Natural Product Synthesis in the 21st Century: Beyond the Mountain Top.

Research into natural products emerged from humanity's curiosity about the nature of matter and its role in the materia medica of diverse civilizations. Plants and fungi, in particular, supplied materials that altered behavior, perception, and well-being profoundly. Many active principles remain well-known today: strychnine, morphine, psilocybin, ephedrine. The potential to circumvent the constraints of natural supply and explore the properties of these materials led to the field of natural product synthesis. This research delivered new molecules with new properties, but also led to fundamental insights into the chemistry of the nonmetal elements H, C, N, O, P, S, Se, and their combinations, i.e., organic chemistry. It also led to a potent culture focused on bigger molecules and races to the finish line, perhaps at the expense of actionable next steps. About 20 years ago, the field began to contract in the United States. Research that focused solely on chemical reaction development, especially catalysis, filled the void. After all, new reactions and mechanistic insight could be immediately implemented by the chemistry community, so it became hard to justify the lengthy procurement of a complex molecule that sat in the freezer unused. This shift coincided with a divestment of natural product portfolios by pharmaceutical companies and an emphasis in academic organic chemistry on applications-driven research, perhaps at the expense of more fundamental science. However, as bioassays and the tools of chemical biology become widespread, synthesis finds a new and powerful ally that allows us to better deliver on the premise of the field. And the hard-won insights of complex synthesis can be better encoded digitally, mined by data science, and applied to new challenges, as chemists perturb and even surpass the properties of complex natural products. The 21st century promises powerful developments, both in fundamental organic chemistry and at the interface of synthesis and biology, if the community of scientists fosters its growth. This essay tries to contextualize natural product synthesis for a broad audience, looks ahead to its transformation in the coming years, and expects the future to be bright.

Carbon quaternization of redox active esters and olefins by decarboxylative coupling.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (SH2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

Alkene Hydrobenzylation by a Single Catalyst That Mediates Iterative Outer-Sphere Steps.

Cross-coupling catalysts typically react and unite functionally distinct partners via sequential inner-sphere elementary steps: coordination, migratory insertion, reductive elimination, etc. Here, we report a single catalyst that cross-couples styrenes and benzyl bromides via iterative outer-sphere steps: metal-ligand-carbon interactions. Each partner forms a stabilized radical intermediate, yet heterocoupled products predominate. The system is redox-neutral and, thus, avoids exogenous oxidants, resulting in simple and scalable conditions. Numerous variations of alkene hydrobenzylation are made possible, including access to the privileged heterodibenzyl (1,2-diarylethane) motif and challenging quaternary carbon variants.

C5 methylation confers accessibility, stability and selectivity to picrotoxinin.

Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.

Inner- and Outer-Sphere Cross-Coupling of High Fsp3 Fragments.

Natural product research originates from a desire to explore, understand, and perturb biological function with atomic precision. To reach these goals at all, let alone efficiently, requires thoughtful and creative problem solving. Often this means bold disconnections that would simplify access to complex structures, if only the methods existed to bridge these theoretical gaps. Whereas biological interrogations provide long-term intellectual value and impetus, methods come as attractive fringe benefits of natural product synthesis. This Account describes strategic, methodological solutions to the syntheses of natural products [(-)-eugenial C, Galbulimima alkaloids GB18, GB22, GB13, and himgaline] featuring new, convergent disconnections as important problem-solving steps, which themselves were inspired by recent methods that arose from our group. Each target required the invention of first-row transition metal-catalyzed cross-coupling procedures to satisfy the biological goals of the project. In these cases, synthetic strategy identified the methodological gap (the absence of stereo- and chemoselective couplings of appropriate fragments), but the tactical advantage conferred by first-row metals met the challenge. These methods were competent to handle the dense, sterically encumbered motifs common to natural products due to, in many cases, elementary steps that did not require bond formation between the hindered substrate and the metal center. Instead, these sterically lenient reactions appeared to involve metal-ligand-substrate reactions (i.e., outer-sphere steps), in contrast to the metal-substrate, coordinative reactions of precious metals (i.e., inner-sphere steps). Key observations from our previous studies, combined with the observations in seminal publications from other laboratories (Mattay, Weix, and MacMillan), led to the optimization of ligand-controlled, stereoselective reactions and the introduction of complementary catalytic cycles that revealed new modes of reactivity and generated novel structural motifs. Optimized access to bioactive natural product space accelerated our timeline of biological characterization, fulfilling a common premise of natural products research. The integration of methodology, complex natural product synthesis, diversification, and bioassay into a single Ph.D. dissertation would have been unmanageable in a prior era. The unique ability of first-row transition metals to effect Csp3-Csp3 cross-coupling with high chemo- and stereoselectivity has significantly lowered the barrier to reach the avowed goal of natural product synthesis and reduced the burden (real or perceived) of integrating natural products into functional campaigns.

