Computational analysis of the autocatalytic posttranslational cyclization observed in histidine ammonia-lyase. A comparison with green fluorescent protein.

Density functional calculations using hybrid functionals (B3LYP) have been performed to study the mechanism of the autocatalytic posttranslational cyclization observed in histidine ammonia-lyase. Two mechanisms were analyzed, the commonly accepted mechanism in which cyclization precedes dehydrogenation (reduced mechanism) and a mechanism in which dehydrogenation precedes cyclization (oxidized mechanism). The reduced pathway is not supported by the calculations, while the alternative oxidized mechanism where a dehydration occurs prior to the formation of the ring yields reasonable energetics for the system. Database searches showed that the oxidative mechanism in which the formation of the dehydro amino acids in residue i + 1 precedes the cyclization is also structurally advantageous as it results in shorter distances between the carbonyl carbon of residue i and the amide nitrogen of residue i + 2 and, therefore, preorganizes the protein for cyclization. Conformational searches showed that these distances were also unusually short and exhibited very little variation in the Delta-Ala143 HAL tetramer, indicating that like GFP the tetrameric form of HAL is rigidly preorganized for cyclization. The monomeric form of HAL is less preorganized than the tetrameric form of HAL. Dehydro amino acids aid in the preorganization, but the main driving force in the rigid tight turn formation is the influence of the surrounding protein.     

Silicon-Directed Nazarov Cyclizations. Part V. Substituent and heteroatom effects on the reaction

The ability to incorporate alkyl, alkenyl, aryl, and heteroatomic groups into substrates for the silicon-directed Nazarov cyclization and their subsequent reactions has been investigated. In general, most of the groups are compatible with the conditions for the cyclization and do not interfere even when directly attached to the divinyl ketone. The influence of substituents on the rate of the cyclization has been addressed and is consistent with a simple mechanistic picture. O- and N-Containing functions are tolerated except when attached to the α-vinyl C-atom of the divinyl ketone. The diastereoface-directing effect of a fused cyclobutane is discussed.     

Formation of polyimide from benzophenonetetracarboxylic acid diester complexes with different diamines. 4. Gas-chromatographic study of thermal cyclization of complexes

Thermal cyclization of H complexes is characterized by one rate constant which significantly distinguishes it from thermal cyclization of polyamido acids. The degree of completion of thermal cyclization of the H complex and its rate are determined by diffusion processes related to the structure of the H complex and mobility (softening) of the system during thermal cyclization.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1006–1011, May, 1991.We would like to thank V. V. Shamanin for discussing the results.     

8-endo versus 7-exo cyclization of alpha-carbamoyl radicals. A combination of experimental and theoretical studies

Atom transfer radical cyclization reactions of N-(4-pentenyl)iodoacetamides were investigated. The reactions were efficiently promoted by BF3.OEt2. For N-alkenyl-substituted iodoamides, excellent regioselectivity in favor of 8-endo cyclization was observed, while both 7-exo and 8-endo cyclization products were formed with the 8-endo cyclization preferred in the cases of N-(2-allylphenyl)-substituted iodoamides. Density functional theory calculations at the B3LYP/6-31G level revealed that both the s-trans and the s-cis conformational transition structures were feasible for the 8-endo cyclization of N-alkenyl-substituted alpha-carbamoyl radicals while 7-exo transition structures were much less stable. For the cyclization of N-(2-allylphenyl)-substituted alpha-carbamoyl radicals, the transition structures for 8-endo and 7-exo cyclizations were of comparable energy. These results were in excellent agreement with the experimental observations.     

Acrylonitrile Copolymerizations. VI. Influence of the Comonomer on the Intramolecular Cyclization Reaction

The intramolecular cyclization reaction involving the polymerization of cyano groups reported in a previous paper for the system acrylonitrile-vinyl chloride is studied for other comonomers with acrylonitrile including vinyl acetate, vinylidene chloride, butadiene, styrene, methyl acrylate, and methyl methacrylate. It is shown that the extent of the reaction is governed by the reactivity of the comonomer-unit ended radical, but the cyclization reaction cannot explain all the kinetic deviations observed.     

