Oxidative Dearomatization of Pyridines.

Dearomatization of pyridines is a well-established synthetic approach to access piperidines. Although remarkably powerful, existing dearomatization processes have been limited to the hydrogenation or addition of carbon-based nucleophiles to activated pyridiniums. Here, we show that arenophile-mediated dearomatizations can be applied to pyridines to directly introduce heteroatom functionalities without prior substrate activation. The arenophile platform in combination with olefin oxidation chemistry provides access to dihydropyridine cis-diols and epoxides. These previously elusive compounds are now readily accessible and can be used for the downstream preparation of diversely functionalized piperidines.

Diversification of Simple Arenes into Complex (Amino)cyclitols.

Highly oxygenated cyclohexanes, including (amino)cyclitols, are featured in natural products possessing a notable range of biological activities. As such, these building blocks are valuable tools for medicinal chemistry. While de novo synthetic strategies have provided access to select compounds, challenges including stereochemical density and complexity have hindered the development of a general approach to (amino)cyclitol structures. This work reports the use of arenophile chemistry to access dearomatized intermediates which are amenable to diverse downstream transformations. Practical guidelines were developed for the synthesis of natural and non-natural (amino)cyclitols from simple arenes through a series of strategic functionalization events.

Elucidating the Mechanism of Metabolism of Cannabichromene by Human Cytochrome P450s.

Cannabichromene (CBC) is a nonpsychoactive phytocannabinoid well-known for its wide-ranging health advantages. However, there is limited knowledge regarding its human metabolism following CBC consumption. This research aimed to explore the metabolic pathways of CBC by various human liver cytochrome P450 (CYP) enzymes and support the outcomes using in vivo data from mice. The results unveiled two principal CBC metabolites generated by CYPs: 8'-hydroxy-CBC and 6',7'-epoxy-CBC, along with a minor quantity of 1″-hydroxy-CBC. Notably, among the examined CYPs, CYP2C9 demonstrated the highest efficiency in producing these metabolites. Moreover, through a molecular dynamics simulation spanning 1 µs, it was observed that CBC attains stability at the active site of CYP2J2 by forming hydrogen bonds with I487 and N379, facilitated by water molecules, which specifically promotes the hydroxy metabolite's formation. Additionally, the presence of cytochrome P450 reductase (CPR) amplified CBC's binding affinity to CYPs, particularly with CYP2C8 and CYP3A4. Furthermore, the metabolites derived from CBC reduced cytokine levels, such as IL6 and NO, by approximately 50% in microglia cells. This investigation offers valuable insights into the biotransformation of CBC, underscoring the physiological importance and the potential significance of these metabolites.

Copper-Catalyzed Dearomative 1,2-Hydroamination.

Catalytic olefin hydroamination reactions are some of the most atom-economical transformations that bridge readily available starting materials-olefins and high-value-added amines. Despite significant advances in this field over the last two decades, the formal hydroamination of nonactivated aromatic compounds remains an unsolved challenge. Herein, we report the extension of olefin hydroamination to aromatic π-systems by using arenophile-mediated dearomatization and Cu-catalysis to perform 1,2-hydroamination on nonactivated arenes. This strategy was applied to a variety of substituted arenes and heteroarenes to provide general access to structurally complex amines. We conducted DFT calculations to inform mechanistic understanding and rationalize unexpected selectivity trends. Furthermore, we developed a practical, scalable desymmetrization to deliver enantioenriched dearomatized products and enable downstream synthetic applications. We ultimately used this dearomative strategy to efficiently synthesize a collection of densely functionalized small molecules.

π-Extended Rubrenes via Dearomative Annulative π-Extension Reaction.

Among a large variety of organic semiconducting materials, rubrene (5,6,11,12-tetraphenyltetracene) represents one of the most prominent molecular entities mainly because of its unusually high carrier mobility. Toward finding superior rubrene-based organic semiconductors, several synthetic strategies for related molecules have been established. However, despite its outstanding properties and significant attention in the field of materials science, late-stage functionalizations of rubrene remains undeveloped, thereby limiting the accessible chemical space of rubrene-based materials. Herein, we report on a late-stage π-extension of rubrene by dearomative annulative π-extension (DAPEX), leading to the generation of rubrene derivatives having an extended acene core. The Diels-Alder reaction of rubrene with 4-methyl-1,2,4-triazoline-3,5-dione occurred to give 1:1 and 1:2 cycloadducts which further underwent iron-catalyzed annulative diarylation. The thus-formed 1:1 and 1:2 adducts were subjected to radical-mediated oxidation and thermal cycloreversion to furnish one-side and two-side π-extended rubrenes, respectively. These π-extended rubrenes displayed a marked red shift in absorption and emission spectra, clearly showing that the acene π-system of rubrene was extended not only structurally but also electronically. The X-ray crystallographic analysis uncovered interesting packing modes of these π-extended rubrenes. Particularly, two-side π-extended rubrene adopts a brick-wall packing structure with largely overlapping two-dimensional face-to-face π-π interactions. Finally, organic field-effect transistor devices using two-side π-extended rubrene were fabricated, and their carrier mobilities were measured. The observed maximum hole mobility of 1.49 × 10-3 cm2V-1 s-1, which is a comparable value to that of the thin-film transistor using rubrene, clearly shows the potential utility of two-side π-extended rubrene in organic electronics.

