Cyclization Path Research Articles

Diverged Plant Terpene Synthases Reroute the Carbocation Cyclization Path towards the Formation of Unprecedented 6/11/5 and 6/6/7/5 Sesterterpene Scaffolds

AbstractSesterterpenoids are a relatively rare class of plant terpenes. Sesterterpene synthase (STS)‐mediated cyclization of the linear C25 isoprenoid precursor geranylfarnesyl diphosphate (GFPP) defines sesterterpene scaffolds. So far only a very limited number of STSs have been characterized. The discovery of three new plant STSs is reported that produce a suite of sesterterpenes with unprecedented 6/11/5 and 6/6/7/5 fused ring systems when transiently co‐expressed with a GFPP synthase in Nicotiana benthamiana. Structural elucidation, feeding experiments, and quantum chemical calculations suggest that these STSs catalyze an unusual cyclization path involving reprotonation, intramolecular 1,6 proton transfer, and concerted but asynchronous bicyclization events. The cyclization is diverted from those catalyzed by the characterized plant STSs by forming unified 15/5 bicyclic sesterterpene intermediates. Mutagenesis further revealed a conserved amino acid residue implicated in reprotonation.

Diverged Plant Terpene Synthases Reroute the Carbocation Cyclization Path towards the Formation of Unprecedented 6/11/5 and 6/6/7/5 Sesterterpene Scaffolds.

Sesterterpenoids are a relatively rare class of plant terpenes. Sesterterpene synthase (STS)‐mediated cyclization of the linear C25 isoprenoid precursor geranylfarnesyl diphosphate (GFPP) defines sesterterpene scaffolds. So far only a very limited number of STSs have been characterized. The discovery of three new plant STSs is reported that produce a suite of sesterterpenes with unprecedented 6/11/5 and 6/6/7/5 fused ring systems when transiently co‐expressed with a GFPP synthase in Nicotiana benthamiana. Structural elucidation, feeding experiments, and quantum chemical calculations suggest that these STSs catalyze an unusual cyclization path involving reprotonation, intramolecular 1,6 proton transfer, and concerted but asynchronous bicyclization events. The cyclization is diverted from those catalyzed by the characterized plant STSs by forming unified 15/5 bicyclic sesterterpene intermediates. Mutagenesis further revealed a conserved amino acid residue implicated in reprotonation.

Unearthing a sesterterpene biosynthetic repertoire in the Brassicaceae through genome mining reveals convergent evolution

Sesterterpenoids are a rare terpene class harboring untapped chemodiversity and bioactivities. Their structural diversity originates primarily from the scaffold-generating sesterterpene synthases (STSs). In fungi, all six known STSs are bifunctional, containing C-terminal trans-prenyltransferase (PT) and N-terminal terpene synthase (TPS) domains. In plants, two colocalized PT and TPS gene pairs from Arabidopsis thaliana were recently reported to synthesize sesterterpenes. However, the landscape of PT and TPS genes in plant genomes is unclear. Here, using a customized algorithm for systematically searching plant genomes, we reveal a suite of physically colocalized pairs of PT and TPS genes for the biosynthesis of a large sesterterpene repertoire in the wider Brassicaceae. Transient expression of seven TPSs from A. thaliana, Capsella rubella, and Brassica oleracea in Nicotiana benthamiana yielded fungal-type sesterterpenes with tri-, tetra-, and pentacyclic scaffolds, and notably (-)-ent-quiannulatene, an enantiomer of the fungal metabolite (+)-quiannulatene. Protein and structural modeling analysis identified an amino acid site implicated in structural diversification. Mutation of this site in one STS (AtTPS19) resulted in premature termination of carbocation intermediates and accumulation of bi-, tri-, and tetracyclic sesterterpenes, revealing the cyclization path for the pentacyclic sesterterpene (-)-retigeranin B. These structural and mechanistic insights, together with phylogenetic analysis, suggest convergent evolution of plant and fungal STSs, and also indicate that the colocalized PT-TPS gene pairs in the Brassicaceae may have originated from a common ancestral gene pair present before speciation. Our findings further provide opportunities for rapid discovery and production of sesterterpenes through metabolic and protein engineering.

Drawing Catalytic Power from Charge Separation: Stereoelectronic and Zwitterionic Assistance in the Au(I)-Catalyzed Bergman Cyclization.

