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Open fractures and prosthetic joints are prone to bacterial infections, especially those involving biofilms, and are worsened by antibiotic inefficacy and resistance. This highlights the need for targeted treatments against orthopedic infections. LL-37, a human cathelicidin, is known for its antimicrobial properties. This study aimed to synthesize and evaluate LL-37-derived antimicrobial peptides (AMPs) for antibacterial efficacy and toxicity. Several truncated LL-37 analogues were created and tested against 18 bacterial strains, both ATCC and orthopedic clinical isolates, using MIC and MBC assays. Synergy with antibiotics and resistance development were also analyzed, alongside cytotoxicity on NIH-3T3 fibroblasts and hemolytic activity assessments. Six AMPs were synthesized, with FK-16 and GF-17 emerging as the most effective. The MIC values ranged from 4.69 to 18.75 µg/mL and 2.34 to 18.75 µg/mL, respectively, against S. epidermidis and S. aureus , with the MBC values matching the MIC values. Cytotoxicity tests showed no toxicity at concentrations below 75 µg/mL for GF-17 and 150 µg/mL for FK-16. Hemolytic activity was below 1% at 18.75 µg/mL for GF-17 and 75 µg/mL for FK-16. These AMPs showed no synergistic effects with antibiotics and no resistance development. FK-16 and GF-17 effectively removed biofilms, particularly against S. epidermidis . Incorporating these AMPs into surgical materials (hydrogels, cements, etc.) could enhance infection control in orthopedic procedures, warranting further in vivo studies.

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., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

We report the development of a sequential C(sp 2 )-C(sp 3 ) Suzuki cross-coupling-asymmetric hydrogenation strategy which allows access to a diverse array of valuable β,β-disubstituted alanine derivatives. This synthesis exhibits broad functional group tolerance, and permits efficient access to β-aryl-β-alkyl, and the more rarely reported β,β-dialkyl Ala derivatives with high yield and excellent enantioselectivity. This transformation has been exhibited on decagram quantity, and can be used to generate Fmoc amino acid derivatives which are useful for SPPS.

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.

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.

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., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

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.

The era of inexpensive genome sequencing and improved bioinformatics tools has reenergized the study of natural products, including the ribosomally synthesized and post-translationally modified peptides (RiPPs). In recent years, RiPP discovery has challenged preconceptions about the scope of post-translational modification chemistry, but genome mining of new RiPP classes remains an unsolved challenge. Here, we report a RiPP class defined by an unusual (S)-N 2 ,N 2 -dimethyl-1,2-propanediamine (Dmp)-modified C-terminus, which we term the daptides. Nearly 500 daptide biosynthetic gene clusters (BGCs) were identified by analyzing the RiPP Recognition Element (RRE), a common substrate-binding domain found in half of prokaryotic RiPP classes. A representative daptide BGC from Microbacterium paraoxydans DSM 15019 was selected for experimental characterization. Derived from a C-terminal threonine residue, the class-defining Dmp is installed over three steps by an oxidative decarboxylase, aminotransferase, and methyltransferase. Daptides uniquely harbor two positively charged termini, and thus we suspect this modification could aid in membrane targeting, as corroborated by hemolysis assays. Our studies further show that the oxidative decarboxylation step requires a functionally unannotated accessory protein. Fused to the C-terminus of the accessory protein is an RRE domain, which delivers the unmodified substrate peptide to the oxidative decarboxylase. This discovery of a class-defining post-translational modification in RiPPs may serve as a prototype for unveiling additional RiPP classes through genome mining., (© 2023. The Author(s).)

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 cm 2 V -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.

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 sp 3 -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.

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., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The phytocannabinoid cannabigerol (CBG) is the central biosynthetic precursor to many cannabinoids, including Δ 9 -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.

