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The article focuses on the study regarding the synthesis of chlorosulfolipid mytilipin via longest linear sequence of only seven steps, which include highly diastereoselective haloallylation, complex vinyl epoxide kinetic resolution, and olefination. The study involves the oxidation with Dess-Martin period-inane and the conversion of sensitive and volatile aldehyde in crude form into vinyl epoxide. The study reveals the possibility for an eight-step enatioselective synthesis of mytilipin A.

Polyamines are polycationic molecules that are crucial in a wide array of cellular functions. Their biosynthesis is mediated by aminopropyl transferases (APTs), which are promising targets for antimicrobial, antineoplastic, and antineurodegenerative therapies. A major limitation in studying APT enzymes, however, is the lack of high-throughput assays to measure their activity. We have developed the first fluorescence-based assay, diacetyl benzene (DAB)-APT, for the measurement of APT activity using 1,2-DAB, which forms fluorescent conjugates with putrescine, spermidine, and spermine, with fluorescence intensity increasing with the carbon chain length. The assay has been validated using APT enzymes from Saccharomyces cerevisiae and Plasmodium falciparum, and the data further validated by mass spectrometry and TLC. Using mass spectrometry analysis, the structures of the fluorescent putrescine, spermidine, and spermine 1,2-DAB adducts were determined to be substituted 1,3-dimethyl isoindoles. The DAB-APT assay is optimized for high-throughput screening, facilitating the evaluation of large chemical libraries. Given the critical roles of APTs in infectious diseases, oncology, and neurobiology, the DAB-APT assay offers a powerful tool with broad applicability, poised to drive advancements in research and drug discovery., Competing Interests: Conflict of interest C. B. M. is listed on a provisional patent application on the use of DAB-APT assay and its use to discover inhibitors of APT enzymes. The other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

On the basis of a streamlined route to the pyrroloiminoquinone (PIQ) core, we made 16 natural products spread across four classes of biosynthetically related alkaloid natural products, and multiple structural analogs, all in ≤8 steps longest linear sequence (LLS). The strategy features a Larock indole synthesis as the key operation in a five-step synthesis of a key methoxy-PIQ intermediate. Critically, this compound was readily diverged via selective methylation of either (or both) of the imine-like or pyrrole nitrogens, which then permitted further divergence by either O- demethylation to o- quinone natural products or displacement of the methoxy group with a range of amine nucleophiles. Based on a single, early report of their potential utility against the malaria parasite, we assayed these compounds against several strains of Plasmodium falciparum , as well as two species of the related protozoan parasite Babesia . In combination with evaluations of their human cytotoxicity, we identified several compounds with potent (low-nM IC 50 ) antimalarial and antibabesial activities that are much less toxic toward mammalian cells and are therefore promising lead compounds for antiprotozoal drug discovery.

We designed and executed an expedient synthesis of a complex analogue of the potent immunosuppressive natural product brasilicardin A. Our successful synthesis featured application of our recently developed MHAT-initiated radical bicyclization, which delivered the targeted, complex analogue in 17 steps in the longest linear sequence. Unfortunately, this analogue showed no observable immunosuppressive activity, which speaks to the importance of the structural and stereochemical elements of the natural core scaffold.

Dry ice is widely used in the chemistry research settings as an excellent coolant. Herein, we report a case study of a graduate student researcher who lost consciousness while retrieving 180 lbs of dry ice from a deep dry ice container. We share the details of the incident and the lessons learned from it to promote safer handling of dry ice in these situations., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

8-Phenylmenthol esters of salicylic acid derivatives undergo efficient Birch reduction and in situ diastereoselective alkylations to afford methoxycyclohexadienes bearing new quaternary stereogenic centers. The use of an ester-based auxiliary is a designed improvement over the use of prolinol-derived amides, which are expensive and often very difficult to cleave.

The evolution of a successful strategy for the synthesis of the strained, cage-like antiviral diterpenoids wickerols A and B is described. Initial attempts to access the carbocyclic core were surprisingly challenging and in retrospect, presaged the many detours needed to ultimately arrive at the fully adorned wickerol architecture. In most cases, conditions to trigger desired outcomes with respect to both reactivity and stereochemistry were hard-won. The successful synthesis ultimately leveraged alkenes in virtually all productive bond-forming events. A series of conjugate addition reactions generated the fused tricyclic core, a Claisen rearrangement was used to install an otherwise unmanageable methyl-bearing stereogenic center, and a Prins cyclization closed the strained bridging ring. This final reaction proved enormously interesting because the strain of the ring system permitted diversion of the presumed initial Prins product into several different scaffolds.

