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PubMed2001

Palladium-catalyzed cyclization of allylsilanes with nucleophilic displacement of the silyl group.

Allylsilanes containing hydroxy or tosylamide groups undergo palladium(II)catalyzed cyclization to afford derivatives of tetrahydrofuran, piperidine, and pyrrolidine. This catalytic reaction proceeds through an (eta3-allyl)palladium intermediate that is generated by allylic displacement of the silyl group of the allylsilane precursors. The internal nucleophilic attack on the (eta3-allyl)palladium intermediates proceeds with high chemo- and regioselectivity. Benzoquinone and copper(II) chloride can be used for regeneration of the palladium(II) catalyst precursor. Mechanistic studies revealed that the copper(II) chloride reoxidant also activates the (eta3-allyl)palladium intermediate towards nucleophilic attack. Kinetic studies on the formation of the (eta3-allyl)palladium intermediates showed that the reaction rate is highly dependent on the concentration of chloride ligand and the solvent. The structure and reactivity of the key intermediates of the palladadesilylation process were studied by density functional theory (DFT) calculations, which showed that coordination of the electrophilic palladium(II) catalyst precursor to allylsilanes leads to a relatively weak beta-silicon effect. The DFT studies also indicate that the cleavage of the carbon-silicon bond takes place by coordination of a chloride ion to the silicon atom.

Journal Article↗

PubMed2002

Synthesis of functionalized indole- and benzo-fused heterocyclic derivatives through anionic benzyne cyclization.

The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or aryllithium compound that undergoes a subsequent intramolecular anionic cyclization. Reaction of the organolithium intermediates with selected electrophiles allows the preparation of a wide variety of indole, tetrahydrocarbazole, dihydrofenantridine, dibenzopyran, and dibenzothiopyran derivatives. Finally, the application of this strategy to the appropriate starting materials allows the preparation of some tryptamine and serotonin analogues.

Journal Article↗

PubMed2002

Enantioselective Norrish-Yang cyclization reactions of N-(omega-oxo-omega-phenylalkyl)-substituted imidazolidinones in solution and in the solid state.

The four N-(omega-oxo-omega-phenyl-alkyl)-substituted imidazolidinones 5-8 were prepared from N-acetylimidazolidinone (4). Upon irradiation, these substrates underwent Norrish-Yang cyclization to the racemic products rac-9-rac-12 (51-75%). The reactions of the N-2-oxoethylimidazolidinones 5 and 6 were conducted in tBuOH, and yielded 1:1 mixtures of exo/endo diastereoisomers rac-9a/rac-9b and rac-10a/rac-10b, accompanied by Norrish type II cleavage products. The reactions of the N-3-oxopropylimidazolidinones 7 and 8 were performed in toluene. The exo diastereoisomers rac-11a and rac-12a were the major diastereoisomers (d.r. approximately equal to 4:1). In the presence of the chiral compounds 1-3, the photocyclization of substrate 8 proceeded with significant enantiomeric excess (5-60% ee). The more sophisticated complexing agents 3 and ent-3 provided better enantiofacial differentiation (up to 60% ee) than the lactams 1 and 2 (up to 26% ee). Low temperatures and an excess of the complexing agent helped to increase the enantioselectivity. The absolute configuration of the major exo product 12a obtained from compound 8 in the presence of complexing agent 3 was unambiguously established by single-crystal X-ray crystallography of its chiral N-methoxyphenylacetyl derivative 15a. In a similar fashion, the absolute configurations of the endo products 12b and ent-12b were established. The N-2-oxoethylimidazolidinone 5, which crystallized in a chiral space group, was irradiated in the solid state. At low levels of conversion, the product 9a/ent-9a was formed with high enantiomeric excess (78% ee). The enantioselectivity deteriorated at higher levels of conversion.

Journal Article↗

PubMed2003

The final steps of the Oppolzer cyclization: mechanism of the insertion of alkenes into allylpalladium(II) complexes.

We report here the results of a computational study on the the mechanism of the Oppolzer cyclization. These results lead us to conclude that the insertion of olefins in Pd-allyl complexes probably takes place directly from the eta(3)-allyl species. The presence of a phosphane ligand in the reagents plays the role of enhancing the electron density on the Pd atom; this makes the alkene moiety more reactive towards insertion by back-donation from the metal. The results also indicate that the configuration of the new stereogenic centers is fixed in the insertion of the alkene into the (eta(3)-allyl)palladium species.

Journal Article↗

PubMed2003

Highly stereoselective radical cyclization of haloacetals controlled by the acetal center.