The synergy between bond formation and bond breaking that is typical for pericyclic reactions is lost in their mechanistic cousins, cycloaromatization reactions. In these reactions, exemplified by the Bergman cyclization (BC), two bonds are sacrificed to form a single bond, and the reaction progress is interrupted at the stage of a cyclic diradical intermediate. The catalytic power of Au(I) in BC stems from a combination of two sources: stereoelectronic assistance of C-C bond formation (i.e., "LUMO umpolung") and crossover from a diradical to a zwitterionic mechanism that takes advantage of the catalyst's dual ability to stabilize both negative and positive charges. Not only does the synergy between the bond-forming and charge-delocalizing interactions lead to a dramatic (>hundred-billion-fold) acceleration, but the evolution of the two effects results in continuous reinforcement of the substrate/catalyst interaction along the cyclization path. This cooperativity converts the BC into the first example of an aborted [3,3] sigmatropic shift where the pericyclic "transition state" becomes the most stable species on the reaction hypersurface. Aborting the pericyclic path facilitates trapping of cyclic intermediate by a variety of further reactions and provides a foundation for the discovery of new modes of reactivity of polyunsaturated substrates. The application of distortion/interaction analysis allows us to quantify the increased affinity of Au-catalysts to the Bergman cyclization transition state as one of the key components of the large catalytic effect.

ChemInform Abstract: Hypervalent Iodine(III)‐Mediated Benzannulation of Enamines with Alkynes: An Efficient Synthesis of Substituted Aminonaphthoic Acid Derivatives.

AbstractWhen meta‐substituted phenyl enamines (I), (VIII) are employed in the reaction, two cyclization paths are detected and ortho‐cyclization products are obtained as the only or major products.

Theoretical study on the azido-cyclization of 3,6-diazido-1,2,4,5-tetrazine (DAT) with the dimethylsulfoxide (DMSO) solvent

The density functional theory (DFT) with B3LYP/6-311G∗ level was used to study the azido-cyclization of 3,6-diazido-1,2,4,5-tetrazine (DAT) with the dimethylsulfoxide (DMSO) solvent based on the self-consistent reaction field (SCRF). The cyclization of DAT mainly occurs in the conversion azido→tetrazole, in which the molecular and electronic structure change significantly. The electrostatic potential was introduced to predict the sites where could be vulnerable to attacks by the electrophile. The thermodynamic analysis shows that all reactions are endothermic and non-spontaneous in DMSO solvent. And DMSO makes the products more stable than in gas phase, while there is a little decrease in the cyclization barrier. The barriers of the first and second cyclization are 24 and 28kcal/mol, and the most possible cyclization path may connect the ap-DAT and the ap-DAT2c. The isomeric products (ap-DAT2c and sp-DAT2c) coexist due to the extremely low barriers of azido-rotation (about 7 and 8kcal/mol). Finally, the rate constants and the Arrhenius equation were evaluated between the temperature ranges of 200 and 1000K.

ChemInform Abstract: Copper‐Catalyzed Oxidative Ring Closure of ortho‐Cyanoanilides with Hypervalent Iodonium Salts: Arylation‐Ring Closure Approach to Iminobenzoxazines.

AbstractA novel, highly modular synthetic methodology with high functional group tolerance is developed for the construction of iminobenzoxazine derivatives from ortho‐cyanoanilides and diaryliodonium triflates via an oxidative arylation—cyclization path.

Hypervalent Iodine(III)‐Mediated Benzannulation of Enamines with Alkynes: an Efficient Synthesis of Substituted Aminonaphthoic Acid Derivatives

Abstract An intermolecular two CC bond formation procedure for the synthesis of carbocycles mediated by hypervalent iodine(III) reagents was developed. This metal free protocol provided a new approach for the synthesis of useful substituted 1‐amino‐2‐naphthoic acid derivatives via benzannulation reactions. Various N‐unsubstituted and N‐alkyl substituted aromatic enamines with terminal alkynes and non‐terminal alkynes can be converted into corresponding 1‐amino‐2‐naphthoic acid derivatives under mild reaction conditions. When meta‐substituted phenyl enamines were employed in the reaction, two cyclization paths were detected in the reaction and ortho‐cyclization products were the only or major products. Good functional group tolerance, readily available material and high atom utilization efficiency make this method a potential procedure which may find broad application in organic synthesis.