We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural product─along with a hypothesis about a biosynthetic relationship to related family members─inspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging cis -to- trans decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama-Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C-N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.

We offer a new biogenetic proposal for the origin of the complex alkaloid alstonlarsine A, through rearrangement of the Strychnos alkaloids alstolucines B and F. Further, we provide evidence of the chemical feasibility of this proposal in the facile conversion of synthetic alstolucines into alstonlarsine A through a short, efficient sequence of N-methylation, β-elimination, and a cascade 1,7-hydride shift/Mannich cyclization. We believe that this is the first biogenetic proposal involving the "tert-amino effect", a hydride-shift-based internal redox trigger of a Mannich cyclization. A further interesting feature of the cascade is that its stereochemical outcome most likely originates in conformational preferences during the hydride shift., (© 2022 Wiley-VCH GmbH.)

A full account of the development of a concise and highly stereoselective synthesis of (+)-7,20-diisocyanoadociane (DICA)─a structurally complex isocyanoditerpene with potent antiplasmodial activity─is described. The strategy that evolved relies on the rapid construction of unsaturated tricyclic precursors designed to undergo stereocontrolled Birch reductions and a subsequent "bay ring" formation to generate the isocycloamphilectane core. This report is divided into three sections: (1) a description of the initial strategy and the results that focused our efforts on a single route to the DICA core, (2) a discussion of the precise choreography needed to enable a first-generation formal synthesis of (±)-DICA, and (3) the execution of a 13-step second-generation synthesis of (+)-DICA that builds on important lessons learned from the first-generation effort.

We report the structural revision via synthesis of the abietane diterpenoid plebeianiol A. The synthesis was accomplished by a short and convergent sequence that featured our previously established cobalt-catalyzed hydrogen-atom-transfer-induced radical bicyclization. We further connected plebeianiol A as the likely biogenetic precursor to another previously reported ether-bridged abietane. Finally, we demonstrated that the key cyclization event is efficient with the A-ring diol protected as two different cyclic acetals or in unprotected form.

The power of cation-initiated cyclizations of polyenes for the synthesis of polycyclic terpenoids cannot be overstated. However, a major limitation is the intolerance of many relevant reaction conditions toward the inclusion in the substrate of polar functionality, particularly in unprotected form. Radical polycyclizations are important alternatives to bioinspired cationic variants, in part owing to the range of possible initiation strategies, and in part for the functional group tolerance of radical reactions. In this article, we demonstrate that Co-catalyzed MHAT-initiated radical bicyclizations are not only tolerant of oxidation at virtually every position in the substrate, oftentimes in unprotected form, but these functional groups can also contribute to high levels of stereochemical control in these complexity-generating transformations. Specifically, we show the effects of protected or unprotected hydroxy groups at six different positions and their impact on stereoselectivity. Further, we show how multiply oxidized substrates perform in these reactions, and finally, we document the utility of these reactions in the synthesis of three aromatic abietane diterpenoids.

An anionic oxy-Cope/transannular Michael addition cascade converts a spirocyclic architecture-readily available by Diels-Alder cycloaddition-into the hydrophenalene carbon skeleton of the pseudopterosin aglycones. Oxidation of the resulting cyclohexenone ring to the phenol that is characteristic of the targets completes a short formal synthesis.

A novel Co II -catalyzed polyene cyclization was developed that is uniquely effective when performed in hexafluoroisopropanol as the solvent. The process is presumably initiated by metal-catalyzed hydrogen-atom transfer (MHAT) to 1,1-disubstituted or monosubstituted alkenes, and the reaction is remarkable for its tolerance of internal alkenes bearing either electron-rich methyl or electron-deficient nitrile substituents. Electron-rich aromatic terminators are required in both cases. Terpenoid scaffolds with different substitution patterns are obtained with excellent diastereoselectivities, and the bioactive C20-oxidized abietane diterpenoid carnosaldehyde was made to showcase the utility of the nitrile-bearing products. Also provided are the results of several mechanistic experiments that suggest the process features an MHAT-induced radical bicyclization with late-stage oxidation to regenerate the aromatic terminator., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

New chemical probes have been designed to facilitate the identification of adenosine-to-inosine (A-to-I) edited RNAs. These reagents combine a conjugate acceptor for selective inosine covalent modification with functional groups for bioorthogonal biotinylation. The resulting biotinylated RNA was enriched and verified with RT-qPCR. This powerful chemical approach provides new opportunities to identify and quantify A-to-I editing sites.