A systematic investigation of radical haloacetal cyclizations (Ueno-Stork reaction) where the acetal center is the unique stereogenic element is reported. This highly diastereoselective reaction can be used for the preparation of polysubstituted tetrahydrofurans and gamma-lactones. We report herein the full experimental details of reactions where up to three new chiral centers are created. To demonstrate the potential of this approach, short syntheses of (+)-eldanolide and of tricyclic acetals related to biologically active lignans have been achieved.

Journal Article↗

PubMed2003

Criteria for the elucidation of the pseudopericyclic character of the cyclization of (Z)-1,2,4,6-heptatetraene and its heterosubstituted analogues: magnetic properties and natural bond orbital analysis.

The electrocyclization of heterosubstituted derivatives of (Z)-1,2,4,6-heptatetraene, (2Z)-2,4,5-hexatrien-1-imine and (2Z)-2,4,5-hexatrienal exhibit some features which suggest a pseudopericyclic mechanism. In order to examine this, a comprehensive study including the determination of magnetic properties to estimate aromaticity and an NBO analysis throughout the reaction path was conducted. The cyclization of 5oxo-2,4-pentadienal, a process of unequivocal pseudopericyclic nature, was studied for comparison. The results suggest that, although the lone electron pair on the heteroatom in the heptatetraene derivatives seemingly plays a crucial role in the reaction mechanism, it does not suffice to deprive the reaction from the essential features of a pericyclic disrotatory electrocyclization.

Journal Article↗

PubMed2004

Polarity matching of radical trapping: high yielding 3-exo and 4-exo cyclizations.

A catalyzed synthesis of cyclopropanes and cyclobutanes via radical chemistry is described. The method that generally proceeds in high yields uses epoxides as radical precursors and titanocene(III) complexes as the electron transfer catalysts (see scheme). The key to the success of the transformation is constituted by the chemoselectivity of radical reduction. Electrophilic enol radicals generated through cyclization are reduced rapidly whereas their precursors, nucleophilic alkyl radicals, remain unaffected.

Journal Article↗

PubMed2005

Pd(II)-catalyzed oxidative dimeric cyclization-coupling reaction of 2,3-allenoic acids: an efficient synthesis of bibutenolide derivatives.

Three sets of convenient catalytic systems have been developed for the oxidative dimeric cyclization coupling of differently substituted 2,3-allenoic acids catalyzed by Pd(II), affording bibutenolides that are not otherwise readily available. The advantages and disadvantages of these systems are discussed. Although the diastereoselectivity for the bicyclization of racemic 2,3-allenoic acids is low, excellent diastereoselectivity was realized in the bicyclization reaction of optically active 2,3-allenoic acids, leading to the optically active bibutenolides in high yields and ee. Based on a mechanistic study, it is believed that the reaction may proceed by means of a double oxypalladation and reductive elimination to yield butenolide 3 and Pd(0) species, which may be reoxidized to the catalytically active Pd(II) species in the presence of alkyl iodide/air, metallic iodide/air, or benzoquinone.

Journal Article↗

PubMed2003

First asymmetric synthesis of (-)-lintetralin via intramolecular Friedel-Crafts-type cyclization.

The asymmetric synthesis of an aryltetralin lignan, (-)-lintetralin, was achieved with an overall yield of 29% with seven steps. Key features of the synthesis are an asymmetric Strecker reaction, a diastereoselective Michael addition of the lithiated amino nitrile product to 5H-furan-2-one, and an intramolecular carbocationic cyclization to provide the desired ring skeleton with the correct configuration.

Indicators and Reagents↗

PubMed2001

Asymmetric catalytic ene-cyclization approach to 2-fluoro-19-nor-1,25-dihydroxyvitamin D(3) A-ring analog with significant transactivation activity.

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)2D3) has been shown to modulate not only proliferation and differentiation, but also apoptosis in malignant cells, indicating that it could be useful for the treatment of cancer and psoriasis. However, little information has been available on the binding conformation of the 1alpha,25(OH)2D3 molecule and its analogs with the vitamin D receptor (VDR). Therefore, we synthesized 2alpha-fluorinated A-ring analogs of 19-nor-1alpha,25(OH)2D3 in order to investigate the VDR-binding conformation of the A-rings on the basis of the (19)F NMR analysis. The 2alpha-fluoro-19-nor-1alpha,25-dihydroxyvitamin D3 A-ring analog thus synthesized via a asymmetric catalytic carbonyl-ene cyclization, shows significant activity in transactivation.

Animals↗

PubMed2004

Studies on the dehydrative cyclization of epimeric 4-(L-xylo and L-lyxo-tetritol-1-yl)-2-phenyl-2H-1,2,3-triazoles. Circular dichroism and NMR assignment of the formed anomeric C-nucleoside L-threofuranosyl triazole analogs.

