Showing papers on "Bicyclic molecule published in 2007"

6-modified bicyclic nucleic acid analogs

Abstract: The present invention provides 6-modified bicyclic nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 6-position. These bicyclicnucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.

5′-modified bicyclic nucleic acid analogs

Abstract: The present invention provides 5′-modified bicyclic nucleoside analogs and oligomeric compounds comprising at least one of these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 5′-carbon. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including for example enhanced nuclease resistance.

Design of C2-symmetric tetrahydropentalenes as new chiral diene ligands for highly enantioselective Rh-catalyzed arylation of N-tosylarylimines with arylboronic acids.

Abstract: A new type of C2-symmetric chiral diene ligand bearing a simple bicyclic [3.3.0] backbone was discovered. (3aS,6aS)-3,6-diphenyl-1,3a,4,6a-tetrahydropentalene was applied successfully in the Rh-catalyzed asymmetric arylation of N-tosylarylimines with arylboronic acids. With the new chiral diene ligand, a broad range of highly enantiomerically enriched diarylmethylamines (98−99% ee) as well as 3-aryl substituted phthalimidines (99% ee) could be easily prepared.

Recent developments in the metal-catalyzed reactions of metallocarbenoids from propargylic esters.

Abstract: The transition-metal-catalyzed intramolecular cycloisomerization of propargylic carboxylates provides functionalized bicyclo[n.1.0]enol esters in a very diastereoselective manner and, depending on the structure, with partial or complete transfer of chirality from enantiomerically pure precursors. The subsequent methanolysis gives bicyclo[n.1.0] ketones, hence resulting in a very efficient two-step protocol for the syntheses of α,β-unsaturated cyclopropyl ketones, key intermediates for the preparation of natural products. The results from mechanistic computational studies suggest that they probably proceed through cyclopropyl metallocarbenoids, formed by endo-cyclopropanation, that undergo a 1,2-acyl migration. Finally, the potential of the intermolecular reaction and the related pentannulation of propargylic esters bearing pendant aromatic rings are also discussed.

Metal‐Free Triazole Formation as a Tool for Bioconjugation

Abstract: The development of selective and site-specific bio-orthogonal conjugation methods is an important topic in chemical biology. A wide range of methods, such as the Staudinger ligation, native chemical ligation, genetic incorporation, expressed-protein ligation, Huisgen azide–alkyne cycloaddition, and the Diels–Alder ligation are currently employed in the selective modification of proteins and other biomolecules. In recent years, the Cu-catalyzed variant of the Huisgen 1,3-dipolar cycloaddition, also referred to as “click reaction”, has been increasingly applied in various fields of chemistry as a versatile and mild ligation method. This method allows for the synthesis of complex materials, which include bioconjugates, glycopeptides, functionalized polymers, virus particles, and therapeutics. However, due to the toxicity of the copper catalyst to both bacterial and mammalian cells applications that involve in vivo ligation are limited. In order to circumvent the use of copper ions, Bertozzi and co-workers have devised a strain-promoted [3+2] cycloaddition reaction that involves azides and a strained cyclooctyne derivative. Recent reports by Ju et al. have also shown successful applications of copper-free 1,3-dipolar cycloaddition by using either elevated temperatures or electron-deficient alkynes. We envisioned that the combination of ring strain and electron deficiency, as occurs in oxa-bridged bicyclic systems 2a and 2b, could also lead to an increased reactivity toward [3+2] cycloaddition reactions. Here, we report a spontaneous tandem [3+2] cycloaddition–retro-Diels–Alder ligation method that results in a stable 1,2,3-triazole linkage. This methodology can be applied to biomacromolecules that contain various functional groups under physiological conditions. The oxabridged bicyclic systems 2a and 2b were prepared by a Diels– Alder reaction of substituted propiolates with furan (Scheme 1). Subsequent hydrolysis provided the desired carboxylic acid derivatives 3a and 3b, in excellent yield. To compare the reactivity of Diels–Alder products 2a and b with the corresponding alkynes, [3+2] cycloaddition reactions were performed under ambient conditions by using benzyl azide, and monitored over time with H NMR spectroscopy (Figure 1). The oxanorbornadienes 2a and 2b and their respective alkynes provided identical 1,4,5-substituted triazoles to the products.

