A Nazarov-Ene Tandem Reaction for the Stereoselective Construction of Spiro Compounds

The different reactivity of trienones under Lewis and Brønsted acids catalysis was investigated, resulting in distinct cyclization products and carbon backbones that originated either from a conjugate Prins cyclization or an interrupted Nazarov cyclization. In particular, an unprecedented Nazarov cyclization tandem reaction is presented, terminating the oxyallyl cation by an ene-type reaction, and leading stereoselectively to bicyclic spiro compounds. The terminal olefin of this motif represents a useful handle for further functionalization, making it a strategic intermediate in total syntheses. The tandem Nazarov/ene cyclization was shown to be preferred over a Nazarov/[3+2] tandem reaction for all our substrates, independent of chain length. Deuteration studies further support the mechanistic hypothesis of the terminating ene reaction.     

Studies on the oxidative cyclization of 3-hydroxyalkyl-1,2,4-trialkoxynaphthalenes and synthetic application for the biologically active natural compound rhinacanthone

The oxidative intramolecular cyclization of 3-hydroxyalkyl-1,2,4-trimethoxynaphthalenes was investigated. A series of 1,2-naphthoquinone fused cyclic ethers were synthesized directly from 3-hydroxyalkyl-1,2,4-trimethoxynaphthalenes by exposure to diammonium cerium (IV) nitrate. To understand the reaction mechanism, the intramolecular cyclization of 3-hydroxyalkyl-naphthoquinones that were formed as reaction intermediates was also examined. The results suggested that the reaction proceeds by a stepwise oxidation–cyclization mechanism. Using this methodology, five-step synthesis of rhinacanthone was achieved with high yield.     

Thermo-chemical reactions and structural evolution of acrylamide-modified polyacrylonitrile

<正>Thermal properties of acrylonitrile(AN)-acrylamide(AM) copolymers for carbon fibers were studied by DSC and in situ FTIR techniques in nitrogen(N_2) and air flows.The cyclization mechanism and stabilization behavior of polyacrylonitrile(PAN) were discussed.In N_2 flow,it was found that AM had the ability to initiate and accelerate cyclization process,which was confirmed by the fact that the initiation of nitriles shifted to a lower temperature.Compared to AN homopolymer,the initiation temperature of cyclization was ahead 32 K by introducing 3.59 mol%AM into the copolymer.The exothermic reaction was relaxed due to the presence of two separated exothermic peaks.Accompanied by DSC,in situ FTIR and calculation of activation energy,the two peaks were proved to be caused by ionic cyclization and free radical cyclization,respectively,and the corresponding cyclization mechanism was proposed.With increasing in AM content,the ionic cyclization tends to be dominant and the total heat liberated first increases and then decreases.For AN homopolymer,the activation energy of cyclization is 179 kJ/mol.For AN-AM copolymer(containing 3.59 mol%AM),the activation energy of ionic cyclization is 96 kJ/mol and that of free radical cyclization is 338 kJ/mol.In air flow,similar cyclization routes occur and the difference is the contribution of oxidation.The oxygen in environment has no remarkable effect on cyclization of AN homopolymer but retards the cyclization of AN-AM copolymers.For AN-AM copolymer with 3.59 mol%AM,the cyclization temperature is postponed 10℃in air.     

Comparative study of ring-chain isomeric transitions of 2-cyano-substituted benzamides and benzenesulfamides

The rate constants of cyclization and the constant of ring-chain equilibrium of N-isopropyl-2-cyano-substituted benzamide and benzamide and benzenesulfamide by the methods of PMR and IR spectroscopy, and it was shown that in the transition from 2-cyanobenzamides to 2-cyanobenzenesulfamides a sharp destabilization of the cyclic isomeric form is observed; however, the cyclization of 2-cyanobenzenesulfamides proceeds at a higher rate than the cyclization of 2-cyanobenzamides.     

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.     

