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Host-associated bacteria are increasingly being recognized as underexplored sources of bioactive natural products with unprecedented chemical scaffolds. A recently identified example is the plant-root-associated marine bacterium Gynuella sunshinyii of the chemically underexplored order Oceanospirillales. Its genome contains at least 22 biosynthetic gene clusters, suggesting a rich and mostly uncharacterized specialized metabolism. Here, in silico chemical prediction of a non-canonical polyketide synthase cluster has led to the discovery of janustatins, structurally unprecedented polyketide alkaloids with potent cytotoxicity that are produced in minute quantities. A combination of MS and two-dimensional NMR experiments, density functional theory calculations of C-13 chemical shifts and semiquantitative interpretation of transverse rotating-frame Overhauser effect spectroscopy data were conducted to determine the relative configuration, which enabled the total synthesis of both enantiomers and assignment of the absolute configuration. Janustatins feature a previously unknown pyridodihydropyranone heterocycle and an unusual biological activity consisting of delayed, synchronized cell death at subnanomolar concentrations. ISSN:1755-4349 ISSN:1755-4330

A method for the enantio- and chemoselective iridium-catalyzed

The enantio- and chemoselective iridium-catalyzed N-allylation of oximes is described for the first time. Intramolecular kinetic resolution provides access to cyclic nitrones and enantioenriched aliphatic allylic alcohols. Salient features of this transformation are its ability to employ E/Z-isomeric mixtures of oxime starting materials convergently and high functional group tolerance. The implementation of N-allylation/1,3-dipolar cycloaddition reaction sequences furnishes tricyclic isoxazolidines in highly enantio- and diastereoselective fashion. The synthetic utility of the approach is demonstrated by the efficient, formal synthesis of the marine natural product (+)-halichlorine. ISSN:1433-7851 ISSN:1521-3773 ISSN:0570-0833

We discuss a number of synthesis routes to complex natural products recently reported from our group. Although the structures are quite varied, we demonstrate the research endeavor as a setting to examine the implementation of cyclizations, cycloadditions, rearrangements, and fragmentations. We showcase how the various transformations enabled access to key core structures and thereby allowed the rapid introduction of complexity. Two different routes to (-)-mitrephorone A, the first case discussed, led to the use of Koser's reagent to effect oxetane formation from diosphenol derivatives. Even though the Diels-Alder cycloaddition reaction represents one of the workhorses of complex molecule synthesis, there are opportunities provided by the complexity of secondary metabolites for discovery, study, and development. In our first approach to (-)-mitrephorone A, Diels-Alder cycloaddition provided access to fused cyclopropanes, while the second synthesis underscored the power of diastereoselective nitrile oxide cycloadditions to access hydroxy ketones. The successful implementation of the second approach required the rigorous stereocontrolled synthesis of tetrasubstituted olefins; this was accomplished by a highly stereoselective Cr-mediated reduction of dienes. The diterpenoid (+)-sarcophytin provided a stage for examining the Diels-Alder cycloaddition of two electron-deficient partners. The study revealed that in the system this unusual combination works optimally with the E,Z-dienoate and proceeds through an exo transition state to provide the desired cycloadduct. Our reported pallambin synthesis showcased the use of fulvene as a versatile building block for the core structure. Fulvene decomposition could be outcompeted by employing it as a diene and using a highly reactive dienophile, which affords a bicyclic product that can in turn be subjected to chemo- and stereoselective manipulations. The synthesis route proceeds with a C-H insertion providing the core structure en route to pallambin A and B. The studies resulting in our synthesis of gelsemoxonine highlight the use of the acid-catalyzed rearrangement/chelotropic extrusion of oxazaspiro[2.4]heptanes to access complex β-lactams, which are otherwise not readily prepared by extant methods in common use. Mechanistic investigations of the intriguing ring contraction supported by computational studies indicate that the reaction involves a concerted cleavage of the N-O bond and cyclopropane ring opening under the extrusion of ethylene. The synthesis of guanacastepenes focused on the use of cyclohexyne in [2+2]-cycloadditions with enolates. The resulting cyclobutene can be enticed to undergo ring opening to give a fused six-seven ring system. The cycloinsertion reaction of cyclohexyne developed for the first time proves useful as a general approach to complex fused ring systems.

Cannabinoid receptor 2 (CB2) is a promising target for the treatment of neuroinflammation and other diseases. However, a lack of understanding of its complex signaling in cells and tissues complicates the therapeutic exploitation of CB2 as a drug target. We show for the first time that benchmark CB2 agonist HU308 increases cytosolic Ca

Chlorosulfolipids are an intriguing class of natural products that have been found across the globe as constituents of aqueous organisms. Their intriguing structure and unclear biological role have raised interest throughout various fields of chemical research, which in turn led to a number of elegant total syntheses of natural products from this family. This chapter provides an overview of methods and strategies for the preparation of chlorosulfolipids as well as challenges involved in their structure determination.

