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PubMed2006

Parallel synthesis of a library of benzoxazoles and benzothiazoles using ligand-accelerated copper-catalyzed cyclizations of ortho-halobenzanilides.

A general method for the formation of benzoxazoles via a copper-catalyzed cyclization of ortho-haloanilides is reported. This approach complements the more commonly used strategies for benzoxazole formation which require 2-aminophenols as substrates. The reaction involves an intramolecular C-O cross-coupling of the ortho-haloanilides and is believed to proceed via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(III) manifold. The reaction is also applicable to the formation of benzothiazoles. A variety of ligands including 1,10-phenanthroline and N,N'-dimethylethylenediamine were shown to provide ligand acceleration/stabilization in the reaction. Optimal conditions for cyclization used a catalyst combination of CuI and 1,10-phenanthroline (10 mol %). The method was amenable to a parallel-synthesis approach, as demonstrated by the synthesis of a library of benzoxazoles and benzothiazoles substituted at various positions in the ring. Most examples utilized the cyclization of ortho-bromoanilides, but ortho-iodoanilides and ortho-chloroanilides also undergo a reaction under these conditions. The rate of reaction of the ortho-haloanilides follows the order I > Br > Cl, consistent with oxidative addition being the rate-determining step.

Anilides↗

PubMed2006

Ortho effect in the Bergman cyclization: comparison of experimental approaches and dissection of cycloaromatization kinetics.

Four different experimental sources of kinetic information were combined to study the effect of ortho substituents on the rate of Bergman cycloaromatization. All methods confirm that the cyclization barrier is highly sensitive to the nature of the ortho substituents. However, the measured activation energies strongly depend on the choice of experimental technique: even the relative trends provided by the different methods agree with each other only in the case of acceptor substituents. Both the onset peaks and the activation energies determined by differential scanning calorimetry (DSC; either in neat enediynes or in their solutions in 10.6 M 1,4-cyclohexadiene (1,4-CHD)) strongly overestimate the reactivity of 1,2-diethynylbenzene, suggesting that DSC cannot be taken as a reliable indicator of enediyne reactivity. This discrepancy is likely to stem from the presence of side reactions with low activation barriers, especially important when the reaction is conducted in neat enediyne. On the other hand, kinetic measurements based on monitoring the concentrations of enediyne reactants and naphthalene products provide reliable general trends that include the parent benzannelated enediyne. These measurements confirm that both ortho-NO2 and ortho-CHO substituents substantially decrease activation energies for the Bergman cyclization, supporting earlier computational predictions. A comparison of theory and experiment suggests that computations at the Moeller-Plesset second-order perturbation theory (MP2)/6-31G level provide an excellent alternative to DFT when an accurate description of the contribution of noncovalent interactions to the activation energy is needed. Activation energies derived from k(eff), the effective rate constant under the pseudo-first-order approximation, depend on the 1,4-CHD concentrations. The true rate constant, k(1), for the cyclization step and the ratio of constants for the retro-Bergman ring opening, k(-1), and the intermolecular H-atom abstraction, k2, were determined from the dependence of cycloaromatization kinetics of ortho- and para-NO2 substituted enediynes on the concentration of 1,4-CHD.

Amino Acids, Cyclic↗

PubMed2006

Syn- and anti-selective Prins cyclizations of delta,epsilon-unsaturated ketones to 1,3-halohydrins with Lewis acids.

Ten acyclic and monocyclic delta,epsilon-unsaturated ketones, with and without methyl substituents on the double bond, underwent halide-terminated Prins (halo-Prins) cyclizations under anhydrous conditions in the presence of Lewis acids. TiCl4, TiBr4, BCl3, and BBr3 promoted syn-selective cyclizations to sterically congested chloro- and bromohydrins, while SnCl4, SnBr4, InCl3, ZrCl4, and several other Lewis acids effected highly anti-selective reactions to furnish the corresponding trans halohydrins. The stronger Lewis acids (TiX4 and BX3) favor the syn process that involves axial delivery of a halide ligand. Competition experiments showed that substitution at the delta carbon (methallyl enones) led to increased rates (40-50-fold), while substitution at the epsilon position (cis and trans crotyl enones) retarded the rate and eroded the selectivity of the cyclizations. The trends in syn vs anti selectivity, reactivity, and effects of different Lewis acidic metal halides are rationalized by competitive reaction pathways proceeding through syn carbocation-halide ion pairs and a higher order transition state that leads to inversion of configuration and formation of trans halohydrins, along with cyclic olefins arising from proton elimination.