Breast cancer is the most common cancer type and a primary cause of cancer mortality among females worldwide. Here, we analyzed the anticancer efficacy of a novel bromochlorinated monoterpene, PPM1, a synthetic analogue of polyhalogenated monoterpenes from Plocamium red algae and structurally similar non-brominated monoterpenes. PPM1, but not the non-brominated monoterpenes, decreased selectively the viability of several triple-negative as well as triple-positive breast cancer cells with different p53 status without significantly affecting normal breast epithelial cells. PPM1 induced accumulation of triple-negative MDA-MB-231 cells with 4N DNA content characterized by decreased histone H3-S10/T3 phosphorylation indicating cell cycle arrest in the G 2 phase. Western immunoblot analysis revealed that PPM1 treatment triggered an initial rapid activation of Aurora kinases A/B/C and p21 Waf1/Cip1 accumulation, which was followed by accumulation of polyploid >4N cells. Flow cytometric analysis showed mitochondrial potential disruption, caspase 3/7 activation, phosphatidylserine externalization, reduction of the amount polyploid cells, and DNA fragmentation consistent with induction of apoptosis. Cell viability was partially restored by the pan-caspase inhibitor Z-VAD-FMK indicating caspase contribution. In vivo, PPM1 inhibited growth, proliferation, and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. Hence, Plocamium polyhalogenated monoterpenes and synthetic analogues deserve further exploration as promising anticancer lead compounds.

Haterumaimide J (hatJ) is reportedly the most cytotoxic member of the lissoclimide family of labdane diterpenoids. The unusual functional group arrangement of hatJ-C18 oxygenation and C2 chlorination-resisted our efforts at synthesis until we adopted an approach based on rarely studied terminal epoxide-based cation-π bicyclizations that is described herein. Using the C2-chlorine atom as a key stereocontrol element and a furan as a nucleophilic terminator, the key structural features of hatJ were rapidly constructed. The 18-step stereoselective synthesis features applications of chiral pool starting materials, and catalyst-, substrate-, and auxiliary-based stereocontrol. Access to hatJ and its acetylated congener hatK permitted their biological evaluation against aggressive human cancer cell lines.

The synthesis of the Securinega alkaloid virosaine A by Hughes and Gleason is a perfect example of the intersection of art and chemical synthesis. An ingenious cascade reaction builds most of the polycyclic architecture, but necessitates a challenging C-H functionalization, which is ultimately accomplished by an unusual directed lithiation reaction., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.

Driven by a new biogenetic hypothesis, the first total synthesis of alsmaphorazine B and several related indole alkaloids has been achieved. Numerous early approaches proved unsuccessful owing to unproductive side reactivity; nevertheless, they provided important clues that guided the evolution of our strategy. Critical to our success was a major improvement in our Zincke aldehyde cycloaddition strategy, which permitted the efficient gram-scale synthesis of akuammicine. The sequential chemoselective oxidations of akuammicine leading up to the key oxidative rearrangement also yielded several biogenetically related indole alkaloids en route to alsmaphorazine B.

The halenaquinol family of naphthoquinol natural products includes a few closely related polycyclic compounds that feature an activated, electrophilic furan ring. This motif is likely responsible for the rich biological activity attributed to these secondary metabolites. Their interesting structures-related via their electrophilic furan to the biologically important furanosteroids-and their activities prompted significant efforts by organic chemists that resulted in many strategically compelling laboratory syntheses of these targets. These different strategies are compared and contrasted in this Microreview, and the authors' recent work on the structurally different but biogenetically related natural product exiguaquinol is put into the context of the previous studies on halenaquinol-type targets.

Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum , the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, some as complex as the natural product and some much simplified and easier to access. Each analogue was tested for blood-stage antimalarial activity using both drug-sensitive and -resistant P. falciparum strains. Many considerably simpler analogues of the kalihinols retained potent activity, as did a compound with a different decalin scaffold made in only three steps from sclareolide. Finally, one representative compound showed reasonable stability toward microsomal metabolism, suggesting that the isonitrile functional group that is critical for activity is not an inherent liability in these compounds.