A synthesis of 6-azabicyclo[3.2.1]octanes. The role of N-substitution

The intramolecular cyclization reactions of aziridines with pi-nucleophiles can be a useful route to a number of heterocyclic and carbocyclic ring systems. We were particularly interested in the use of this cyclization reaction for the synthesis of 6-azabicyclo[3.2.1]octanes. We report here the development of a new synthesis of the aziridine necessary for the aziridine--pi-nucleophile cyclization. We also report on the cyclization of aziridines with three different substitutions on the aziridine nitrogen. We have found that N-diphenylphospinyl and N-H aziridines, while participating in the initial ring-opening reaction, do not lead to the desired bicyclic ring systems. In contrast, a nosyl group on the aziridine nitrogen leads efficiently to the bicyclic ring system and can be readily deprotected.     

Catalytic cyclization of o-alkynylbenzaldehyde acetals and thioacetals. Unprecedented activation of the platinum catalyst by olefins. Scope and mechanism of the reaction

A general protocol for the synthesis of functionalized indenes from o-alkynylbenzaldehyde acetals and thioacetals has been elaborated. Acetals uniformly give cyclization products having the alkyl group from the starting acetylene migrated to the alpha-position, whereas the cyclization of the corresponding thioacetals proceeds without alkyl migration. Optimization of the catalytic system for the cyclization of o-alkynylbenzaldehyde acetals revealed an unknown activation effect: PtCl(2) was found to be a better catalyst for the cyclization of acetals in the presence of olefins than without. A similar catalytic system (PtCl(2)/benzoquinone) has been found to be appropriate for the cyclization of cyclic acetals, whereas the optimal catalyst for the reaction of thioacetals is PdI(2). NMR monitoring of two reactions, acetal 3a + Pd(CH(3)CN)Cl(2) in CD(3)CN and thioacetal 5j + PdI(2) in CD(2)Cl(2), revealed that in both reactions similar cationic species are formed at the early stage of the transformation. Computational data (B3LYP/SDD level of theory) suggest that the difference in the reaction pathways for acetals and thioacetals can be rationalized by taking into account the relative stabilities of the corresponding vinylpalladium intermediates (22 vs 20 and 19 vs 21), which suggests a reversible thermodynamically controlled alkyl migration in the intermediate vinylcationic species.     

Computational studies on the cyclization of polycyclic aromatic hydrocarbons in the synthesis of curved aromatic derivatives.

Computational studies on the cyclization reactions of some polycyclic aromatic hydrocarbons (PAHs) were performed at the DFT level. Compounds C26H14 and C24H14, which show the connectivity of C60 fullerene fragments, were chosen as suitable models to study the formation of curved derivatives by six- or five-membered ring formation, upon oxidation to their radical cations. Four possible pathways for the cyclization process were considered: a) initial C-C bond formation to afford a curved derivative, followed by dehydrogenation; b) homolytic C-H cleavage prior to cyclization; c) initial concerted H2 elimination and subsequent cyclization; and d) deprotonation of the radical cations prior to cyclization. Computed reaction and activation energies for these reactions show that direct cyclization from radical cations (pathway a) is the lowest-energy mechanism. The formation of five-membered rings is somewhat more favourable than benzannulation. After new cycle formation, homolytic C-H dissociation to afford the corresponding cations is the most favourable process. These cations react with H* without barrier to give H2* Intermediate deprotonations are strongly disfavoured. The relatively low activation energies compared with carbon cage rearrangements suggest that ionization of PAHs can be used for the tailored preparation of nonplanar derivatives from suitable precursors.     

Novel heterocycles. 5. Lactone fused quinazolines

Quinazoline fused lactones were synthesized. The six-membered lactone 7 was prepared by the interaction of ethyl pyruvate with hydroxyethylanthranilamide 11 , followed by hydrolysis and cyclization using 1-methyl-2-choropyridinium iodide. The corresponding seven-membered lactone 10 was prepared by reaction of 11 with ethyl propiolate, followed by hydrolysis and cyclization as above. Quinazolines possessing functionalities capable of forming either a six- or seven-membered lactone were cyclized in xylene in the presence of sodium methoxide. Only the six-membered lactone 14 formed.     

Cyclizations of N-alkylazinium cations with bifunctional nucleophiles. 18. Synthesis and structure of heterocyclic systems based on quinoxaline

N-Methylquinoxalinium iodide reacts with ethylenediamine, o-phenylenediamine, and o-aminophenol to give cyclization products of the type involving [2,3-b] annelation of the six-membered heteroring. Two molecules of the quinoxaline participate in the cyclization with 2-aminoethanol to give a complex polycyclic compound.See [1] for communication 17.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1116–1124, August, 1985.     

