Polycyclic System Research Articles

Model Studies Directed toward the Alkaloid Mersicarpine Utilizing a Rh(II)-Catalyzed Insertion/Cycloaddition Sequence

Model studies dealing with the rhodium(II)-catalyzed carbenoid insertion/cyclization/cycloaddition cascade of several α-diazo dihydroindolinones have been carried out as an approach to the alkaloid mersicarpine. The cascade reaction of α-diazo dihydroindolinone 21 proceeded in high yield with excellent diastereoselectivity to give cycloadduct 22, which possesses the required stereochemistry of the two adjacent quaternary carbon centers present in mersicarpine. The overall reaction enabled the rapid assemblage of a polycyclic ring system that contains three new stereocenters and three continuous quaternary carbons in a single operation in high yield with excellent diastereoselectivity. The 3-indolinone derivative 36 was eventually formed from cycloadduct 22 by an acid-induced hydrolysis of 22 to give 23, which was subsequently converted in several steps to 36. The synthesis of this compound constitutes a successful construction of the tricyclic core of mersicarpine. Reduction of the nitrile group of 36 followed by a subsequent reductive cyclization/ring-opening aromatization cascade, as was found to occur with the related compound 29, will be employed for an eventual synthesis of demethylmersicarpine.

Synthesis of the polycyclic core of vincorine via cascade reactions

We developed a six-step synthesis of the polycyclic core of vincorine using two cascades of reactions. A cascade of Michael–Mannich reactions was employed for one-pot preparation of a polycyclic intermediate, which was transformed into the desired polycyclic pyrroloindoline ring system using a cascade of methanolysis-N-imine cyclization reactions.

Activation and characterization of a cryptic polycyclic tetramate macrolactam biosynthetic gene cluster

Polycyclic tetramate macrolactams (PTMs) are a widely distributed class of natural products with important biological activities. However, many of them have not been characterized. Here we apply a plug and play synthetic biology strategy to activate a cryptic PTM biosynthetic gene cluster SGR810-815 from Streptomyces griseus and discover three potential PTMs. This gene cluster is highly conserved in phylogenetically diverse bacterial strains and contains an unusual hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) which resembles iterative PKSs known in fungi. To further characterize this gene cluster, we use the same synthetic biology approach to create a series of gene deletion constructs and elucidate the biosynthetic steps for the formation of the polycyclic system. The strategy we employ bypasses the traditional laborious processes to elicit gene cluster expression and should be generally applicable to many other silent or cryptic gene clusters for discovery and characterization of new natural products.

Synthesis and antiproliferative activity of new derivatives containing the polycyclic system 5,7:7,13-dimethanopyrazolo[3,4-b]pyrazolo[3′,4′:2,3]azepino[4,5-f]azocine

The reaction under reflux between 1-phenyl-3-R-5-methylaminopyrazoles and 2,5-hexanedione lead to 5,7:7,13-dimethanopyrazolo[3,4-b]pyrazolo[3′,4′:2,3]azepino[4,5-f]azocine derivatives 3b–g. These unusual molecules show the structural complexity of many biologically active natural products and are endowed with the chemical diversity that is required in drug discovery. The compounds 3b,e were reduced by hydrogen in the presence of Palladium on activated charcoal to give the dihydro derivatives 5b,e. Compounds 3b–f and 5b,e were selected by the NCI to evaluate their in vitro antiproliferative activity against 60 human cell lines derived from nine clinically isolated cancer types (leukaemia, lung, colon, melanoma, renal, ovarian, brain, breast, and prostate). The most active compound of this series, caused a block in G0–G1 phase of cell cycle. Analysis of pRb expression showed that this compound favours pRb dephosphorylation.

A Dicyanomethylene‐Substituted Triangulene: Effects of Molecular‐Symmetry Reduction and Electron‐Accepting Substituents on a Fused Polycyclic Neutral π‐Radical System

A triangulene-based C2-symmetric 33 π-conjugated stable neutral π-radical, 2(·), which possesses two dicyanomethylene groups and one oxo group, has been designed, synthesized, and isolated as an analogue of tris(dicyanomethylene) derivative 1(·) and trioxo derivative TOT(·) with C3 symmetry. Effects of molecular-symmetry reduction and electron-accepting substituents on this fused polycyclic neutral π-radical system were studied in terms of their molecular structure, electronic-spin structure, and electrochemical and optical properties with the help of theoretical calculations. Interestingly, this system (2(·)) has a four-stage redox ability, like TOT(·), as well as low frontier energy levels and a small SOMO-LUMO gap, similar to 1(·), in spite of the loss of the degenerate LUMOs in symmetry-lowered 2(·), which is associated with the attachment of the weaker electron-accepting oxo group instead of the dicyanomethylene group in 1(·). These prominent results are attributable to the structural and electronic properties in the triangulene-based highly delocalized fused polycyclic neutral π-radical system.