Delineating the molecular nanoscale organization of the surfaceome is pre-requisite for understanding cellular signaling. Technologies for mapping the spatial relationships of cell surface receptors and their extracellular signaling synapses would open up theranostic opportunities and the possibility to engineer extracellular signaling. Here, we developed an optoproteomic technology termed LUX-MS that exploits singlet oxygen generators (SOG) for the light-triggered identification of acute protein interactions on living cells. Using SOG-coupled antibodies, small molecule-drugs, biologics and intact viral particles, we show that not only ligand-receptor interactions can be decoded across organisms, but also the surfaceome receptor nanoscale organization ligands engage in with direct implications for drug action. Furthermore, investigation of functional immunosynapses revealed that intercellular signaling inbetween APCs and CD8+T cells can be mapped now providing insights into T cell activation with spatiotemporal resolution. LUX-MS based decoding of surfaceome signaling architectures provides unprecedented molecular insights for the rational development of theranostic strategies.

The following joint Editorial was originally published in ACS Applied Materials & Interfaces (DOI: 10.1021/acsami.0c10979). We confront the terrible reality that systemic racism and discrimination impacts the daily personal and professional lives of many members of the scientific community and broader society. In the U.S., the brutal killing of George Floyd while in police custody is one of the most recent examples of the centuries of systemic violence suffered by Black Americans. This moment and its aftermath lay bare the legacies of racism and its exclusionary practices. Let us be clear: we, the Editors, Staff, and Governance Members of ACS Publications condemn the tragic deaths of Black people and stand in solidarity with Black members of the science and engineering community. Moreover, ACS condemns racism, discrimination, and harassment in all forms. We will not tolerate practices and viewpoints that exclude or demean any member of our community. Despite these good intentions, we recognize that our community has not done enough to provide an environment for Black chemists to thrive. Rep. Eddie Bernice Johnson, Chairwoman of the U.S. House Committee on Science, Space, and Technology said, “So far, we have gotten by with a STEM workforce that does not come close to representing the diversity of our nation. However, if we continue to leave behind so much of our nation’s brainpower, we cannot succeed.”(1) Indeed, the U.S. National Science Foundation notes that Blacks and other under-represented minority groups continue to be under-represented in science and engineering education and employment.(2) What is abundantly clear in this moment is that this lack of representation is a symptom of systemic racism across all levels of education and professional life. We know that supportive words are not enough. We must develop and implement a concrete plan for changing our trajectory. Publications and citations are academic currency, and while we like to think publishing a manuscript is “just about the science”, we know that is not true for everyone. We have seen the biases (largely through the lens of gender and in Western countries because of the limitations in bibliometric analyses) and applaud our colleagues at the RSC for their massive study that explored these gender barriers in the publishing pipeline(3) and their recent Inclusion and Diversity Framework.(4) At the present time, unfortunately, less is known about the effects of race and ethnicity on publishing success. A study published in PeerJ, however, found that unprofessional reviewer comments had a disproportionate effect on authors from under-represented groups.(5) As the world’s leading society publisher, we have a responsibility to aggressively combat bias in all aspects of the publishing process, including systemic under-representation of Blacks in this endeavor (no ACS journal is currently led by a Black Editor-in-Chief). Within ACS Publications, we actively track gender and geographic diversity of editors, advisors, authors, and reviewers, and we anecdotally report on race of editors. Diversity encompasses many more dimensions than these, and we acknowledge that we can do much more than we have. We affirm that diversity and inclusion strengthen the research community and its impact, and we are committed to developing, implementing, tracking, and reporting on our progress to ensure that our editors, advisors, reviewers, and authors are more diverse and that all authors receive the same fair treatment and opportunity to publish in our journals. We acknowledge that we do not have all the answers now, but we seek to hear from and listen to our community on how we can improve our journals to be more diverse and inclusive. As first steps, we commit to the taking the following actions: Gathering and making public our baseline statistics on diversity within our journals, encompassing our editors, advisors, reviewers, and authors; annually reporting on progress Training new and existing editors to recognize and interrupt bias in peer review Including diversity of journal contributors as an explicit measurement of Editor-in-Chief performance Appointing an ombudsperson to serve as a liaison between Editors and our Community Developing an actionable diversity plan for each ACS journal These are only initial plans and the start of a conversation: other ideas are beginning to germinate, and we commit to sharing them with you regularly. We invite you contribute your ideas on how we can do better via our Axial website. We are listening carefully. We encourage you to take immediate action in your own circles. In a recent editorial, JACS Associate Editor Melanie Sanford(6) offered practical steps to take now. Take a moment to find out more about these actions and how to bring them into your work and your life. We all have a responsibility to eradicate racism and discrimination in the science and engineering community; indeed, to make a real difference, we need to be antiracist. The tragic events we have seen in the Black community provide great urgency to this goal. The work will be difficult and will force us to confront hard realities about our beliefs and actions. We fully expect that you, and everyone in the community, will hold us accountable.