Acids↗

PubMed2006

C5'-adenosinyl radical cyclization. A stereochemical investigation.

A variety of substituted 2'-deoxyadenosin-5'-yl radicals 3 were generated under different reaction conditions. Radicals 3 underwent intramolecular cyclization onto the C8-N7 double bond of the adenine moiety leading to aminyl radicals (5'S,8R)-4 and (5'R,8R)-4 and, eventually, to the corresponding cyclonucleosides 5 and 6. The effect of the solvent, the nature of the substituents, and the generation method of radicals 3 on the stereoselectivity of the C5'-radical cyclization have been considered. The observed increase of the (5'S)/(5'R) ratio by increasing the bulkiness of the R1 group is explained in terms of steric repulsion between R1 and the purine moiety which favors the C5'-endo conformation, whereas the effect of the water solvent in promoting the (5'R)-stereoselective cyclization is ascribed to intermolecular hydrogen bonding stabilizing the C5'-exo conformation.

Cyclization↗

PubMed2006

Zn(OTf)2-catalyzed cyclization of proparyl alcohols with anilines, phenols, and amides for synthesis of indoles, benzofurans, and oxazoles through different annulation mechanisms.

Zn(OTf)2 (10 mol %) catalyzed the cyclization of propargyl alcohols with PhXH (X = O, NH) in hot toluene (100 degrees C) without additive and gave indole and benzofuran products with different structures. In such transformations, alpha-carbonyl intermediates A and C were isolated as reaction intermediates. The 1,2-nitrogen shift in the formation of indole is catalyzed by Zn(OTf)2, and its mechanism has been elucidated. This catalytic cyclization is also applicable to the synthesis of oxazoles through the cyclization of propargyl alcohols and amides without a 1,2-nitrogen shift.

Alcohols↗

PubMed2000

A novel route to 5-substituted 3-isoxazolols. Cyclization of N, O-DiBoc beta-keto hydroxamic acids synthesized via acyl Meldrum's acids.

3-Isoxazolols are most often synthesized from a beta-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N, O-diBoc-protected beta-keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3-isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N, O-bis(tert-butoxycarbonyl)hydroxylamine, lead to the N, O-diBoc-protected beta-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3-isoxazolols.

Agaricales↗

PubMed2000

Photochemical and thermal bergman cyclization of a pyrimidine enediynol and enediynone.

[reaction: see text] Novel 10-membered pyrimidine enediynes (3 and 4) were synthesized in seven and eight steps, respectively. These compounds were compared for their abilities to undergo Bergman cyclization both thermally and photochemically. Alcohol 3 readily cyclized both thermally and photochemically in (i)PrOH, while ketone 4 only showed efficient thermal cyclization. Both compounds were also shown to cleave dsDNA under the appropriate conditions.

Antineoplastic Agents↗

PubMed2001

Chiral auxiliaries for asymmetric radical cyclization reactions: application to the enantioselective synthesis of (+)-triptocallol.

[figure: see text] A series of epimeric 8-aryl menthyl derivatives 5a-d and 6a-l, prepared from the same chiral source (R)-pulegone, were employed as chiral auxiliaries in the asymmetric radical cyclization reactions of beta-keto esters mediated by Mn(OAc)3. Chiral precursors 8c and 8d provided the cyclization products 10c and 10d, respectively, as single isomers (dr > 99:1), whereas the cyclization of precursor 9k gave 13k with good stereoselectivity (dr = 24:1). Diastereomer 13e was employed as the key intermediate in the enantioselective synthesis of (+)-triptocallol in 90% ee.

Biological Factors↗

PubMed2001

Role of 2-oxonia Cope rearrangements in Prins cyclization reactions.