Alkaloids isolated from members of the Amaryllidaceae plant family are promising anticancer agents. The purpose of the current study was to determine if the isocarbostyrils narciclasine, pancratistatin, lycorane, lycorine, crinane, and haemanthamine inhibit phenomena related to cancer progression in vitro. To achieve this, we examined the proliferation, adhesion, and invasion of cultured human colon cancer cells via MTT assay and Matrigel-coated Boyden chambers. In addition, Luminex assays were used to quantify the secretion of matrix metalloproteinases (MMP) and cytokines associated with poor clinical outcomes. We found that all alkaloids decreased cell proliferation regardless of TP53 status, with narciclasine exhibiting the greatest potency. The effects on cell proliferation also appear to be specific to cancer cells. Narciclasine, lycorine, and haemanthamine decrease both adhesion and invasion but with various potencies depending on the cell line. In addition, narciclasine, lycorine, and haemanthamine decreased the secretion of MMP-1, -2, and -7, as well as the secretion of the cytokines pentraxin 3 and vascular endothelial growth factor. In conclusion, the present study shows that Amaryllidaceae alkaloids decrease phenomena and cytokines associated with colorectal cancer progression, supporting future investigations regarding their potential as multifaceted drug candidates.

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., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

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.

Aminoglycosides (AGs) represent a large group of pseudoglycoside natural products, in which several different sugar moieties are harnessed to an aminocyclitol core. AGs constitute a major class of antibiotics that target the prokaryotic ribosome of many problematic pathogens. Hundreds of AGs have been isolated to date, with 1,3-diaminocyclohexanetriol, known as 2-deoxystreptamine (2-DOS), being the most abundant aglycon core. However, owning to their diverse and complex architecture, all AG-based drugs are either natural substances or analogues prepared by late-stage modifications. Synthetic approaches to AGs are rare and lengthy; most studies involve semi-synthetic reunion of modified fragments. Here we report a bottom-up chemical synthesis of the 2-DOS-based AG antibiotic ribostamycin, which proceeds in ten linear operations from benzene. A key enabling transformation involves a Cu-catalyzed, enantioselective, dearomative hydroamination, which set the stage for the rapid and selective introduction of the remaining 2-DOS heteroatom functionality. This work demonstrates how the combination of a tailored, dearomative logic and strategic use of subsequent olefin functionalizations can provide practical and concise access to the AG class of compounds., Competing Interests: Competing Interests Statement: The authors declare no competing financial interest.

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.

This study assessed the effects of a diet containing avocado meal (AMD), an underutilized by-product avocado oil processing, on apparent total tract digestibility (ATTD) and fecal fermentative end-products when compared with beet pulp (BPD) and cellulose (CD) diets targeting 15% total dietary fiber (TDF). The concentration of persin, a natural fungicidal toxin present in avocado, was also determined on several parts of the fruit and avocado meal. Nine intact female beagles (4.9 ± 0.6 yr and 11.98 ± 1.76 kg) were randomly grouped in a 3 × 3 replicated Latin square design. Periods were 14 d long, with 10 d of adaptation followed by 4 d of total fecal and urine collection for apparent total tract digestibility (ATTD) calculations. Fresh fecals were analyzed for fermentative end-products. The BPD (87.0 g/d) caused higher (P < 0.05) fecal output (as-is basis) than AMD (62.3 g/d) and CD (58.0 g/d). Fecal score for the BPD (3.1) was greater (P < 0.05) than for AMD (2.8) or CD (2.6). Acid-hydrolyzed fat ATTD was lower (P < 0.05) for the BPD (94.1%) than for the AMD (95.5%) and CD (95.7%). Crude protein ATTD was greater (P < 0.05) for the CD (88.5%) than the AMD (82.2%) or BPD (83.7%). Dogs fed AMD (49.9%) or BPD (51.0%) exhibited greater (P < 0.05) TDF ATTD than CD. The fermentative profile for the AMD (233.4, 70.9, 8.8, and 12.0 μmole/g DM, respectively) was similar (P > 0.05) to the CD (132.9, 61.7, 7.5, and 9.5 μmole/g DM, respectively) profile, with lower (P < 0.05) concentrations of acetate and propionate and higher (P < 0.05) concentrations of isovalerate and indoles compared to the BPD. Dogs fed AMD (47.0 μmole/g DM) or BPD (54.2 μmole/g DM) exhibited similar (P > 0.05) fecal butyrate concentrations greater (P < 0.05) than for CD (24.7 μmole/g DM). Given these results, avocado meal appears to be an adequate dietary fiber source when compared with traditional fiber sources used in canine diets. No health adverse effects were observed in dogs fed extruded diet containing as much as 18% of avocado meal (as-is basis)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 (10 3 -10 6 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.