New Catalytic Reactions of Oxa- and Azabicyclic Alkenes

Abstract: Bicyclic alkenes, including oxa- and azabenzonorbornadienes and their derivatives, can be readily activated by transition metal complexes face-selectively due to their unsymmetrical bicyclic structure and the intrinsic angle strain on the carbon-carbon double bond. We have developed several stereo-, regio-, and chemoselective reactions catalyzed by nickel and palladium complexes using these bicyclic alkenes as substrates, providing a unique means of constructing a variety of synthetically useful carbocycles and heterocycles with high efficiency not generally accessible by traditional methods. This Account outlines these new metal-catalyzed reactions that include couplings, cycloadditions, and cyclization reactions.

Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 3. Structure-activity relationships of fused rings at the 7,8-positions.

Abstract: As a continuation of our efforts to discover and develop the apoptosis-inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of fused rings at the 7,8-positions. It was found that a five-member aromatic ring, such as pyrrolo with nitrogen at either the 7- or 9-position, is preferred. A six-member aromatic ring, such as benzo or pyrido, also led to potent compounds. The SAR of the 4-aryl group was found to be similar for chromenes with a fused ring at the 7,8-positions. These compounds were found to inhibit tubulin polymerization, indicating that cyclization of the 7,8-positions into a ring does not change the mechanism of action. Compound 2h was identified to be a highly potent apoptosis inducer with an EC 50 of 5 nM and a highly potent inhibitor of cell proliferation with a GI 50 of 8 nM in T47D cells.

Photoinduced-Electron-Transfer Chemistry: From Studies on PET Processes to Applications in Natural Product Synthesis

Abstract: The application of photoinduced electron transfer (PET) for the construction of heterocyclic ring systems is an appealing route in synthetic organic photochemistry. Electronically excited carbonyl chromophors in ketones, aldehydes, amides, or imides are strong electron acceptors that oxidize alkenes, amines, thioethers, or carboxylates. In subsequent steps, the radical anions formed thereof either are operating as secondary electron donors and initiate a photon-driven chain reaction or combine with electrophilic species and form products. These reactions are applied in the synthesis of heterocyclic compounds. The basic structures of these target molecules are bicyclic tertiary amines from the pyrrolizidine, benzopyrrolizidine, and indolizidine families, cyclic oligopeptides, macrocyclic ring systems, and many more.

Gold(I)-catalyzed synthesis of functionalized cyclopentadienes.