Theoretical elucidation of kinetic and thermodynamic control of radical addition regioselectivity

The cyclizations of two structurally similar 2-oxo-5-hexenyl-type radicals have been investigated by ab initio and density functional (UB3LYP/6-31+G**//UHF/6-31G* and UB3LYP/6-31G*//UB3LYP/6-31G*) calculations. The origin of apparently contradictory reports of 6-endo and 5-exo cyclizations is determined. Kinetic control favors 6-endo cyclization, while thermodynamic control gives 5-exo cyclization, and the observation of different products from different research groups arises from the difference in experimental conditions used by the two groups. The outcome of a new cyclization reaction was predicted by using these theoretical techniques. Kinetic control is predicted to yield exclusively the products of 6-endo cyclization, while thermodynamic control would lead to an approximately equal mixture of one 6-endo and one 5-exo cyclized product. Experimental studies revealed that the reaction yields only the products of 6-endo cyclization through kinetic control.     

Effective synthesis of cyclic peptide yunnanin C and analogues via Ser/Thr ligation (STL)-mediated peptide cyclization

Cyclic peptide yunnanin C isolated from the root of Stellaria yunnanensis was efficiently synthesized in which the linear peptide was prepared by Boc-SPPS and the cyclization was realized by serine/threonine ligation (STL)-mediated cyclization. In addition, nine yunnanin C analogues, including mutations of Tyr7Gly, Tyr7Val, Tyr7Pro, Tyr7Phe, Ser1Thr, Pro2Val, Gly5Pro, Phe6Ala and Ile4Ala, were prepared in the same fashion. Here, we demonstrated that STL-mediated peptide cyclization could be an effective approach to construct cyclic peptides. Except that proline at the C-terminus could retard the cyclization process, cyclization of yunnanin C analogues with various C-terminal amino acids proceeded with fast cyclization rate (<4 h) and only trace amount of dimers (<5%) at a working concentration of 5 mM.     

Total syntheses of melinonine-E and strychnoxanthine: Evolution of the synthetic strategy enabled by novel method development

In this full account, the evolution of a synthetic strategy was detailed from a nitroso-ene cyclization to an aza-Wacker reaction for ring construction in the syntheses of melinonine-E and strychnoxanthine. The aza-Wacker cyclization to form the bridged ring was successfully developed and applied in the first asymmetric syntheses of melinonine-E and strychnoxanthine in 5–6 steps from a readily available chiral lactone. The proposed biogenesis of these two rare β-carbolinium alkaloids was revised based on their absolute configurations. Moreover, the substrate scope of the aza-Wacker cyclization demonstrated its potential for accessing various bridged ring skeletons. The mechanistic investigation established that the profound effect of the N-substituent on the amide was crucial to the success of the cyclization via the tunable amidopalladation pathway.     

A reductive cyclization approach to attenol A

A reductive cyclization strategy was applied to the synthesis of attenol A. This nontraditional approach to the spiroacetal structure illustrated several advantages of the reductive cyclization methodology. The attenol A core was formed in a carbon-carbon bond coupling that gave rise to a previously inaccessible spiroacetal epimer, a new method to synthesize thioketene acetals from a phenyl sulfone was realized, and the configurational stability of a nonanomeric spiroacetal was evaluated. A minor byproduct in the reductive cyclization reaction was identified that for the first time allowed direct evaluation of the stereoselectivity in a reductive cyclization of a dialkyloxy alkyllithium reagent.     

Intramolecular proton transfer in the cyclization of geranylgeranyl diphosphate to the taxadiene precursor of taxol catalyzed by recombinant taxadiene synthase

BACKGROUND: The committed step in the biosynthesis of the anticancer drug taxol in yew (Taxus) species is the cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene. The enzyme taxadiene synthase catalyzes this complex olefin cation cyclization cascade involving the formation of three rings and three stereogenic centers. RESULTS: Recombinant taxadiene synthase was incubated with specifically deuterated substrates, and the mechanism of cyclization was probed using MS and NMR analyses of the products to define the crucial hydrogen migration and terminating deprotonation steps. The electrophilic cyclization involves the ionization of the diphosphate with closure of the A-ring, followed by a unique intramolecular transfer of the C11 proton to the re-face of C7 to promote closure of the B/C-ring juncture, and cascade termination by proton elimination from the beta-face of C5. CONCLUSIONS: These findings provide insight into the molecular architecture of the first dedicated step of taxol biosynthesis that creates the taxane carbon skeleton, and they have broad implications for the general mechanistic capability of the large family of terpenoid cyclization enzymes.     