Copper‐Catalyzed Oxidative Ring Closure of ortho‐Cyanoanilides with Hypervalent Iodonium Salts: Arylation–Ring Closure Approach to Iminobenzoxazines

AbstractA novel, highly modular synthetic methodology with high functional group tolerance was developed for the construction of iminobenzoxazine derivatives from ortho‐cyanoanilides and diaryliodonium triflates via an oxidative arylation–cyclization path. The reaction is supposed to involve the formation of highly active aryl‐copper(III) species. In this novel transformation, copper(II) triflate was used as catalyst in 1,2‐dichloroethane or ethyl acetate and the reaction takes place at 75 °C in 2–16 h.magnified image

DFT study of the stereo-selectivity of oxygenated heterocycles from 10 to 12 links

Intra-molecular Diels–Alder (IMDA) reactions of tethered trienes can furnish two distinct diastereoisomeric products, the cis (i.e., endo) stereoisomer and the trans (i.e., exo) stereoisomer. Experimental evidence shows a quite high cis stereo-selectivity for 10-link compounds (cis/trans = 70:30), while 11- and 12-links compounds exhibit no particular selectivity. DFT (B3LYP/6-31G*) computations provide useful insights into the origins of this amazing stereo-selectivity. The cyclization path towards trans stereo-isomer is always thermodynamically favored, whatever the size of the system. The high cis stereo-selectivity displayed by the 10-link system is kinetically controlled by a tug-of-war between ring strain and electronic effects in the transition structure. The dual descriptor of chemical reactivity, a conceptual DFT based descriptor designed to delineate electronic effects, has been used to unravel the stabilizing processes that take place at the TSs.

DFT-Assisted Mechanism Evolution of the Carbonylation of Ethylene Glycol to Ethylene Carbonate by Urea over Zn(NCO)2·2NH3 Catalyst

Zn(NCO)2·2NH3 catalyst has been synthesized, characterized by X-ray diffraction and IR spectroscopy, and used as a catalyst for the cyclization of urea and ethylene glycol (EG) to ethylene carbonate (EC) for the first time. A maximum yield of 40% has been obtained with a urea/EG mole ratio of 1:1.5 and a temperature of 150 ± 2 °C. An attempt has been made to predict the mechanism of the reaction with the help of density functional theory calculations. Our calculations suggest the reaction to be a consecutive one. In the first step, urea decomposes to ammonia and isocyanic acid (HNCO). HNCO reacts with EG to produce 2-hydroxyethyl carbamate (2-HEC). At the last step, 2-HEC cyclizes over Zn(NCO)2·2NH3 to EC. Calculations suggest the cyclization of 2-HEC to follow a charge-controlled intramolecular nucleophilic elimination cyclization path.

Tuning Selectivity of Anionic Cyclizations: Competition between 5-Exo and 6-Endo-Dig Closures of Hydrazides ofo-Acetylenyl Benzoic Acids and Based-Catalyzed Fragmentation/Recyclization of the Initial 5-Exo-Dig Products

Depending on the reaction conditions and the nature of substituents at the triple bond, anionic cyclizations of hydrazides of o-acetylenyl benzoic acids can be selectively directed along three alternative paths, each of which provides efficient access to a different class of nitrogen heterocycles. The competition between 5-exo and 6-endo cyclizations of the "internal" nitrogen nucleophile is controlled by the nature of alkyne substituents under the kinetic control conditions. In the presence of KOH, the initially formed 5-exo products undergo a new rearrangement that involves a ring-opening followed by recyclization to the formal 6-exo-products and rendered irreversible by a prototropic isomerization. DFT computations provide insight into the nature of factors controlling relative rates of 5-exo, 6-endo, and 6-exo cyclization paths, ascertain the feasibility of direct 6-exo closure and relative stability for the anionic precursor for this process, provide, for the first time, the benchmark data for several classes of anionic nitrogen cyclizations, and dissect stereoelectronic effects controlling relative stability of cyclic anionic intermediates and influencing reaction stereoselectivity. We show that the stability gain due transformation of a weak pi-bond into a stronger sigma-bond (the usual driving force for the cyclizations of alkynes) is offset in this case by the transformation of a stable nitrogen anion into an inherently less stable carbanionic center. As a result, the cyclizations are much more sensitive to external conditions and substituents than similar cyclizations of neutral species. However, the exothermicity of such anionic cyclizations is increased dramatically upon prototropic isomerization of the initially formed carbanions into the more stable N-anions. Such tautomerizations are likely to play the key role in driving such cyclizations to completion but may also prevent future applications of such processes as the first step in domino cyclization processes.

Study of the intramolecular cyclization of N-methyl-3-phenyl- N-(2-( E)-phenylethenyl)- trans( cis)-oxiranecarboxamide – Syntheses of Homoclausenamide and Dehydroclausenamide

Homoclausenamide was synthesized for the first time, and the intramolecular cyclization study of N-methyl-3-phenyl- N-(2-( E)-phenylethenyl)- trans( cis)-oxiranecarboxamide well demonstrated how the stereochemistry affects the cyclization paths.

