Studies on Comprehensive Total Synthesis of Natural and Pseudo-Natural Products for Drug Discovery.

Natural products are important for the development of pharmaceuticals and agrochemicals; thus, their synthesis and medicinal chemistry research is critical. Developing a total synthesis pathway for natural products confirms their structure and provides the opportunity to modify the structure in a targeted manner. A simple modification of a single oxidation step can increase the biological activity, or the complexity of the molecule can alter the property. Herein, we discuss the asymmetric total synthesis of dihydroisocoumarin-type natural products, the creation of novel antibacterial compounds through partial structural modification, and the development of antioxidants with high activity and low toxicity through dimerization strategies.

Late-stage benzenoid-to-troponoid skeletal modification of the cephalotanes exemplified by the total synthesis of harringtonolide.

Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners - representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner-Curtius-Schlotterbeck reaction of a p-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions.

Total Synthesis of Bipenicilisorin and Assignment of the Absolute Configuration.

The first total synthesis of bipenicilisorin (1) isolated from Penicillium chrysogenum SCSIO 41001 via its monomer natural product, penicilisorin (2), was achieved. Penicilisorin was synthesized in four steps from a o-bromobenzaldehyde derivative via the Pd-catalyzed one-pot fluorocarbonylation/lactonization/ß-elimination cascade reaction. Iodination of penicilisorin gave 7-iodopenicilisorin which was dimerized by Pd-catalyzed homodimerization to provide (±)-bipenicilisorin. The unknown absolute configuration of naturally occurring (+)-bipenicilisorin was examined by optical resolution of the (±)-synthetic bipenicilisorin and a comparison of experimental and theoretical electronic circular dichroism (ECD) spectra. These results support the absolute configuration of the natural product to be Sa. A cytotoxic activity test of (+)-and (-)-bipenicilisorin using A549 cells revealed that (+)-1 has a lower IC50 value than (-)-1.

Cinnamosyn, a Cinnamoylated Synthetic-Bioinformatic Natural Product with Cytotoxic Activity.

Most biosynthetic gene clusters (BGCs) are functionally inaccessible by using fermentation methods. Bioinformatic-coupled total synthesis provides an alternative approach for accessing BGC-encoded bioactivities. To date, synthetic bioinformatic natural product (synBNP) methods have focused on lipopeptides containing simple lipids. Here we increase the bioinformatic and synthetic complexity of the synBNP approach by targeting BGCs that encode N-cinnamoyl lipids. This led to our synthesis of cinnamosyn, a 10-mer N-cinnamoyl-containing peptide that is cytotoxic to human cells.

Total synthesis/semi-synthesis of natural isopentenyl flavonoids with inhibitory activity on NLRP3 inflammasome.

Inflammation is the body's defense response to stimuli. When the homeostatic balance is disturbed, disease may result. Flavonoids have clear anti-inflammatory effects and the isopentenyl group significantly enhances the pharmacological activity of flavonoids. Therefore, isopentenyl flavonoids have the potential to serve as lead compounds for the development of anti-inflammatory drugs. Throughout this research, eight natural compounds were synthesized, including 5,7-dihydroxy-4'-methoxy-8-prenylflavonoid (1), 4'-O-Methylatalantoflavone (2), Kushenol W (3) and Racemoflavone (5), which were totally synthesized for the first time. Additionally, three flavonols: Licoflavonol (6), 3,5,7,3',4'-pentahydroxy-6-prenylflavonol (7) and Macarangin (8), can be one-step synthesized by direct C-isopentenylation. In the process, an economical and efficient C-isopentenylation method was also simultaneously explored that could facilitate the efficient synthesis of natural products. These compounds were evaluated for their potential anti-inflammatory activities via the NLRP3 signaling pathway. Notably, Macarangin (8) manifested the most potent inhibitory effect. The SAR (Structure-Activity Relationships) also showed the introduction of the isopentenyl group was determined to enhance these effects, whereas simple flavonoid frameworks or cyclization of isopentenyl groups all diminished anti-inflammatory activity.

Scalable Total Synthesis of (+)-Desmethylxestospongin B.