Abstract: mechanistic pathways: a concerted rearrangement (path a) involving direct addition of the olefin on the epoxide or a stepwise mechanism (path b) through a Nazarov cyclization of an oxypentadienyl cation (2, X=O ). The regioselectivity of the cyclization is dictated by donation of the oxyanion into the resulting cation leading to the formation of a ketone. Recently, stabilization of developing positive charge through back-bonding from phosphinegold(I) complexes has been implicated in a number of rearrangement reactions. Therefore, we hypothesized that coordination of cationic phosphinegold(I) complexes to a vinyl allene might mimic these reaction pathways through similar back-bonding, leading to metal–carbenoid intermediate 3 (X=R3PAu ). These intermediates would further rearrange into substituted cyclopentadienes, important building blocks in organic and organometallic chemistry. 7] In light of our recent success in using [Ph3PAuCl] with AgSbF6 in dichloromethane for carbon–carbon bond-forming reactions, we chose this system for preliminary studies of the proposed cycloisomerization (Table 1). Treatment of vinyl allene 4 with 2 mol% cationic triphenylphosphinegold(I) afforded the desired cyclopentadiene 5 as a single regioisomer in 97% yield after 1 min at 0 8C (Table 1, entry 1). Similar results were obtained when a lower temperature or lower catalyst loading were used (Table 1, entries 2 and 3). Control experiments employing either 5 mol% [Ph3PAuCl] or 5 mol% AgSbF6 as the sole catalyst did not lead to any conversion of 4 into 5 (Table 1, entries 4 and 5). Other transition-metal complexes showed no catalytic activity; however, gold(III) chloride rapidly consumed 4 to afford a small amount of 5 (Table 1, entry 6). With optimal conditions in hand, the scope of the gold(I)catalyzed cycloisomerization of vinyl allenes was examined. We were pleased to find that the reaction allowed for the regiospecific synthesis of functionalized cyclopentadienes in high yields with a variety of substitution patterns (Table 2). Substitution at the allene terminus was well tolerated, encompassing linear alkyl (Table 2, entries 8 and 9), oxygenated (entries 3–7), secondary benzyl (entry 1), and phenyl substituents (entry 2). Notably, the gold(I)-catalyzed reaction can be easily carried out on a gram scale albeit with a slightly diminished yield (Table 2, entry 1). Furthermore, the stability of acid-labile protecting groups, such as tetrahydropyranyl (Table 2, entry 9) and silyl ethers (entries 3, 4, 6, and 7), isopropylidene acetal (entry 5), and an N-Boc amine (entry 6), is a testament to the mildness of the reaction conditions. Bicyclic cyclopentadienes are readily produced from the cycloisomerization of vinyl allenes containing cyclic alkenes (Table 2, entries 1–6). Additionally, the gold(I)catalyzed reaction can be employed for the synthesis of cyclopentadienes with a quaternary carbon center (Table 2, entries 2 and 3). The use of a more electron-rich gold(I) complex, [tBu3PAuCl], as a catalyst gave improved yields for some vinyl allenes (Table 2, entries 5, 6, 8, and 9). For example, switching the gold catalyst from [Ph3PAuCl] to [tBu3PAuCl] resulted in an improved yield for the formation of cyclopentadiene 21 (Table 2, entry 8). Table 1: Catalyst optimization.

A computationally designed Rh(I)-catalyzed two-component [5+2+1] cycloaddition of ene-vinylcyclopropanes and co for the synthesis of cyclooctenones

Abstract: Through the combined use of computational (density functional theory) and experimental studies, a new [Rh(CO)2Cl]2 catalyzed two-component [5+2+1] cycloaddition of ene-vinylcyclopropanes and CO for the synthesis of fused bicyclic cyclooctenones has been designed and experimentally realized. The key point behind this design is to turn a disfavored reductive elimination of (sp3)C−Rh−C(sp3) to an easier migratory reductive elimination of (sp3)C−Rh−CO−C(sp3) by the introduction of CO. These reactions proceed in good yields for substrates with various tether types and substituents, providing a flexible, convenient, efficient, and stereocontrolled method for the construction of bicyclic cyclooctenones.

Even-electron ions: a systematic study of the neutral species lost in the dissociation of quasi-molecular ions.

Abstract: The collision-induced dissociations of the even-electron [M + H](+) and/or [M - H](-) ions of 121 model compounds (mainly small aromatic compounds with one to three functional groups) ionized by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) have been studied using an ion trap instrument, and the results are compared with the literature data. While some functional groups (such as COOH, COOCH(3), SO(3)H in the negative ion mode, or NO(2) in both the positive and negative ion modes) generally promote the loss of neutrals that are characteristic as well as specific, other functional groups (such as COOH in the positive ion mode) give rise to the loss of neutrals that are characteristic, but not specific. Finally, functional groups such as OH and NH(2) in aromatic compounds do not lead to the loss of a neutral that reflects the presence of these substituents. In general, the dissociation of [M + H](+) and [M - H](-) ions generated from aliphatic compounds or compounds containing an aliphatic moiety obeys the even-electron rule (loss of a molecule), but deviations from this rule (loss of a radical) are sometimes observed for aromatic compounds, in particular for nitroaromatic compounds. Thermochemical data and ab initio calculations at the CBS-QB3 level of theory provide an explanation for these exceptions. When comparing the dissociation behaviour of the even-electron [M + H](+) and/or [M - H](-) ions (generated by ESI or APCI) with that of the corresponding odd-electron [M](+) ions (generated by electron ionization, EI), three cases may be distinguished: (1) the dissociation of the two ionic species differs completely; (2) the dissociation involves the loss of a common neutral, yielding product ions differing in mass by one Da, or (3) the dissociations lead to a common product ion.

