Tetracyclic Skeleton Research Articles

Diphenyl Ether Derivative Rhexocerins and Rhexocercosporins from the Endophytic Fungus Rhexocercosporidium sp. Dzf14 Active against Gram-Positive Bacteria with Multidrug-Resistance.

Ten new diphenyl ether polyketides, including rhexocerins A-D (1-4) and rhexocercosporins A-F (5-10), together with three known congeners (11-13), were isolated from the endophytic fungus Rhexocercosporidium sp. Dzf14 obtained from Dioscorea zingiberensis. Their structures were elucidated by analysis of NMR and HRESIMS data, and their absolute configurations were determined by quantum chemical ECD calculations and X-ray crystallography. Compounds 1-4 featured an unprecedented tetracyclic carbon skeleton (6/7/5/6). Among them, compounds 1 and 5-9 showed antibacterial activities against methicillin-resistant S. aureus T144 and vancomycin-resistant E. faecalis 10.

Concise Total Synthesis of Complanadine A Enabled by Pyrrole-to-Pyridine Molecular Editing

AbstractThe Lycopodium alkaloid complanadine A, isolated in 2000, is a complex and unsymmetrical dimer of lycodine. Biologically, it is a novel and promising lead compound for the development of new treatments for neurodegenerative disorders and persistent pain management. Herein, we report a concise synthesis of complanadine A using a pyrrole-to-pyridine molecular editing strategy. The use of a nucleophilic pyrrole as the precursor of the desired pyridine enabled an efficient and one-pot construction of the tetracyclic core skeleton of complanadine A and lycodine. The pyrrole group was converted into a 3-chloropyridine via Ciamician–Dennstedt one-carbon ring expansion. A subsequent C–H arylation between the 3-chloropyridine and a pyridine N-oxide formed the unsymmetrical dimer, which was then advanced to complanadine A. Overall, from a readily available known compound, the total synthesis of complanadine A was achieved in 11 steps. The pyrrole-to-pyridine molecular editing strategy enabled us to significantly enhance the overall synthetic efficiency. Additionally, as demonstrated by Suzuki–Miyaura cross-coupling, the 3-chloropyridine product from the Ciamician–Dennstedt rearrangement is amenable for further derivatization, offering an opportunity for simplified analogue synthesis.

Asymmetric Synthesis of Bicyclic Isoxazolines via Dearomative Cycloaddition of 4-Nitroisoxazoles with Zwitterionic π-Allyl Palladium Species.

Enantioselective dearomative cycloadditions of 4-nitroisoxazoles with vinylethylene carbonate (2) proceeded in the presence of Pd2(dba)3 and (S)-DTBM-SEGPHOS to give the corresponding bicyclic isoxazolines 3 and 4 in good to high yields with excellent enantioselectivities (≤99% ee). This synthetic approach could be applied to N-tosyl vinyl aziridine and 2-methylidenetrimethylene carbonate. Further transformations of the resulting cycloadducts 4a and 4i yielded not only its derivatives 10 and 11 but also the novel tetracyclic skeleton 12.

Radical cascade cyclization for the green and simple synthesis of silylated indolo[2,1-a]isoquinoline derivatives via visible light-mediated Si–H bonds activation

Photocatalytic and photoinduced silyl radicals cascade cyclization procedures for the green and simple preparation of fused tetracyclic skeleton silylated indolo[2,1-a]isoquinoline-6(5H)-ones from 2-aryl-N-acryloyl indoles with hydrosilanes are developed. The photocatalytic reaction is carried out with 9,10-dicyanoanthracene (DCA) as an organophotocatalyst and 3-acetoxyquinuclidine as hydrogen atom transfer (HAT) catalyst at room temperature under metal- and oxidant-free conditions. The keys to the success of photoredox-catalytic conversion include (1) the reductive quenching of DCA* [E1/2(*P/P–) = +1.97 V vs. SCE in MeCN] by 3-acetoxyquinuclidine (Ep = +1.22 V vs. SCE in MeCN), and (2) the thermodynamic feasibility of hydrogen atom abstraction from hydridic Si–H bond by electrophilic N+•. Particularly, the simple photoinduced cascade cyclization using (TMS)3SiH with 2-aryl-N-acryloyl indoles was exploited via an electron−donor−acceptor (EDA) complex under visible light irradiation.