Herein, the execution of synthetic strategies solving scalability issues observed in the original route is reported, increasing the total yield by 50% compared to the previously disclosed synthesis. A notable restructuring of the route's initial steps to reach a common allylic alcohol intermediate employs a highly stereoselective epoxidation method and avoids superfluous protecting group manipulations while limiting dependence on kinetic resolution in establishing stereochemistry for four of the six chiral centers in (+)-desmethylxestospongin B. Different protecting group strategies to avoid problems with their subsequent removal were considered and enacted; to this end, material was retained as byproducts were suppressed. While the lactam semireduction under Birch conditions requires further investigation, the updated synthesis of (+)-desmethylxestospongin B reported here made it more scalable, affording 0.37 g of this natural product for continued biological studies.

Coumarin-Synthetic Methodologies, Pharmacology, and Application as Natural Fluorophore.

Coumarins are secondary metabolites made up of benzene and α-pyrone rings fused together that can potentially treat various ailments, including cancer, metabolic, and degenerative disorders. Coumarins are a diverse category of both naturally occurring as well as synthesized compounds with numerous biological and therapeutic properties. Coumarins as fluorophores play a key role in fluorescent labeling of biomolecules, metal ion detection, microenvironment polarity detection, and pH detection. This review provides a detailed insight into the characteristics of coumarins as well as their biosynthesis in plants and metabolic pathways. Various synthetic strategies for coumarin core involving both conventional and green methods have been discussed comparing advantages and disadvantages of each method. Conventional methods discussed are Pechmann, Knoevenagel, Perkin, Wittig, Kostanecki, Buchwald-Hartwig, and metal-induced coupling reactions such as Heck and Suzuki, as well as green approaches involving microwave or ultrasound energy. Various pharmacological applications of coumarin derivatives are discussed in detail. The structural features and conditions responsible for influencing the fluorescence of coumarin core are also elaborated.

Total Synthesis of 4-epi-Bengamide E.

Bengamide E is a bioactive natural product that was isolated from Jaspidae sponges by Crews and co-workers in 1989. It displays a wide range of biological activities, including antitumor, antibiotic, and anthelmintic properties. With the aim of investigating the structural feature essential for their activity, several total syntheses of Bengamide E and its analogues have been reported in the literature. Nevertheless, no synthesis of the stereoisomer with modification of its configuration at C-4 carbon has been reported so far. Here, we report the first total synthesis of the 4-epi-Bengamide E. Key reactions in the synthesis include a chemoenzimatic desymmetrization of biobased starting materials and a diastereoselective Passerini reaction using a chiral, enantiomerically pure aldehyde, and a lysine-derived novel isocyanide.

Natural product inspired diastereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones and their in-silico studies.

Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano[3,2-c]quinolones utilizing 1-C-formyl glycal and 4-hydroxy quinolone annulation. This methodology will open a route to synthesize nature inspired pyrano[3,2-c]quinolones. This is the first report for the stereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones, where 100% stereoselectivity was observed. A total of sixteen compounds have been synthesized in excellent yields with 100% stereoselectivity. The molecular docking of the synthesized novel natural product analogues demonstrated their binding modes within the active site of type II topoisomerase. The results of the in-silico studies displayed more negative binding energies for the all the synthesized compounds in comparison to the natural product huajiosimuline A, indicating their affinity for the active pocket. Ten out of the sixteen novel synthesized compounds were found to have comparative or relatively more negative binding energy in comparison to the standard anti-cancer drug, doxorubicin. Additionally, the scalability and viability of this protocol was illustrated by the gram scale synthesis.

Expansive discovery of chemically diverse structured macrocyclic oligoamides.

Small macrocycles with four or fewer amino acids are among the most potent natural products known, but there is currently no way to systematically generate such compounds. We describe a computational method for identifying ordered macrocycles composed of alpha, beta, gamma, and 17 other amino acid backbone chemistries, which we used to predict 14.9 million closed cycles composed of >42,000 monomer combinations. We chemically synthesized 18 macrocycles predicted to adopt single low-energy states and determined their x-ray or nuclear magnetic resonance structures; 15 of these were very close to the design models. We illustrate the therapeutic potential of these macrocycle designs by developing selective inhibitors of three protein targets of current interest. By opening up a vast space of readily synthesizable drug-like macrocycles, our results should considerably enhance structure-based drug design.

Novel partially reversible NDM-1 inhibitors based on the naturally occurring houttuynin.