Post-harvesting silvicultural treatments in logging gaps: A comparison between enrichment planting and tending of natural regeneration

Despite greatly improved forest management in recent decades, long-term assessments show that if current harvesting volumes and cutting cycles are maintained, future volume yields of commercial species will decrease. A possible solution is to apply post-harvesting silvicultural treatments to increase the number of valuable trees. In this study we compared during 4years two treatments: tending naturally established seedlings/saplings of commercial species in logging gaps, and enrichment planting+tending seedlings of commercial species. In both treatments, competition was artificially reduced by liberating each focal seedling/sapling from competitors (i.e. other tree seedlings/saplings, lianas, or herbs). The experiment was carried out in an area of ombrophilous dense forest managed by the Orsa Florestal forestry company in Jari Valley, eastern Amazon, Brazil (01°09′S and 52°38′W). The company applies reduced-impact logging in a polycyclic silvicultural system. We sampled 64 2-year-old logging gaps (average area 427.2m2). Thirty-four gaps were used for the planting+tending, 15 gaps underwent the tending treatment, and there were 15 gaps in the control treatment (i.e. no intervention). The tending treatment showed lower mortality rate, faster growth rate, and required less liberation from overstorey plants and lianas than the other two treatments. Half of the species responded positively to tending: the long-lived pioneers Goupia glabra and Laetia procera, and the partially shade-tolerant Dinizia excelsa, Tachigali myrmecophila, and Trattinnickia sp. Similarly to tending, individuals subjected to the enrichment planting+tending treatment also presented higher growth rates. Based on these results we recommend tending be applied to areas with sufficient natural regeneration of commercial species. Enrichment planting+tending should be applied when regeneration of commercial species is scare, ideally using species that have high initial growth rates, and high commercial or conservation value.

Microwave Synthesis of Water‐Soluble 2‐, 5‐ and 9‐Substituted Benzo[a]phenoxazinium Chlorides in Comparison with Conventional Heating

AbstractMicrowave irradiation was used for the first time in an efficient synthesis of benzo[a]phenoxazinium chlorides. The main advantage of this protocol is the notable reduction in reaction times and good to excellent yields of the products in comparison to those obtained under classical heating conditions. These new series of compounds possess 5‐amine and/or 2‐hydroxyl substituents in the polycyclic system to improve their solubility in aqueous media, in addition to the functional groups as terminals in the side chains, allowing their further use in covalent labeling. Fundamental photophysical studies carried out in ethanol and water at physiological pH revealed that all cationic fluorophores absorbed and emitted at 610–628 and 630–652 nm, respectively, with relative fluorescent quantum yields of 0.16–0.96.

(25R)-6α-Hydroxy-5α-spirostan-3β-yl tosylate

The title steroid, C34H50O6S, is an inter­mediate on the synthetic route between diosgenin and brassinosteroids, which possess the A ring modified with the 2α,3α-diol functionality. The polycyclic spiro­stan system has the expected conformation, with six-membered rings adopting chair forms and the five-membered rings envelope forms (flap atoms are the methine C atom in the C/D-ring junction and the spiro C atom connecting rings E and F). The 3β-tosyl­ate group is oriented in such a way that S=O bonds are engaged in inter­molecular hydrogen bonds with O—H and C—H donors. Chains of mol­ecules are formed along [100] via O—H⋯O hydrogen bonds, and secondary weak C—H⋯O inter­actions connect two neighbouring chains in the [001] direction.

Polycyclic π-Electron System with Boron at Its Center

We disclose a new planarized triarylborane in which the tri-coordinated boron atom is embedded in a fully fused polycyclic π-conjugated skeleton. The compound shows high stability toward oxygen, water, and silica gel, despite the absence of steric protection around the B atom. Reflecting the electron-donating character of the π-skeleton and the electron-accepting character of the B atom, this compound shows broad absorption bands that cover the entire visible region and a fluorescence in the visible/near-IR region. In addition, this compound shows dramatic property changes upon formation of a tetra-coordinated borate, such as thermochromic behavior in the presence of pyridine.

