Ring Junction Research Articles

(20R,24R,25S)-3α,7α,12α,27-Tetraacetoxy-24,26-epoxy-5β-cholestane

In the title anhydro­scymnol tetra­acetate, C35H54O9, the fused chair conformation of the cyclo­hexane A/B ring junction is cis with a 5β-H configuration. The compound has a trimethyl­ene oxide ring at position 24,26 and four acetate groups at the 3α,7α,12α,27 positions.

Modulation of the Transient Receptor Potential Vanilloid Channel TRPV4 by 4α-Phorbol Esters: A Structure−Activity Study

The mechanism of activation of the transient receptor potential vanilloid 4 (TRPV4) channel by 4alpha-phorbol esters was investigated by combining information from chemical modification of 4alpha-phorbol-didecanoate (4alpha-PDD, 2a), site-directed mutagenesis, Ca(2+) imaging, and electrophysiology. Binding of 4alpha-phorbol esters occurs in a loop in the TM3-TM4 domain of TRPV4 that is analogous to the capsaicin binding site of TRPV1, and the ester decoration of ring C and the A,B ring junction are critical for activity. The lipophilic ester groups on ring C serve mainly as a steering element, affecting the orientation of the diterpenoid core into the ligand binding pocket, while the nature of the A,B ring junction plays an essential role in the Ca(2+)-dependence of the TRPV4 response. Taken together, our results show that 4alpha-phorbol is a useful template to investigate the molecular details of TRPV4 activation by small molecules and obtain information for the rational design of structurally simpler ligands for this ion channel.

N-(2-Pyridylmethyleneamino)dehydroabietylamine

The title compound {systematic name: 1-[(1R,4aS,10aR)-7-isopropyl-1,2,3,4,4a,9,10,10a-octa­hydro­phenanthren-1-yl]-N-[(E)-2-pyridylmethyleneamino]methanamine}, C26H33N2, has been synthesized from dehydro­abietylamine. The two cyclo­hexane rings form a trans ring junction with classic chair and half-chair conformations, respectively, whereas the benzene and pyridine rings are almost planar, and the dihedral angle between them is 80.4°. The two methyl groups directly attached to the tricyclic nucleus are on the same side of the tricyclic hydro­phenanthrene structure.

ChemInform Abstract: Pyrolytic Desulfurization Ring Contraction of Condensed Thiadiazines as a General Route Towards Pyrazoloazines and Pyrazoloazoles with a Bridgehead (Ring Junction) Nitrogen Atom.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

On the absolute configuration of matrine: Crystal structure of matrin-1-IUM-trichlorozincate

The title compound crystallizes in the monoclinic space group P21 with a = 7.804(1)A, b = 13.597(2) A c = 9.093(1) A, β= 108.41(1)°, V = 915.5(2)A3, Z = 4, R = 0.0231, wR2 = 0.0475 (Siemens P4 diffractometer with MoKα radiation, 3994 reflections collected at room temperature, 204 parameters refined). It is a zwitterionic complex (having Zn-O coordination bond of 2.003(2) A) with a positive charge on the N1 atom of matrine molecule and a negative charge on the ZnCl3 group. In the matrine molecule, N16 and H11 atoms are located on the opposite sides of the plane defined by C11, C15, C17 atoms and deviate from the plane by 0.075(3) A and 0.839(3) A, respectively, indicating a trans C-D ring junction. Therefore, the compound can be named trans-matrine. The D ring of matrinium demonstrates a distorted sofa conformation, while the other rings adopt chair forms. The A-B, A-C, B-C and C-D ring pairs have trans, cis, cis and trans junctions, respectively. The absolute configuration of the matrine molecule is 1S, 5S, 6S, 7S, 11R, 16R.

アレンと多重結合間の分子内付加環化反応

Allene functionality has the potential to create interesting and useful reactions in organic synthesis. We have developed the following several novel cycloaddition reactions between allenyl π-bond and carbon-carbon multiple bond: (i) Intramolecular Pauson-Khand-type reaction of allene-alkyne substrates (allenynes) leading to construction of bicyclo[5.3.0]decadienone framework has been realized with the aid of Rh(I) catalyst under CO atmosphere. (ii) The allenynes were found to produce cycloheptene derivatives and/or bicyclo[5.2.0]nonadiene compounds depending on the substitution pattern at the allenic terminus under N2. (iii) Thermal[2+2]cycloaddition of allenynes was shown to be applicable to the construction of bicyclo[6.2.0]skeleton. (iv) We also found that the Pauson-Khand-type reaction of allene-alkenes (allenenes) and bisallenes resulted in the easy preparation of bicyclo[4.3.0]nonenone skeleton having an alkyl appendage at the ring juncture and bicyclo[6.3.0]undecadienone derivatives, respectively.

