Bicyclic Skeleton Research Articles

Synthesis of Gem-Dimethyl Bicyclic [3.1.0] Proline as an Antiviral Drug Intermediate

Abstract: Gem-dimethyl bicyclic [3.1.0] proline, an azadicyclohexane derivative, constitutes a prevalent skeleton structure in drugs, which serves an important role in the synthesis of antiviral drugs, such as Nirmatrelvir, Boceprevir, Narlaprevir, etc. This study offers a comprehensive overview of the documented synthetic strategies for gem-dimethyl bicyclic [3.1.0] proline methyl ester and delves into the application characteristics of each synthetic strategy. These synthetic approaches can be divided into three major types: the first synthetic method uses proline derivatives as the starting material, the second one uses cyclopropane derivatives as the starting material, and the third one uses the bicyclic skeleton as the starting material. Of these strategies, the third method stands out as the most extensively adopted.

Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus.

Drimane-type sesquiterpenoids (DMTs) are characterized by a distinctive 6/6 bicyclic skeleton comprising the A and B rings. While DMTs are commonly found in fungi and plants, their presence in bacteria has not been reported. Moreover, the biosynthetic pathways for DMTs have been primarily elucidated in fungi, with identified P450s only acting on the B ring. In this study, we isolated and characterized three bacterial DMTs, namely 3β-hydroxydrimenol (2), 2α-hydroxydrimenol (3), and 3-ketodrimenol (4), from Streptomyces clavuligerus. Through genome mining and heterologous expression, we identified a cav biosynthetic gene cluster responsible for the biosynthesis of DMTs 2-4, along with a P450, CavA, responsible for introducing the C-2 and C-3 hydroxy groups. Furthermore, the substrate scope of CavA revealed its ability to hydroxylate drimenol analogs. This discovery not only broadens the known chemical diversity of DMTs from bacteria, but also provides new insights into DMT biosynthesis in bacteria.

Towards high conductivity and stability diblock poly(norbornene)s-based anion exchange membranes crosslinked with alkyl quaternary ammonium cationic clusters

Anion exchange membranes (AEMs) with exceptional comprehensive performance, combining high conductivity, alkaline and dimensional stability, have been indispensable for the practical application in fuel cells. Herein, a robust addition poly(norbornene)s-based AEMs with an all-carbon-hydrogen bicyclic skeleton were fabricated by cross-linking of alkyl quaternary ammonium cationic clusters and further quaternization. The partially crosslinked AEMs adopt a synergistic strategy that combines diblock copolymer backbone, cationic cluster crosslinking structure, and long flexible spacer suspended with cationic head groups. Benefiting from these structural design advantages, the prepared AEMs possessed excellent hydroxide conductivity (133.9–146.9 mS cm−1) and low swelling ratio (SR ≦ 20%) at 80 °C. The robust crosslinked AEMs exhibited good mechanical properties and high thermostability, with onset of decomposition temperatures up to 240 °C. Furthermore, after 44 days treatment in 1 M NaOH solution at 80 °C, the hydroxide conductivity of AEMs maintained at 79.4–85.7% of the initial value depending on the crosslinking degree, demonstrating excellent alkaline stability. In addition, the H2/O2 single cell equipped with CL20-aPNB-TAT-QA-1.75 achieved a peak power density of 338.0 mW cm−2 at 80 °C. The study provided a meaningful insight to exploit the practical application of multi-cation clusters crosslinked addition poly(norbornene)s-based AEMs in fuel cells.

