Total Synthesis Research Articles

Discovery, Total Synthesis, and Anti-Inflammatory Evaluation of Naturally Occurring Naphthopyrone-Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors.

Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A-C (1-3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17-895, which represent the first naturally occurring naphthopyrone-macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro-inflammatory cytokine IL-1β release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome.

Discovery, Total Synthesis, and Anti‐Inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors

AbstractNumerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain‐containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A‐C (1–3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17‐895, which represent the first naturally occurring naphthopyrone‐macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro‐inflammatory cytokine IL‐1β release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome.

Asymmetric Total Synthesis of Alstrostine G Utilizing a Catalytic Asymmetric Desymmetrization Strategy

AbstractA highly effective enantioselective monobenzoylation of 1,3‐diols has been developed for the synthesis of 1,1‐disubstituted tetrahydro‐β‐carbolines. The chemistry has been successfully applied to the asymmetric total synthesis of (+)‐alstrostine G, which also features a cascade Heck/hemiamination reaction enabling facile construction of the pivotal pentacyclic core.

Molecular Editing of Pyrroles to Benzenes/Naphthalenes by N2O Deletion

Molecular editing promises to facilitate the rapid diversification of complex molecular architectures by rapidly and conveniently altering core frameworks. This approach has the potential to accelerate both drug discovery and total synthesis. In this study, we present a novel protocol for the molecular editing of pyrroles. Initially, N‐Boc pyrroles and alkynes are converted into N‐bridged compounds through a Diels‐Alder reaction. These compounds then undergo deprotection of the Boc group, nitrosylation, and cheletropic N2O extrusion to yield benzene or naphthalene products. By using benzyne as a substrate, this method can be conceptually viewed as a fusion of skeletal editing of the pyrrole ring and site‐selective peripheral editing of the benzene ring. Furthermore, this proof‐of‐concept protocol has demonstrated its potential to transform the (hetero)arene motif from commercially available drugs, offering the possibility of generating new biologically active compounds.

Molecular Editing of Pyrroles to Benzenes/Naphthalenes by N2O Deletion.

Molecular editing promises to facilitate the rapid diversification of complex molecular architectures by rapidly and conveniently altering core frameworks. This approach has the potential to accelerate both drug discovery and total synthesis. In this study, we present a novel protocol for the molecular editing of pyrroles. Initially,N-Boc pyrroles and alkynes are converted intoN-bridged compounds through a Diels-Alder reaction. These compounds then undergo deprotection of the Boc group, nitrosylation, and cheletropic N2O extrusion to yield benzene or naphthalene products. By using benzyne as a substrate, this method can be conceptually viewed as a fusion of skeletal editing of the pyrrole ring and site-selective peripheral editing of the benzene ring. Furthermore, this proof-of-concept protocol has demonstrated its potential to transform the (hetero)arene motif from commercially available drugs, offering the possibility of generating new biologically active compounds.

Modular, Scalable Total Synthesis of Lapparbin with a Noncanonical Biaryl Linkage

This work reports the development of a novel synthetic approach for the highly strained atrop‐Tyr C‐6‐to‐Trp N‐1' linkage, which can be executed on a decagram scale using a modular strategy involving Pd‐catalyzed C‐H arylation followed by Larock macrocyclization. Moreover, the first total synthesis of lapparbin (1) was achieved by applying this synthetic strategy. Furthermore, the modular synthesis utilizing C‐H arylation and Larock macrocyclization, discovered in the total synthesis of lapparbin (1), was demonstrated to be applicable to various arbitrary biaryl linkages, including non‐natural types.

Modular, Scalable Total Synthesis of Lapparbin with a Noncanonical Biaryl Linkage.

This work reports the development of a novel synthetic approach for the highly strained atrop-Tyr C-6-to-Trp N-1' linkage, which can be executed on a decagram scale using a modular strategy involving Pd-catalyzed C-H arylation followed by Larock macrocyclization. Moreover, the first total synthesis of lapparbin (1) was achieved by applying this synthetic strategy. Furthermore, the modular synthesis utilizing C-H arylation and Larock macrocyclization, discovered in the total synthesis of lapparbin (1), was demonstrated to be applicable to various arbitrary biaryl linkages, including non-natural types.

Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA

The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.

Stereodivergent Total Synthesis of Ethyl Plakortide Z.