[reaction--see text] The 2-oxonia Cope rearrangement is undetectable in typical Prins cyclization reactions. We have investigated the Cope rearrangement in a Prins cyclization reaction using a competitive reduction of the oxocarbenium ion intermediate, and a racemization reaction mediated by the rearrangement. In our unactivated substrate, the 2-oxonia Cope rearrangement was much faster than Prins cyclization. An enantioselective allyl transfer reaction also was developed using a 2-oxonia Cope rearrangement.

Allyl Compounds↗

PubMed2002

Comparative study of anionic and radical cyclization for the preparation of 1,3-dimethylindans: highly stereoselective preparation of cis-1,3-disubstituted indans via intramolecular carbolithiation.

[reaction: see text] The preparation of 1,3-dimethylindans from 4-(2-bromophenyl)-1-pentene (1) and 2-(2-iodo-1-methylethyl)styrene (2) substrates via radical-mediated cyclization and intramolecular carbolithiation has been investigated. Although cyclization of the radical derived from either substrate proceeds with modest selectivity for the cis-isomer, as does cycloisomerization of the aryllithium derived from substrate 1 (cis/trans approximately 2), intramolecular cyclization of the alkyllithium derived from substrate 2 is a highly cis-selective process (cis/trans = 12).

Anions↗

PubMed2005

Molybdenum oxides as highly effective dehydrative cyclization catalysts for the synthesis of oxazolines and thiazolines.

In the presence of molybdenum oxide the dehydrative cyclization of N-acylserines, N-acylthreonines, and N-acylcysteines can be carried out under Dean-Stark conditions in toluene to give oxazolines and thiazolines. The ammonium salts (NH(4))(6)Mo(7)O(24).4H(2)O and (NH(4))(2)MoO(4) have excellent catalytic activities for the dehydrative cyclization of serine and threonine derivatives, and the acetylacetonate complex MoO(2)(acac)(2) has a remarkable catalytic activity for the dehydrative cyclization of cysteine derivatives. In addition, polyaniline-supported MoO(2)(acac)(2) can easily be recovered and reused.

Catalysis↗

PubMed2005

Synthesis of the spirofungin B core by a reductive cyclization strategy.

[reaction: see text] A reductive decyanation approach to the synthesis of the core of spirofungin B has been developed. Spirofungin B has only one anomeric stabilization in the spiroacetal and was isolated along with its spiroacetal epimer, spirofungin A. The cyclization precursor was constructed from readily available starting materials. The reductive cyclization reaction was both efficient and stereoselective. The reductive cyclization strategy to spiroacetals is convergent and effective.

Cyclization↗

PubMed2006

Stereoselective cascade reactions that incorporate a 7-exo acyl radical cyclization.

[reaction: see text] Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two stereocenters are created by the reaction, and a single isomeric product was obtained from each of the five substrates examined. The relative configurations of the products are consistent with cyclizations occurring via chairlike or pseudochairlike transition states.

Alkaloids↗

PubMed2006

Synthesis of the bis-spiroacetal moiety of the shellfish toxins spirolides B and D using an iterative oxidative radical cyclization strategy.

The enantioselective synthesis of the bis-spiroacetal fragment of the shellfish toxins, spirolides B 1 and D 2, is reported. The carbon framework was constructed via a Barbier reaction of dihydropyran 10 with aldehyde 11, followed by two oxidative radical cyclizations to construct the bis-spiroacetal ring system. A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor 21. The initial unsaturated bis-spiroacetals 9a-d underwent equilibration during epoxidation to trans-epoxide 24 that was converted to tertiary alcohol 7.

Animals↗

PubMed2004

l-3,4-Dihydroxyphenyl alanine-extradiol cleavage is followed by intramolecular cyclization in lincomycin biosynthesis.