Ab Initio Conformational Analysis of 3,7-Diacetyl-3,7-Diazabicyclo[3.3.1]Nonanes

Introduction: The importance of the conformational behavior comprehension for proper prediction of properties for a certain compound or for a class of compounds is indisputable. For 3,7-diacylbispidines (3,7-diacyl-3,7-diazabicyclo[3.3.1]nonanes), only “double chair” (CC) conformers were prior found experimentally in the condensed phase, which differ only in the acyl groups relative orientation, “parallel,” pa or “antiparallel,” ap. However, 2 other conformer families, “boat-chair,” BC and “double twist,” TT, are known for other bicyclo[3.3.1]nonane derivatives. Features of these conformers would be useful for the accurate prediction of properties and activities of the compounds. Methods: Second-order perturbation theory ab initio techniques (MP2) in the triple-zeta correlation-consistent orbital basis set cc-pVTZ was employed to optimize the electronic energy for structures, to characterize the optimized structures as potential energy surface minima by energy hessian eigenvalue calculations and to calculate zero-point energy corrections for the minima using the “rigid rotor-harmonic oscillator” approximation to model the molecular ensemble thermodynamics. Additionally, the computational chemical thermodynamics benefits much from the concept of the molecular strain and its energy assessed successfully through the bond separation energy formalism. We combine both approaches in our investigation to find and consistently characterize the conformers previously unknown for the compounds under the studies. Results: Six possible conformers were found for the investigated 3,7-diacetyl-3,7-diazabicyclo[3.3.1]nonanes 1-4, formed by combining the skeletal conformation changes with the internal rotation of acyl substituents. The conformational behavior is quite similar for all investigated molecules. In all cases, the CC conformation is optimal for the bicyclic skeleton and ap orientation prevails over pa for 2 acetyl groups. This prevalence is 4-5 kcal mol−1 in CC and less than 1 kcal mol−1 in other skeletal forms, making rotation of 2 acyl groups in BC and TT almost independent. Concerning the skeletal conformations, the common energy sequence CC < BC < TT is found. While the relative BC energy is 6-7 kcal mol−1 over the optimal CC structure, TT forms are all strained by more than 12 kcal mol−1. Conclusions: For the first time, both BC and TT conformers of 3,7-diacetylbispidines were characterized by their strain and conformation energies together with known less strained CC forms. On the basis of our calculations, the relative energies of BC conformers are expected to be close to those of the CC acetyl amide bond rotamers found previously in experiment, therefore, their exclusion from the conformational behavior would look unjustified. On the contrary, TT conformers are found to be much more strained enough to be neglected in the conformational ensemble modeling.

Construction of Diverse Pyrrolidine-Based Skeletons through the Ag-Catalyzed Stereoselective Addition-Elimination Reaction of Azomethine Ylides with Nitroallyl Acetates.

Because scaffold diversity has a pronounced impact on biological screening, the efficient and expedient construction of skeletally diverse compound collections is a fundamental demand in drug discovery. In this regard, we report here an asymmetric tandem conjugate addition-elimination reaction of pyrroline esters with nitroallyl acetates and its application to the construction of various types of fused or spirocyclic pyrrolidines. A AgOAc/(R,Sp)-ThioClickFerrophos (TCF) catalyst efficiently promotes the addition-elimination reaction, setting vicinal chiral stereocenters featuring a tetrasubstituted carbon with excellent enantio- and diastereoselectivity while leaving the versatile nitroolefin moiety. The broad substrate scope of this reaction and the transformability of the resulting nitroolefin, imine, and ester moieties allow for the construction of diverse pyrrolidine-based fused or spiro bicyclic skeletons in optically active forms by various intramolecular cyclization processes.

Euphzycopins A − D, macrocyclic diterpenoids with potential anti-inflammatory activity from Euphorbia Helioscopia

Four new diterpenoids (1–4) and four known diterpenoids (5–8) were purified from the whole plant of Euphorbia helioscopia L. Compounds 1 and 2 were jathophanes diterpenoids with a 5/12 polycyclic systems, compound 3 was rhamofolane diterpenoid with a 5/10 bicyclic skeleton and compound 4 was a rare class of euphorbia diterpenes featuring an unusual 5/10 fused ring system. Anti-inflammatory activity tests were conducted on the separated compounds, indicating that compound 4 had significant inhibitory effect on NLRP3 inflammasome with an IC50 value of 7.75 μM. Further, the inhibitory effect of 4 was determined using immunofluorescence assays.

Total synthesis of highly oxygenated phomopsol B via acid-induced etherification to construct a bridged structure.

The first total synthesis of phomopsol B has been achieved in a racemic form. The synthesis comprises a deacetylative cyclization to construct a bicyclic skeleton followed by primary alcohol-assisted dihydroxylation, ether cyclization to construct a dioxabicyclo [3.2.1] skeleton and γ-lactone formation based on oxidation by TEMPO.