Five- and Six-Membered Conformationally Locked 2',4'-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies

Abstract: Two unusual reactions involving the 5-hexenyl or the 6-heptenyl radical cyclization of a distant double bond at C4‘ and the radical center at C2‘ of the ribofuranose ring of thymidine have been used as key steps to synthesize North-type conformationally constrained cis-fused bicyclic five-membered and six-membered carbocyclic analogues of LNA (carbocyclic-LNA-T) and ENA (carbocyclic-ENA-T) in high yields. Their structures have been confirmed unambiguously by long range 1H−13C NMR correlation (HMBC), TOCSY, COSY, and NOE experiments. The carbocyclic-LNA-T and carbocyclic-ENA-T were subsequently incorporated into the antisense oligonucleotides (AONs) to show that they enhance the Tm of the modified AON/RNA heteroduplexes by 3.5−5 °C and 1.5 °C/modification for carbocyclic-LNA-T and carbocyclic-ENA-T, respectively. Whereas the relative RNase H cleavage rates with carbocyclic-LNA-T, carbocyclic-ENA-T, aza-ENA-T, and LNA-T modified AON/RNA duplexes were found to be very similar to that of the native counterpar...

Compounds and methods for synthesis of bicyclic nucleic acid analogs

Abstract: The present invention provides compounds and methods of using them for preparing bicyclic nucleosides. The bicyclic nucleosides are useful for preparing chemically modified oligomeric compounds. Oligomeric compounds comprising these bicyclic nucleosides have enhanced properties such as increased nuclease resistance.

Concise, asymmetric, stereocontrolled total synthesis of stephacidins A, B and notoamide B.

Abstract: Concise asymmetric total syntheses of the fungal metabolites (-)-stephacidin A, (+)-stephacidin B, and (+)-notoamide B are described. Key features of these total syntheses include (1) a facile synthesis of (R)-allyl proline methyl ester, (2) a revised route toward the pyranoindole ring system, (3) a novel cross-metathesis strategy for the introduction of important functional groups, and (4) an SN2' cyclization to form the [2.2.2] bridged bicyclic ring system. Furthermore, our synthesis has taken advantage of microwave heating to shorten reaction times as well as increase yields for the preparation of vital intermediates.

Pyrido[1,2-a]pyrimidin-4-one derivatives as a novel class of selective aldose reductase inhibitors exhibiting antioxidant activity.

Abstract: 2-Phenyl-pyrido[1,2-a]pyrimidin-4-one derivatives bearing a phenol or a catechol moiety in position 2 were tested as aldose reductase (ALR2) inhibitors and exhibited activity levels in the micromolar/submicromolar range. Introduction of a hydroxy group in position 6 or 9 gave an enhancement of the inhibitory potency (compare 18, 19, 28, and 29 vs 13 and 14). Lengthening of the 2-side chain to benzyl determined a general reduction in activity. The lack or the methylation of the phenol or catechol hydroxyls gave inactive (10-12, 21, 22, 25-27) or scarcely active (15, 17, 20) compounds, thus demonstrating that the phenol or catechol hydroxyls are involved in the enzyme pharmacophoric recognition. Moreover, all the pyridopyrimidinones displayed significant antioxidant properties, with the best activity shown by the catechol derivatives. The theoretical binding mode of the most active compounds obtained by docking simulations into the ALR2 crystal structure was fully consistent with the structure-activity relationships in the pyrido[1,2-a]pyrimidin-4-one series.