Dehydrative cyclization of epimeric 4-(L-xylo- and L-lyxo-tetritol-1-yl)-2-phenyl-2H-1,2,3-triazoles afforded the anomeric alpha and beta-L-threofuranosyl analogs. The anomeric configuration of the formed anomeric C-nucleoside analogs was determined by circular dichroism and NMR spectroscopy.

Chemistry↗

PubMed2003

Cyclization triggered by deprotonation: the gas-phase acidity of 1,8-chalcogen-bridged naphthalenes.

High-level density functional theory computations have been used to estimate the gas-phase (intrinsic) acidities of the complete series of 1,8-chalcogen-bridged naphthalene derivatives. The existence of a chalcogen-chalcogen bond in chalcogen-bridged naphthalene derivatives plays a crucial role in the intrinsic acidity of the system. For 1,8-naphthalenedilylbis(oxy), where this bond does not exist, the para C-H group is the most acidic site, whereas for the remaining compounds, deprotonation of the ortho CH groups is the most favorable process. Deprotonation of the aromatic rings has a large effect on the strength of the bonds of the five-membered ring. These effects depend on the nature of the heteroatoms forming the X-Y bridge, and modulate the acidity of the molecule. Also importantly, when one of the heteroatoms is oxygen, ortho and para deprotonation lead to cleavage of the X-Y bridge. This bond fission favors the formation of a CYC (Y = S, Se, Te) three-membered ring that enhances the stability of the anion and, therefore, increases the acidity of these compounds. We have shown that, whereas this cyclization process is energetically favorable for oxygen-containing compounds, it is not favorable for the remaining derivatives.

Journal Article↗

PubMed1993

Substituted thiosemicarbazides and corresponding cyclized 1,3,4-oxadiazoles and their anti-inflammatory activity.

Several 1-(4-biphenoxyacetyl)-4-substituted arylthiosemicarbazides and their corresponding cyclized 2-(4-biphenoxymethyl)-5-arylamino-1,3,4- oxadiazoles were synthesized and characterized by elemental analyses and IR, mass, and nuclear magnetic resonance spectra. All compounds were evaluated for anti-inflammatory activity by determining their ability to provide protection against carrageenin-induced edema in rat paw. The anti-inflammatory activity possessed by substituted thiosemicarbazides [100 mg/kg, intraperitoneal(ip)] ranged from 22 to 68%, whereas substituted 1,3,4-oxadiazoles (100 mg/kg, ip) provided protection of 10-76%. Hydrocortisone (10 mg/kg, ip) and oxyphenbutazone (40 mg/kg, ip), used as standard reference drugs, decreased edema in rat paw by 44.6 and 52.9%, respectively. All compounds (1 mM) possessed antiproteolytic activity that was reflected by their ability to cause in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin. This inhibition ranged between 43 and 72% for substituted thiosemicarbazides and 30 and 83% for substituted 1,3,4-oxadiazoles.

Animals↗

PubMed1994

Cyclization reactions leading to beta-hydroxyketo esters.

The purpose of the research was to synthesize beta-diketo esters and to evaluate them for anticonvulsant activity. The reaction of methyl vinyl ketone with dimethyl malonate in the presence of potassium carbonate gave an uncyclized product that underwent a Claisen condensation to yield methyl 2-hydroxy-4-oxocyclohex-2-en-1-oate (5a). Similarly, other cyclized beta-hydroxyketo esters were prepared, and their spectrometric data confirmed that the enol tautomers were preferred to the beta-diketo tautomers. The synthetic work clarified the reaction pathway for the Michael addition of malonate esters to enones. Of the intermediates and products tested for anticonvulsant activity, dimethyl 2,2-bis-(3-oxobutyl)malonate (9a) was found to possess anticonvulsant property. However, it is emphasized that the beta-hydroxyketo esters could be useful intermediates in the synthesis of enaminone anticonvulsants.

Animals↗

PubMed2001

Highly potent side-chain to side-chain cyclized enkephalin analogues containing a carbonyl bridge: synthesis, biology and conformation.

Six novel cyclic enkephalin analogues have been synthesized. Cyclization of the linear peptides containing basic amino acid residues in position 2 and 5 was achieved by treatment with bis(4-nitrophenyl)carbonate. It was found that some of the compounds exibit unusually high mu-opioid activity in the guinea pig ileum (GPI) assay. The 18-membered analogue cyclo(N(epsilon),N(beta)-carbonyl-D-Lys2,Dap5)-enkephalinamide turned out to be one of the most potent mu-agonists reported so far. NMR spectra of the peptides were recorded and structural parameters were determined. The conformational space was exhaustively examined for each of them using the electrostatically driven Monte Carlo method. Each peptide was finally described as an ensemble of conformations. A model of the bioactive conformation of this class of opioid peptides was proposed.