Plakortides make up a subclass of marine endoperoxides with diverse biological activities. Their structural particularity is derived from the C4 and C6 positions of the endoperoxide, which are substituted by ethyl groups. The ethyl plakortide Z has the simplest side chain among its congeners and is an excellent target for testing a universal strategy for the synthesis of this subfamily. Accordingly, we have synthesized for the first time a six-membered pla-kortide using asymmetric Enders alkylation, regioselective cyclobutanol oxidative expansion, and peroxycarbenium ion-mediated diastereoselective C-C bond formation as key steps. Preparative HPLC separation of the various diastereomers yielded a pure sample of synthetic ethyl plakortide Z, constituting the first total synthesis. Despite the lack of selectivity inherent in the synthesis of peroxide linkages involving radical reactions, the diastereomer separation step was offset by an efficient synthesis in just 11 steps and 4.2% overall yield.

The Total Synthesis of Hyperfirin via a Cyclooctadiene Strategy.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) combine compelling structural complexity with effective biological activity. The total synthesis of Hyperfirin is reported as one linear sequence. Key to this novel modular strategy is to access the bicyclo[3.3.1]nonane-2,4,9-trione framework via transannular acylation of a decorated eight-membered ring, followed by late stage bridgehead substitution. The described route adds flexibility to PPAP construction and broadens the scope of eight-membered ring chemistry.

Total Synthesis of (±)-Baphicacanthcusine A Enabled by Sequential Ring Contractions.

Reported herein is the first total synthesis of the poly-pseudoindoxyl natural product baphicacanthcusine A. The synthesis leverages the oxidative rearrangement of indoles to pseudoindoxyls to install vicinal pseudoindoxyl heterocycles in a diastereoselective manner. Key steps include an acid-mediated cyclization/indole transposition, two diastereoselective oxidative ring contractions, and a site-selective C--H oxygenation. The synthesis of the oxidation precursors was guided by recognition of an element of hidden symmetry. This work provides a foundation for the chemical synthesis of other poly-pseudoindoxyl alkaloids.

Phenyl substituted cyclo(meta)polyphenylenes: one more step towards the total synthesis of diameter‐controlled Zig‐Zag carbon nanotubes.

the calixarene‐templated synthesis of new Cyclo(meta‐ polyphenylene (CMPs) is described. These compounds are functionalised with added aromatic units, that are suitably oriented for oxidative aromatisation to be envisioned. This could pave the way towards the synthesis of elongated segments of Zig‐Zag type Single Walled Carbon Nanotubes.

Total Synthesis of the Bacterial ortho-Quinol (+)-Strepantibin A through Iodyl-Type λ5-Iodane-Promoted Asymmetric Hydroxylative Phenol Dearomatization.

An enantioselective synthesis of the bacterial metabolite (+)-strepantibin A, a novel inhibitor of the hexokinase II (HK2) in cancer cells, is described. Its monomethylated resorcinolic para-terphenyl core was conveniently prepared through a Danheiser benzannulation. The elaboration of its ortho-quinolic chiral center was accomplished by relying on an iodyl-promoted regio- and enantioselective hydroxylative dearomatization. The olefinic side-chain of the resulting ortho-quinol was finally oxygenated under Wacker-type conditions to generate the propanone appendage of (+)-strepantibin A.

Natural hypoglycaemic bioactives: Newer avenues and newer possibilities.

The incidences of endocrine and metabolic disorders like diabetes have increased worldwide. Several proposed molecular pathways mechanisms for the management of diabetes have been identified, but glycaemic control is still a challenging task in the drug discovery process. Most of the drug discovery processes lead to numerous scaffolds that are prominent in natural products. The review deals with the natural bioactives as an α-amylase inhibitors, α-glucosidase inhibitors, protein tyrosine phosphatase-1B inhibitors, dipeptidyl peptidase-IV inhibitors, G-protein coupled receptors-40 agonists, PPAR-γ agonists and the activators of 5'-adenosine monophosphate-activated protein kinase and glucokinase. So, in this review, we focused on the hypoglycaemic bioactives, which will assist scientific developers, traditional medicinal practitioners, and readers to discover some potent antidiabetic molecules. Strategies like chemometric approaches, scaffold hopping, and total synthesis of natural products by group modification or ring opening/closing mechanism could be useful for the development of novel hit/lead antidiabetic molecules. The study concludes that each phyto molecule inherits a potential to get explored by repurposing techniques for various antidiabetic targets and offer an alternative antidiabetic therapeutic medicinal potential.

α-Halocarbonyls as a Valuable Functionalized Tertiary Alkyl Source.