In this Review, we highlight recent advances in the understanding and design of N-functionalized pyridinium scaffolds as redox-active, single-electron, functional group transfer reagents. We provide a selection of representative methods that demonstrate reactivity and fundamental advances in this emerging field. The reactivity of these reagents can be divided into two divergent pathways: homolytic fragmentation to liberate the N-bound substituent as the corresponding radical or an alternative heterolytic fragmentation that liberates an N-centered pyridinium radical. A short description of the elementary steps involved in fragmentation induced by single-electron transfer is also critically discussed to guide readers towards fundamental processes thought to occur under these conditions.

Controlling inflammation is critical for preventing many diseases including cancer, autoimmune disorders and hypersensitivity reactions. NF-E2-related factor 2 (Nrf2) is a key transcription factor that controls the cellular antioxidant and cytoprotective response. Moreover, Nrf2 has been implicated in the regulation of inflammatory processes, although the ultimate mechanism by which this is achieved is unknown. Here, we investigated mechanisms of inflammation and cell death pathways induced by a variety of Nrf2 activators including dimethyl fumarate (DMF) and the endogenous metabolite itaconate. We found that exposure of bone marrow-derived dendritic cells (BMDCs) to low concentrations of a variety of electrophilic Nrf2 activators including itaconate prior to Toll-like receptor (TLR) stimulation inhibits transcription of pro-inflammatory cytokines (such as interleukin [IL]-12 and IL-1β) by activation of Nrf2. By contrast, high doses of these electrophilic compounds after TLR activation promote inflammatory apoptosis and caspase-8-dependent IL-1β processing and release independently of Nrf2. Interestingly, tert-butylhydroquinone (tBHQ), a non-electrophilic Nrf2-activator, failed to induce IL-1β production. These results have important implications for clinical application of electrophilic compounds., Redox Biology, 36, ISSN:2213-2317

Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp2 )-H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N-X pyridinium reagents mediated by visible light.

Last year, Organic Letters celebrated its 20-year anniversary. To younger authors and readers, it is hard to appreciate that Organic Letters, as the new kid on the block back then as far as ACS journals go, was trail-blazing in its approach to all aspects of scientific publications—a letters journal that rapidly published top-shelf, rigorously peer-reviewed research. It is hard to believe now that two decades have elapsed since the journal’s launch with Professor Amos B. Smith III as the founding Editor-in-Chief. Under Prof. Smith’s visionary, steady leadership, Organic Letters quickly skyrocketed to the preeminent position it holds today as the leading organic chemistry journal. Organic Letters has benefitted from a close-knit group of Associate Editors that enjoys the broad respect of the community at large, because they are active scientists engaged in all aspects of research, including publication of high-caliber science. This is reassuring to scientists—authors who entrust their hard work to the rigors of peer review.

Oxidized lipids play a critical role in a variety of diseases with two faces: pro- and anti-inflammatory. The molecular mechanisms of this Janus-faced activity remain largely unknown. Here, we have identified that cyclopentenone-containing prostaglandins such as 15d-PGJ2 and structurally related oxidized phospholipid species possess a dual and opposing bioactivity in inflammation, depending on their concentration. Exposure of dendritic cells (DCs)/macrophages to low concentrations of such lipids before Toll-like receptor (TLR) stimulation instigates an anti-inflammatory response mediated by nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent inhibition of nuclear factor κB (NF-κB) activation and downstream targets. By contrast, high concentrations of such lipids upon TLR activation of DCs/macrophages result in inflammatory apoptosis characterized by mitochondrial depolarization and caspase-8-mediated interleukin (IL)-1β maturation independently of Nrf2 and the classical inflammasome pathway. These results uncover unexpected pro- and anti-inflammatory activities of physiologically relevant lipid species generated by enzymatic and non-enzymatic oxidation dependent on their concentration, a phenomenon known as hormesis. ISSN:2666-3864 ISSN:2211-1247

Enantiopure (P)₄⁻ and (M)₄-configured alleno-acetylenic cage (AAC) receptors offer a highly defined interior for the complexation and structure elucidation of small molecule fragments of the stereochemically complex chlorosulfolipid danicalipin A. Solution (NMR), solid state (X-ray), and theoretical investigations of the formed host–guest complexes provide insight into the conformational preferences of 14 achiral and chiral derivatives of the danicalipin A chlorohydrin core in a confined, mostly hydrophobic environment, extending previously reported studies in polar solvents. The conserved binding mode of the guests permits deciphering the effect of functional group replacements on Gibbs binding energies ΔG. A strong contribution of conformational energies toward the binding affinities is revealed, which explains why the denser packing of larger apolar domains of the guests does not necessarily lead to higher association. Enantioselective binding of chiral guests, with energetic differences ΔΔG_(293 K) up to 0.7 kcal mol⁻¹ between diastereoisomeric complexes, is explained by hydrogen- and halogen-bonding, as well as dispersion interactions. Calorimetric studies (ITC) show that the stronger binding of one enantiomer is accompanied by an increased gain in enthalpy ΔH but at the cost of a larger entropic penalty TΔS stemming from tighter binding.

