Pentacycloundecane Research Articles

Design and Synthesis of Out/Out, Out/In, and In/In Epoxides in Polycyclic Cage Frameworks

AbstractWe report a useful synthetic approach to assemble in/in epoxide, in/out epoxide, and out/out epoxide in cage systems using the Corey–Chaykovsky reaction and the Peterson olefination as key steps. In this regard, a variety of pentacycloundecane (PCUD) based cage compounds containing oxirane rings with diverse stereochemical disposition were synthesized via a simple synthetic sequence. Five cage diones were used for this purpose, and the starting cage diones were prepared with easily accessible starting materials such as 1,4-hydroquinone derivatives and cyclopentadiene. Here, we have used the Diels–Alder (DA) reaction, a [2+2] photocycloaddition, the Corey–Chaykovsky reaction, and the Peterson olefination as crucial steps to prepare the target molecules.

Synthetic Approach toward Diverse Oxa-Cages via Olefin Metathesis.

This article demonstrates a late-stage modification of the cage propellanes that are transformed into intricate oxa-cycles via ring-rearrangement metathesis (RRM) and regioselective ring-closing metathesis (RCM) as crucial steps. In addition, we also report the extended pentacycloundecane (PCUD)-based oxa-cages involving the domino cycloetherification followed by olefin metathesis. These oxa-cages involve a domino sequence in which the PCUD core unit remains intact. [Ru]-based Grubbs catalysts are used to execute the metathesis step to assemble these higher-order oxa-cage systems. Spectroscopic data assigned structures of various products and were further supported by single-crystal X-ray diffraction analysis. The synthetic approach to these cage polycycles involves high complexity generating processes such as Diels-Alder reaction, [2 + 2] photocycloaddition, and RRM as well as RCM.

Molecular Acrobatics in Polycyclic Frames: Synthesis of "Kurmanediol" via Post-synthetic Modification of Cage Molecules by Olefinic Metathesis.

We report late-stage ring-opening metathesis (ROM), ring-rearrangement metathesis (RRM), and ring-closing metathesis (RCM) approaches to generate expanded pentacycloundecane (PCUD) cage derivatives. These higher-order intricate polycyclic cage systems are aesthetically pleasing and structurally intriguing. Their assembly maintains molecular symmetry during the entire synthetic sequence. To this end, metathesis-based catalysts are used to execute the ROM, RRM, and RCM strategies. The synthetic approach to these cage polycycles involves the Diels-Alder reaction, [2 + 2] photocycloaddition, RRM, ROM, and RCM as key steps.

Design and Synthesis of Nitro Cage Heterocycles as Energetic Materials Derived from Pentacycloundecane (PCUD) Systems

AbstractA variety of pentacycloundecane (PCUD) based cage compounds containing nitro groups were synthesized via a simple synthetic method starting with cage diones. Eight PCUDs were used for nitro functionalization. These cage diones were prepared starting with easily accessible starting materials such as 2,3‐dimethylhydroquinone, 1,4‐dihydroxybenzene, and cyclopentadiene. Here, we have used Diels‐Alder (DA) reaction, [2+2] photocycloaddition, and Henry reaction as key steps. Transannular cyclization plays an important role to generate a nitro substituted cage heterocycles via base promoted reaction using nitromethane as a reagent. Some of these oxa‐cage structures have been further supported by single‐crystal X‐ray diffraction studies. Energetic performance of the title compounds was evaluated using DFT based calculations. These bis(nitromethyl)octahydro‐1H‐1,3,4,6(epiethane‐[1,1,2,2]tetrayl)‐pentaleno[1,6‐bc]furan analogues (11 b–18 b) owned the densities in the range of 1.37–1.60 g/cm3. All the studied compounds possess high positive enthalpy of formation (33.68–230.48 kJ/mol, except compound with dimethyl groups (16 b, −11.38 kJ/mol) and very good thermal (Tm=99–147 °C) and kinetic stabilities. Ammonium perchlorate based various propulsion formulations suggests that these compounds could be excellent candidates in the solid rocket propulsion.