Sarcocinerenoids A—J, Eight Rare Capnosane‐Type and Two New Cage‐Type Cembranoids with Promoting Angiogenesis Activity from the South China Sea Soft Coral Sarcophyton cinereum

Comprehensive SummaryEight rare capnosane‐type cembranoids, sarcocinerenoids A—H (1—8) and two new cage‐type cembranoids sarcocinerenoids I—J (9—10) were isolated from the soft coral Sarcophyton cinereum. The 5/11 bicyclic carbon skeleton is the same in Sarcocinerenoids A—H (1—8), and they collocate distinctive oxygen rings. Sarcocinerenoids I—J (9—10) with a cage‐type structure have been discovered to have an oxygen bridge and an uncommon seven‐membered ring. Extensive spectroscopic investigation, X‐ray diffraction analysis, estimated ECD, and DP4+ probability assessments were used to ascertain the structures of the two types of diterpenoids. Moreover, compounds 1, 4 showed promoting angiogenesis activity in zebrafish assays.

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis.

Terpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC-like enzymes are known but are very rare. In this study, we genome-mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane derived diterpenoids, aridacins A-C (1-3), that possess a 6/7/5-fused tricyclic scaffold. In vivo and in vitro experiments systematically established a noncanonical two-step biosynthetic pathway for diterpene skeleton formation. First, a class I TC (AriE) cyclizes geranylgeranyl diphosphate (GGPP) into a 6/10-fused bicyclic cis-eunicellane skeleton. Next, a cytochrome P450 (AriF) catalyzes cyclization of the eunicellane skeleton into the 6/7/5-fused tricyclic scaffold through C2-C6 bond formation. Based on the results of quantum chemical computations, hydrogen abstraction followed by electron transfer coupled to barrierless carbocation ring closure is shown to be a viable mechanism for AriF-mediated cyclization. The biosynthetic logic of skeleton construction in the aridacins is unprecedented, expanding the catalytic capacity and diversity of P450s and setting the stage to investigate the inherent principles of carbocation generation by P450s in the biosynthesis of terpenoids.

Terpene Synthases in the Biosynthesis of Drimane-Type Sesquiterpenes across Diverse Organisms.

Drimane-type sesquiterpenes (DTSs) are significant terpenoid natural products characterized by their unique C15 bicyclic skeleton. They are produced by various organisms including plants, fungi, bacteria and marine organisms, and exhibit a diverse array of bioactivities. These bioactivities encompass antifeedant, anti-insecticidal, anti-bacterial, anti-fungal, anti-viral and anti-proliferative properties. Some DTSs contribute to the pungent flavor found in herb plants like water pepper, while others serve as active components responsible for the anti-cancer activities observed in medicinal mushrooms such as (-)-antrocin from Antrodia cinnamomea. Recently, DTS synthases have been identified in various organisms, biosynthesizing drimenol, drim-8-ene-11-ol and (+)-albicanol, which all possess the characteristic drimane skeleton. Interestingly, despite these enzymes producing chemical molecules with a drimane scaffold, they exhibit minimal amino acid sequence identity across different organisms. This Concept article focuses on the discovery of DTS synthases and the tailoring enzymes generating the chemical diversity of drimane natural products. We summarize and discuss their key features, including the chemical mechanisms, catalytic motifs and functional domains employed by these terpene synthases to generate DTS scaffolds.

Heterolactone and Heterolactams A-M, Verticillane Diterpenoids with Anti-Inflammatory and Hepatoprotective Activities from the Soft Coral Heteroxenia ghardaqensis.

Fourteen new verticillane diterpenoids, heterolactone (1) and heterolactams A-M (2-14), were isolated from the soft coral Heteroxenia ghardaqensis. They structurally share the same 6/12 bicyclic carbon skeleton that is not commonly encountered in marine organisms. The structures, including the absolute configurations, were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, calculated ECD spectra, and DP4+ probability analyses. Compounds 5, 8, and 9 showed anti-inflammatory activities, and 2, 8, and 12 displayed hepatoprotective activities in zebrafish assays.