6,7,8,14,15,16-Hexaphenyldibenzo[c,gh]naphtho[3,2,1,8-pqra]tetraphene-5,13-dione dichloromethane monosolvate

The main mol­ecule of the title compound, C66H38O2·CH2Cl2, is centrosymmetric, the asymmetric unit is composed of two half-mol­ecules, located on inversion centers, and a mol­ecule of dichloro­methane. The large π-conjugated fused polycyclic system including eight six-membered rings is nearly planar, with r.m.s. deviations of 0.2114 and 0.2081 Å in the two independent mol­ecules.

Elucidation of π‐Conjugation Modes in Diarene‐Fused 1,2‐Dihydro‐1,2‐diborin Dianions

A series of diarene-fused 1,2-dihydro-1,2-diborins were prepared as a new B-B-bond-embedded polycyclic π-electron system. The reduction of these compounds with metals produced their corresponding dianions, the π-conjugation modes of which varied from 6π-conjugation within the central 1,2-diborin skeleton to 14π peripheral conjugation over the tricyclic skeleton, depending on the nature of the reduced biaryl framework. Moreover, the countercation to the dianions had a significant effect on the absorption spectra, with a dramatic color change from yellow to deep blue, depending on the distance between the tricyclic dianion skeleton and the countercation.

Asymmetric Synthesis of the Oxygenated Polycyclic System of (+)-Harringtonolide

A straightforward asymmetric synthesis of the cage oxygenated structure of (+)-harringtonolide has been accomplished for the first time. The key steps involved (i) a templated stereoselective IMDA reaction to build a highly functionalized cyclohexene ring D, (ii) functionalization of the cycloadduct, (iii) ring-closing metathesis providing the five-membered ring C, and finally (iv) a challenging one-step cascade cyclization of an epoxy-alcohol toward the target structure, whose mechanism was investigated.

Diversity-Oriented Synthesis of Polycyclic Diazinic Scaffolds

An efficient and versatile synthesis of a polycyclic diazinic system starting from oxazine has been developed using a two-step Michael/retro Michael and cyclization sequence. The substrates were synthesized with good to high yields giving rapid access to molecular diversity.

Dramatic influence of the substitution of alkylidene-5H-furan-2-ones in Diels–Alder cycloadditions with o-quinonedimethide as diene partner: en route to the CDEF polycyclic ring system of lactonamycin

An efficient and rapid synthesis of the CDEF ring system of lactonamycinone is reported via a highly chemo- and diastereoselective intermolecular Diels-Alder cycloaddition between trans-1,2-disilyloxybenzocyclobutene and the appropriate γ-alkylidenebutenolide. The feasibility and the total chemoselectivity of the [4 + 2] cycloaddition for the construction of a spirolactone moiety via an intramolecular approach (IMDA) using both partners is also described demonstrating the versatility of the γ-alkylidenebutenolide building block.

Predicting the effect of steroids on membrane biophysical properties based on the molecular structure

The relationship between sterol structure and the resulting effects on membrane physical properties is still unclear, owing to the conflicting results found in the current literature. This study presents a multivariate analysis describing the physical properties of 83 steroid membranes. This first structure–activity analysis supports the generally accepted physical effects of sterols in lipid bilayers. The sterol chemical substituents and the sterol/phospholipid membrane physical properties were encoded by defining binary variables for the presence/absence of those chemical substituents in the polycyclic ring system and physical parameters obtained from phospholipid mixtures containing those sterols. Utilizing Principal Coordinates Analysis, the steroid population was grouped into five well-defined clusters according to their chemical structures. An examination of the membrane activity of each sterol structural cluster revealed that a hydroxyl group at C3 and an 8–10 carbon isoalkyl side-chain at C17 are mainly present in membrane active sterols having rigidifying, molecular ordering/condensing effects and/or a raft promoting ability. In contrast, sterol chemical structures containing a keto group at C3, a C4–C5-double bond, and polar groups or a short alkyl side-chain at C17 (3 to 7 atoms) are mostly found in sterols having opposite effects. Using combined multivariate approaches, it was concluded that the most important structural determinants influencing the physical properties of sterol-containing mixtures were the presence of an 8–10 carbon C17 isoalkyl side-chain, followed by a hydroxyl group at C3 and a C5–C6 double bond. Finally, a simple Logistic Regression model predicting the dependence of membrane activity on sterol chemical structure is proposed.