Anthraceno-perylene bisimides: the precursor of a new acene

A controlled synthesis strategy for a anthracene-fused perylene bisimide was developed from the cyclization of an anthracene unit pendant to a perylene diimide scaffold. The direct cyclization led to a zigzag molecule, while a Diels-Alder strategy influenced the regiochemistry of cyclization to afford the linear precursor of a new acene.     

Critical Switching of Cyclization Modes of Polyepoxides in Acidic Aqueous Media and Neutral Water: Synthesis and Revised Structure of a Nerolidol‐Type Sesquiterpenoid

Biomimetic epoxide‐opening cascades of polyepoxides enable the efficient and rapid construction of polyether frameworks. Herein, we show that the epoxide‐opening cascade cyclization that affords tetrahydrofuran products in acidic aqueous media produces tetrahydropyran (THP) in neutral water. THP formation proceeded by simply heating polyepoxides in neutral water and followed a different cyclization mode from those observed so far. The novel cascade cyclization in H₂O was applied to the synthesis of a new nerolidol‐type sesquiterpenoid, resulting in revision of the proposed structure and determination of the absolute configuration.     

Transannular cyclization of (4S,5S)-germacrone-4,5-epoxide into guaiane and secoguaiane-type sesquiterpenes

Germacrone (1) and (4S,5S)-germacrone-4,5-epoxide (2) were isolated, along with guaiane and secoguaiane-type sesquiterpenes, from Curcuma aromatica plants. Compound 2 was derived from 1 and cyclized through transannular (T-A) reactions into various guaiane and secoguaiane-type sesquiterpenes in C. aromatica. The cyclization reaction of 2 was initiated by protonation at an epoxide oxygen atom, followed by cleavage of the epoxide ring and the formation of a C-C bond between C-1 and C-5 to give guaiane-type derivatives. Acidic and thermal treatments of 2 produced twelve sesquiterpenes having guaiane and secoguaiane skeletons. The structures of these products were elucidated by spectral methods, including 2D-NMR spectroscopy. Most were identified as sesquiterpenes isolated from C. aromatica as natural products. The T-A cyclization of 2 occurred via two transition states, a cross conformation and a parallel conformation. The mechanism of the T-A cyclization reaction of 2 is discussed.     

(2,5)-Ene cyclization catalyzed by mesoporous solid acids: isotope labeling study and ab initio calculation for continuum from concerted to stepwise ene mechanism

(2,5)-Ene reactions catalyzed by mesoporous solid acids are reported from the mechanistic point of view. The continuum (2,5)-ene mechanism from the concerted to the cationic cyclization followed by 1,2-hydride shift is evaluated. The solid-acid-catalyzed cyclization of the oxonium ion intermediate 4 derived from cyclic allylic lactol ether 3 bearing allylic hydroxy group affords the (2,5)-ene product as the enol form, eventually tautomerizing to the corresponding aldehyde 6. The continuum from the concerted to stepwise mechanism is experimentally and theoretically verified in the present ene cyclization of the oxonium ion intermediate such as 4. The stepwise cyclization leading to aldehyde 6 is thus shown to associate with the concerted version as a result of the stabilization of the beta-hydroxycarbenium ion intermediate.     

含内环化与不含内环化固化理论间的对应关系

含内环化与不含内环化固化理论间的对应关系黄旭日，肖兴才，李泽生，孙家，唐敖庆（吉林大学理论化学研究所，长春，１３００２３）关键词内环化，非线性缩聚反应，数量分布函数，高分子矩在研究非线性缩聚反应体系的固化问题时，Ｆｌｏｒｙ和Ｓｔｏｃｋｍａｙｅｒ等［１...     

合成5-氯-1-甲基-4-硝基咪唑的工艺改进

以草酸二乙酯为原料,经酰胺化、环合、成盐及硝化反应合成了5-氯-1-甲基-4-硝基咪唑,总收率61.3%,其结构经1H NMR, IR和MS表征.本方法有两点改进: (1)在酰胺化反应中用30%～40%甲胺水溶液代替甲胺气体; (2)在成盐反应中直接向环化产物的丙酮溶液加硝酸析出5-氯-1-甲基咪唑硝酸盐晶体.     

