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Hybridized spirobisnaphthalene derivatives, triantaspirols A-C ( 1 - 3 ) and paraphaeolactones C1 and C2 ( 4 and 5 ), were identified from the culture broth of the fungus Paraphaeosphaeria sp. KT4192. The NMR spectra of 2 and 3 , as well as 4 and 5 , closely resembled each other, indicating that these were pairs of diastereomers. Although this NMR spectral resemblance made it challenging to distinguish their relative configurations, detailed analysis of the electronic circular dichroism (ECD) spectra and NOE correlations allowed us to deduce them. The CP3 metric with the DFT-based NMR chemical shifts was found to distinguish configurations of diastereomers in a highly sensitive and accurate manner that DP4 could not account for because of the very close chemical shift differences in the experimental NMR spectra. The reliability of this method was assessed using 23 published examples which could not be distinguished by DP4 protocol.

Scale-up isolation of (+)-(5 Z )-(8 S )-(14 Z )-mycothiazole ( 1 ) from Vanuatu specimens of C. mycofijiensis to semisynthesize (+)-(5 Z )-(8 S )-8- O -acetyl-(14 Z )-mycothiazole ( 2 ) revealed a new diastereomer, (-)-(5 E )-(8 R )-(14 Z )-mycothiazole ( 4 ). The structure of 4 was determined using HRMS, NMR, and comparing optical rotation to (-)-(5 Z )-(8 R )-(14 Z )-mycothiazole ( 3 ) and 2 . The maximum tolerated dose of 2 in mice was 0.1 mg/kg. The IC 50 of 4 in PANC-1 and HepG2 cancer cell lines was 111.6 and 115.0 nM. Evaluation of 4 in C. elegans showed similar oxygen consumption compared to 1 - 2 , and all compounds significantly increased the lifespan. The Z orientation at Δ 5,6 is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.

Imported fire ants are significant agricultural pests. Repellents can be used to prevent foraging fire ants from entering sensitive areas, including electrical equipment, nursing homes, and hospitals. Bioassay-guided fractionation of the essential oil extracted from gurjun balsam ( Dipterocarpus turbinatus ) resulted in the identification of (-)-α-copaene ( 1 ) as the repellent constituent with a minimum repellent effective dose (MRED) of 15.6 μg/g against both red imported fire ants ( Solenopsis invicta ) and hybrid imported fire ants ( Solenopsis invicta × Solenopsis richteri ). Stereoselective oxidation of 1 via autoxidation and chemical methods produced (-)-5 R -hydroperoxy-α-copaene ( 2 ), (+)-3 S -hydroperoxycopa-4-ene ( 3 ), (-)-α-copaene oxide ( 4 ), (+)-β-copaen-4α-ol ( 5 ), copaenediol ( 6 ), and copaene ketol ( 7 ). Reduction of 2 and 3 with triphenylphosphine afforded (-)-5 R -hydroxy-α-copaene ( 2a ) and (+)-3 S -hydroxycopa-4-ene ( 3a ), respectively, which led to the structural revision of copa-3-en-2α-ol and copa-2-en-4-ol as 2a and 3 , respectively. The configurational assignment of compound 4 in the literature was also clarified by the detailed analysis of 2D NMR spectroscopic data. Compounds 2 - 7 showed repellency with MREDs ranging from 3.9 to 15.6 μg/g against hybrid and red imported fire ants, indicating that chemical modification can enhance the repellent effect of (-)-α-copaene.

A new synthetic route to access the natural product phytocannabinoid cannabitwinol ( 1 ) starting from commercially available raw materials is disclosed. We have also demonstrated the synthesis of other related dimers, including their enantiomers, using the present sequence. This route avoids the legal constraints concerning the acquisition of cannabis plant material or CBD.

Chemical investigation of n -hexane extract from the marine sponge Leucetta sp. led to the isolation of five new lipids, 1 - 5 , each characterized by a substituted dioxolane core. The structures of 1 - 5 were established based on the interpretation of NMR and HRESIMS data. To assign the absolute configuration at C-1', model systems consisting of diastereomers at C-2, C-4, and C-1' of the dioxolane core were prepared from a chiral glycerol dimethylacetal. 1 H NMR inspection of model compounds revealed that a pair of C-1' epimers, 11a/c and 11b/d , was indistinguishable, restricting structural assignment by direct comparison of NMR data. In addition, the lack of chromophores in the dioxolane core resulted in unreliable ECD results, with Cotton effects appearing below 190 nm. As an alternative, a chiral NMR method using Eu(hfc) 3 revealed notable lanthanide-induced shifts, allowing the spectroscopic discrimination of 11a/c and ent- 11a/c . Therefore, the absolute configuration of all five new lipids was determined to be 2 S , 4 S , 1' S by direct comparison with the Eu(hfc) 3 -induced 1 H NMR data.

