Cyclization Mode Research Articles

０価パラジウム触媒と有機ホウ素試薬を用いた分子内求電子剤を有するアルキン・アレンの付加・環化反応

We have developed palladium(0)/monophosphine-catalyzed trans-selective alkylative cyclization reactions of alkyne- and allene-aldehydes with organoboron reagents leading to 3-substituted 2-cycloalken-1-ols and 3-cycloalken-1-ols, respectively. Three-component reaction involving secondary aliphatic amines as the third component affords the corresponding tertiary amines via in situ generated iminium ions. These cyclization reactions allow a combinatorial synthesis of biologically important indenes bearing three different substituents at 1,2,3-positions from available o-ethynylbenzaldehyde derivatives. 6-Endo-trig cyclizations of alkynyl- and allenyl-iminium ions, in situ prepared from 3-butynylamine and 2,3-butadienylamine with formaldehyde, afford 1,4-disubstituted 1,2,3,6-tetrahydropyridines. The remarkable trans-selectivity of these processes would result from the novel reaction mechanism involving “anti-Wacker”-type oxidative addition. Changes of the cyclization mode when enones were employed as electrophiles suggest that low tendency of palladium(0) catalyst to form π-complex with carbonyls and iminium ions cause the trans-selectivity.

A simple and mild synthesis of 1H-isochromenes and (Z)-1-alkylidene-1,3-dihydroisobenzofurans by the iodocyclization of 2-(1-alkynyl)benzylic alcohols.

A variety of iodo-substituted isochromenes, dihydroisobenzofurans, and pyranopyridines are readily prepared in good to excellent yields under mild conditions by the iodocyclization of readily available 2-(1-alkynyl)benzylic alcohols or 2-(1-alkynyl)-3-(hydroxymethyl)pyridines. Reactions are carried out in MeCN at 25 degrees C with 3 equiv of I(2) as the iodine source and NaHCO(3) (3 equiv) as the base. The regiochemical outcome of the reaction strongly depends on the substitution pattern of the starting material. In particular, the 5-exo-dig cyclization mode, leading to dihydroisobenzofurans, is observed in the case of substrates bearing a tertiary alcoholic group, owing to the gem-dialkyl effect, while the 6-endo-dig cyclization mode, leading to isochromene or pyranopyridines, is the usually preferred pathway in the case of substrates bearing a primary or secondary alcoholic group.

ChemInform Abstract: Novel Synthesis of Medium‐Sized Heterocycles by Palladium‐Catalyzed Intramolecular Heck Reaction via 9‐endo‐trig Mode of Cyclization.

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.

The influence of electronic factors on Pd-mediated cycloisomerization: a systematic investigation of competitive 6- exo-dig versus 7- endo-dig cyclizations of sugar alkynols

Pd-mediated cycloisomerization of 3- C-propargyl- ribo- and allofuranose derivatives was investigated in detail to understand the influence of electronic factors on the regioselectivity (6- exo- vs 7- endo) of alkynol cycloisomerization leading either to a six- or seven-membered ring. In general, the 6- exo-dig mode of cyclization is facile and is independent of electronic factors. With some of the alkynols, a regioselective (7- endo?) hydration of the alkyne unit was observed and this has been attributed to the participation of C(3)–OH. When the C(3)–OH was protected as its benzyl ether, cycloisomerization of these alkynols occurred exclusively in a 6- exo-dig mode resulting in the corresponding [3.2.1]-bicyclic ketals. Additional control experiments conducted were in support of the participation of C(3)–OH in regioselective alkyne hydration.

ChemInform Abstract: Synthesis of Highly Substituted Dibenzoazocine Derivatives by the aza‐Claisen Rearrangement and Intramolecular Heck Reaction via 8‐exo‐Trig Mode of Cyclization.

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.