Benzofurans as Efficient Dienophiles in Normal Electron Demand [4 + 2] Cycloadditions

Dearomatization of electron-poor benzofurans is possible through involvement of the aromatic 2,3-carbon-carbon double bond as dienophile in normal electron demand [4 + 2] cycloadditions. The tricyclic heterocycles thereby produced bear a quaternary center at the cis ring junction, a feature of many alkaloids such as morphine, galanthamine, or lunaridine. The products arising from the reaction have been shown to depend on different factors among which the type of the electron-withdrawing substituent of the benzofuran, the nature of the reacting diene, and the method of activation. In the presence of all-carbon dienes, the reaction yields the expected Diels-Alder adducts. When thermal activation is insufficient, a biactivation associating zinc chloride catalysis and high pressure is required to generate the cycloadducts in good yields and high stereoselectivities, for instance, when cyclohexadiene is involved in the process. The use of more functionalized dienes, such as those bearing alkoxy or silyloxy substituents, also shows the limits of the thermal activation, and hyperbaric conditions are, in this case, well-suited. The involvement of Danishefsky's diene induces a competition in the site of reactivity. The aromatic 2,3-carbon-carbon double bond is unambiguously the most reactive dienophile, and the 3-carbonyl unit becomes a competitive site of reactivity with benzofurans bearing substituents prone to heterocyloaddition, in particular under Lewis acid activation. The sequential involvement of both the aromatic double bond and the carbonyl moiety as dienophiles is then possible by using an excess of diene under high-pressure activation. In line with the experimental results, DFT computations suggest that the Diels-Alder process involving the aromatic double bond is preferred over the hetero-Diels-Alder route through an asynchronous concerted transition state. However, Lewis acid catalysis appears to favor the heterocycloaddition pathway through a stepwise mechanism in some cases.

Highly Regioselective Derivatization of Trimetallic Nitride Templated Endohedral Metallofullerenes via a Facile Photochemical Reaction

Photochemically generated benzyl radicals react with Sc(3)N@C(80)-I(h) to produce a dibenzyl adduct [Sc(3)N@C(80)(CH(2)C(6)H(5))(2)] in 82% yield and high regioselectivity. The adduct's (1)H spectrum revealed high symmetry: only one AB pattern was observed for the methylene protons. The (13)C NMR spectrum suggested a C(2)-symmetrical structure. DFT calculations reveal that a 1,4-adduct is more favorable than a 1,2-adduct by >10 kcal/mol. The 1,4-structure on [566] ring junctions was unambiguously confirmed by X-ray crystallographic analysis. UV-vis spectra revealed that the removal of two p orbitals from the pi system of the cage together with the benzylic substituents change the electronic properties of the metallofullerene in a manner similar to those reported for disilirane and trifluoromethyl moieties. Under the same conditions from Lu(3)N@C(80)-I(h) we prepared (63% yield) Lu(3)N@C(80)(CH(2)C(6)H(5))(2), which demonstrated properties similar to the 1,4-dibenzyl adduct of Sc(3)N@C(80)-I(h).

Probes for Narcotic Receptor Mediated Phenomena. 37. Synthesis and Opioid Binding Affinity of the Final Pair of Oxide-Bridged Phenylmorphans, the Ortho- and Para-b-Isomers and Their N-Phenethyl Analogues, and the Synthesis of the N-Phenethyl Analogues of the Ortho- and Para-d-Isomers

In the isomeric series of 12 racemic topologically rigid N-methyl analogues of oxide-bridged phenylmorphans, all but two of the racemates, the ortho- and para-b-oxide-bridged phenylmorphans 20 and 12, have remained to be synthesized. The b-isomers were very difficult to synthesize because of the highly strained 5,6-trans-fused ring junction that had to be formed. Our successful strategy required functionalization of the position para (or ortho) to a fluorine atom on the aromatic ring using an electron-withdrawing nitro group to activate that fluorine. The racemic N-phenethyl analogues 24 and 16 were moderately potent kappa-receptor antagonists in the [(35)S]GTPgammaS assay. We synthesized the N-phenethyl-substituted oxide-bridged phenylmorphans in the ortho- and para-d-oxide-bridged phenylmorphan series (51 and 52) which had not been previously evaluated using contemporary receptor binding assays to see whether they also have higher affinity for opioid receptors than their N-methyl relatives 46 and 47.