The title marine natural products have been prepared by total synthesis and in the case of congeners 3 , 6 , and 7 for the first time. Each of these was obtained by manipulation of readily prepared denigrin B ( 2 ). The structure, 3 , assigned to denigrin C is shown to be incorrect. Reaction of compound 2 with DDQ has led, in high yield, to the related natural product spirodactylone ( 16 ), while treating the corresponding permethyl ether 15 with PIFA/BF 3 ·Et 2 O provides compound 20 , embodying an isomeric framework.

The microbial production, isolation, and structure elucidation of four new napyradiomycin congeners (1-4) is reported. The structures of these compounds, which are new additions to the marine-derived meroterpenoids, were defined by comprehensive spectroscopic analysis and by X-ray crystallography. Using fluorescence-activated cell sorting (FACS) analysis, napyradiomycins 1-4 were observed to induce apoptosis in the colon adenocarcinoma cell line HCT-116, indicating the possibility of a specific biochemical target for this class of cytotoxins.

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/β-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 S a . A cytotoxic activity test of (+)-and (-)-bipenicilisorin using A549 cells revealed that (+)- 1 has a lower IC 50 value than (-)- 1 .

Cannabidiol (CBD), a prominent phytocannabinoid found in various Cannabis chemotypes, is under extensive investigation for its therapeutic potential. Moreover, because it is nonpsychoactive, it can also be utilized as a functional ingredient in foods and supplements in certain countries, depending on its legal status. From a chemical reactivity point of view, CBD can undergo conversion into different structurally related compounds both during storage and after the consumption of CBD-based products. The analytical determination of these compounds is of paramount concern due to potential toxicity and the risk of losing the active ingredient (CBD) title. Consequently, the complete stereoselective total synthesis of representative CBD-derived compounds has become a matter of great interest. The synthesis of pure CBD-derived compounds, achievable in a few synthetic steps, is essential for preparing analytical standards and facilitating biological studies. This paper details the transformation of the readily available CBD into Δ 8 -THC, Δ 9 -THC, Δ 8 - iso -THC, CBE, HCDN, CBDQ, Δ 6 - iso -CBD, and 1,8-cineol cannabinoid (CCB). The described protocols were executed without the extensive use of protecting groups, avoiding tedious purifications, and ensuring complete control over the structural features.

The first and stereoselective synthesis of xylodonin A and 22-hydroxyxylodonin A, two drimane-type sesquiterpenoid natural products, was developed from the readily available (+)-sclareolide. This route features an allylic oxidation and acid-promoted dehydration for construction of the key intermediate 6-hydroxyisodrimenin. Representative analogues were synthesized, and their previously unknown bioactivities were revealed after biological evaluation. The analogue 19a exhibited cytotoxic activity against liver cancer HepG2 cells (IC 50 : 8.8 vs 5.9 μM) that was comparable to that of the clinical anticancer drug etoposide with lower toxicity to normal liver HL7702 cells (IC 50 > 100 μM).

PC-A ( 1 ), a bromo nor-eremophilane, showed selective antiproliferative activity against a triple-negative breast cancer (TNBC) cell line. This unique activity prompted us to establish a total synthesis to facilitate a structure-activity relationship (SAR) study and selectivity optimization. An enantioselective first total synthesis of 1 was achieved starting from ( R )-carvone through a side chain extension with a Mukaiyama aldol reaction and decalin construction. The synthesized decalin derivatives and debromo PC-A ( 2 ) were evaluated for antiproliferative activity against five human tumor cell lines, including TNBC, to assess preliminary SAR correlations.

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 (13 R ,14 S ,15 R )-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 IC 50 values in biological assays addressing the inhibition of cellular inflammatory responses.

As an important bioactive molecular backbone, drimane meroterpenoids have drawn a great deal of attention from both pharmacologists and chemists. Inspired by the prevalidated success of conformational restriction in the discovery of novel pharmaceutical leads, two distinct tetracyclic drimane meroterpenoids, (-)-pelorol and (+)-aureol, were synthesized from the inexpensive starting material (-)-sclareol through 10 and 8 steps with 5.6% and 5.4% overall yield, respectively. The mild conditions, operational facility, and scalability enabled the expedient synthesis and biological exploration of not only natural products themselves but also their mimics. The first agrochemical exploration showed (-)-pelorol and (+)-aureol possessed good antifungal activity against Rhizoctonia solani , with EC 50 values of 7.7 and 6.9 μM, respectively. This revealed that tetracyclic drimane meroterpenoids are valuable models for antifungal lead discovery.