Total Syntheses of Scabrolide A and Yonarolide.

The concise total syntheses of oxidized norcembranoid terpenoids (-)-scabrolide A and (-)-yonarolide have been accomplished in 10 and 11 steps, respectively. The carbocyclic skeleton was efficiently constructed from two chiral-pool-derived fragments, including a [5,5]-bicyclic lactone accessed through a powerful Ni-catalyzed pentannulation of functionalized cyclopentenone with methylenecyclopropane and subsequent fragmentation. Additional features included a Liebeskind-Srogl coupling, induction of a cyclization/elimination cascade by a zinc-amido base, and installation of a sensitive enedione motif by late-stage γ-oxidation.

Metabolites of Cannabigerol Generated by Human Cytochrome P450s Are Bioactive.

The phytocannabinoid cannabigerol (CBG) is the central biosynthetic precursor to many cannabinoids, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Though the use of CBG has recently witnessed a widespread surge because of its beneficial health effects and lack of psychoactivity, its metabolism by human cytochrome P450s is largely unknown. Herein, we describe comprehensive in vitro and in vivo cytochrome P450 (CYP)-mediated metabolic studies of CBG, ranging from liquid chromatography tandem mass spectrometry-based primary metabolic site determination, synthetic validation, and kinetic behavior using targeted mass spectrometry. These investigations revealed that cyclo-CBG, a recently isolated phytocannabinoid, is the major metabolite that is rapidly formed by selected human cytochrome P450s (CYP2J2, CYP3A4, CYP2D6, CYP2C8, and CYP2C9). Additionally, in vivo studies with mice administered with CBG supported these studies, where cyclo-CBG is the major metabolite as well. Spectroscopic binding studies along with docking and modeling of the CBG molecule near the heme in the active site of P450s confirmed these observations, pointing at the preferred site selectivity of CBG metabolism at the prenyl chain over other positions. Importantly, we found out that CBG and its oxidized CBG metabolites reduced inflammation in BV2 microglial cells stimulated with LPS. Overall, combining enzymological studies, mass spectrometry, and chemical synthesis, we showcase that CBG is rapidly metabolized by human P450s to form oxidized metabolites that are bioactive.

Total Synthesis of Darobactin A.

The collaborative total synthesis of darobactin A, a recently isolated antibiotic that selectively targets Gram-negative bacteria, has been accomplished in a convergent fashion with a longest linear sequence of 16 steps from d-Garner's aldehyde and l-serine. Scalable routes toward three non-canonical amino acids were developed to enable the synthesis. The closure of the bismacrocycle was realized through sequential, halogen-selective Larock indole syntheses, where the proper order of cyclizations proved crucial for the formation of the desired atropisomer of the natural product.

Correction: Dearomative logic in natural product total synthesis.

Correction for 'Dearomative logic in natural product total synthesis' by Christopher J. Huck et al., Nat. Prod. Rep., 2022, https://doi.org/10.1039/d2np00042c.

Dearomative logic in natural product total synthesis.

Covering: 2011 to 2022The natural world is a prolific source of some of the most interesting, rare, and complex molecules known, harnessing sophisticated biosynthetic machinery evolved over billions of years for their production. Many of these natural products represent high-value targets of total synthesis, either for their desirable biological activities or for their beautiful structures outright; yet, the high sp3-character often present in nature's molecules imparts significant topological complexity that pushes the limits of contemporary synthetic technology. Dearomatization is a foundational strategy for generating such intricacy from simple materials that has undergone considerable maturation in recent years. This review highlights the recent achievements in the field of dearomative methodology, with a focus on natural product total synthesis and retrosynthetic analysis. Disconnection guidelines and a three-phase dearomative logic are described, and a spotlight is given to nature's use of dearomatization in the biosynthesis of various classes of natural products. Synthetic studies from 2011 to 2021 are reviewed, and 425 references are cited.

Total Synthesis of Stelletins through an Unconventional Annulation Strategy.