Nanographenes and polycyclic aromatic hydrocarbons (PAHs) are among the most important classes of compounds, with potential applications in nearly all areas of science and technology. While the theoretically possible number of nanographene structures is extraordinary, most of these molecules remain synthetically out of reach due to a lack of programmable and diversity-oriented synthetic methods, and their potentially huge structure-property diversity has not been fully exploited. Herein we report a diversity-oriented, growth-from-template synthesis of nanographenes enabled by iterative annulative π-extension (APEX) reactions from small PAH starting materials. The developed dearomative annulative π-extension (DAPEX) reaction enables π-elongation at the less-reactive M-regions of PAHs, and is successfully combined with complementary APEX reactions that occur at K- and bay-regions to access a variety of previously untapped nanographenes.

Heterogeneity of meroterpenoids arising from their dual biosynthetic origins is constantly provoking synthetic chemists to utilize their ingenuity and revise their retrosynthetic logic. By studying recent publications on meroterpenoid synthesis, tremendous advances in the field of synthetic organic chemistry can be witnessed. This minireview covers some of the most intriguing total syntheses and synthetic studies towards the meroterpenoid class of natural products from the last five years.

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.

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 GI 50 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 13 C 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.

Dabbing and vaping cannabis extracts have gained large popularity in the United States as alternatives to cannabis smoking, but diversity in both available products and consumption habits make it difficult to assess consumer exposure to psychoactive ingredients and potentially harmful components. This work studies the how relative ratios of the two primary components of cannabis extracts, Δ 9 -tetrahydrocannabinol (THC) and terpenes, affect dosage of these and exposure to harmful or potentially harmful components (HPHCs). THC contains a monoterpene moiety and has been previously shown to emit similar volatile degradation products to terpenes when vaporized. Herein, the major thermal degradation mechanisms for THC and β-myrcene are elucidated via analysis of their aerosol gas phase products using automated thermal desorption-gas chromatography-mass spectrometry with the aid of isotopic labelling and chemical mechanism modelling. Four abundant products - isoprene, 2-methyl-2-butene, 3-methylcrotonaldehyde, and 3-methyl-1-butene - are shown to derive from a common radical intermediate for both THC and β-myrcene and these products comprise 18-30% of the aerosol gas phase. The relative levels of these four products are highly correlated with applied power to the e-cigarette, which indicates formation of these products is temperature dependent. Vaping THC-β-myrcene mixtures with increasing % mass of β-myrcene is correlated with less degradation of the starting material and a product distribution suggestive of a lower aerosolization temperature. By contrast, dabbing THC-β-myrcene mixtures with increasing % mass of β-myrcene is associated with higher levels of HPHCs, and isotopic labelling showed this is due to increased reactivity of β-myrcene relative to THC., Competing Interests: RPJ is a founder and Vice President of Florascience Inc., an Oregon hemp company. All other authors have no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

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.