Intramolecular metal—double bond interactions : VII. Intramolecular cyclization of alkenyl derivatives of lithium,aluminum, gallium and indium

The intramolecular cyclization reactions of tri-1-hex-5-enyl Group III derivatives and of 1-hex-5-enyllithium have been investigated and it is proposed that the reactions may be depicted as internal addition across the terminal double bonds of the alkenyl species. The cyclization reaction proceeds more readily for the 1-hex-5-enyl derivatives than for any other chain length and is dependent on temperature, concentration and solvent. ¹H NMR data and cryoscopic molecular weight data are presented for several diisobutyialkenyl- and diisobutylalkyl-aluminum derivatives. These data have been interpreted in terms of a direct intramolecular interaction between the metal center and the π-electron system of the olefinic site. The intramolecular cyclization reactions for the 1-hept-6-enyl, 1-oct-7-enyl- and 1-undec-10-enylaluminum derivatives also were investigated and it was found that cyclization occurred only for the 1-hept-6-enyl derivative.     

UDFT and MCSCF descriptions of the photochemical Bergman cyclization of enediynes.

Several singlet and triplet potential energy surfaces (PES) for the Bergman cyclization of cis-1,5-hexadiyne-3-ene (1a) have been computed by UDFT, CI, CASCI, CASSCF, and CASMP2 methods. It is found that the first six excited states of 1a can be qualitatively described as linear combinations of the configurations of weakly interacting ethylene and acetylene units. Although the symmetry relaxation from C2nu to C2 makes cyclization of the 13B state Woodward-Hoffmann allowed, it also increases the probability of competing cis-trans isomerization. Hydrogen atom abstraction is another plausible pathway because the terminal alkyne carbons possess a large radical character. In view of the competing processes, we conclude that the Bergman cyclization along the 13B path is unlikely despite its exothermicity (Delta = -42 kcal/mol). Calculations on cyclic analogues of 1a lead to similar conclusions. A less exothermic, but more plausible pathway for photochemical cyclization lies on the 2(1)A PES (Delta = -18 kcal/mol). Compared to the 1(1)A(1) and 1(3)B states, the 2(1)A state has less in-plane electron repulsion which may facilitate cyclization. The resulting p-benzyne intermediate has an unusual electronic structure combining singlet carbene and open-shell diradical features. Deactivation of the 2(1)A state of 1a is a competing pathway.     

Round trip radical reactions from acyclic precursors to tricyclo [5.3.1.0]undecanes. A new cascade radical cyclization approach to (+/-)-isogymnomitrene and (+/-)-gymnomitrene

The synthesis and "round trip radical cyclization" of 11-iodo-2,7,11-trimethyldodec-6-en-5-one are described. The round trip cyclization is a sequence of 5-exo, 6-endo, and 5-exo cyclizations in which the last radical cyclization occurs at the same carbon atom as the initial radical generation. The key second (6-endo) cyclization produces two stereoisomers, one of which cyclizes efficiently to isogymnomitrene ketone, while the other cyclizes inefficiently to gymnomitrene ketone. Efforts to influence the kinetic or thermodynamic outcome of the second cyclization were not successful, and the results are contrasted with a related cyclization of Jung and Rayle where thermodynamic control was readily established.     

Enantio- and diastereoselective stepwise cyclization of polyprenoids induced by chiral and achiral LBAs. A new entry to (-)-ambrox, (+)-podocarpa-8,11,13-triene diterpenoids, and (-)-tetracyclic polyprenoid of sedimentary origin

An enantio- and diastereoselective stepwise cyclization of polyprenoids induced by Lewis acid-assisted chiral Br?nsted acids (chiral LBAs) and achiral LBAs is described. In particular, the absolute stereocontrol in the initial cyclization of polyprenoids to form an A-ring induced by chiral LBAs and the importance of the nucleophilicity of the internal terminator in polyprenoids for the relative stereocontrol in subsequent cyclization are demonstrated. (-)-Ambrox was synthesized via the enantioselective cyclization of (E,E)-homofarnesyl triethylsilyl ether with tin(IV) chloride-coordinated (R)-2-(o-fluorobenzyloxy)-2'-hydroxy-1,1'-binaphthyl ((R)-BINOL-o-FBn) and subsequent diastereoselective cyclization with CF(3)CO(2)H.SnCl(4) as key steps. Protection of (E,E)-homofarnesol by a triethylsilyl group increased the enantioselectivity of chiral LBA-induced cyclization and both the chemical yield and diastereoselectivity in the subsequent cyclization. The enantioselective cyclization of homo(polyprenyl)arenes possessing an aryl group was also induced by (R)-BINOL-o-FBn.SnCl(4). Several optically active podocarpa-8,11,13-triene diterpenoids and (-)-tetracyclic polyprenoid of sedimentary origin were synthesized (75-80% ee) by the enantioselective cyclization of homo(polyprenyl)benzene derivatives induced by (R)-BINOL-o-FBn.SnCl(4) and subsequent diastereoselective cyclization induced by BF(3).Et(2)O/EtNO(2) or CF(3)CO(2)H .SnCl(4).     