Mitochondrial dysfunction is a hallmark of cancer biology. Tumor mitochondrial metabolism is characterized by an abnormal ability to function in scarce oxygen conditions through glycolysis (the Warburg effect), and accumulation of mitochondrial DNA defects are present in both hereditary neoplasia and sporadic cancers. Mitochondrial Lon is a major regulator of mitochondrial metabolism and the mitochondrial response to free radical damage, and plays an essential role in the maintenance and repair of mitochondrial DNA. Despite these critical cellular functions of Lon, very little has been reported regarding its role in glioma. Lon expression in gliomas and its relevance with patient survival was examined using published databases and human tissue sections. The effect of Lon in glioma biology was investigated through siRNA targeting Lon. We also tested the in vitro antitumor activity of Lon inhibitor, CC4, in the glioma cell lines D-54 and U-251. High Lon expression was associated with high glioma tumor grade and poor patient survival. While Lon expression was elevated in response to a variety of stimuli, Lon knockdown in glioma cell lines decreased cell viability under normal conditions, and dramatically impaired glioma cell survival under hypoxic conditions. Furthermore, the Lon inhibitor, CC4, efficiently prohibited glioma cell proliferation and synergistically enhanced the therapeutic efficacy of the chemotherapeutic agents, temozolomide (TMZ) and cisplatin. We demonstrate that Lon plays a key role in glioma cell hypoxic survival and mitochondrial respiration, and propose Lon as a promising therapeutic target in the treatment of malignant gliomas.

7,20-Diisocyanoadociane (DICA) is a potent antimalarial isocyanoterpene endowed with a fascinating tetracyclic structure composed of fused chair cyclohexanes. We report a highly stereocontrolled synthesis of a late-stage intermediate, the "Corey dione", from which DICA has been made previously. This formal synthesis features a rapid buildup of much of the complexity of the target through a sequence of enone tandem vicinal difunctionalization, Friedel-Crafts cyclodehydration, and sequential stereocontrolled reductions. Most importantly, this success establishes the broader feasibility of our previously developed general synthesis approach to the isocyanoterpene family and provides a blueprint for a very direct synthesis of DICA and related natural products., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

At last count, nearly 5000 halogenated natural products have been discovered. In approximately half of these compounds, the carbon atom to which the halogen is bound is sp(3) -hybridized; therefore, there are an enormous number of natural products for which stereocontrolled halogenation must be a critical component of any synthesis strategy. In this Review, we critically discuss the methods and strategies used for stereoselective introduction of halogen atoms in the context of natural product synthesis. Using the successes of the past, we also attempt to identify gaps in our synthesis technology that would aid the synthesis of halogenated natural products, as well as existing methods that have not yet seen application in complex molecule synthesis. The chemistry described herein demonstrates yet again how natural products continue to provide the inspiration for critical advances in chemical synthesis., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Methods for the practical, intermolecular functionalization of aliphatic C-H bonds remain a paramount goal of organic synthesis. Free radical alkane chlorination is an important industrial process for the production of small molecule chloroalkanes from simple hydrocarbons, yet applications to fine chemical synthesis are rare. Herein, we report a site-selective chlorination of aliphatic C-H bonds using readily available N-chloroamides and apply this transformation to a synthesis of chlorolissoclimide, a potently cytotoxic labdane diterpenoid. These reactions deliver alkyl chlorides in useful chemical yields with substrate as the limiting reagent. Notably, this approach tolerates substrate unsaturation that normally poses major challenges in chemoselective, aliphatic C-H functionalization. The sterically and electronically dictated site selectivities of the C-H chlorination are among the most selective alkane functionalizations known, providing a unique tool for chemical synthesis. The short synthesis of chlorolissoclimide features a high yielding, gram-scale radical C-H chlorination of sclareolide and a three-step/two-pot process for the introduction of the β-hydroxysuccinimide that is salient to all the lissoclimides and haterumaimides. Preliminary assays indicate that chlorolissoclimide and analogues are moderately active against aggressive melanoma and prostate cancer cell lines.