A Suzuki Cross‐Coupling and Intramolecular Aza‐Michael Addition Reaction Sequence Towards the Synthesis of 1,10b‐epi‐7‐Deoxypancratistatins and Their Cytotoxicity Studies

AbstractThe development of an efficient approach to the construction of a phenanthridone is described. The convergent strategy commences with the preparation of Suzuki cross‐coupling reaction precursors, arylboronic acid 12 and α‐iodo enone 19, from piperonylamine (9) and (–)‐D‐quinic acid (10), respectively. The coupling of 12 and 19 followed by a key intramolecular aza‐Michael addition produced phenanthridone 21 featuring a cis‐fused B–C ring junction. The syntheses of compounds 25 and 26, both of which are C‐1 and C‐10b epimers of the naturally occurring potent antitumor agent 7‐deoxypancratistatin (2), from 21 are elaborated in detail in this paper. The cytotoxicities of 25 and 26 were evaluated against three different cancer cell lines. Compound 26 served as a moderate growth inhibitor of THP‐1 monocytic cells (GI50 = 14.5 μg/mL).(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Structural determinants of monohydroxylated bile acids to activate β1 subunit-containing BK channels

Lithocholate (LC) (10-300 microM) in physiological solution is sensed by vascular myocyte large conductance, calcium- and voltage-gated potassium (BK) channel beta(1) accessory subunits, leading to channel activation and arterial dilation. However, the structural features in steroid and target that determine LC action are unknown. We tested LC and close analogs on BK channel (pore-forming cbv1+beta(1) subunits) activity using the product of the number of functional ion channels in the membrane patch (N) and the open channel probability (Po). LC (5beta-cholanic acid-3alpha-ol), 5alpha-cholanic acid-3alpha-ol, and 5beta-cholanic acid-3beta-ol increased NPo (EC(50) approximately 45 microM). At maximal increase in NPo, LC increased NPo by 180%, whereas 5alpha-cholanic acid-3alpha-ol and 5beta-cholanic acid-3beta-ol raised NPo by 40%. Thus, the alpha-hydroxyl and the cis A-B ring junction are both required for robust channel potentiation. Lacking both features, 5alpha-cholanic acid-3beta-ol and 5-cholenic acid-3beta-ol were inactive. Three-dimensional structures show that only LC displays a bean shape with clear-cut convex and concave hemispheres; 5alpha-cholanic acid-3alpha-ol and 5beta-cholanic acid-3beta-ol partially matched LC shape, and 5alpha-cholanic acid-3beta-ol and 5-cholenic acid-3beta-ol did not. Increasing polarity in steroid rings (5beta-cholanic acid-3alpha-sulfate) or reducing polarity in lateral chain (5beta-cholanic acid 3alpha-ol methyl ester) rendered poorly active compounds, consistent with steroid insertion between beta(1) and bilayer lipids, with the steroid-charged tail near the aqueous phase. Molecular dynamics identified two regions in beta(1) transmembrane domain 2 that meet unique requirements for bonding with the LC concave hemisphere, where the steroid functional groups are located.

Protein Kinase Cθ Regulates Stability of the Peripheral Adhesion Ring Junction and Contributes to the Sensitivity of Target Cell Lysis by CTL

Destruction of virus-infected cells by CTL is an extremely sensitive and efficient process. Our previous data suggest that LFA-1-ICAM-1 interactions in the peripheral supramolecular activation cluster (pSMAC) of the immunological synapse mediate formation of a tight adhesion junction that might contribute to the sensitivity of target cell lysis by CTL. Herein, we compared more (CD8(+)) and less (CD4(+)) effective CTL to understand the molecular events that promote efficient target cell lysis. We found that abrogation of the pSMAC formation significantly impaired the ability of CD8(+) but not CD4(+) CTL to lyse target cells despite having no effect of the amount of released granules by both CD8(+) and CD4(+) CTL. Consistent with this, CD4(+) CTL break their synapses more often than do CD8(+) CTL, which leads to the escape of the cytolytic molecules from the interface. CD4(+) CTL treatment with a protein kinase Ctheta inhibitor increases synapse stability and sensitivity of specific target cell lysis. Thus, formation of a stable pSMAC, which is partially controlled by protein kinase Ctheta, functions to confine the released lytic molecules at the synaptic interface and to enhance the effectiveness of target cell lysis.