Marine ecosystems present the largest source of biodiversity on the planet and an immense reservoir of novel chemical entities. Sessile marine organisms such as sponges produce a wide range of complex secondary metabolites, many of these with potent biological activity engineered for chemical defense. That such compounds exert dynamic effects outside of their native context is perhaps not surprising, and the realm of marine natural products has attracted considerable attention as a largely untapped repository of potential candidates for drug development. Only a handful of the more than 15 000 marine natural products that have been isolated to date have advanced to the clinic, and more are to be expected. The rich chemical information encoded in the intricate three-dimensional structures of many marine natural products facilitates highly discriminating interactions with cell signaling pathways, and especially within cancer cells such nuanced effects offer an exciting opportunity for the development of targeted therapies that lack the side effects and general toxicity of conventional chemotherapeutics. The isomalabaricanes are a rare class of marine triterpenoids that have been hailed as promising cytotoxic lead compounds for the treatment of cancer, and they have attracted a flurry of excitement from researchers because of their potent cytotoxicity in certain human cancer cell lines along with a range of other antineoplastic effects. Most notably, their inhibitory activity is highly cell-selective, characterized by large deviations from their mean GI50 concentrations across 3 orders of magnitude in the NCI-60 Human Tumor Cell Lines screen, suggesting mechanistic specificity rather than general and unbridled toxicity. Despite these auspicious preliminary reports, the isomalabaricane scaffold remains largely unexplored as a potential anticancer lead because of lack of material. This Account describes our recent efforts to develop a general, modular synthesis of the isomalabaricanes, as exemplified by the successful total syntheses of rhabdastrellic acid A, stelletin E, and stelletin A. The unorthodox trans-syn-trans configuration of their perhydrobenz[e]indene core severely circumscribes the synthetic methods available for its construction and required several generations of strategy to assemble. Ultimately, a series of unconventional transformations were identified that were capable of building this highly strained motif, and the syntheses of rhabdastrellic acid A and stelletin E were completed in racemic fashion. Subsequently, a second-generation approach to these natural products was developed, rendering the synthesis enantioselective as well as providing access to stelletin A. These synthetic efforts were greatly assisted by computational techniques such as 13C NMR prediction, which enabled structural assignments of hydrocarbon diastereomers, as well as relaxed surface scan conformational analysis, which informed a campaign for directed hydrogenation of an alkene. High-throughput experimentation methods were brought to bear during optimization of a late-stage Suzuki coupling on stelletin A. Finally, preliminary structure-activity relationship studies in glioblastoma and nonsmall cell lung cancer cell lines were conducted on stelletin A, revealing that the singular trans-syn-trans perhydrobenz[e]indene core is essential for the cytotoxic activity of the isomalabaricane triterpenoids.

Synthesis of the Cannabimovone and Cannabifuran Class of Minor Phytocannabinoids and Their Anti-inflammatory Activity.

Despite centuries-long use of Cannabis in human culture and the now ubiquitous claims of its medicinal value, only a small handful of phytocannabinoids have been rigorously evaluated for pharmacological properties. While more than 100 distinct minor cannabinoids have been documented to date, a paucity of studies on their biological activities have been conducted due to a lack of routine access to sufficient quantities for testing. Herein, we report a strategy to prepare several structurally diverse minor cannabinoids deriving synthetically from readily available cannabidiol. Furthermore, we examined their ability to polarize activated microglia toward an anti-inflammatory phenotype using LPS-stimulated BV2 microglial cells. The minor cannabinoids studied, especially cannabielsoin, dehydrocannabielsoin, cannabimovone, and 3'-epicannabimovone, inhibited the production of prototypical pro-inflammatory biomarkers. This study represents the beginning of a systematic mapping of the roles minor cannabinoids may play in the medicinal properties of cannabis used for the treatment of pain and inflammation.

Dearomative Ring Expansion of Polycyclic Arenes.

Benzocycloheptenes constitute a common structural motif embedded in many natural products and biologically active compounds. Herein, we report their concise preparation from non-activated polycyclic arenes using a two-step sequence involving dearomative [4+2]-cycloaddition with arenophile in combination with palladium-catalyzed cyclopropanation, followed by cycloreversion-initiated ring expansion. The described strategy provides a working alternative to the Buchner reaction, which is limited to monocyclic arenes. Overall, this methylene-insertion molecular editing approach enables rapid and direct conversion of simple (hetero)arenes into a range of substituted (aza)benzocycloheptatrienes, which can undergo a myriad of downstream functionalizations.

Bioinspired Total Synthesis of Pyritide A2 through Pyridine Ring Synthesis.