Phosphine-catalyzed intramolecular formal [3+2] cycloaddition for highly diastereoselective synthesis of bicyclo[n.3.0] compounds.

Abstract: Ylides have been widely applied in constructing small-ring compounds such as epoxides, cyclopropanes, and aziridines. Recently, several ylide cyclizations that go beyond the formation of three-membered rings have also been developed. Lu and co-workers demonstrated in a number of elegant studies that phosphines are good catalysts for the construction of cyclopentenes. Krische and co-workers developed the first intramolecular variant of the cycloaddition. Catalytic asymmetric [3+2] cycloadditions have been reported by both Zhang and Fu, with their respective coworkers. Recently, Aggarwal and co-workers documented an elegant protocol for the asymmetric synthesis of epoxideand aziridine-fused heterocycles through a sulfur ylide route. In a previous study on ylide chemistry, we reported a tandem ylide Michael addition–elimination–substitution reaction for the controllable synthesis of 2H-chromenes 2a and 4H-chromenes 2a’ (Scheme 1). To further extend the reaction scope, 3a was synthesized and subjected to the reaction. However, the desired compound 4a’was obtained in only 15% yield under the same conditions. To improve the yield, other potential catalysts such as PPh3 and 1,4diazabicyclo[2.2.2]octane (DABCO) were tested instead of THT. When triphenylphosphine was used, the bicyclic compound 4a was, unexpectedly, isolated as the sole product in 30% yield with excellent diastereoselectivity (Scheme 1). Herein, we wish to report the preliminary results of this cyclization. Further studies showed that the desired product was not observed in the absence of PPh3. In the presence of PPh3 (20 mol%) with Na2CO3 as a base, bromide 3b afforded the corresponding benzobicyclo[4.3.0] compounds (4b/4b’) in 95% yield with excellent diastereoselectivity (entry 1, Table 1). To study the generality of the current reaction,

Organocatalytic Asymmetric 1,6-Additions of β-Ketoesters and Glycine Imine

Abstract: The first organocatalytic enantioselective 1,6-addition of β-ketoesters and benzophenone imine to electron-poor δ-unsubstituted dienes using cinchona alkaloids under phase-transfer conditions is demonstrated. The scope of the reaction for the β-ketoesters is outlined for reactions with different δ-unsubstituted dienes having ketones, esters, and sulfones as electron-withdrawing substituents giving the corresponding optically active products in good yields and enantioselectivities in the range of 90−99% ee. The 1,6-addition also proceeds with a number of cyclic β-ketoesters having different ring sizes, ring systems and substituents in high yields and enantioselectivities. The potential of this new organocatalytic 1,6-addition for β-ketoesters is demonstrated by a two-step synthesis of the bicyclo[3.2.1]octan-8-one structure, a bicyclic bridged skeleton occurring in a variety of natural compounds. Benzophenone imines also undergo the organocatalytic asymmetric 1,6-addition to the activated dienes in high yi...

Saliniketals A and B, bicyclic polyketides from the marine actinomycete Salinispora arenicola.

Abstract: An extensive study of the secondary metabolites produced by several strains of the marine actinomycete Salinispora arenicola has led to the isolation of two unusual bicyclic polyketides, saliniketals A and B (1, 2). The structures, which contain a new 1,4-dimethyl-2,8-dioxabicyclo[3.2.1]octan-3-yl ring, were assigned mainly by 2D NMR spectroscopic methods. Unexpectedly, chemical derivatization of saliniketal A with Mosher's acid chloride resulted in a functional group interconversion of an unsaturated primary amide to the corresponding nitrile in a quantitative yield under unusually mild conditions. Saliniketals A and B were found to inhibit ornithine decarboxylase induction, an important target for the chemoprevention of cancer, with IC50 values of 1.95 +/- 0.37 and 7.83 +/- 1.2 microg/mL, respectively.

Synthesis of dibenzo[g,p]chrysenes from bis(biaryl)acetylenes via sequential ICl-induced cyclization and Mizoroki-Heck coupling.