The LmbB1 protein, participating in the biosynthesis of lincomycin, was heterologously expressed in Escherichia coli, purified in its active form, and characterized as a dimer of identical subunits. Methods for purification and analysis of the LmbB1 reaction product were developed. Molecular mass and fragmentation pattern of the product revealed by capillary electrophoresis-mass spectrometry were in agreement with its proposed structure, 4-(3-carboxy-3-oxo-propenyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid. The LmbB1 is therefore a dioxygenase catalysing the 2,3-extradiol cleavage of the l-3,4-dihydroxyphenyl alanine aromatic ring. The final LmbB1 reaction product, a unique compound found in biosynthesis of lincomycin and expected in anthramycins, arises through subsequent cyclization of the primary cleavage product, 2,3-secodopa. A possible role of LmbB1 in 2,3-secodopa cyclization and alternative ways of the cyclization in the formation of biosynthetically related compounds, muscaflavin and stizolobinic acid, are discussed.

Chromatography, Ion Exchange↗

PubMed2004

Development of conformationally restricted analogues of bradykinin and somatostatin using constrained amino acids and different types of cyclization.

The structure-based design of peptide drugs requires the knowledge of the bioactive conformation. Studies on this receptor-bound 3D structure require linear or cyclic analogues with strongly reduced flexibility, but high biological activity, since only analogues with retained potency have preserved the bioactive conformation. Constrained amino acids containing double bonds or bulky substituents at the N(alpha)-, C(alpha)- and C(beta)-atom as well as at the aromatic ring atom were successfully applied to obtain potent and stable analogues of bradykinin and somatostatin, which due to their restricted conformation were suitable objects for conformational studies. Besides the generation of constrained cyclic analogues with improved biological and pharmacological properties, cyclic peptides were used as convenient models for the study of turn formations. Cyclization of the linear peptide bradykinin was performed by linking the N-terminus and the C-terminus, and in both bradykinin and somatostatin by cyclization using the amino acid side chains and by backbone cyclization. The later requires the introduction of N(alpha)-functionalised amino acids for ring closure which can be performed either through incorporation of N(alpha)-functionalised amino acids or dipeptide building units. Conformational analysis of a cyclic bradykinin analogue by means of NMR-studies together with molecular dynamics simulation led to a quasicyclic 3D structure with two turns and together with other 3D structures provided a pharmacophore model of bradykinin antagonists.

Amino Acids↗

PubMed2002

Cyclization strategies in peptide derived drug design.

The choice of peptides as prototype modulators of biological function, is justified on the grounds that peptides are natural constituents of living systems. They exist as hormones, biochemical inhibitors, antigens, growth factors, transmembrane carriers and, indeed they are comprised of the building blocks of all proteins. As such, the natural and mutated analogs of these functional entities provide a rich variety of pharmacophore models for further development. Peptidomimetic modification of active peptides can provide biostable analogs. Moreover, cyclization of linear peptides is frequently used as an attractive venue to provide both conformationally more restricted as well as more biostable analogs. The objective of this review is to report an updated summary of the more recently developed methodologies for the design and synthesis of cyclized peptides, citing selected examples of the effect of cyclization on both proteolytic stability and biological activity.

Animals↗

PubMed2002

The kinetics of cyclization reactions on polyaromatics from first principles.

Ab initio density functional theory calculations are presented on cyclization reactions of polyaromatics involved in coke formation during the thermal cracking of hydrocarbons. During coke formation, cyclization can take place at various sites, differing from each other by the local polyaromatic structure. This local structure also determines the minimum number of carbon atoms that must be added to allow the formation of a new ring. Kinetic parameters are calculated for the various ring-closure reactions by means of transition state theory. The activation energy is largely affected by the local structure of the polycyclic aromatic hydrocarbon, whereas the frequency factor varies significantly in terms of the length of the attached alkyl chain. The calculations, as presented, give a microscopic insight into the mechanisms that contribute to barrier formation and to the value of the frequency factor. The relative importance of cyclization at different sites, under conditions typical for an industrial cracking unit is studied on the basis of the calculated rate constants at various temperatures. The results suggest that the nature of coke formation is autocatalytic: the larger the macroradicals, the faster the subsequent reactions that lead to further growth of the polyaramatic surface. This type of calculation is the first step towards the development of structural relations for the kinetic parameters in terms of the local structure of the coke matrix.

Carbon↗