Discovering novel NDM-1 inhibitors is an urgent task for treatment of 'superbug' infectious diseases. In this study, we found that naturally occurring houttuynin and its sulfonate derivatives might be effective NDM-1 inhibitors with novel mechanism, i.e. the attribute of partially covalent inhibition of sulfonate derivatives of houttuynin against NDM-1. Primary structure-activity relationship study showed that both the long aliphatic side chain and the warhead of aldehyde group are vital for the efficiency against NDM-1. The homologs with longer chains (SNH-2 to SNH-5) displayed stronger inhibitory activities with IC50 range of 1.1-1.5 µM, while the shorter chain the weaker inhibition. Further synergistic experiments in cell level confirmed that all these 4 compounds (at 32 µg/mL) recovered the antibacterial activity of meropenem (MER) against E. coli BL21/pET15b-blaNDM-1.

Natural products from the human microbiome: an emergent frontier in organic synthesis and drug discovery.

Often referred to as the "second genome", the human microbiome is at the epicenter of complex inter-habitat biochemical networks like the "gut-brain axis", which has emerged as a significant determinant of cognition, overall health and well-being, as well as resistance to antibiotics and susceptibility to diseases. As part of a broader understanding of the nexus between the human microbiome, diseases and microbial interactions, whether encoded secondary metabolites (natural products) play crucial signalling roles has been the subject of intense scrutiny in the recent past. A major focus of these activities involves harvesting the genomic potential of the human microbiome via bioinformatics guided genome mining and culturomics. Through these efforts, an impressive number of structurally intriguing antibiotics, with enhanced chemical diversity vis-à-vis conventional antibiotics have been isolated from human commensal bacteria, thereby generating considerable interest in their total synthesis and expanding their therapeutic space for drug discovery. These developments augur well for the discovery of new drugs and antibiotics, particularly in the context of challenges posed by mycobacterial resistance and emerging new diseases. The current landscape of various synthetic campaigns and drug discovery initiatives on antibacterial natural products from the human microbiome is captured in this review with an intent to stimulate further activities in this interdisciplinary arena among the new generation.

Pd-catalyzed stereoselective synthesis of chromone C-glycosides.

Herein, we present an efficient Pd-catalysed method for stereoselective synthesis of chromone C-glycosides from various glycals. We successfully applied this method to various glycals with different protecting groups, yielding the corresponding glycosides in 41-78% yields. Additionally, we investigated the potential of this approach for the late-stage modification of natural products and pharmaceutical compounds linked to glycals, leading to the synthesis of their respective glycosides. Furthermore, we extended our research to gram-scale synthesis and demonstrated its applicability in producing various valuable products, including 2-deoxy-chromone C-glycosides. In summary, our work introduces a novel library of chromone glycosides, which holds promise for advancing drug discovery efforts.

Total Synthesis, Structure Reassignment, and Biological Evaluation of the Anti-Inflammatory Macrolactone 13-Hydroxy-14-deoxyoxacyclododecindione.

Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two threo-derivatives, and two Z-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13R,14S,15R)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV-vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced E/Z double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC50 values in biological assays addressing the inhibition of cellular inflammatory responses.

Harnessing alcohols as sustainable reagents for late-stage functionalisation: synthesis of drugs and bio-inspired compounds.

Alcohol is ubiquitous with unparalleled structural diversity and thus has wide applications as a native functional group in organic synthesis. It is highly prevalent among biomolecules and offers promising opportunities for the development of chemical libraries. Over the last decade, alcohol has been extensively used as an environmentally friendly chemical for numerous organic transformations. In this review, we collectively discuss the utilisation of alcohol from 2015 to 2023 in various organic transformations and their application toward intermediates of drugs, drug derivatives and natural product-like molecules. Notable features discussed are as follows: (i) sustainable approaches for C-X alkylation (X = C, N, or O) including O-phosphorylation of alcohols, (ii) newer strategies using methanol as a methylating reagent, (iii) allylation of alkenes and alkynes including allylic trifluoromethylations, (iv) alkenylation of N-heterocycles, ketones, sulfones, and ylides towards the synthesis of drug-like molecules, (v) cyclisation and annulation to pharmaceutically active molecules, and (vi) coupling of alcohols with aryl halides or triflates, aryl cyanide and olefins to access drug-like molecules. We summarise the synthesis of over 100 drugs via several approaches, where alcohol was used as one of the potential coupling partners. Additionally, a library of molecules consisting over 60 fatty acids or steroid motifs is documented for late-stage functionalisation including the challenges and opportunities for harnessing alcohols as renewable resources.