Pentacycloundecane (PCUD)‐Based Cage Frameworks as Potential Energetic Materials: Syntheses and Characterization

AbstractA new variety of cage frameworks containing pentacycloundecane (PCUD) were synthesized. These compounds contain azide and triazole units. Four new cage frameworks were designed and constructed starting from easily accessible starting materials such as 2,3‐dimethylhydroquinone, 1,4‐dimethoxybenzene, and dicyclopentadiene using [2+2] photocycloaddition as the key step. The structures of these symmetrical cage bis‐azide and cage bis‐triazole compounds have been confirmed by single‐crystal X‐ray diffraction studies. DFT analysis at different levels of theory were used to optimize the geometries and compute the heats of formation of the title compounds. Their propulsive and explosive properties were also calculated using suitable computational methods. The thermodynamic stability of the title compounds was theoretically analysed based on their bond dissociation energies. The thermal stability was evaluated by TGA‐coupled FTIR analysis.

A new skeletal rearrangement of 1,7-dimethyl Cookson's cage dione catalyzed by a Lewis acid.

A methyl-substituted polycyclic cage dione containing the PCUD framework has undergone an unprecedented ring rearrangement approach. Here, the PCUD framework with the aid of a Lewis acid such as BF3·MeOH gave unusual fragmentation products. Two new products were isolated via the skeletal rearrangement process involving carbocation mediated intermediates. The substituents in the succinyl bond present in the strained PCUD skeleton produce a driving force for the rearrangement in an unprecedented manner. Interestingly, the cyclobutane ring was transformed to cyclopentane through the cleavage of the C1-C7 bond during the ring-expansion process of PCUD via the carbocation intermediates. Unexpectedly, solvent (benzene) was captured during the ring-homologation process due to the presence of methyl substituents placed at the cyclobutane ring of the cage framework. It appears that this is the first report where an unexpected ring-rearrangement, ring-homologation, and ring-fragmentation occur with the aid of the BF3·MeOH complex.

Serendipitous discovery of new pentacycloundecane molecules

This study explored the rearrangement process which occurred during Grignard reactions of the pentacycloundecane (PCU) dione, 1. This compound was reacted with vinyl and allyl magnesium bromide to afford PCU-vinyl cyclic ether, 2, and PCU-allyl cyclic ether, 4, which upon ozonolysis afforded compounds PCU dilactone, 3 and PCU-cyclic ether monoacid, 5 respectively. This resulted in the discovery of three novel cage compounds, 2, 4 and 5. The Baeyer-Villiger oxidation of 1 was proposed and investigated experimentally as an alternative synthetic route for the PCU dilactone. The unsymmetrical nature of compounds 2, 4 and 5 resulted in overlapping signals of the methine protons and carbons observed in the 1H and 13C NMR spectra, however, the complexity of the spectra was resolved by using 2D NMR techniques to successfully elucidate these compounds. Herein, the three novel cage compounds including compound 3 were fully characterized by IR and NMR spectroscopy, HRMS. Single crystal X-ray crystallography analysis was also performed on compounds 3 and 5.

Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study.

BackgroundNovel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC50 values of less than 1.00 μM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC50) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS peptides.ResultsThe PCU-lactam model exhibited more negative calculated binding free energies of solvation than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC50 = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC50 = 0.850 μM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and compared. The Gibbs theoretical free solvation energies of solvation (∆Gsolv) were also considered.ConclusionsA general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC50 data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users.

Design and synthesis of novel bis-annulated caged polycycles via ring-closing metathesis: pushpakenediol.

Intricate caged molecular frameworks are assembled by an atom economical process via a Diels–Alder (DA) reaction, a Claisen rearrangement, a ring-closing metathesis (RCM) and an alkenyl Grignard addition. The introduction of olefinic moieties in the pentacycloundecane (PCUD) framework at appropriate positions followed by RCM led to the formation of novel heptacyclic cage systems.