Pepluenone, a new pepluane-type diterpenoid with inhibitory activity on the release of NO from the whole plant of Euphorbia peplus L.

One new pepluane-type diterpenoid, pepluenone (1), and four known compounds were isolated from the whole plant of Euphorbia peplus L. Compound 1 possesses a 5/6/5/6 tetracyclic skeleton with a unique aromatic ring D. Its structure was determined based on spectroscopic data and X-ray crystallography. The biogenetic pathway of 1 was proposed, in which chemical transformation verified the aromatization step. In vitro anti-inflammatory activity tests indicated that Compounds 1 and 3 had a strong inhibitory effect on releasing NO from mouse macrophage RAW264.7 induced by LPS.

Di- and Triterpenoids from the Rhizomes of Isodon amethystoides and Their Anti-inflammatory Activities.

Amethystoidesic acid (1), a triterpenoid with an unprecedented 5/6/6/6 tetracyclic skeleton, and six undescribed diterpenoids, amethystoidins A-F (2-7), were isolated from the rhizomes of Isodon amethystoides along with 31 known di- and triterpenoids (8-38). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. Compound 1 is the first example of a triterpenoid possessing a rare ring system (5/6/6/6) derived from a contracted A-ring and the 18,19-seco-E-ring of ursolic acid. Compounds 6, 16, 21, 22, 24, and 27 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, which could be partly mediated by the downregulation of LPS-induced inducible nitric oxide synthase (iNOS) protein expression.

Total Synthesis of Lucidumone through Convenient One-pot Preparation of the Tetracyclic Skeleton by Claisen Rearrangement and Subsequent Intramolecular Aldol Reaction.

The total synthesis of lucidumone (1), a Ganoderma meroterpenoid, was accomplished in racemic form from easily prepared 6 and 7 in 10 steps as the longest linear sequence. The synthesis was completed through one-pot preparation of the tetracyclic core skeleton by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo [2.2.2] octane skeleton fused to an indanone structure. The enantioselective total synthesis of 1 was also described via a chiral transfer strategy in the Claisen rearrangement.

Total Synthesis of Lucidumone through Convenient One‐pot Preparation of the Tetracyclic Skeleton by Claisen Rearrangement and Subsequent Intramolecular Aldol Reaction

AbstractThe total synthesis of lucidumone (1), a Ganoderma meroterpenoid, was accomplished in racemic form from easily prepared 6 and 7 in 10 steps as the longest linear sequence. The synthesis was completed through one‐pot preparation of the tetracyclic core skeleton by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo [2.2.2] octane skeleton fused to an indanone structure. The enantioselective total synthesis of 1 was also described via a chiral transfer strategy in the Claisen rearrangement.

Schomburginones A‒J, geranylated benzophenones from the leaves of Garcinia schomburgkiana and their cytotoxic and anti-inflammatory activities

Ten undescribed benzophenones, schomburginones A−J, together with 14 known analogs were isolated from the leaves of Garcinia schomburgkiana, an edible plant native to the Indochina region. The structures of the undescribed compounds were elucidated by NMR combined with HRMS spectroscopy, while their absolute configurations were determined using ECD and single-crystal X-ray diffraction analysis. The isolated metabolites represent benzophenone derivatives containing a modified monoterpene unit, including tri- and tetracyclic skeletons, which are rarely found in genus Garcinia. The cytotoxic evaluation on three cancerous cell lines demonstrated that schomburginone G, schomburginone H, and 3-geranyl-2,4,6-trihydroxybenzophenone were active against HeLa cells with IC50 values in the range of 12.2–15.7 μM, respectively, and selective compared to the non-cancerous L929 cells (SI > 3.5). In addition, the three cytotoxic compounds together with clusiacyclol A showed significant NO inhibitory activity in RAW 264.7 macrophage cells over 85% inhibition without obvious cytotoxicity at a final concentration of 100 μM. The promising activities of these compounds in cytotoxic and anti-inflammatory assays make them attractive for further study in the development of anticancer drugs.