Pogocablanols A–G, a new class of sesquiterpenoids with an unprecedented bicyclic sesquiterpenoid skeleton from Pogostemon cablin (patchouli) and their activities

Pogocablanols A–G (1–7), seven new compounds with an unprecedented sesquiterpenoid skeleton, were isolated from the aerial parts of Pogostemon cablin. This novel type of sesquiterpenoids, named pogocablane-type sesquiterpenoids, possesses a bicyclic nonisoprenoid system, including a five-membered carbocycle with a methyl group, a six-membered carbocycle with two methyl groups, and a methylene connecting the two carbocycles. Particularly, three isomers have an interesting 1-oxaspiro[4,4]nonane moiety. Their structures and absolute configurations were determined using extensive spectroscopic evidence, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Pogocablanols A–D (1–4) exhibited a concentration-dependent inhibitory effect on rat jejunum smooth muscle contraction induced by acetylcholine, with Emax values varying from 48.87 ± 4.01% to 69.02 ± 7.54%. Preliminary structure–activity relationship analysis suggested that the oxaspirocycle and the pyran ring in pogocablanols are important structural features for the relaxing effects on jejunum smooth muscle. This study offered crucial support for more investigation and development of P. cablin by showing that these pogocablane-type sesquiterpenoids had the potential to be applied in pharmaceutical and functional food formulations.

Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation

Abstract(−)‐Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X‐ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio‐ and stereoselective hydrogenation, and subsequent merged MBH–Tsuji–Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)‐euptox A (2) in 8 steps from commercially available monoterpene (−)‐carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2O2‐treated SH‐SY5Y and PC12 cells.

Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation.

(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9 ]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptox A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2 O2 -treated SH-SY5Y and PC12 cells.

Discovery of estrogen receptor α targeting caged hypoxia-responsive PROTACs with an inherent bicyclic skeleton for breast cancer treatment

In view of the potential off-target effects of antitumor drugs, including proteolysis targeting chimera (PROTAC), certain toxic effects may be caused in normal tissues. Herein, based on the characteristics of the tumor microenvironment, we reported the first estrogen receptor α (ERα) targeting hypoxia-responsive PROTACs in order to improve their safety in breast cancer treatment by introducing two hypoxia-activated groups, nitroimidazole and nitrobenzene, into the ER ligand or E3 ligand of an active PROTAC, which has certain cytotoxicity in normal cells. Bioactivity studies showed that these hypoxia-responsive PROTACs exhibited excellent hypoxic responsiveness and ERα degradation activity under hypoxic conditions, and thus improved the toxic effects of the active PROTAC in normal cells. It is expected that our caged compounds provide a new strategy for precise functional control of PROTAC drugs for breast cancer treatment.

Structurally diverse new eudesmane sesquiterpenoids with anti-inflammatory activity from the fruits of Alpinia oxyphylla

The phytochemical investigation of the fruits of Alpinia oxyphylla led to the isolation and identification of 40 structurally diverse sesquiterpenoids, including 17 new eudesmane sesquiterpenoids (1–17) and 23 known analogues (18–40). Among the isolates, 14 and 17 were unusual rearranged eudesmane sesquiterpenoids, featuring rare 5/6-fused and 6/8-fused bicyclic carbon skeleton, respectively; 15 and 16 were the novel 6,7-seco-eudesmane sesquiterpenoids isolated from plant-origin for the first time, 1 and 3–6 were rare nor-eudesmane sesquiterpenoids. Their structures were elucidated by comprehensive spectroscopic data analysis (NMR, HRESIMS, IR, UV), single crystal X-ray diffraction, and quantum chemistry calculations (ECD and 13C NMR). Moreover, all isolates were evaluated by measuring their inhibitory effect on nitric oxide (NO) in LPS-stimulated BV-2 cells. As a result, compounds 11, 20, 24 and 40 showed moderate to strong inhibition on NO productions, with IC50 values ranging from 21.63 to 60.70 μM. Meanwhile, these compounds also partially decreased the secretion of TNF-α and IL-6 in LPS-stimulated BV-2 cells. Furthermore, 20 could down-regulate protein expressions (COX-2 and iNOS) and observably inhibit the mRNA expressions of TNF-α, IL-6, COX-2 and iNOS. In this study, the discovery of structurally diverse anti-inflammatory sesquiterpenoids from the fruits of A. oxyphylla could benefit the further development and utilization of this plant.

