses construction of the synthetically challenging spirocyclic tetrahydrofuran motif as well as several other key stereochemical problems. This work demonstrates as treamlined synthetic platform to complex ophiobolins leveraging disparate termination modes of ar adical polycyclization cascade for divergent elaboration and functionalization.