Enantioselective Total Syntheses of Grayanane Diterpenoids and (+)-Kalmanol: Evolution of the Bridgehead Carbocation-Based Cyclization and Late-Stage Functional Group Manipulation Strategies

Grayanane diterpenoids contain over 300 highly oxidized and structurally complex members, many of which possess important biological activities. Full details are provided for the development of the concise, enantioselective and divergent total syntheses of grayanane diterpenoids and (+)-kalmanol. The unique 7-endo-trig cyclization based on a bridgehead carbocation was designed and implemented to construct the 5/7/6/5 tetracyclic skeleton, demonstrating the practical value of the bridgehead carbocation-based cyclization strategy. Extensive studies of late-stage functional group manipulation were performed to forge the C1 stereogenic center, during which a photoexcited intramolecular hydrogen atom transfer reaction was discovered and the mechanism was further studied through density functional theory (DFT) calculations. The biomimetic 1,2-rearrangement from the grayanoid skeleton provided a 5/8/5/5 tetracyclic framework and resulted in the first total synthesis of (+)-kalmanol.

A concise approach for the synthesis of the tetracyclic framework of Lycibarbarines A and B

A simple approach for the construction of the tetracyclic spiroketal skeleton of Lycibarbarine A and B has been described. Employing a solvent free condition for epoxide opening with tetrahydroquinoline as a key reaction to couple both the fragments, an oxidation followed by TBAF-mediated silyl deprotection spiroketalization establishes the complete tetracyclic core present in these natural products.

Concise Enantioselective Total Synthesis of Isopavine Alkaloids.

Herein, we report a concise asymmetric total synthesis of isopavine alkaloids, which feature a special azabicyclo[3.2.2]nonane tetracyclic skeleton. The key steps include iridium-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids, Curtius rearrangement, and Eschweiler-Clarke methylation, which enable an enantioselective approach to isopavine alkaloids in 6-7 linear steps. Furthermore, for the first time, isopavine alkaloids, especially (-)-reframidine (3), are found to display effective antiproliferative effects on various cancer cell lines.

Synthetic Studies on Tetracyclic Diquinane Lycopodium Alkaloids Magellanine, Magellaninone and Paniculatine.

(-)-Magellanine, (+)-magellaninone, and (+)-paniculatine are three natural products isolated from the Lycopodium family that share a unique 6-5-5-6-fused tetracyclic diquinane core skeleton. Several members of this family have potent s anti-inflammatory and acetylcholinesterase-inhibitory properties and are under development for the treatment of Alzheimer's and other neurodegenerative diseases. Several research groups have undertaken the formal and total syntheses of this class of natural products. This review highlights over 20 reported total syntheses of these three alkaloids and the development of synthetic methods for the assembly of their core skeletons.

Asymmetric Total Synthesis of Twin Bufogargarizins A and B.

The first and asymmetric total synthesis of bufogargarizins A and B, two unusual and highly oxygenated twin steroids with rearranged A/B rings, was achieved. The synthetically challenging [7-5-6-5] tetracyclic ring system of bufogargarizin A was efficiently constructed by the first intramolecular Ru-catalyzed [5 + 2] cycloaddition reaction of a vinyl ether cyclopropane-yne. Notably, the interesting [5-7-6-5] tetracyclic skeleton of bufogargarizin B was diastereoselectively reassembled by unique retro-aldol/transannular aldol cascade reactions from the [7-5-6-5] tetracyclic framework.

Alscholarines A and B, two rearranged monoterpene indole alkaloids from Alstonia scholaris.

Alscholarines A and B (1 and 2), two unprecedented rearranged monoterpene indole alkaloids, were isolated from Alstonia scholaris. Alscholarine A (1) features an imidazole ring fused with a rearranged vallesamine-type alkaloid possessing an unparalleled 6/5/6/6 tetracyclic skeleton through an unprecedented C7-C-19 connectivity. Alscholarine B (2), incorporating an unusual 7-oxa-1-azabicyclo[3.2.1]octane moiety, represents a unique rearranged vallesamine-type alkaloid with a 6/5/6/6/5 ring system via an unprecedented C-6-C-20 connectivity. Their structures were established by spectroscopic analysis, X-ray crystallography, and quantum-chemical calculations. Their plausible biosynthetic pathways were proposed. The vasorelaxant and anti-inflammatory activities of them were also evaluated. Compounds 1-3 showed moderate vasorelaxant activities.