M2@C79N (M = Y, Tb): isolation and characterization of stable endohedral metallofullerenes exhibiting M-M bonding interactions inside aza[80]fullerene cages.

Y2@C79N and Tb2@C79N have been prepared by conducting the Kratschmer-Huffman electric-arc process under 20 Torr of N2 and 280 Torr of He with metal oxide-doped graphite rods. These new heterofullerenes were separated from the resulting mixture of empty cage fullerenes and endohedral fullerenes by chemical separation and a two-stage chromatographic process. Crystallographic data for Tb2@C79N x Ni(OEP) x 2 C6H6 demonstrate the presence of an 80-atom cage with idealized I(h) symmetry and two, widely separated Tb atoms inside with a Tb-Tb separation of 3.9020(10) A for the major terbium sites. The EPR spectrum of the odd-electron Y2@C79N indicates that the spin density largely resides on the two equivalent yttrium ions. Computational studies on Y2@C79N suggest that the nitrogen atom resides at a 665 ring junction in the equator on the fullerene cage and that the unpaired electron is localized in a bonding orbital between the two yttrium ions of this stable radical. Thus, the Tb-Tb bond length of the single-electron bond is an exceedingly long metal-metal bond.

Pyrolytic desulfurization ring contraction of condensed thiadiazines as a general route towards pyrazoloazines and pyrazoloazoles with a bridgehead (ring junction) nitrogen atom

Pyrolytic conversion of [1,2,4]triazino[3,4- b][1,3,4]thiadiazin-4-ones, [1,3,4]thiadiazino[2,3- b]quinazolin-10-ones and [1,2,4]triazolo[3,4- b][1,3,4]thiadiazines into their corresponding pyrazolo[5,1- c][1,2,4]triazin-4-ones, pyrazolo[4,3- b]quinazolin-9-ones and pyrazolo[5,1- b][1,2,4]triazoles via desulfurization ring contraction is described. The starting condensed 1,3,4-thiadiazines were prepared from the corresponding readily available 4-amino-3-thioxo-1,2,4-triazin-5(4 H)-ones, 3-amino-2,3-dihydro-2-thioxoquinazolin-4(1 H)-one and 4-amino-3(2 H)-thioxo-1,2,4-triazoles upon reaction with the appropriate α-haloketones in two steps, or directly in one step in ethylpyridinium tetrafluoroborate (ionic liquid, IL).

Diversity‐Oriented Synthesis of Enantiomerically Pure Steroidal Tetracycles Employing Stille/Diels–Alder Reaction Sequences

Various steroid analogues were synthesized by Stille coupling of bicyclo[4.3.0]nonenylstannanes cis-/trans-8 and 14 with cyclohexenol triflates 17 and 18 and subsequent Diels-Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0]nonenylstannanes cis- and trans-8 were prepared in good yields via the enol triflates cis- and trans-7, obtained from the bicyclo[4.3.0]non-2-en-3-one 5. The alkenylstannane 14 was obtained from the [2+2] cycloadduct 10 a produced from addition of dichloroketene to the enantiomerically pure and protected bishydroxycyclohexadiene 9 a (65 %). Treatment of 10 a with diazomethane, reduction of the dichloromethylene group, and trapping with tributyltin chloride after lithium-for-bromine exchange, yielded the bicyclo[4.3.0]nonenylstannane 14 (23 % over four steps). Stille couplings provided the tricyclic dienes cis-/trans-19 in good yields (73-77 %), whereas the tricyclic diene 20 was obtained in only 34 % yield at best. Diels-Alder reactions of trans-19 with various reactive dienophiles yielded the novel steroidal compounds trans-21 to trans-26 with complete diastereoselectivity. Heating the dienes cis-19 or 20 with maleic acid derivatives provided the corresponding tetracycles cis-23alpha,beta and 27alpha,beta with a cis-C,D ring junction, each as mixtures of two diastereomers. Less reactive dienophiles required higher temperatures to promote the relevant cycloaddition with trans-19 to furnish several stereoisomeric forms of trans-28 and trans-29 in significantly lower yields (31-45 %). The selected steroid analogues trans-22 and trans-23 were deprotected in two steps by using acid catalysis to provide trans-31 and trans-33 (91 and 80 % over two steps). Cyclopropanation of trans-30 yielded the cyclopropasteroid analogue 34 (74 %), treatment of which with trifluoroacetic acid furnished the cyclopropasteroid 35 and the 2-methyl-substituted steroid analogue 36 in 40 and 12 % yield, respectively. Aromatic B-ring steroids 38 (69 %) and 39 (5 %) were accessed by dehydrogenation of trans-24 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Hoodigogenin A from Hoodia gordonii.