Preferential mode of cyclization of tetrahydrofuran amino acids containing peptides: some theoretical insights

AbstractTheoretical insights have been provided for the observed preference of cyclodimerization over intramolecular cyclization reactions in linear tripeptides containing “2,5‐cis” (2S,5R)‐tetrahydrofuran amino acid as well as in those containing “2,5‐trans” (2S,5S)‐tetrahydrofuran amino acid, using quantum chemical methods. The geometries of species involved as well as the feasibility of cyclization reactions are studied at the B3LYP/6‐31G(d,p) level of theory in gas phase as well as in solvent phase. Thermodynamic data from Hessian calculations favor the intermolecular cyclization. Analysis of optimized geometries reveals the existence of additional stabilizing hydrogen bonding interactions in intermolecularly cyclized products. The existence of these second‐order interactions is substantiated by topological (atoms in molecules (AIM)) and natural bond orbital (NBO) analyses. Such interactions are absent in the intramolecular cyclization products. Further justification for the presence of stabilizing interactions in intermolecularly cyclized products comes from the molecular electrostatic potentials and electron density surfaces. Kinetic control favoring the intermolecularly cyclized products due to additional entropy of activation in the intramolecular case is surmised. Copyright © 2009 John Wiley & Sons, Ltd.

Cyclopolymerization Reactions of Diallyl Monomers: Exploring Electronic and Steric Effects Using DFT Reactivity Indices

The regioselectivity in the cyclopolymerization of diallyl monomers is investigated using DFT-based reactivity indices. In the first part, the experimentally observed mode of cyclization (exo versus endo) of 11 selected radicals involved in this process is reproduced by the computation of activation energies, entropies, enthalpies, and Gibb's free energies for the 5- and 6-membered cyclization reactions. The application of a recently proposed energy partitioning of the activation barriers shows that the regioselectivity cannot be explained by the steric effect alone. Next, a number of relevant DFT-based reactivity indices, such as non-spin-polarized and spin-polarized Fukui functions, spin densities, and dual descriptors, were applied to probe the role of the polar and stereoelectronic effects in this reaction. The dual descriptor has been found to reproduce best the experimental trends, confirming the important role of the stereoelectronic effects.

Divergent and Expeditious Access to Fused Skeletons Inspired by Indole Alkaloids and Transtaganolides

We report the development of a divergent synthetic process entailing four-step access to the elaborate fused skeletons reminiscent of aspidophytines and transtaganolides. A variety of branched precursors were synthesized on the basis of Ugi condensations and installation of diazoimide and subjected to rhodium-catalyzed tandem reactions. Switching of cyclization modes was demonstrated by the choice of the amine building blocks installed at site C.

Novel Synthesis of Medium-Sized Heterocycles by Palladium-Catalyzed Intramolecular Heck Reaction via 9-endo-trig Mode of Cyclization

An efficient and high yielding method for the synthesis of nine-membered heterocyclic skeletons has been developed by palladium-catalyzed intramolecular Heck reaction via an unusual 9-endo-trig mode of cyclization.

Manganese(III)-Mediated Transformations of Phloroglucinols: A Formal Oxidative [4 + 2] Cycloaddition Leading to Bicyclo[2.2.2]octadiones

Manganese(III)-mediated oxidative transformations of dearomatized phloroglucinol (1,3,5-trihydroxybenzene) derivatives are reported. A number of cyclization modes have been observed, including polycyclization to afford bicyclo[2.2.2]octadiones via a formal oxidative radical [4 + 2] cycloaddition.

Discussion of substantially identical gel points among multiallyl monomers based on characterization of resultant network polymer precursors consisting of oligomeric primary polymer chains