Lewis Acid and Substituent Effects on the Molecular Mechanism for the Nazarov Reaction of Penta-1,4-dien-3-one and Derivatives. A Topological Analysis Based on the Combined Use of Electron Localization Function and Catastrophe Theory.

The joint use of the topological analysis provided by the electron localization function (ELF) and catastrophe theory (CT), at the B3LYP/6-31G(d) calculation level, allows us to examine the Lewis acid (protonation H(+) and presence of BH3) and the role of an electron donor substituent (-OCH3) at α and β positions along the course of the molecular mechanism for the Nazarov rearrangement of penta-1,4-dien-3-one and eight derivatives. The progress of the reaction is monitored by the changes of the ELF structural stability domains (SSDs), each change being controlled by a turning point derived from CT. These SSDs and the corresponding turning points are associated with a sequence of elementary chemical steps. Along the cyclization path of penta-1,4-diene-3-one, four SSDs as well as three turning points (cusp1-fold1-cusp2) have been characterized. The first and second SSDs correspond to a polarization of the C-O bond and electronic redistribution among the C-C bonds, respectively, and they can be associated with the formation of an oxyallyl structure. The third and fourth SSDs can be assigned to the ring closure process. Protonation of the oxygen atom shifts the reactive directly into the second SSD, greatly reducing the activation and reaction energies. The electronic effects due to Lewis acids and electron donor substituents have been rationalized in terms of calculations of mesomeric structures from ELF basin populations. The combination of Lewis acids together with α and β -OCH3 substitutions renders a cooperative and competitive effect on activation and reaction free energies, respectively.

Synthesis of Heterocyclic Compounds Containing Perfluoroalkyl Groups. Reactions of Perfluoro(2‐methyl‐2‐pentene) and Perfluoro(5‐aza‐4‐nonene) with N,S‐Dinucleophiles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Heterocyclic Compounds Containing Perfluoroalkyl Groups. Reactions of Perfluoro(2-methyl-2-pentene) and Perfluoro(5-aza-4-nonene) with N,S-Dinucleophiles

Perfluoro(2-methyl-2-pentene) and perfluoro(5-aza-4-nonene) react with 1,4,5,6-tetrahydropyrimi-dine-2-thiol, pyridine-2-thiol, and 1,2,4-triazole-3-thiol to afford fused heterocyclic systems, while their reactions with tetrahydrothiazole-2-thione and pyrimidine-2-thiol result in replacement of the fluorine atom at the double bond. Treatment of 3,3,3-trifluoro-1-pentafluoroethyl-2-trifluoromethyl-1-pentenyl isothiocyanate with ammonia gives N-(3,3,3-trifluoro-1-pentafluoroethyl-2-trifluoromethyl-1-propenyl)thiourea which undergoes ring closure to 4-tetrafluoroethylidene-5,5-bis(trifluoromethyl)-4,5-dihydrothiazol-2-amine. Possible cyclization paths and the effect of the 1,3(N,S)-dinucleophile nature on the direction of nucleophilic addition at the double bond are discussed.

Synthesis and Transformations of 3‐Ethoxycarbonyl‐2‐(N‐R‐thioureido)thiophenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and Transformations of 3-Ethoxycarbonyl-2-(N-R-thioureido)thiophenes

3-Ethoxycarbonyl-2-(N-R-thioureido)-4,5,6,7-tetrahydrobenzo[b]thiophenes were obtained by the reaction of 2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene with isothiocyanates and of 3-ethoxycarbonyl-2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]thiophene with primary and secondary amines. The cyclization paths of the products leading to derivatives of thieno[2,3-d]pyrimidine and thieno[2,3-d]-1,3-thiazine were studied. The corresponding S-substituted derivatives were obtained by the alkylation of 3-R-2-thioxo-3,4,5,6,7,8-hexahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones.

PRACTICAL SYNTHETIC ROUTE TO BENZIMIDAZOLE-2-CARBOXYLATE DERIVATIVES VIA I2-INDUCED OVERALL 5-ENDO-TRIG CYCLIZATION

A practical synthetic route for benzimidazole-2-carboxylate derivatives has been developed, in which an iodine-induced 5-endo-trig cyclization path is involved as a key step. © 1997 Elsevier Science Ltd.

An unexpected cyclization path to some pyrazoles

The treatment of ketal hydrazones of arylglyoxals (2) with 75% sulfuric acid leads to 3-aroyl-4-phenyl-1-methylpyrazoles (6) as well as 4-phenyl-1-methylpyrazole (7) and the corresponding benzoic acids. Possible mechanisms are discussed.