This review introduces the synthetic organic chemical value of α-bromocarbonyl compounds with tertiary carbons. This α-bromocarbonyl compound with a tertiary carbon has been used primarily only as a radical initiator in atom transfer radical polymerization (ATRP) reactions. However, with the recent development of photo-radical reactions (around 2010), research on the use of α-bromocarbonyl compounds as tertiary alkyl radical precursors became popular (around 2012). As more examples were reported, α-bromocarbonyl compounds were studied not only as radicals but also for their applications in organometallic and ionic reactions. That is, α-bromocarbonyl compounds act as nucleophiles as well as electrophiles. The carbonyl group of α-bromocarbonyl compounds is also attractive because it allows the skeleton to be converted after the reaction, and it is being applied to total synthesis. In our survey until 2022, α-bromocarbonyl compounds can be used to perform a full range of reactions necessary for organic synthesis, including multi-component reactions, cross-coupling, substitution, cyclization, rearrangement, stereospecific reactions, asymmetric reactions. α-Bromocarbonyl compounds have created a new trend in tertiary alkylation, which until then had limited reaction patterns in organic synthesis. This review focuses on how α-bromocarbonyl compounds can be used in synthetic organic chemistry.

Divergent Synthesis of 17-nor-Cephalotane Diterpenoids through Developed Ynol-diene Cyclization.

On the basis of a novel ynol-diene cyclization developed as a rapid access to tropone unit, the first divergent strategy to 17-nor-cephalotane diterpenoids has been successfully established. Combining with a bioinspired stereoselective dual hydrogenation, the divergent total synthesis of (+)-3-deoxyfortalpinoid F, (+)-harringtonolide, (-)-fortalpinoids M/N/P, and analog (-)-20-deoxocephinoid P have been achieved in 14-17 linear longest steps starting from commercially available materials.

Divergent Synthesis of 17‐nor‐Cephalotane Diterpenoids through Developed Ynol‐diene Cyclization

On the basis of a novel ynol‐diene cyclization developed as a rapid access to tropone unit, the first divergent strategy to 17‐nor‐cephalotane diterpenoids has been successfully established. Combining with a bioinspired stereoselective dual hydrogenation, the divergent total synthesis of (+)‐3‐deoxyfortalpinoid F, (+)‐harringtonolide, (−)‐fortalpinoids M/N/P, and analog (−)‐20‐deoxocephinoid P have been achieved in 14‐17 linear longest steps starting from commercially available materials.

Disrupting Substance Use Disorder: The Chemistry of Iboga Alkaloids

The iboga alkaloids are a family of monoterpene indole alkaloids first discovered from the root of Tabernanthe iboga. The major alkaloid constituent in the root, ibogaine, has garnered interest for its anti‐addictive properties. Ibogaine has been shown to reduce opiate, amphetamine, alcohol, and nicotine self‐administration in rodents. However, ibogaine itself is less than optimal as a treatment in humans for Substance Abuse Disorder (SUD) due to its cardiotoxicity and hallucinogenic potential. Alternatively, it is an attractive lead for drug discovery efforts. Several notable programs have been launched to both elucidate ibogaine’s mechanism of action and reduce its toxicity. While there have been over twenty total syntheses of ibogamine, ibogaine, and closely related family members, there are far fewer syntheses of recently isolated iboga alkaloids. In this targeted review, we discuss the synthetic strategies applied to the synthesis of classical and non‐classical iboga alkaloids.

Disrupting Substance Use Disorder: The Chemistry of Iboga Alkaloids

The iboga alkaloids are a family of monoterpene indole alkaloids first discovered from the root of Tabernanthe iboga. The major alkaloid constituent in the root, ibogaine, has garnered interest for its anti‐addictive properties. Ibogaine has been shown to reduce opiate, amphetamine, alcohol, and nicotine self‐administration in rodents. However, ibogaine itself is less than optimal as a treatment in humans for Substance Abuse Disorder (SUD) due to its cardiotoxicity and hallucinogenic potential. Alternatively, it is an attractive lead for drug discovery efforts. Several notable programs have been launched to both elucidate ibogaine’s mechanism of action and reduce its toxicity. While there have been over twenty total syntheses of ibogamine, ibogaine, and closely related family members, there are far fewer syntheses of recently isolated iboga alkaloids. In this targeted review, we discuss the synthetic strategies applied to the synthesis of classical and non‐classical iboga alkaloids.

Total Synthesis of a Peptide Diatom Sex Pheromone Bearing a Sulfated Aspartic Acid.

The peptide sex-inducing pheromone SIP+ (1) bearing an unusual sulfated aspartic acid residue induces sexual reproduction in diatom populations. Herein, we report the first total synthesis of SIP+ using both a sulfated building block approach and a solid-phase peptide synthesis (SPPS)-compatible late-stage sulfation strategy to assemble the natural product. The modular approaches provide concise routes to useful quantities of the natural product for future structure activity relationship studies examining the role of SIP+ in diatom biology.