AbstractNo difference in the actual gel points was substantially observed among three isomeric diallyl phthalates such as diallyl phthalate (DAP), diallyl isophthalate, and diallyl terephthalate (DAT); this interesting gelation behavior was discussed further in terms of the correlation between gelation and the difference in cyclization modes, and also, the difference in reactivity between the uncyclized and cyclized radicals for cross‐linking. In the present work, we tried to extend the preceding discussion to the polymerization of triallyl trimellitate (TAT) because the molecular structure of TAT is presumed to essentially involve the characteristics of three isomeric diallyl phthalates and, therefore, the enhanced gelation was expected in TAT polymerization. However, no enhancement of gelation was observed. For a full understanding of the gelation in multiallyl cross‐linking polymerization, we explored further the polymerizations of DAP, DAT, and TAT, especially focusing on the characterization of resultant network polymer precursors (NPPs) using SEC‐MALLS‐viscometry providing the correlation of [η] versus Mw of fractionated samples. Notably, the structure of NPP consisting of oligomeric primary polymer chains generated from specific allyl polymerization would become core‐shell type dendritic with the progress of polymerization. The correlation between delayed gelation and decreased reactivity of dendritic NPP for intermolecular cross‐linking is discussed. Conclusively, the reactivity for intermolecular cross‐linking between NPPs decreased with the progress of polymerization leading to a delayed gelation. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2871–2881, 2009

Cyclization Reactions of 1‐Amino‐5‐trifluoromethyl‐5‐thienyl‐1‐azapenta‐1,4‐dien‐3‐ones under Superelectrophilic Conditions: Synthesis of Novel Benzothiophenols, Cyclopentenols and Dihydrodiazepinols

AbstractTrifluoromethyl‐substituted 1‐amino‐5‐thienyl‐1‐aza‐1,4‐dien‐3‐ones 5, which are accessible in good yields from keto esters 1 in a three‐step procedure, undergo three different types of cyclization reactions upon treatment with a large excess of trifluoromethanesulfonic acid, depending on the substitution pattern. Thus, starting materials 5a–f without a halogen substituent at the 3‐position of the thienyl subunit undergo 1,6‐cyclization reactions (hydroxyannulation) to give benzothiophenol derivatives 6. In contrast, 5‐(3‐bromothienyl)‐substituted compounds 5g–j undergo Nazarov 1,5‐cyclization reactions to produce cyclopentenols 7a–d. Finally, 1‐dimethylamino‐substituted 1‐azadienones 5k,l undergo 1,7‐cyclization reactions to form novel dihydrodiazepinones 8a,b after tautomerization. On the basis of quantum chemical calculations we interpret these different types of multistep reactions to be cyclization reactions that proceed under superelectrophilic conditions through both mono‐ and dicationic intermediates. Electrophilic and pericyclic cyclization modes are discussed on the basis of the results of NICS calculations. Several of the compounds 6, 7 and 9 were characterized by X‐ray diffraction.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Synthesis of highly substituted dibenzoazocine derivatives by the aza-Claisen rearrangement and intramolecular Heck reaction via 8- exo-trig mode of cyclization

The synthesis of highly substituted dibenzo-azocine systems is still lacking. An efficient synthetic protocol utilizing the sequential aromatic aza-Claisen rearrangement followed by the implementation of the intramolecular Heck reaction as a key step has been developed for the synthesis of various dibenzo-azocine derivatives of biological relevance.

Biogenetic-Like Cyclization of Denudatenone A to Dolabellane-Type Diterpenoids Induced by Samarium(II) Iodide: A Ketyl-Olefin Radical Coupling Reaction Forming Five-Membered Carbocycles

Denudatenone A was treated with SmI2 in THF with or without the additives to form dolabellane-type diterpenoids as a result of 5-exo-trig mode of cyclization. The cyclized products were effectively obtained when water or HMPA was added. This constitutes the biogenetic-type transformation of vibsane to dolabellane diterpenoids.

Skeletal and Stereochemical Diversification of Tricyclic Frameworks Inspired by Ca2+-ATPase Inhibitors, Artemisinin and Transtaganolide D

Inspired by the common skeletal motifs of Ca(2+)-ATPases inhibitors involving artemisinin and transtaganolide D, small molecule collections with the three-dimensional structural diversity of tricyclic systems were designed and expeditiously synthesized (4-5 steps). A synthetic strategy featuring stereochemical diversification of ring-junctions and control of cyclization modes was devised to access varied molecular architectures in a systematic fashion.