A new polycyclic system containing the 1,4-benzodiazepine and isoindolinone fragments: synthesis and structure

Dehydration of 2-(3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]-diazepin-11-yl)benzoic acid (3a) and 2-(3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e] [1,4]diazepin-11-yl)-5,6-dimethoxybenzoic acid (3b) in boiling acetic or propionic anhydride gave 7,7-dimethyl-4b,7,8,9-tetrahydro-6H-dibenzo[2,3:5,6][1,4]diazepino[7,1-a]-isoindole-5,15-dione (5a) and 1,2-dimethoxy-7,7-dimethyl-4b,7,8,9-tetrahydro-6H-dibenzo-[2,3:5,6][1,4]diazepino[7,1-a]isoindole-5,15-dione (5b), respectively. The products obtained are representatives of a novel fused pentacyclic system. The structures of compounds 3b and 5a were unambiguously proved by X-ray diffraction.

Diastereoselective Total Synthesis of (±)‐Schindilactone A

Schindilactone A (1) and structures 2–4 (Scheme 1a) are representative members of a novel group of nortriterpenoids isolated by Sun and co-workers from the plants of Schisandraceae, which have been used in China for the treatment of rheumatic lumbago and related diseases. Preliminary biological assays indicated that some of them possess biological activities for inhibiting hepatitis, tumors, and HIV-1. The synthetic challenge posed by 1 stems from the complexity of its molecular structure: a highly oxygenated framework bearing 12 stereogenic centers, eight of which are contiguous chiral centers located in the FGH tricyclic ring system, and an oxa-bridged ketal that lies within an unprecedented 7–8 fused carbocyclic core. The structural complexity together with the attractive biological activities has rendered 1 a target for synthetic studies. Herein we report our efforts on the development of synthetic methods and a strategy centered on the construction of the polycyclic ring system that allowed the first total synthesis of ( )-schindilactone A. This concise strategy opens a pathway for the syntheses of other compounds related to schindilactone A (2–4, Scheme 1a), as well as their derivatives and analogues.

ChemInform Abstract: Development of Practical Synthetic Method Toward Mechanistic Elucidation of Biologically Active Natural Products

AbstractReview: ca. 50 refs.

Contributions of the D-Ring to the Activity of Etoposide against Human Topoisomerase IIα: Potential Interactions with DNA in the Ternary Enzyme–Drug–DNA Complex

Etoposide is a widely prescribed anticancer drug that stabilizes covalent topoisomerase II-cleaved DNA complexes. The drug contains a polycyclic ring system (rings A-D), a glycosidic moiety at C4, and a pendant ring (E-ring) at C1. Interactions between human topoisomerase IIα and etoposide in the binary enzyme--drug complex appear to be mediated by substituents on the A-, B-, and E-rings of etoposide. These protein--drug contacts in the binary complex have predictive value for the actions of etoposide within the ternary topoisomerase IIα--drug--DNA complex. Although the D-ring of etoposide does not appear to contact topoisomerase IIα in the binary complex, etoposide derivatives with modified D-rings display reduced cytotoxicity against murine leukemia cells [Meresse, P., et al. (2003) Bioorg. Med. Chem. Lett. 13, 4107]. This finding suggests that alterations in the D-ring may affect etoposide activity toward topoisomerase IIα in the ternary enzyme--drug--DNA complex. Therefore, to address the potential contributions of the D-ring to the activity of etoposide, we characterized drug derivatives in which the C13 carbonyl was moved to the C11 position (retroetoposide and retroDEPT) or the D-ring was opened (D-ring diol). All of the D-ring alterations decreased the ability of etoposide to enhance DNA cleavage mediated by human topoisomerase IIα in vitro and in cultured cells. They also weakened etoposide binding in the ternary enzyme--drug--DNA complex and altered sites of enzyme-mediated DNA cleavage. On the basis of these findings, we propose that the D-ring of etoposide has important interactions with DNA in the ternary topoisomerase II cleavage complex.

Asymmetric Catalytic Oxidative Cleavage of Polycyclic Systems: The Synthesis of Atropisomeric Diazonanes and Diazecanes

Oxidative cleavage of internal double bonds in polycyclic systems can give access to compounds containing medium- to large-sized rings. In this example, the nine- and ten-membered ring containing compounds that resulted from the mCPBA-mediated (mCPBA=meta-chloroperoxybenzoic acid) oxidative cleavage reaction were shown to exhibit atropisomerism. The reaction of the polycyclic system with catalytic amounts of ruthenium tetraoxide followed by diol cleavage achieved the same synthetic goal. Use of the Nishiyama-Beller ruthenium-based catalysts enabled the synthesis of optically-enriched samples, providing the first example of an atropselective oxidative cleavage reaction.