The structural and functional characterization of natural products is vastly outpaced by the bioinformatic identification of biosynthetic gene clusters (BGCs) that encode such molecules. Uniting our knowledge of bioinformatics and enzymology to predict and synthetically access natural products is an effective platform for investigating cryptic/silent BGCs. We report the identification, biosynthesis, and total synthesis of a minimalistic class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with the responsible BGCs encoding a subset of enzymes known from thiopeptide biosynthesis. On the basis of the BGC content, these RiPPs were predicted to undergo enzymatic dehydration of serine followed by [4+2]-cycloaddition to produce a trisubstituted, pyridine-based macrocycle. These RiPPs, termed "pyritides", thus contain the same six-membered, nitrogenous heterocycle that defines the thiopeptide RiPP class but lack the ubiquitous thiazole/thiazoline heterocycles, suggesting that thiopeptides should be reclassified as a more elaborate subclass of the pyritides. One pyritide product was obtained using an 11-step synthesis, and the structure verified by an orthogonal chemoenzymatic route using the precursor peptide and cognate pyridine synthase. This work exemplifies complementary bioinformatics, enzymology, and synthesis to characterize a minimalistic yet structurally intriguing scaffold that, unlike most thiopeptides, lacks growth-suppressive activity toward Gram-positive bacteria.

The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more than 50 years, its unsafe preparation, as well as purification by sublimation, hampered its widespread applicability on a larger scale. Herein we report a scalable and safe route to MTAD, which avoids the generation of methyl isocyanate. Moreover, we demonstrate that sublimation can be circumvented by the application of judicious oxidation conditions, followed by simple filtration. Overall, up to 25 g of MTAD was prepared in a single batch from commercial starting materials in three steps, with recrystallization serving as the only purification in the sequence. When employed in dearomative methodologies, the MTAD obtained by this protocol displayed synthetic efficiency equivalent to that of MTAD purified by sublimation., Competing Interests: The authors declare no competing financial interest.

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.

Dearomatization is a fundamental chemical transformation, and it underlies some of the most efficient tactics for generating three-dimensional complexity from basic two-dimensional precursors. The dearomative toolbox, once restricted to only a handful of reactions, has begun to grow more sophisticated as novel methods are added, introducing more functionality under milder conditions and with more control over chemo-, regio-, and stereoselectivity than ever before. Over the past two decades, major developments in dearomative processes have bolstered significant total-synthesis endeavors and greatly expanded the scope and complexity of chemical building blocks accessible from feedstock arenes. In this Perspective, we highlight some of the recent advances and key challenges that remain in this vibrant area of organic chemistry.

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.

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.

A palladium-catalyzed dearomative syn-1,4-oxyamination protocol using non-activated arenes has been developed. This one-pot procedure utilizes arenophile chemistry, and the corresponding para-cycloadducts are treated with oxygen nucleophiles via formal allylic substitution, providing direct access to syn-1,4-oxyaminated products. The reaction conditions permit a range of arenes, as well as different O-nucleophiles, such as oximes and benzyl alcohols. Moreover, this process was established in an asymmetric fashion, delivering products with high enantioselectivity. The dearomatized products are amenable to a multitude of further derivatizations ranging from olefin chemistry to C-H activation, giving rise to a diverse set of new functionalities. Overall, this dearomative functionalization offers rapid and controlled formation of molecular complexity, enabling straightforward access to functionalized small molecules from simple and readily available arenes., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Synthesis of natural products remains a daring task. Their richly diverse and intricate structures often encompass a large degree of unsaturation, contain fused and/or bridged rings, or possess numerous stereogenic centers. Thus, their preparation requires significant synthetic overhead, detracting from their overall practicality as well as hampering the ability of medicinal chemists to synthesize derivatives for pharmaceutical optimization and structure-activity relationship studies. The purpose of this Minireview is to showcase recent examples of efficient total syntheses. Emphasis was not given to the evaluation of ideality or economies (quality), but rather to the practicality (quality with quantity)., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first total syntheses of (±)-rhabdastrellic acid A and (±)-stelletin E, highly cytotoxic isomalabaricane triterpenoids, have been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The exceptionally strained  trans-syn-trans- perhydrobenz[ e ]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner through a rapid, complexity-generating sequence. This process features a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung α-substitution of a p -toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.