The title mol­ecule (systematic name: 12-O-β-tigloyl-3β,14β-dihydroxy­pregn-5-en-20-one), C26H38O5, isolated from aerial parts of Hoodia gordonii, has its steroid A and C rings in chair conformations, its B ring in a half-chair conformation, and its five-membered ring in an envelope conformation. The OH group at the C/D ring junction forms an intra­molecular hydrogen bond with the keto substituent. The OH group on the A ring forms an inter­molecular hydrogen bond with the tiglate C=O group, propagating [010] chains in the crystal structure.

Flexible Strategy for the Synthesis of Pyrrolizidine Alkaloids

A general strategy for the production of pyrrolizidine alkaloids is described, starting from intermediate (+)-9. The key features are diastereoselective dihydroxylation, inversion at the ring junction by hydroboration of an enamine, and ring closure to form the bicyclo ring system. This route is attractive because of its brevity and versatility; four natural products were prepared with differing stereochemistry and substitution patterns. Finally, this work allowed assignment of the absolute stereochemistry of 2,3,7-triepiaustraline and hyacinthacine A 7.

Synthesis and crystal structure of maleopimaric acid

The title compound maleopimaric acid was synthesized by a Diels–Alder reaction between maleic anhydride and Pinus elliottii engelm oleoresin at room temperature and it was characterized by single crystal X-ray diffraction. The white crystals crystallized in the orthorhombic system, space group P2 12121 with cell dimensions: a = 7.6960 (15) Å, b = 11.851 (2) Å, c = 24.577 (5) Å, α = 90°, β = 90°, γ = 90°, V = 2241.6(8) Å3, and R 1 = 0.0716, wR 2 = 0.1975. The two fused and unbridged cyclohexane rings form a trans ring junction with chair conformation with two methyl groups in axis positions, the anhydride ring is planar. Crystal water existed in the molecular and stabilized the structure through intermolecular hydrogen bonds.

Di-tert-butylN,N′-(octahydropentalene-2,5-diyl)dicarbamate

In the molecule of the title compound, C18H32N2O4, the central bicyclo­[3.3.0]octane (octa­hydro­penta­lene) has a rigid ring junction. Both rings of the bicyclo­[3.3.0]octane unit adopt an envelope conformation, and the flexible tert-butyl­carbamoyl side chains each have an extended conformation. Such a constrained bicyclo­[3.3.0]octane aliphatic template is of inter­est with respect to the design of novel self-assembling motifs. Mol­ecules related by c-glide symmetry are linked via inter­molecular N—H⋯O hydrogen bonds, forming a two-dimensional layer structure. Neighboring layers are weakly associated along the a axis due to the close approach of the tert-butyl­carbamoyl groups (2.55 Å).

Rac-9-Ethyl-12a-hydroxytetradecahydrotriphenylene-1,5(2H,4bH)-dione: stabilization of a new isomer of a functionalized perhydrotriphenylene through a tandem Michael addition–aldol reaction

The title compound, C20H30O3, is a new functionalized perhydrotriphenylene derivative formed via a tandem Michael addition-aldol reaction. The structural study reveals that the system of fused rings approximates a C2 point symmetry, with trans-cis-cis ring junctions, while highly symmetric all-trans perhydrotriphenylene, previously characterized, approximates a D3 symmetry. The perhydrotriphenylene nucleus of the title compound corresponds to the third stable stereoisomer isolated for this polycyclic system. Considering that the C(s) isomer was obtained recently through a similar tandem reaction, a general strategy is proposed which may help to obtain other stable stereoisomers of perhydrotriphenylene.