The mammalian paraoxonases (PONs 1, 2 and 3) are a family of esterases that are highly conserved within and between species. They exhibit antioxidant and anti-inflammatory activities. However, their physiological function(s) and native substrates are uncertain. Previous structure-activity relationship studies demonstrate that PONs have a high specificity for lipophilic lactones, suggesting that such compounds may be representative of native substrates. This report describes the ability of PONs to hydrolyze two bioactive δ-lactones derived from arachidonic acid, 5,6-dihydroxy-eicosatrienoic acid lactone (5,6-DHTL) and cyclo-epoxycyclopentenone (cyclo-EC). Both lactones were very efficiently hydrolyzed by purified PON3. PON1 efficiently hydrolyzed 5,6-DHTL, but with a specific activity about 15-fold lower than PON3. 5,6-DHTL was a poor substrate for PON2. Cyclo-EC was a poor substrate for PON1 and not hydrolyzed by PON2. Studies with the PON inhibitor EDTA and a serine esterase inhibitor indicated that the PONs are the main contributors to hydrolysis of the lactones in human and mouse liver homogenates. Studies with homogenates from PON3 knockout mouse livers indicated that >80% of the 5,6-DHTL and cyclo-EC lactonase activities were attributed to PON3. The findings provide further insight into the structural requirements for PONs substrates and support the hypothesis that PONs, particularly PON1 and PON3, evolved to hydrolyze and regulate a class of lactone lipid mediators derived from polyunsaturated fatty acids.

The biologically active and structurally complex secondary metabolite epicolactone is a member of the natural product pool found in cash crop endophytes of the genus Epicoccum. By exploiting inherent reactivity, a total synthesis of this highly oxygenated and polycyclic molecule met chemo- and regioselectivity challenges. The key buildup of complexity was accomplished via an intramolecular [2+2] photocycloaddition between a quinone and an electron-deficient diene followed by a cyclobutane ring expansion. The use of a dioxene as an acyl anion equivalent and an intramolecular carbonyl methenylation furnished the natural product.

2,2-Bis(3-methylbut-2-enyl)-3-oxobutanenitrile [2,2-bis(prenyl)-3-oxobutyronitrile], an unusual bifunctional nitrile odorant with a fruity rosy, green odor was found to exhibit surprising differences in its detection thresholds (0.25 ng/L air for hyperosmics; 19 ng/L air for hyposmics) and perceived odor characters. To investigate this remarkable phenomenon, 13 derivatives of 2,2-bis(3-methylbut-2-enyl)-3-oxobutanenitrile were synthesized by either monoalkylation of 3-oxo-2-phenylbutanenitrile, or by dialkylation of sodium 1-cyano-2-oxopropan-1-ide or methyl or ethyl cyanoacetate, or by direct derivatization of 2,2-bis(3-methylbut-2-enyl)-3-oxobutanenitrile via its vinyl triflate and Negishi cross coupling. These systematic permutations of the substitution pattern allowed some insight to be gained into the underlying structure–odor relationships and the construction of a simple olfactophore model, albeit no final conclusion could be drawn as to whether the nitrile or carbonyl function acts as the prime osmophore of the bifunctional compounds. Depending on slight genetic variations and the corresponding differences in the receptor morphology both can engage in H-bond interactions with the olfactory receptors, which might explain the observed largely diverging sensitivities. Methyl 2-cyano-2,2-bis(3-methylbut-2-enyl)acetate with a uniform odor threshold of 0.38 ng/L air turned out to be the most interesting floral, rosy odorant of this study, followed by 3-methyl-2,2-bis(3-methylbut-2-enyl)but-3-enenitrile with only a nitrile function and varying odor thresholds (0.40 ng/L air vs. 125 ng/L air).

A total synthesis of the cembranoid (+)-sarcophytin is presented, featuring a Diels-Alder cycloaddition of an enone as the dienophile with an ester-derived dienoate. The study highlights a peculiar geometric preference for the Z dienoate to furnish the cycloadduct. The endgame involves a reaction cascade, including lactone opening, alcohol oxidation, and ketone epimerization to complete an efficient synthesis. A salient feature of the synthesis is the resulting reassignment of the absolute configuration, which corrects the previously reported nominal structure.