Total synthesis of applanatumol A.

The first total synthesis of applanatumol A has been achieved in a highly stereocontrolled manner. The synthetic method includes assembly of the contiguous chiral centers by convergent Fráter-Seebach alkylation, construction of the seven-membered ring by intramolecular aldol reaction, and stereoselective tandem cyclization to form the tetracyclic skeleton.

Identification of new bisabosqual-type meroterpenoids reveals non-enzymatic conversion of bisabosquals into seco-bisabosquals.

Bisabosqual-type meroterpenoids are fungi-derived polyketide-terpenoid hybrids bearing a 2,3,3a,3a1,9,9a-hexahydro-1H-benzofuro[4,3,2-cde]chromene skeleton (6/6/6/5 ring system) or its seco-C-ring structure, and exhibit diverse bioactivities. Their unique structural architecture and impressive biological activities have led to considerable interest in discovering new analogues. However, to date, only nine analogues have been identified. Herein, we reported the isolation and identification of six new bisabosqual-type meroterpenoids stachybisbins C-H (1-6), together with one known compound bisabosqual C (7), from Stachybotrys bisbyi PYH05-7. Intriguingly, we found that 7, which contains the intact tetracyclic skeleton, can be non-enzymatically converted into its seco derivative stachybisbin I (8), unveiling the biosynthetic relationship between bisabosquals and seco-bisabosquals. Moreover, based on CRISPR/Cas9-mediated gene disruption, we revealed that the three-gene cluster responsible for the formation of LL-Z1272β is associated with the biosynthesis of bisabosqual-type meroterpenoids, and then proposed a plausible route to 1-8.

Synthetic study toward the diterpenoid aberrarone.

An approach to aberrarone, an antimalarial diterpenoid natural product with tetracyclic skeleton is reported. Key to the stereoselective preparation of the 6-5-5 tricyclic skeleton includes the mediation of Nagata reagent for constructing the C1 all-carbon quaternary centers and gold-catalyzed cyclopentenone synthesis through C-H insertion.

Total Synthesis of (-)-Principinol C.

We have achieved the first total synthesis of (-)-principinol C, which possesses an intriguing and complex 5/7/6/5 tetracyclic skeleton with eight contiguous stereocenters. The 5/7/6/5 tetracyclic skeleton of principinol C was assembled using an intramolecular Pauson-Khand reaction as the key step. This synthetic route represents the first application of the intramolecular Pauson-Khand reaction of enyne to construct the 7,5-bicyclic ring system in natural product synthesis.

Single-step approach for synthesis of a novel tetracyclic skeleton: Investigation of X-ray analysis, fluorescence spectra, TD-DFT calculations and biological activities

Tetracyclic molecules show important properties such as biological activities and fluorescence sensors. Hence, in this study, we have reported unknown tetracyclic skeleton. N-propargylated C-2 and C-4 disubstituted imidazole derivatives were reacted by 2-aminomethyl piperidine without using any transition metal. The reaction unveiled 16 different imidazo[1,2-a]pyrido[1′,2′:3,4]imidazo[2,1-c]pyrazine skeletons. Cyclization reaction tolerated phenyl, naphthyl, bi-phenyl, 2-thienyl, and many substituents on the benzene ring such as OMe, CF3, and halogens. We have uncovered the exact structure of the tetracyclic skeleton using single-crystal X-ray analysis. Significant fluorescence emission of tetracyclic molecules was investigated, and derivatives bearing electron-withdrawing groups, CF3, and the 2-thienyl group possessed a bathochromic effect (shift to longer wavelength) which was confirmed by not only steady-state experiments but HOMOs and LUMOs calculations. The antimicrobial effects of the synthesized molecules on six different organisms were tested. Considerable activities of molecules 5p and 5n on many organisms were determined. Docking modeling and Lipinski, Ghose, and Veber compatibility studies of two different molecules were performed.