Molecular modelling studies of synthesized pentacyclo-undecane peptides as potential HIV-1 wild type C-SA protease inhibitors

Increasing numbers of HIV infected patients along with severe treatment-associated complications and related deaths make the AIDS pandemic [1]. These inhibitors reduced the virus proliferation and this success made the HIV aspartic protease the prime target for AIDS therapies [2]. In this study, we present the first account of pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors with nanomolar activity against the resistance-prone wild type C-South African HIV-protease (C-SA). NMR and molecular docking were employed to determine a logical correlation between the inhibitory concentration (IC50) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. In addition, docking studies confirmed the observed EASY-ROESY results and the experimental IC50 activity profile of the considered inhibitors. Due to theoretical importance of nuclear quadrupole resonance data [3] for characterization of molecular dynamics, DFT calculations are carried out to obtain 17O and 14N- NQR parameters. The studies reported in this work were undertaken to establish whether the NQR method could be used to derive a rational structure-activity relationship for these inhibitors. These findings open up useful applications for this family of inhibitors, considering the vast number of alternative disease related proteases that may exist.

Neighboring Effect in Fragmentation Pathways of Cage Guanylhydrazones in the Gas Phase

ESI-MS/MS investigation of the mono- and bis(guanylhydrazone) derivatives 1-5 based on adamantane and pentacycloundecane (PCU) skeleton was described. Elimination of neutral guanidine is the most abundant reaction channel in the case of 2,4-adamantyl and PCU derivatives 4 and 5, while the elimination of CH2N2 fragment is preferred for other compounds. This was attributed to the cage opening of adamantane or PCU skeletons in the former case leading to the formation of the cyclohexyl- or cyclopropylcarbinyl carbocation stabilized by the conjugation with the guanylhydrazone subunit. The main fragmentation pathways observed experimentally were analyzed by using DFT calculations. All investigated bis(guanylhydrazone)s formed dications and their abundances were found to be proportional to the interguanidine distance in the considered ions. Calculation of the first and the second proton affinities supported qualitative interpretation of the dication abundance. Close contact of two guanidine subunits is thus confirmed to be crucial in determining preferential fragmentation pathway and to suppress formation of the dication.

Synthesis and NMR elucidation of pentacycloundecane-derived hydroxy acid peptides as potential anti-HIV-1 agents

The synthesis and NMR elucidation of eight novel peptides incorporating the pentacycloundecane (PCU)-derived hydroxy acid are reported. The PCU cage amino acids were synthesized as racemates and the incorporation of the PCU-derived hydroxy acid with natural (S)-amino acids produced inseparable diastereomeric peptides. A series of overlapping signals from the cage and that of the peptide side chain was observed in the 1H- and 13C-NMR spectra, complicating the elucidation thereof. Two-dimensional NMR techniques proved to be a very useful tool in overcoming these difficulties. These compounds are potential HIV protease inhibitors.

Synthesis, screening and computational investigation of pentacycloundecane-peptoids as potent CSA-HIV PR inhibitors

Herein, we present the first pentacycloundecane (PCU) diol peptoid derived HIV protease inhibitors with IC50 values ranging from 6.5 to 0.075 μM. Five derivatives were synthesized in an attempt to understand the structure activity relationship of this class of compounds for HIV protease inhibition. NMR spectroscopy (new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy, EASY-ROESY) was employed to determine the predominant conformation of the active compound. In this study docking studies and MD simulations provided insight into the binding theme of this class of peptoid inhibitors to the CSA-HIV PR active site. Conserved and stable hydrogen bonding between the hydroxyl groups of the inhibitors and the active site Asp25/Asp25′ residues were observed from the docking and along the MD trajectories.

Pentacycloundecane‐diol‐Based HIV‐1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies

Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC(50) values in the 0.5-0.6 μM range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space (1)H,(1)H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.

Theoretical study on the formation of a pentacyclo-undecane cage lactam

A quantum-chemical mechanistic investigation of the multistep mechanism of the one pot annular conversion of pentacyclo-undecane (PCU) cage lactam formation was carried out using density functional theory (DFT) level with the B3LYP hybrid functional in both the gas phase and with the self consistent reaction-field (SCRF) solvent model with the 6-31+G(d) basis set. The kinetic and thermodynamic properties of all species involved were investigated. The theoretical results suggest that the final product obtained is both thermodynamically and kinetically preferred. Moreover, the observed rate determining step compared favourably to the experimentally observed intermediate that was isolated before.

Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors

In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC50 values ranging from 0.5 up to 0.75 µM against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC50(0.5 µM), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC50 values (0.5–10 µM). The PCU-peptides and peptoides were several orders less toxic (145 μM for 11 and 102 μM for 11 peptoid) to human MT-4 cells than lopinavir (0.025 μM). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases.Graphical abstract: PCU-diastereomers peptide and peptoid inhibitors with arrows showing the observed EASY-ROESY correlations.

Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: A hybrid 2D NMR and docking/QM/MM/MD approach

Pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors were synthesized and nanomolar activity against the resistance-prone wild type C-South African HIV protease is reported. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. EASY-ROESY NMR experiments gave information about the 3D structure of the cage peptides and 3D solution structure could be linked to the experimental IC 50 activity profile of the considered inhibitors. QM/MM/MD simulations of the inhibitors in solution confirmed the NMR observed conformations. Docking experiments and QM/MM/MD simulations of the inhibitor-HIV PR complexes were also performed. These computational results complimented the experimental inhibition activities and enabled us to report a unique binding mode for PCU-based inhibitors at the active site of HIV-protease enzyme. A conserved hydrogen bonding pattern between the norstatine type functional group of the PCU hydroxylactam and active site residues, ASP25/ASP25′, was observed in all active compounds. The biological significance and possible mode of inhibition by PCU-based HIV PR inhibitors discussed herein provide us with a deeper understanding of the mode of action of these novel inhibitors. The PCU-peptides are between 6000 and 8500 time less toxic to human MT-4 cells than Lopinavir. This potentially creates new application avenues for these putative inhibitors to be investigated against a vast number of other disease-related proteases.

Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease

In this study, we present the first account of pentacycloundecane (PCU) peptide based HIV-protease inhibitors. The inhibitor exhibiting the highest activity made use of a natural HIV-protease substrate peptide sequence, that is, attached to the cage (PCU-EAIS). This compound showed nanomolar IC(50) activity against the resistance-prone wild type C-South African HIV-protease (C-SA) catalytic site via a norstatine type functional group of the PCU hydroxy lactam. NMR was employed to determine a logical correlation between the inhibitory concentration (IC(50)) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. The results from docking experiments coincided with the experimental observed activities. These findings open up useful applications for this family of cage peptide inhibitors, considering the vast number of alternative disease related proteases that exist.

In Vitro Antifungal and Antibacterial Activities of Pentacycloundecane Tetra‐Amines

The antifungal and antimicrobial activities of three pentacycloundecane (PCU) tetra-amine derivatives are reported herein. The in vitro activity of these PCU derivatives against yeasts (Candida albicans and non-albicans species) and filamentous fungi was evaluated using the Clinical and Laboratory Standards Institute (CLSI) M27-A2 and M38-A2 guidelines and the 2H-tetrazolium salt, (MTS) colorimetric method. The minimum inhibitory concentration against most of the tested clinical fungal strains for GKM8 and GKM9 derivatives ranges from 15.6 to 62.5 μg/mL while GKM11 ranged from 3.9 to 7.8 μg/mL. The GKM11 derivative was also active against fluconazole-resistant strains of fungi. The GKM11 derivative also exhibited promising activity against filamentous fungi in that it was 2.5 times more active than amphotericin B against Sporothrix schenckii. Antibacterial activity was determined using the broth microdilution method (BMM) and the iodonitrotetrazolium chloride (INT) colorimetric method. The GKM11 derivative was mainly active against Gram-positive bacteria with MIC ranging from 3.9 to 7.8 μg/mL. Activity against Gram-negative bacteria tested was limited to Escherichia coli and Elizabethkingia meningoseptica (MIC of 31 μg/mL).

Endo-11-(Dibenzylamino)tetracyclo[5.4.0.03,10.05,9]undecane-8-one

The structure of the title compound, C25H27NO, is a mono-ketone penta­cyclo­undecane (PCU) mol­ecule bearing a tertiary amine group. One of the methyl­ene groups in the PCU is disordered over two orientations with site-occupancy factors of 0.621 (7) and 0.379 (7).