Animals↗

PubMedDate not supplied

Highly potent side chain-main chain cyclized dermorphin-deltorphin analogues: an integrated approach including synthesis, bioassays, NMR spectroscopy and molecular modelling.

Our continuing efforts to study structure-activity relationships of peptide opioids have resulted in the synthesis of a series of cyclic opioids related to dermorphins and deltorphins. The biological activities of the compounds have been determined and the conformational analyses carried out using 1H-NMR spectroscopy and molecular modelling. The three compounds in the series Tyr-c[D-Orn-Phe-Ala], Tyr-c[D-Lys-Phe-Ala], and Tyr-c[A2bu-Phe-Ala-Leu] are cyclized via a lactam bridge from the side-chain of the residue at the second position with the carboxyl terminus of each compound. The molecules incorporate 12-, 13- and 14-membered rings, respectively. They include a phenylalanine at the third position which is a distinguishing characteristic of dermorphins and deltorphins. The guinea pig ileum and mouse vas deferens assays show that the compounds are highly active at both mu- and delta-opioid receptors. The compounds are all highly effective antinociceptive agents as measured by the intrathecal rat hot plate test. Conformational analyses of the molecules indicate that they can adopt topochemical arrays required for bioactivity at both mu- and delta-receptors which explains their high activity in both guinea pig ileum and mouse vas deferens in vitro assays. The results support our models for mu- and delta-receptor activity for constrained peptide opioids.

Amino Acid Sequence↗

PubMed2000

Heterologous expression and characterization of a "Pseudomature" form of taxadiene synthase involved in paclitaxel (Taxol) biosynthesis and evaluation of a potential intermediate and inhibitors of the multistep diterpene cyclization reaction.

The diterpene cyclase taxadiene synthase from yew (Taxus) species transforms geranylgeranyl diphosphate to taxa-4(5),11(12)-diene as the first committed step in the biosynthesis of the anti-cancer drug Taxol. Taxadiene synthase is translated as a preprotein bearing an N-terminal targeting sequence for localization to and processing in the plastids. Overexpression of the full-length preprotein in Escherichia coli and purification are compromised by host codon usage, inclusion body formation, and association with host chaperones, and the preprotein is catalytically impaired. Since the transit peptide-mature enzyme cleavage site could not be determined directly, a series of N-terminally truncated enzymes was created by expression of the corresponding cDNAs from a suitable vector, and each was purified and kinetically evaluated. Deletion of up to 79 residues yielded functional protein; however, deletion of 93 or more amino acids resulted in complete elimination of activity, implying a structural or catalytic role for the amino terminus. The pseudomature form of taxadiene synthase having 60 amino acids deleted from the preprotein was found to be superior with respect to level of expression, ease of purification, solubility, stability, and catalytic activity with kinetics comparable to the native enzyme. In addition to the major product, taxa-4(5),11(12)-diene (94%), this enzyme produces a small amount of the isomeric taxa-4(20), 11(12)-diene ( approximately 5%), and a product tentatively identified as verticillene ( approximately 1%). Isotopically sensitive branching experiments utilizing (4R)-[4-(2)H(1)]geranylgeranyl diphosphate confirmed that the two taxadiene isomers, and a third (taxa-3(4),11(12)-diene), are derived from the same intermediate taxenyl C4-carbocation. These results, along with the failure of the enzyme to utilize 2, 7-cyclogeranylgeranyl diphosphate as an alternate substrate, indicate that the reaction proceeds by initial ionization of the diphosphate ester and macrocyclization to the verticillyl intermediate, followed by a secondary cyclization to the taxenyl cation and deprotonation (i.e., formation of the A-ring prior to B/C-ring closure). Two potential mechanism-based inhibitors were tested with recombinant taxadiene synthase but neither provided time-dependent inactivation nor afforded more than modest competitive inhibition.

Antineoplastic Agents↗

PubMed2001

Intein-mediated ligation and cyclization of expressed proteins.

Protein splicing is a posttranslational processing event that releases an internal protein sequence from a protein precursor. During the splicing process the internal protein sequence, termed an intein, embedded in the protein precursor self-catalyzes its excision and the ligation of the flanking protein regions, termed exteins. The dissection of the splicing pathway, which involves the precise cleavage and formation of peptide bonds, and the identification of key catalytic residues at the splice junctions have led to the modulation of the protein splicing process as a protein engineering tool. Novel strategies have been developed to use intein-catalyzed reactions for the production and manipulation of proteins and peptides. These new approaches have broken down the size limitation barrier of chemical synthetic methods and are less technically demanding. The purpose of this article is to describe how to use self-splicing inteins in protein semisynthesis and backbone cyclization. The first two sections of the article provide a brief review of the distinct chemical steps that underlie protein splicing and intein enabled technology.

Bacterial Proteins↗