A protocol for palladium-catalyzed dearomative functionalization of simple, nonactivated arenes with Grignard reagents has been established. This one-pot method features a visible-light-mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium-catalyzed allylic substitution of the resulting cycloadduct with a Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn-1,4-selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted into sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Anthracyclines are archetypal representatives of the tetracyclic type II polyketide natural products that are widely used in cancer chemotherapy. Although the synthesis of this class of compounds has been a subject of several investigations, all known approaches are based on annulations, relying on the union of properly prefunctionalized building blocks. Herein, we describe a conceptually different approach using a polynuclear arene as a starting template, ideally requiring only functional decorations to reach the desired target molecule. Specifically, tetracene was converted to (±)-idarubicinone, the aglycone of the FDA approved anthracycline idarubicin, through the judicious orchestration of Co- and Ru-catalyzed arene oxidation and arenophile-mediated dearomative hydroboration. Such a global functionalization strategy, the combination of site-selective arene and dearomative functionalization, provided the key anthracycline framework in five operations and enabled rapid and controlled access to (±)-idarubicinone.

Herein we report a dearomative syn-1,4-diamination protocol using simple nonactivated arenes and amines. This one-pot method utilizes arene-arenophile para-cycloadducts, formed via visible-light-mediated [4+2]-photocycloaddition that undergoes formal allylic substitution with amine nucleophiles under Pd-catalysis. The products are obtained with exclusive syn-1,4-selectivity; the method permits enantioselective desymmetrization of naphthalene, as well as elaborations of amine-containing drug molecules. Furthermore, the resulting unsaturated products are amenable to numerous options for diversification. Overall, this novel dearomative functionalization strategy offers rapid and straightforward access to complex building blocks, which are difficult to prepare otherwise, from simple arenes.

Enantioselective total syntheses of the anticancer isocarbostyril alkaloids (+)-7-deoxypancratistatin, (+)-pancratistatin, (+)-lycoricidine, and (+)-narciclasine are described. Our strategy for accessing this unique class of natural products is based on the development of a Ni-catalyzed dearomative trans-1,2-carboamination of benzene. The effectiveness of this dearomatization approach is notable, as only two additional olefin functionalizations are needed to construct the fully decorated aminocyclitol cores of these alkaloids. Installation of the lactam ring has been achieved through several pathways and a direct interconversion between natural products was established via a late-stage C-7 cupration. Using this synthetic blueprint, we were able to produce natural products on a gram scale and provide tailored analogs with improved activity, solubility, and metabolic stability.

Dearomatization reactions provide a synthetic connection between readily available, simple aromatic starting materials and more saturated intermediates of greater molecular complexity and synthetic utility. The last decade has witnessed a steady increase in the development of dearomative methods, providing new synthetic approaches to high-value building blocks and natural products. This review highlights advances both in the area of dearomatization methodologies for the most chemically inert arenes and in synthetic applications of such strategies.

We describe the development of an arenophile-mediated, nickel-catalyzed dearomative trans-1,2-carboamination protocol. A range of readily available aromatic compounds was converted to the corresponding dienes using Grignard reagents as nucleophiles. This strategy provided products with exclusive trans-selectivity and high enantioselectivity was observed in case of benzene and naphthalene. The utility of this methodology was showcased by controlled and stereoselective preparation of small, functionalized molecules.

A dearomative 1,4-carboamination of arenes has been achieved using arenophile cycloaddition and subsequent palladium-catalyzed substitution with nonstabilized lithium enolates. This protocol delivers products with exclusive syn-1,4-selectivity and can be also conducted in an asymmetric fashion. The method allows rapid dearomative difunctionalization of simple aromatic compounds into functional small molecules amenable to further diversification.

The total synthesis of lycoricidine and narciclasine is enabled by an arenophile-mediated dearomative dihydroxylation of bromobenzene. Subsequent transpositive Suzuki coupling and cycloreversion deliver a key biaryl dihydrodiol intermediate, which is rapidly converted into lycoricidine through site-selective syn-1,4-hydroxyamination and deprotection. The total synthesis of narciclasine is accomplished by the late-stage, amide-directed C-H hydroxylation of a lycoricidine intermediate. Moreover, the general applicability of this strategy to access dihydroxylated biphenyls is demonstrated with several examples., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)