When Synthesis Gets It Wrong: Unexpected Epimerization Using PyBOP in the Synthesis of the Cyclic Peptide Thermoactinoamide A.

Chemical synthesis is commonly seen as the final proof of the structure of complex natural products, but even a seemingly easy and well-established synthetic procedure may lead to an unexpected result. This is what happened with the synthesis of thermoactinoamide A (1a), an antimicrobial and antitumor nonribosomal cyclic hexapeptide produced by the thermophilic bacterium Thermoactinomyces vulgaris. The synthetic thermoactinoamide A outsourced to a company and the one described in a synthetic paper showed spectroscopic data identical to each other but different from those of the natural product. After a detailed spectroscopic, degradative, and synthetic study, the synthetic compound was shown to be an epimer (1b) of the intended target compound, originating during the cyclization reaction by extensive epimerization at the activated C-terminal amino acid. This allowed confirmation of the structure of the natural product.

Advances Toward Amphidinolides C, F and U: Isolations, Synthetic Studies and Total Syntheses.

Amphidinolides C, F, and U, including C2-C4 analogs, are highly cytotoxic marine macrolides, mainly isolated from dinoflagellates of the genus Amphidinium. All these polyketides share a 75 % or more similar structure, highlighted by a macrolactone ring, at least one trans-2,5-substituted-THF motif and a characteristic polyenic side chain. From their isolation and absolute configurational assignment, the total synthesis of these marine macrolides represented an intense challenge to the organic synthesis community over the last 15 years, with around 14 research groups engaged in this inspiring task. In the first part of this review, we present the different approaches to the isolation and characterization of these natural products, including the most recent analogs, which may cast doubt on the biogenetic origin of these compounds. The various synthetic approaches to the total synthesis of C, F, and U amphidinolides are presented in a second part, focusing on key reactions and/or innovative strategies. The review concludes in a third section summarizing the successful approaches leading to the total synthesis of one of the members of this amphidinolide subfamily.

The Kornblum DeLaMare rearrangement in natural product synthesis: 25 years of innovation.

Covering: 1998 up to the end of 2023Since its initial disclosure in 1951, the Kornblum DeLaMare rearrangement has proved an important synthetic transformation and has been widely adopted as a biomimetic step in natural product synthesis. Utilising the base catalysed decomposition of alkyl peroxides to yield a ketone and alcohol has found use in many syntheses as well as a key strategic step, including the unmasking of furans, as a biomimetic synthetic tool, and the use of the rearrangement to install oxygen enantioselectively. Since ca. 1998, its impact as a synthetic transformation has grown significantly, especially given the frequency of use in natural product syntheses, therefore this 25 year time period will be the focus of the review.

Computational prediction of complex cationic rearrangement outcomes.

Recent years have seen revived interest in computer-assisted organic synthesis1,2. The use of reaction- and neural-network algorithms that can plan multistep synthetic pathways have revolutionized this field1,3-7, including examples leading to advanced natural products6,7. Such methods typically operate on full, literature-derived 'substrate(s)-to-product' reaction rules and cannot be easily extended to the analysis of reaction mechanisms. Here we show that computers equipped with a comprehensive knowledge-base of mechanistic steps augmented by physical-organic chemistry rules, as well as quantum mechanical and kinetic calculations, can use a reaction-network approach to analyse the mechanisms of some of the most complex organic transformations: namely, cationic rearrangements. Such rearrangements are a cornerstone of organic chemistry textbooks and entail notable changes in the molecule's carbon skeleton8-12. The algorithm we describe and deploy at https://HopCat.allchemy.net/ generates, within minutes, networks of possible mechanistic steps, traces plausible step sequences and calculates expected product distributions. We validate this algorithm by three sets of experiments whose analysis would probably prove challenging even to highly trained chemists: (1) predicting the outcomes of tail-to-head terpene (THT) cyclizations in which substantially different outcomes are encoded in modular precursors differing in minute structural details; (2) comparing the outcome of THT cyclizations in solution or in a supramolecular capsule; and (3) analysing complex reaction mixtures. Our results support a vision in which computers no longer just manipulate known reaction types1-7 but will help rationalize and discover new, mechanistically complex transformations.

Complex molecule synthesis by electrocatalytic decarboxylative cross-coupling.

Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2-4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.