Synthesis of (-)-Cotylenol, a 14-3-3 Molecular Glue Component.

Small molecules that modulate the 14-3-3 protein-protein interaction (PPI) network represent valuable therapeutics and tool compounds. However, access has been lost to 14-3-3 PPI molecular glues of the cotylenin class, leading to investigations into the practical chemical syntheses of congeners and analogues. Here we report a concise synthesis of (-)-cotylenol via a 10-step asymmetric entry into a diversifiable 5-8-5 core. This route features a mild Liebeskind-Srogl fragment coupling that tolerates unprecedented steric hindrance to produce a highly congested ketone, and a tandem Claisen-ene cascade that establishes the 8-membered ring. Late-stage control of stereochemistry and functionality leads to (-)-cotylenol and sets the stage for focused library synthesis.

A Route to Potent, Selective, and Biased Salvinorin Chemical Space.

The salvinorins serve as templates for next generation analgesics, antipruritics, and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind with high affinity and selectivity via complex polyoxygenated scaffolds that have frustrated deep-seated modification by synthesis. Here we describe a short asymmetric synthesis that relies on a sterically confined organocatalyst to dissociate acidity from reactivity and effect Robinson annulation of an unactivated nucleophile/unstable electrophile pair. Combined with a cobalt-catalyzed polarized diene-alkyne cycloaddition, the route allows divergent access to a focused library of salvinorins. We appraise the synthesis by its generation of multiple analogs that exceed the potency, selectivity, stability, and functional bias of salvinorin A itself.

Iron-Catalyzed Hydrobenzylation: Stereoselective Synthesis of (-)-Eugenial C.

Metal-hydride hydrogen atom transfer (MHAT) has emerged as a useful tool to form quaternary carbons from alkenes via hydrofunctionalization. Methods to date that cross-couple alkenes with sp3 partners rely on heterobimetallic catalysis to merge the two cycles. Here, we report an iron-only cross-coupling via putative MHAT/SH2 steps that solves a key stereochemical problem in the synthesis of meroterpenoid eugenial C and obviates the need for nickel. The concise synthesis benefits from a conformationally locked o,o'-disubstituted benzyl bromide and a locally sourced chiral pool terpene coupling partner.

Hidden Lives. Early Childhood Care as an Academic: The Slow Burn.

As the inaugural entry in the new series Hidden Lives, this Viewpoint Article highlights challenges in early childhood care faced by academicians. Research centers must adapt to societal shifts in family structure, uncertainty around research funding, expanded job responsibilities and upheavals brought about by the pandemic. These problems represent opportunities for change at the technological, cultural and policy levels. It is crucial that we recognize those in need and help where we can.

Asymmetric Syntheses of (+)- and (-)-Collybolide Enable Reevaluation of kappa-Opioid Receptor Agonism.

The fungal metabolite collybolide has attracted attention as a non-nitrogenous, potent, and biased agonist of the kappa-opioid receptor (KOR). Here, we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, indicating that collybolide has been mischaracterized as a KOR agonist. Given the pharmaceutical, medical, and societal interest in collybolide as a next-generation antipruritic and analgesic, this refutation of KOR activity has important ramifications for ongoing studies. Classification of collybolide as a new non-nitrogenous, KOR-selective, potent agonist with the same clinical potential as salvinorin A seems to have been premature.

Synthesis and target annotation of the alkaloid GB18.

Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans1-4. Limited, variable supply of GB alkaloids5, however, has impeded their biological exploration and clinical development6. Here we report a solution to the supply of GB18, a structural outlier and putative psychotropic principle of Galbulimima bark. Efficient access to its challenging tetrahedral attached-ring motif required the development of a ligand-controlled endo-selective cross-electrophile coupling and a diastereoselective hydrogenation of a rotationally dynamic pyridine. Reliable, gram-scale access to GB18 enabled its assignment as a potent antagonist of κ- and µ-opioid receptors-the first new targets in 35 years-and lays the foundation to navigate and understand the biological activity of Galbulimima metabolites.

Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction.