Engineered biosynthesis of bacterial aromatic polyketides in Escherichia coli

Bacterial aromatic polyketides are important therapeutic compounds including front line antibiotics and anticancer drugs. It is one of the last remaining major classes of natural products of which the biosynthesis has not been reconstituted in the genetically superior host Escherichia coli. Here, we demonstrate the engineered biosynthesis of bacterial aromatic polyketides in E. coli by using a dissected and reassembled fungal polyketide synthase (PKS). The minimal PKS of the megasynthase PKS4 from Gibberella fujikuroi was extracted by using two approaches. The first approach yielded a stand-alone Ketosynthase (KS)_malonyl-CoA:ACP transferase (MAT) didomain and an acyl-carrier protein (ACP) domain, whereas the second approach yielded a compact PKS (PKS_WJ) that consists of KS, MAT, and ACP on a single polypeptide. Both minimal PKSs produced nonfungal polyketides cyclized via different regioselectivity, whereas the fungal-specific C2-C7 cyclization mode was not observed. The kinetic properties of the two minimal PKSs were characterized to confirm both PKSs can synthesize polyketides with similar efficiency as the parent PKS4 megasynthase. Both minimal PKSs interacted effectively with exogenous polyketide cyclases as demonstrated by the synthesis of predominantly PK8 3 or NonaSEK4 6 in the presence of a C9-C14 or a C7-C12 cyclase, respectively. When PKS_WJ and downstream tailoring enzymes were expressed in E. coli, the expected nonaketide anthraquinone SEK26 was recovered in good titer. High-cell density fermentation was performed to demonstrate the scale-up potential of the in vivo platform for the biosynthesis of bacterial polyketides. Using engineered fungal PKSs can therefore be a general approach toward the heterologous biosynthesis of bacterial aromatic polyketides in E. coli.

Au-Catalyzed Cycloisomerization of N-Alkenyl Alkynylamides to 2-Pyridones

Reported is a Au(I)/PPh3-catalyzed cycloisomerization of N-alkenyl alkynylamides to substituted 2-pyridones in fair to good yields. The starting amides were readily obtained by N-acylation of imines with alkynoyl chlorides. A cationic Au(I)/PPh3 complex gave the highest conversion while the use of a neutral Au(I)/PPh3 complex was catalytically inactive. The reaction appears to proceed through an endo-dig cyclization mode. Although little versatility in substitution patterns was achieved, 5,6-cyclofused 2-pyridones were obtained in high yields.

“Ligand-Free” CuI-Catalyzed Highly Efficient Intramolecular S-Vinylation of Thiols with Vinyl Chlorides and Bromides

With CuI as the catalyst and K(3)PO(4) x 3 H(2)O as the base, highly efficient intramolecular S-vinylation of thiols with vinyl chlorides or bromides was successfully implemented without the help of an additional ligand. Moreover, the competition experiments revealed that the 4-exo cyclization is fundamentally preferred over other modes (5-exo, 6-exo, and 6-endo) of cyclization.

A facile rearrangement of pyrroloindoline derivative to pyrroloquinoline: A new analogues of duocarmycins

Abstractmagnified imageFree‐radical generated at C‐7 position of indole derivative bearing N‐(3′‐chloroallyl) group prompted a regioselective intramolecular cyclization to furnish pyrroloindoline derivative, through the more favorable 5‐exo‐trig cyclization mode. The pyrroloindoline compound smoothly rearranged to pyrroloquinoline under mild conditions.

Preference of β-Lactam Formation in Cu(I)-Catalyzed Intramolecular Coupling of Amides with Vinyl Bromides

A general and highly efficient synthesis of 4-alkylidene-2-azetidinones was achieved by the Cu(I)-catalyzed intramolecular C-N coupling of amides with vinyl bromides. This 4-exo ring closure was found to be fundamentally preferred over other modes (5-exo, 6-exo, and 6-endo) of cyclization under copper catalysis. Tandem C-N bond formation was then successfully developed to allow the convenient generation of medium-sized lactams.