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.

The plant Goniothalamus leiocarpus of the Annonaceae family is used as an alternative medicine in tropical regions. Applying high-speed counter current chromatography (HSCCC), eight new bioactive styrylpyrone isomers, including 6 R ,7 S ,8 R ,2' S -goniolactone B ( 1 ), 6 S ,7 S ,8 S ,2' S -goniolactone B ( 2 ), 6 R ,7 R ,8 R ,2' S -goniolactone B ( 3 ), 6 R ,7 S ,8 S ,2' S -goniolactone C ( 4 ), 6 R ,7 S ,8 R ,2' S -goniolactone C ( 5 ), 6 S ,7 R ,8 S ,2' S -goniolactone C ( 6 ), and two positional isomers, 6 R ,7 R ,8 R ,2' S -goniolactone G ( 7 ) and 6 S ,7 R ,8 R ,2' S -goniolactone G ( 8 ), were isolated from a chloroform fraction (2.1 g) of G. leiocarpus , which had a prominent spot by TLC analysis. The structures of the new compounds were elucidated by MS, NMR, IR, and UV spectra, and their absolute configurations were determined by Mosher's method, ECD, and X-ray diffraction analysis. The isolates are characteristic components found in plants of the genus Goniothalamus and consist of two structural moieties: a styrylpyrone and a dihydroflavone unit. The isolation of the eight new compounds demonstrates the effectiveness of HSCCC in separating the isomers of natural styrylpyrone. In a bioactivity assessment, compounds 1 and 6 exhibited cytotoxic effects against the human colon carcinoma cell lines LS513 and SW620 with IC 50 values ranging from 1.6 to 3.9 μM. Compounds 1 , 2 , 7 , and 8 showed significant synergistic activity against antibiotic-resistant Staphylococcus aureus strains.

The bridged polycyclic sesquiterpenoids derived from sativene, isosativene, and longifolene have unique structures, and many chemical synthesis approaches with at least 10 steps have been reported. However, their biosynthetic pathway remains undescribed. A minimal biosynthetic gene cluster (BGC), named bip , encoding a sesquiterpene cyclase (BipA) and a cytochrome P450 (BipB) is characterized to produce such complex sesquiterpenoids with multiple carbon skeletons based on enzymatic assays, heterologous expression, and precursor experiments. BipA is demonstrated as a versatile cyclase with (-)-sativene as the dominant product and (-)-isosativene and (-)-longifolene as minor ones. BipB is capable of hydroxylating different enantiomeric sesquiterpenes, such as (-)-longifolene and (+)-longifolene, at C-15 and C-14 in turn. The C-15- or both C-15- and C-14-hydroxylated products are then further oxidized by unclustered oxidases, resulting in a structurally diverse array of sesquiterpenoids. Bioinformatic analysis reveals the BipB homologues as a discrete clade of fungal sesquiterpene P450s. These findings elucidate the concise and divergent biosynthesis of such intricate bridged polycyclic sesquiterpenoids, offer valuable biocatalysts for biotransformation, and highlight the distinct biosynthetic strategy employed by nature compared to chemical synthesis.

Enzyme screening of crude sponge extracts prioritized a 2005 Papua New Guinea collection of Hyrtios sp. for further study. The MeOH extract contained puupehenone and four puupehenone analogues (1, 2, 3, 5, and 7) along with a new diastereomer, 20-epi-hydroxyhaterumadienone (4), and a new analogue, 15-oxo-puupehenoic acid (6). The drimane terpene core of 4 and 6 was rapidly dereplicated, and the modified Mosher's method identified 4, while 1D and 2D NMR techniques were used to solve 6. These compounds plus noteworthy repository natural products and standards were tested against three lipoxygenase isozymes, human 5-, 12-, and 15-lipoxygenases. Significant potency and selectivity profiles were exhibited in the human 5-lipoxygenase assay by puupehenone (1) and jaspaquinol (9) and structural factors responsible for activity identified.