Neuroactive metabolites from the bark of Galbulimima belgraveana occur in variable distributions among trees and are not easily accessible through chemical synthesis because of elaborate bond networks and dense stereochemistry. Previous syntheses of complex congeners such as himgaline have relied on iterative, stepwise installation of multiple methine stereocenters. We decreased the synthetic burden of himgaline chemical space to nearly one-third of the prior best (7 to 9 versus 19 to 31 steps) by cross-coupling high fraction aromatic building blocks (high Fsp2) followed by complete, stereoselective reduction to high fraction sp3 products (high Fsp3). This short entry into Galbulimima alkaloid space should facilitate extensive chemical exploration and biological interrogation.

Stereodivergent Attached-Ring Synthesis via Non-Covalent Interactions: A Short Formal Synthesis of Merrilactone A.

A strategy to control the diastereoselectivity of bond formation at a prochiral attached-ring bridgehead is reported. An unusual stereodivergent Michael reaction relies on basic vs. Lewis acidic conditions and non-covalent interactions to control re- vs. si- facial selectivity en route to fully substituted attached-rings. This divergency reflects differential engagement of one rotational isomer of the attached-ring system. The successful synthesis of an erythro subtarget diastereomer ultimately leads to a short formal synthesis of merrilactone A.

Synthesis of psychotropic alkaloids from Galbulimima.

Efficient syntheses of valuable natural products open gateways from kind learning environments to wicked worlds, where long-term, interdisciplinary research questions can be asked and answered. In this Perspective, we discuss the Galbulimima (GB) alkaloids, metabolites of a rainforest canopy tree that exhibit potent but poorly understood effects in humans, including accounts of hallucination. Recent syntheses from our group have opened up GB alkaloid chemical space for investigation by way of new cross-coupling reactions and gram-scale target production. Although natural product synthesis can be challenging, its objective is obvious. Realization of long-term, enabling goals will be a circuitous journey at the interface of chemistry, pharmacology and neuroscience-a potent mix to foster discovery in the coming century.

Revision of the Unstable Picrotoxinin Hydrolysis Product.

The plant metabolite picrotoxinin (PXN) is a widely used tool in neuroscience for the identification of GABAergic signaling. Its hydrolysis in weakly alkaline media has been observed for over a century and the structure of the unstable hydrolysis intermediate was assigned by analogy to the degradation product picrotoxic acid. Here we show this assignment to be in error and we revise the structure of the hydrolysis product by spectroscopic characterization in situ. Counterintuitively, hydrolysis occurs at a lactone that remains closed in the major isolable degradation product, which accounts for the longstanding mistake in the literature.

Natural Product Synthesis through the Lens of Informatics.

Retrosynthetic analysis emerged in the 1960s as a teaching tool with profound implications. Its educational value can be appreciated by a glance at total synthesis manuscripts over 50 years later, most of which contain a retrosynthesis on page one. Its vision extended to computer language-a pioneering idea in the 20th century that continues to expand the frontiers today. The same principles that guide a student to evaluate, expand, and refine a series of bond dissections can be programmed, so that computer assistance can perform the same tasks but at faster speeds.The slow step in the synthesis of complex structures, however, is seldom route design. Compression of molecular information into close proximity (Cm/Å3) requires exploration and empiricism, a close connection between theory and experiment. Here, retrosynthetic analysis guides the choice of experiment, so that the most simplifying-but often least assured-disconnection is prioritized: a high-risk, high reward strategy. The reimagining of total synthesis in a future era of retrosynthetic software may involve, counterintuitively, target design, as discussed here.Compared to the 1960s, retrosynthetic analysis in the 21st century finds itself among computers of unimaginable power and a biology that is increasingly molecular. Put together, the logic of retrosynthesis, the insight of structural biology, and the predictions of computation have inspired us to imagine an integration of the three. The synthetic target is treated as dynamic-a constellation of related structures-in order to find the nearest congener with the closest affinity but the shortest synthetic route. Such an approach merges synthetic design with structural design toward the goal of improved access for improved function.In this Account, we detail the evolution of our program from its inception in traditional natural product (NP) total synthesis to its current expression through the lens of chemical informatics: a view of NPs as aggregates of molecular parameters that define single points in a chemical space. Early work on synthesis and biological annotation of apparent metal pool binders and nonselective covalent electrophiles (asmarine alkaloids, isocyanoterpenes, Nuphar dimers) gave way to NPs with well-defined protein targets. The plant metabolite salvinorin A (SalA) potently and selectively agonizes the κ-opioid receptor (KOR), rapidly penetrates the brain, and represents an important lead for next-generation analgesics and antipruritics. To synthesize and diversify this lead, we adopted what we now call a dynamic approach. Deletion of a central methyl group stabilized the SalA scaffold, opened quick synthetic access, and retained high potency and selectivity. The generality of this idea was then tested against another neuroactive class. As an alternative hypothesis to TrkB channels, we proposed that the so-called "neurotrophic" Illicium terpenes may bind to γ-aminobutyric acid (GABA)-gated ion channels to cause weak, chronic excitation. Syntheses of (-)-jiadifenolide, 3,6-dideoxy-10-hydroxypseudoanisatin, (-)-11-O-debenzoyltashironin, (-)-bilobalide, and (-)-picrotoxinin (PXN) allowed this hypothesis to be probed more broadly. Feedback from protein structure and synthetic reconnaissance led to a dynamic retrosynthesis of PXN and the identification of 5MePXN, a moderate GABAAR antagonist with greater aqueous stability available in eight steps from dimethylcarvone. We expect this dynamic approach to synthetic target analysis to become more feasible in the coming years and hope the next generation of scientists finds this approach helpful to address problems at the frontier of chemistry and biology.