An N-oxide fragmentation/hydroxylamine oxidation/intramolecular 1,3-dipolar cycloaddition cascade efficiently converted an oxidized congener of akuammicine into the complex, hexacyclic architecture of the alsmaphorazine alkaloids. This dramatic structural change shows the chemical feasibility of our novel proposal for alsmaphorazine biogenesis. Critical to these endeavors was a marked improvement in our previously reported Zincke aldehyde cycloaddition approach to indole alkaloids, which permitted the gram-scale synthesis of akuammicine. The chemoselective oxidations of akuammicine leading up to the key rearrangement also generated several biogenetically related alkaloids of the alstolucine and alpneumine families.

Since the initial discovery of the chlorosulfolipids in 1969, the chemical synthesis community largely ignored these compounds for nearly four decades, perhaps because they contain a high density of chlorine atoms, which suggested that these molecules and any projected synthetic intermediates might be unstable. Beginning in 2008, a sudden flurry of synthesis activity by several research groups, including our own, appeared in the literature. In this Account, we highlight our work from the last several years on the chemical synthesis of the chlorosulfolipids. Our work in this area began with attempts to stereoselectively generate the abundant dichloroalcohol functional group arrangements in these natural targets. In these early studies, we learned that many polychlorinated intermediates were far more stable than anticipated. We also developed a method for the diastereoselective dichlorination of allylic alcohol derivatives that permitted access to the syn,syn-dichloroalcohol stereotriad found in several chlorosulfolipids. Concurrently, we investigated an approach to mytilipin A that included multiple intermediates bearing aldehydes with β-leaving groups, but this route proved intractable. However, we leveraged what we had learned from this approach into our first success in this area: we synthesized danicalipin A via a route that introduced all of the polar functional groups using alkene oxidation reactions. By adapting this relatively general strategy, we completed an enantioselective synthesis of malhamensilipin A. This body of work also resulted in the full stereochemical elucidation of danicalipin A and the structural revision of malhamensilipin A. Finally, with the advent of Z-selective alkene cross metathesis, we developed a second-generation synthesis that featured this strategy in place of a poorly performing Wittig olefination that plagued our first approach. In addition to this new convergent step, we developed a reliable protocol for diastereoselective addition to highly sensitive α,β-dichloroaldehydes and a method for kinetic resolution of complex vinyl epoxides. Altogether, these advances led to a synthesis of enantioenriched mytilipin A in only eight steps. In the context of this work, we discovered a number of highly stereoselective reactions that might offer new, broadly applicable lessons in acyclic stereocontrol. Moreover, this research testifies to the stability of polychlorinated molecules and should inspire confidence in the use of aliphatic chlorides in other applications, including in discovery chemistry.

A Diels-Alder reaction, a desymmetrizing aldol reaction, and a reductive Heck cyclization are employed in a short synthesis of a tetracycle relevant to exiguaquinol, a potential antibiotic. Ground-state energies of this advanced model system and the natural product rationalize the incorrect hemiaminal configuration experimentally obtained and point to the importance of the sulfonate in dictating the relative configuration of the natural product.

The beautiful orchestration of new methods and synthesis design was instrumental to the very efficient synthesis of the manzamine alkaloid (-)-nakadomarin A. In only six operations, the two relatively simple compounds shown were converted into the hexacyclic natural product., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Zincke aldehydes, which are readily available from the ring-opening reaction of pyridinium salts, are easily converted into delta-tributylstannyl-alpha,beta,gamma,delta-unsaturated aldehydes (stannyldienals) by the action of tributylstannyllithium. This reaction appears to proceed via 1,6-stannyllithium addition/elimination of lithium dialkylamide. Several stannyldienals of significant utility for the synthesis of polyene natural products have been made by this route, which proceeds in modest yields, but is successful on multigram scale using inexpensive reagents. Simple stannylenals and stannylenones are similarly available from the corresponding vinylogous amides.

The (salen)Al-catalyzed asymmetric conjugate addition of salicylaldoxime to alpha,beta-unsaturated imides is the key step in an efficient and highly enantioselective two-step formal hydration of these electron-deficient olefins. This reaction constitutes the first example of an enantioselective conjugate addition of an oxygen-centered nucleophile to alpha,beta-unsaturated carboxylic acid derivatives. Application of this method to chiral, nonracemic substrates revealed a high level of catalyst-induced diastereoselectivity, underscoring its potential utility for polyketide natural product synthesis.