This Perspective illustrates the defining characteristics of free radical chemistry, beginning with its rich and storied history. Studies from our laboratory are discussed along with recent developments emanating from others in this burgeoning area. The practicality and chemoselectivity of radical reactions enable rapid access to molecules of relevance to drug discovery, agrochemistry, material science, and other disciplines. Thus, these reactive intermediates possess inherent translational potential, as they can be widely used to expedite scientific endeavors for the betterment of humankind.

Radicals: Reactive Intermediates with Translational Potential

The year 2017 marks the twentieth anniversary of terpenoid cyclase structural biology: a trio of terpenoid cyclase structures reported together in 1997 were the first to set the foundation for understanding the enzymes largely responsible for the exquisite chemodiversity of more than 80000 terpenoid natural products. Terpenoid cyclases catalyze the most complex chemical reactions in biology, in that more than half of the substrate carbon atoms undergo changes in bonding and hybridization during a single enzyme-catalyzed cyclization reaction. The past two decades have witnessed structural, functional, and computational studies illuminating the modes of substrate activation that initiate the cyclization cascade, the management and manipulation of high-energy carbocation intermediates that propagate the cyclization cascade, and the chemical strategies that terminate the cyclization cascade. The role of the terpenoid cyclase as a template for catalysis is paramount to its function, and protein engineering can...

Structural and Chemical Biology of Terpenoid Cyclases.

In this review, recent examples featuring C–H functionalization in the synthesis of complex natural products are discussed. A focus is given to the way in which C–H functionalization can influence the logical process of retrosynthesis, and the review is organized by the type and method of C–H functionalization.

Recent applications of C–H functionalization in complex natural product synthesis

Complex molecular architectures containing cyclopropanes present significant challenges for any synthetic chemist. This review aims to highlight the strategic considerations for introduction of the cyclopropane motif in a collection of recent total syntheses. At first, an overview of the most important and widely used cyclopropanation techniques is presented, followed by a discussion of elegant approaches and clever solutions that have been developed to enable the synthesis of various unique cyclopropane natural products or use of cyclopropanes as versatile strategic intermediates.

Cyclopropanation Strategies in Recent Total Syntheses

Since the dawn of the 20th century, the average life expectancy at birth has nearly doubled due to advances in science and medicine. As medical records grew more reliable, it became apparent that, while overall life span was increasing, there were significant epidemiological differences between geographical regions, with people from countries such as Japan, France, and Switzerland enjoying longer life expectancy as compared to other regions of the world. The causative factors for these disparities in both mortality and morbidity have been attributed not only to genetics but also to the contributions of highly variable lifestyle and environmental influences.1 Barring differences in modernization and public health policy, diet is the most significant epidemiological factor cross-culturally and is thought to be a profoundly important contributor to health and overall well-being.

Prior to the early 1990s, there was a general consensus in support of the belief that moderate alcohol consumption significantly lowered the risk of coronary heart disease (CHD).2 However, it was not clear whether this was true of all alcoholic beverages or which constituents in the drinks were responsible for these beneficial properties.3 In 1992, Siemann and Creasy4 reported that resveratrol (1) was present in significant concentrations in red wine, drawing attention to the fact that it was also an active principle found in Japanese and Chinese folk medicines used to treat ailments related to the liver, skin, heart, and lipid metabolism.5 The discovery of resveratrol in wine was particularly timely; although the correlation between high fat and cholesterol consumption and coronary heart disease was widely accepted,6 certain populations, namely the French, had a low incidence of CHD mortality despite a diet and lifestyle that exposed these individuals to elevated risk factors.7 The cardioprotective ability of resveratrol, its oligomers, along with other phytochemicals present in wine, appeared to resolve this “French Paradox” and advanced the notion that a chemical constituent of one’s diet could be beneficial to health.8 Although the reality of the French Paradox remains contentious,9,10 research into the health benefits of resveratrol has exploded as a result. The reported biological activities of resveratrol are numerous, including antioxidant,11 anticancer,12 antidiabetic,13,14 cardioprotective,15 and even antiaging properties,16 to name a few. The body of literature regarding the biological activity of resveratrol is expansive and beyond of the scope of this review. We invite the readers to the following resources for background on this exciting and ongoing field of research.17−21

Despite its enormous popularity, resveratrol is but a single compound in a large, structurally diverse class of oligomeric stilbenoids that are present in the wines and foods that we consume.22,23 Until recently, access to these oligomeric natural products was limited to isolation from natural sources, which severely hampered their biological evaluation. The scientific interest in resveratrol has undoubtedly instigated the renewed attention in these compounds by the chemical community. Advances in the characterization, isolation techniques, and synthesis of these natural products have significantly enriched our understanding of their chemistry and biology. Our review seeks to document the history and recent progress in the isolation, chemical synthesis, and biology of this fascinating class of phytochemicals, while providing new insight on the biosynthesis and future prospects for the field as a whole.

Chemistry and Biology of Resveratrol-Derived Natural Products

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.

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

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. Here 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 allowed us to efficiently forge the intricate 5-8-5 fused ring systems found in numerous complex natural product classes and also 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 efficient synthesis of terpenoid ring systems of interest in medicinal research, particularly those that have been historically challenging to access.

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Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade.

Structural revision and total synthesis of caraphenol B and C.

Continuous Flow Enables Metallaphotoredox Catalysis in a Medicinal Chemistry Setting: Accelerated Optimization and Library Execution of a Reductive Coupling between Benzylic Chlorides and Aryl Bromides

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.

Zachary G. Brill

Papers

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade.

Structural revision and total synthesis of caraphenol B and C.

Continuous Flow Enables Metallaphotoredox Catalysis in a Medicinal Chemistry Setting: Accelerated Optimization and Library Execution of a Reductive Coupling between Benzylic Chlorides and Aryl Bromides

Total Synthesis of (+)-6-epi-Ophiobolin A