Abstract: We report a facile synthesis of functionalized dibenzo[g,p]chrysenes via initial ICl-promoted cyclization of bis(biaryl)acetylenes, followed by the Mizoroki−Heck coupling reaction. This new approach works well for various bis(biaryl)acetylenes to afford dibenzo[g,p]chrysenes bearing various functionalities. With substrates of one special type including 4‘-methoxy-2-ethynylbiphenyls, we found that the ICl treatment led to ipso cyclization to give bicyclic spirocyclohexadienones. In the presence of MeOH/H2SO4, these spiroketone products undergo rearrangement to give 9-iodophenanthrenes through a selective 1,2-alkenyl migration. We prepared various 4‘-methoxy-2-ethynylbiphenyl compounds to show the generalization of such an ipso cyclization and 1,2-alkenyl shift. This ipso-cyclization approach can be extended to the preparation of dibenzo[g,p]chrysenes.

Antidiabetic bicyclic compounds

Abstract: Tricyclic compounds containing a cyclopropyl carboxylic acid or carboxylic acid derivative (e.g. amide) fused to a bicyclic ring, including pharmaceutically acceptable salts and prodrugs thereof, are agonists of G-protein coupled receptor 40 (GPR40) and are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Palladium-catalyzed asymmetric silaborative C-C cleavage of meso-methylenecyclopropanes.

Abstract: An enantioselective silaborative C−C cleavage of meso-methylenecyclopropanes (meso-MCPs) was achieved by using a palladium catalyst bearing a chiral monodentate phosphine ligand. The (R)-2-bis(3,5-dimethylphenyl)phosphino-1,1‘-binaphthyl gave the highest enantioselectivity in the reactions with (methyldiphenylsilyl)pinacolborane at 50 °C, affording derivatives of 2-boryl-4-silyl-1-butene in high yields with high enantiomeric excesses. The reactions of bicyclic MCPs that have fused five- to eight-membered rings gave the corresponding products with 89−91% ee, whereas a little lower ee was observed in the reaction of a non-fused MCP (81% ee). Synthetic applications of the products were demonstrated through synthesis of β-silyl ketones by H2O2 oxidation and synthesis of stereodefined homoallylic alcohols via homologation−allylboration sequence, in which the chiral β-substituent of the allylborane has critical impact on the diastereochemical outcome.

Chiral Bicyclic Guanidine as a Versatile Brønsted Base Catalyst for the Enantioselective Michael Reactions of Dithiomalonates and β‐Keto Thioesters

Abstract: A chiral bicyclic guanidine was developed as a versatile Bronsted base catalyst for the enantioselective Michael reactions of dithiomalonates and β-keto thioesters using a range of acceptors including maleimides, cyclic enones, furanone and acyclic 1,4-dicarbonylbutenes.

Selective ruthenium-catalyzed transformations of enynes with diazoalkanes into alkenylbicyclo[3.1.0]hexanes.

Abstract: Reaction of a variety of C⋮CH bond-containing 1,6-enynes with N2CHSiMe3 in the presence of RuCl(COD)Cp* as catalyst precursor leads, at room temperature, to the general formation of alkenylbicyclo[3.1.0]hexanes with high Z-stereoselectivity of the alkenyl group and cis arrangement of the alkenyl group and an initial double-bond substituent, for an E-configuration of this double bond. The stereochemistry is established by determining the X-ray structures of three bicyclic products. The same reaction with 1,6-enynes bearing an R substituent on the C1 carbon of the triple bond results in either cyclopropanation of the double bond with bulky R groups (SiMe3, Ph) or formation of alkylidene−alkenyl five-membered heterocycles, resulting from a β elimination process, with less bulky R groups (R = Me, CH2CHCH2). The reaction can be applied to in situ desilylation in methanol and direct formation of vinylbicyclo[3.1.0]hexanes and to the formation of some alkenylbicyclo[4.1.0]heptanes from 1,7-enynes. The catalytic ...