Dragmacidin E synthesis studies. Preparation of a model cycloheptannelated indole fragment

[reaction: see text] The conversion of N-2,2-dichloropropionyl indole methyl ester into a tetracyclic cycloheptannelated indole model compound for the synthesis of dragmacidin E was accomplished in 10 steps. Key reactions include a Witkop cyclization to fashion a C-C bond at C(4) of the indole nucleus and a subsequent Dieckmann cyclization to deliver the desired cycloheptanoid ring.     

Ringschlüsse an Chinonylmethanfarbstoffen und analogen Merocyaninen. 3. Mitteilung. Chinoide Derivate des anellierten Tetrahydro-isochinolino-chinoxalins. Ringschluss nach 1,7-Verschiebung von Wasserstoff?

Cyclization Reactions of Quinonylmethane Dyes and Analogous Merocyanines. 3. Communication. Quinoid Derivatives of the Anellated Tetrahydro-quinoxalino-quinoxaline. Cyclization Following 1,7-Hydrogene-Shift? The title compounds were obtained by proton catalyzed cyclization of the corresponding 2-(1-alkyl-3-methyl-1,2-dihydroquinoxalin-2-ylidenmethyl)-1,4-naphtho- and 1,4-anthraquinones. The visible and ¹H-NMR.- and some mass spectra of the dyes are given. Mechanistic aspects of the new-type cyclization reaction are discussed.     

Anodic Cyclizations,Seven‐Membered Rings,and the Choice of Radical Cation vs. Radical Pathways

While many steps in an oxidative cyclization reaction can be important, it is the cyclization step itself that plays the central role. If this step does not proceed well, then optimization of the rest of the sequence is futile. We report here that the key to the cyclization is channeling the reaction down the correct pathway. Some reactions require the use of a radical pathway and some require the use of a radical cation pathway. An example of each is provided along with a strategy for accessing both pathways using a common intermediate.     

Combinatorial synthetic design. Solution and polymer-supported synthesis of heterocycles via intramolecular aza Diels-Alder and imino alcohol cyclizations

A flexible synthetic strategy for combinatorial chemical applications has been developed on the basis of an aldehyde-bridge-alkene motif as the key component in several intramolecular cycloaddition reactions. This strategy was explored most extensively with the formal aza Diels-Alder cyclization, which affords a series of configurationally and functionally diverse heterocyclic compounds. The substrates included substituted salicylaldehydes, glyoxylic esters and amides, and N-acyl-alpha-aminoaldehydes; all reacted with a variety of anilines to yield different tetrahydroquinoline products. The cyclization of the aminoaldehydes was also translated from solution and optimized for solid phase. The stepwise mechanism of this cycloaddition suggested that the cationic intermediate from initial ring closure could be trapped by a variety of nucleophiles. This suggestion was confirmed by cyclization of amino alcohols and related compounds.     

Convenient access to isoindolinones via carbamoyl radical cyclization. Synthesis of cichorine and 4-hydroxyisoindolin-1-one natural products

An efficient and convenient access to 2-tert-butylisoindolin-1-ones via an oxidative radical cyclization process from stable carbamoylxanthates, derived from secondary tert-butylamines, is described. The proposed mechanism for this transformation involves, the generation of a carbamoyl radical, its cyclization to the aromatic system, and the dilauroyl peroxide (DLP) mediated rearomatization to generate the isoindolinone ring system. Additionally, the syntheses of cichorine and 4-hydroxyisoindolin-1-one natural products were carried out to underscore the synthetic potential of this xanthate-based carbamoyl radical-oxidative cyclization.     

gem-Dinitro compounds in organic synthesis. 2. Synthesis of 4-nitropyrazoles from dinitromethane and its derivatives

A series of 4-nitropyrazoles was synthesized from dinitromethane and other gemdinitro derivatives. New cyclization reactions of aliphatic azines with dinitro-methane and an intramolecular cyclization of dinitroacetazines have been discovered, with which 4-nitropyrazoles substituted at the 3- and 5-positions of the pyrazole ring can be obtained in one stage.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 12, pp. 2825–2828, December, 1991.