Pyritides belong to the ribosomally synthesized and post-translationally modified peptide class of natural products that were recently genome-predicted and are structurally defined by unique pyridine-containing macrocycles. Inspired by their biosynthesis, proceeding through peptide modification and cycloaddition to form the heterocyclic core, we report the chemical synthesis of pyritide A2 involving pyridine ring synthesis from an amino acid precursor through aza-Diels-Alder reaction. This strategy permitted the preparation of the decorated pyridine core with an appended amino acid residue in two steps from a commercially available arginine derivative and secured pyritide A2 in ten steps. Moreover, the synthetic logic enables efficient preparation of different pyridine subunits associated with pyritides, allowing rapid and convergent access to this new class of natural products and analogues thereof.

Electrochemical Dearomatization of Commodity Polymers.

Dearomatizations are widely adopted strategies in synthetic organic chemistry that convert arenes into compounds of broader utility; however, these transformations are virtually nonexistent in macromolecular chemistry. Herein, we report the first systematic investigations into electroreductive dearomatization of common polymers, delivering polyolefinic materials without significant molecular weight changes across several orders of magnitude (103-106 Da) and with a controlled and broad range of reduction. The dearomatized and further elaborated products provided new material space that could not be obtained by using any existing polymerization or functionalization methods. This study also represents a rare example of solution-based electrosynthesis involving macromolecules and revealed an interesting electrochemical phenomenon between the molecular weight of polymer and conversion.

Synthetic Studies on Selective, Proapoptotic Isomalabaricane Triterpenoids Aided by Computational Techniques.

The isomalabaricanes comprise a large family of marine triterpenoids with fascinating structures that have been shown to be selective and potent apoptosis inducers in certain cancer cell lines. In this article, we describe the successful total syntheses of the isomalabaricanes stelletin A, stelletin E, and rhabdastrellic acid A, as well as the development of a general strategy to access other natural products within this unique family. High-throughput experimentation and computational chemistry methods were used in this endeavor. A preliminary structure-activity relationship study of stelletin A revealed the trans-syn-trans core motif of the isomalabaricanes to be critical for their cytotoxic activity.

Total Synthesis and Computational Investigations of Sesquiterpene-Tropolones Ameliorate Stereochemical Inconsistencies and Resolve an Ambiguous Biosynthetic Relationship.

The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono- and bistropolones, including (-)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (-)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.

Chemical Equivalent of Arene Monooxygenases: Dearomative Synthesis of Arene Oxides and Oxepines.

Direct epoxidation of aromatic nuclei by cytochrome P450 monooxygenases is one of the major metabolic pathways of arenes in eukaryotes. The resulting arene oxides serve as versatile precursors to phenols, oxepines, or trans-dihydrodiol-based metabolites. Although such compounds have an important biological and chemical relevance, the lack of methods for their production has hampered access to their utility. Herein, we report a general arenophile-based strategy for the dearomative synthesis of arene oxides. The mildness of this method permits access to sensitive monocyclic arene oxides without any noticeable decomposition to phenols. Moreover, this method enables direct conversion of polycyclic arenes and heteroarenes into the corresponding oxepines. Finally, these studies provided direct connection between simple aromatic precursors and complex small organic molecules via arene oxides and oxepines.

Visible-Light-Induced Dearomatizations.

The dearomatization of aromatic compounds is an important synthetic strategy used in accessing complex three-dimensional structures from simple aromatic precursors. This minireview aims to provide an overview of recent advancements in this area, with a specific focus on visible-light-mediated dearomative transformations. Compared to the conventional high-energy ultraviolet (UV) light-promoted processes, not only these new approaches offer milder reaction conditions to accommodate wider variety of substrates with sensitive functionalities, but also enable the use of photocatalysts and other promoters, significantly expanding the reaction space. Application of these transformations to the synthesis of bioactive compounds are also discussed.

Arenophile-Mediated Photochemical Dearomatization of Nonactivated Arenes.

Aromatic compounds are one of the most abundant classes of organic molecules and find utility as precursors for alicyclic hydrocarbon building blocks. While many established dearomatization reactions are exceptionally powerful, dearomatization with concurrent introduction of functionality, i.e. dearomative functionalization, is still a largely underdeveloped field. This review aims to provide an overview of our recent efforts and progress in the development of dearomative functionalization of simple and nonactivated arenes using arenophile-arene cycloaddition platform. These cycloadducts, formed via a visible-light-mediated [4+2]-photocycloaddition, can be elaborated in situ through olefin chemistry or transition-metal-catalyzed ring-opening with carbon-, nitrogen-, and oxygen-based nucleophiles, providing access to diverse structures with functional and stereochemical complexity. Moreover, the dearomatized products are amenable to further elaborations, which effectively install other functionalities onto the resulting alicyclic carbocycles. The utility of the arenophile-mediated dearomatization methods are also highlighted by the facile syntheses of natural products and bioactive compounds through novel disconnections.