Change the channel: CysLoop receptor antagonists from nature.

Vertebrate and invertebrate ligand-gated ion channels (LGICs) exhibit significant structural homology and often share ligands. As a result, ligands with activity against one class can be brought to bear against another, including for development as insecticides. Receptor selectivity, metabolism and distribution must then be optimized using chemical synthesis. Here we review natural products (NPs) that ligate and inhibit the Cys-loop family of LGICs, which benefit from the unique physicochemical properties of natural product space but often present a high synthetic burden. Recent advances in chemical synthesis, however, have opened practical entries into these complex structures, several of which are highlighted. © 2020 Society of Chemical Industry.

Cobalt-catalyzed alkene hydrogenation by reductive turnover.

Earth abundant metal catalysts hold advantages in cost, environmental burden and chemoselectivity over precious metal catalysts. Differences in reactivity for a given metal center result from ligand field strength, which can promote reaction through either open- or closed-shell carbon intermediates. Herein we report a simple protocol for cobalt-catalyzed alkene reduction. Instead of using an oxidative turnover mechanism that requires stoichiometric hydride, we find a reductive turnover mechanism that requires stoichiometric proton. The reaction mechanism appears to involve coordination and hydrocobaltation of terminal alkenes.

Synthetic, Mechanistic, and Biological Interrogation of Ginkgo biloba Chemical Space En Route to (-)-Bilobalide.

Here we interrogate the structurally dense (1.64 mcbits/Å3) GABAA receptor antagonist bilobalide, intermediates en route to its synthesis, and related mechanistic questions. 13C isotope labeling identifies an unexpected bromine migration en route to an α-selective, catalytic asymmetric Reformatsky reaction, ruling out an asymmetric allylation pathway. Experiment and computation converge on the driving forces behind two surprising observations. First, an oxetane acetal persists in concentrated mineral acid (1.5 M DCl in THF-d8/D2O); its longevity is correlated to destabilizing steric clash between substituents upon ring-opening. Second, a regioselective oxidation of des-hydroxybilobalide is found to rely on lactone acidification through lone-pair delocalization, which leads to extremely rapid intermolecular enolate equilibration. We also establish equivalent effects of (-)-bilobalide and the nonconvulsive sesquiterpene (-)-jiadifenolide on action potential-independent inhibitory currents at GABAergic synapses, using (+)-bilobalide as a negative control. The high information density of bilobalide distinguishes it from other scaffolds and may characterize natural product (NP) space more generally. Therefore, we also include a Python script to quickly (ca. 132 000 molecules/min) calculate information content (Böttcher scores), which may prove helpful to identify important features of NP space.

Chemical syntheses of the salvinorin chemotype of KOR agonist.

Covering: 2000 to 2020 The hallucinogenic diterpene salvinorin A potently and selectively agonizes the human kappa-opioid receptor (KOR). Its unique attributes-lack of a basic nitrogen, rapid brain penetrance, short half-life-combined with the potential of KOR as an emerging target for analgesics have stimulated extensive medicinal chemistry based on semi-synthesis from extracts of Salvia divinorum. Total synthesis efforts have delivered multiple, orthogonal routes to salvinorin A, its congeners and related analogs with the goal of optimizing its activity towards multiple functional endpoints. Here we review total syntheses of the salvinorin chemotype and discuss outstanding problems that synthesis can address in the future.