The stereoselective total synthesis of dechlorotrichotoxin A, alongside the synthesis of a 1:1 10 E / Z mixture of trichotoxin A, was successfully achieved, commencing from the natural monoterpenoid (-)-citronellal. Key steps in the synthesis involved introducing three alkenes and establishing a stereogenic secondary alcohol center. These transformations were accomplished through olefin cross-metathesis, Tebbe olefination, and enantioselective allylation using a chiral phosphoric acid. A comparison of the spectroscopic data between the synthetic dechlorotrichotoxin A and the reported spectra confirmed that the polyketide isolated from a Smenospongia species corresponds to trichotoxin A rather than dechlorotrichotoxin A.

Herein, we report the first total synthesis of α-glycosidase inhibitor (3 R , 4 S )-6-acetyl-3-hydroxy-2,2-dimethylchroman-4-yl ( Z )-2-methylbut-2-enoate as well as its enantiomer. Our synthesis confirms the chromane structure separately proposed by Navarro-Vazquez and Mata, on the basis of DFT computations. Furthermore, our synthesis allowed us to determine the absolute configuration of the natural compound as (3 S , 4 R ) and not (3 R , 4 S ).

Paraphaeolactones A1, A2, B1, and B2 ( 1 - 4 , respectively), known arthropsadiol D ( 5 ), massariphenone ( 6 ) and its positional isomer 7 , and massarilactones E ( 8 ) and G ( 9 ) were isolated from the culture broth of Paraphaeosphaeria sp. KT4192. Although the structural resemblance between 1 and 2 implies that these comprised a diastereomeric pair at the C-2 stereogenic center, electronic circular dichroism (ECD) spectral analyses revealed that they were pseudo-enantiomers possessing the common (2 R )-configuration. Paraphaeolactones B1 and B2 ( 3 and 4 ) were the derivatives of 2 , which equipped the 3-(1-hydroxy-2-oxopropyl)-4-methylcatechol moiety via an acetal bond at C-10. The relative configurations of their acetal carbons were elucidated by NOE experiments, and those of C-8' were deduced independently by ECD spectral analysis. The present study disclosed that 1 - 5 , 8 , and 9 contain a methylcyclohexene substructure with the same absolute configuration. This prompted us to reinvestigate the absolute configurations of known structurally related fungal metabolites, allowing us to conclude that the methylcyclohexene moieties of these natural products have the same absolute configuration despite the variety of configurations of other stereogenic centers. The plausible biosynthetic routes for 1 - 9 are discussed on the basis of the above conclusion. We propose a Favorskii rearrangement as the key transformation for biosyntheses of 1 - 4 .

Asymmetric total syntheses of aplysiaenal ( 1 ) and nhatrangin A ( 2 ), truncated derivatives of the aplysiatoxin/oscillatoxin family of marine natural products, from configurationally defined intermediates are described. NMR spectra of our synthesized nhatrangin A did not match with either those obtained from authentic samples of the natural product or material obtained via two other total syntheses, but were similar to that obtained from a sample obtained in a third total synthesis. By independently synthesizing the fragments used in its total syntheses, we were able to confirm the configuration of nhatrangin A and clarified that the discrepancy in the spectroscopic data is due to salt formation of the carboxylic acid moiety.

The first total synthesis of the natural product (13 R ,14 S ,15 R )-13-hydroxy-14-deoxyoxacyclododecindione, which was isolated in 2018 as a member of the oxacyclododecindione family, is reported. A synthetic strategy through intramolecular Friedel-Crafts acylation combined with the stereoselective synthesis of a new triol key fragment allowed the preparation of the macrolactone. Due to mismatching physical data of the synthetic product, a revision of the configuration of the natural product isolated in 2018 is required. Light-induced E / Z -isomerism of the macrolactone backbone is described for the first time in the class of oxacyclododecindione-type macrolactones. The hydroxylated macrolactone prepared herein was found to show highly promising IC 50 values in biological assays addressing the inhibition of inflammatory responses.

Five integrasone derivatives, integrasone C ( 1 ), isointegrasone C ( 2 ), integrasone D1 ( 3 ), integrasone D2 ( 4 ), and integrasone E ( 5 ), were isolated from the culture broth of Lepteutypa sp. KT4162. Neither conventional NMR analyses nor DFT (density functional theory)-based computationally assisted chemical shift discussions were sufficient to elucidate the relative configuration of the 1,4-epoxydiol moiety. A combined analysis using the calculated n J CH values and HMBC spectra was helpful to establish the relative configuration. The absolute configurations of 1 - 5 were determined using DFT-based ECD (electronic circular dichroism) spectral analysis. Biological assays of these compounds revealed that 2 potently inhibits HIV-1 integrase without cytotoxicity.