Gold(I)‐Catalyzed Alkynylation of N,O‐Acetals: An Access to Alkynylated Saturated N‐heterocycles

AbstractA synthetic route for the preparation of alkynylated saturated N‐heterocycles via a sequential combination of a Shono oxidation and a gold(I)‐catalyzed alkynylation reaction has been developed. The electrochemical Shono oxidation allowed an efficient access to a variety of N,O‐acetals via a direct C−H bond functionalization of cyclic amines. The reaction conditions were amenable with functionalized pyrrolidine, tetrahydroisoquinoline and pyrrolidine‐cyclopropyl fused bicyclic skeletons. The gold‐catalyzed process allowed the introduction of aryl acetylene partners bearing electron‐donating and moderate electron‐withdrawing. The efficiency of the gold process is remarkable and could be scaled up to 5 mmol of N,O‐acetal. Post‐functionalization reactions were performed based on the reactivity of the alkyne, showing the broad interest of our methodology. Promising preliminary results on an asymmetric version were obtained (e.r. up to 84.5:15.5).magnified image

Rapid construction of bicyclic triazoline skeletons with dual-state emissionviacycloaddition reaction of 4-phenyl-1,2,4-triazoline-3,5-dione with vinyl azides

Fluorescent bicyclic triazolines with excellent photophysical properties were easily and conveniently synthesized and showed intense deep-blue photoluminescence with quantum yields of up to 78% and 87% in solution and the solid state, respectively.

New tocopherol and acylphloroglucinol derivatives from Dryopteris crassirhizoma and their antimicrobial activities

Nine previously undescribed compounds including six tocopherol derivatives (1–6) and three acylphloroglucinol derivatives (7–9) were isolated and characterized from the plants of Dryopteris crassirhizoma. Their structures with absolute configurations were determined by extensive spectroscopic analyses, including IR, HRESIMS, NMR, and calculated electronic circular dichroism (ECD). Compounds 1 and 2 are the first tocopheroid derivatives possessing unique 2,5-dimethylcyclopent-4-ene-1,3-dione carbon skeleton, and compounds 3–6 were new 5a-norcyclopentenones having a spirofused bicyclic carbon skeleton. The biosynthetic pathway of compounds 1–6 was postulated. When combined with fluconazole (FLC), compound 3 showed significant antifungal activity against standard Candida albicans with MIC50 value of 1.19 μg/mL (FLC: 3.41 μg/mL). Furthermore, the anti-plant pathogenic fungi and bacterial activities have been evaluated in vitro, compounds 5 and 8 showed anti-Verticillium dahlia and Sclerotinia sclerotiorum with MIC value of 50 μg/mL, respectively. Compounds 1 and 5 exhibited moderate antibacterial activities against Micrococcus luteus with MIC value of 50 μg/mL, respectively.

Studies on the Regioselective Rearrangement of Azanorbornanic Aminyl Radicals into 2,8-Diazabicyclo[3.2.1]oct-2-ene Systems.

Aminyl radicals are nitrogen-centered radicals of interest in synthetic strategies involving C-N bond formation due to their high reactivity. These intermediate radicals are generated by the reaction of an organic azide with tributyltin hydride (Bu3SnH) in the presence of substoichiometric amounts of azobisisobutyronitrile (AIBN). In this work, we report the regioselective rearrangement of azanorbornanic ([2.2.1]azabicyclic) aminyl radicals into 2,8-diazabicyclo[3.2.1]oct-2-ene systems. With the aim to establish the structural requirements for this ring expansion, we have studied the effect of different bridgehead atoms of the [2.2.1]bicyclic system and the presence of an alkyl substituent at C4. Attempts to perform this ring expansion on a monocyclic analogue have been also explored to evaluate the influence of the bicyclic skeleton on the rearrangement. A detailed mechanistic proposal supported by computational studies is reported.