Synthesis of Polysubstituted γ‐Butenolides via a Radical Pathway: Cyclization of α‐Bromo Aluminium Acetals and Comparison with the Cyclization of α‐Bromoesters at High Temperature

Polysubstituted butenolides were obtained in good to high yields from α‐bromoesters derived from propargyl alcohols by a one‐pot reaction involving the radical cyclization of α‐bromo aluminium acetals, followed by the oxidation of the resulting cyclic aluminium acetals in an Oppenauer‐type process and migration of the exocyclic C?C bond into the α,β‐position. Comparison with the direct cyclization of α‐bromoesters at high temperature and under high dilution conditions is described. Deuterium‐labelling experiments allowed us to uncover “invisible” 1,5‐hydrogen atom transfers (1,5‐HATs) that occur during these cyclization processes, together with the consequences of the latter in the epimerization of stereogenic centres. Compared to the classical approach, the cyclization of aluminium acetals proved to be highly chemoselective and its efficiency was illustrated by the short total syntheses of optically enriched γ‐butenolides isolated from Plagiomnium undulatum and from Kyrtuhrix maculans.     

An extremely facile aza-Bergman rearrangement of sterically unencumbered acyclic 3-aza-3-ene-1,5-diynes

The factors that affect the kinetics of the aza-Bergman cyclization of aza-enediynes (C,N-dialkynyl imines) have not previously been elucidated. Here we report our kinetic studies of the aza-Bergman reactions of a series of 6-triisopropylsilyl and 6-unsubstituted 1-phenyl-4-aryl-3-aza-3-ene-1,4-diynes in which the aryl group is phenyl, o-(methoxy)phenyl, or p-(methoxy)phenyl. These aza-enediynes are prepared as single isomers in modest yield from the corresponding 1-aryl-3-(triisopropylsilyl)propynone oximes. These aza-enediynes undergo aza-Bergman reaction followed by a rapid retro-aza-Bergman cyclization to afford beta-alkynyl acrylonitrile products. In no case are products corresponding to trapping the intermediate 2,5-didehydropyridine diradical isolated. While the rate of aza-Bergman cyclization is not greatly affected by the nature of the 4-aryl substituent, the rate is very dependent on the nature of the 6-substituent. 1-Phenyl-4-aryl-3-aza-3-ene-1,5-diynes that lack a 6-substituent undergo aza-Bergman cyclization spontaneously at 20 degrees C with first-order half-lives of 36-78 min. The effect of solvent on the kinetics of aza-Bergman cyclization of 1,4-diphenyl-3-aza-3-ene-1,5-diyne was investigated. The rate of this cyclization is solvent dependent, proceeding more rapidly in less polar solvents.     

Tandem Pummerer/Mannich cyclization cascade of alpha-sulfinylamides as a method to prepare aza-heterocycles

A series of alpha-sulfinylenamides was conveniently prepared by the condensation of a primary amine with a ketone, followed by reaction of the resulting imine with ethylsulfenylacetyl chloride and subsequent oxidation with sodium periodate. When treated with p-TsOH, cyclization occurred to produce fused isoquinoline lactams by a mechanism that involves an initial Pummerer reaction followed by a subsequent cyclization of the resulting N-acyliminium ion onto the tethered aromatic ring. The isolation of a single diastereomer was rationalized in terms of a Nazarov-type 4pi-electrocyclic reaction followed by pi-cyclization onto the least hindered side of the N-acyliminium ion. Another method that was used to generate the alpha-acylthionium ion intermediate involved the reaction of bis(ethylsulfenylacetyl)acetamides with dimethyl(methyl)thiosulfonium tetrafluoroborate (DMTSF). Treatment of several bis-ethylsulfenylenamides with DMTSF delivered novel spiro-heterocycles as single diastereomers in good yield by a related process. The convergency and stereochemical control associated with this cascade sequence make it particularly suited for the assembly of natural product scaffolds. Some preliminary studies were directed toward both mesembrine and deethylibophyllidine. When the model Z-enamido sulfoxide 33 was heated with p-TsOH, a 80% yield of tosylate 34 was obtained as a single diastereomer. In this case, the carbocation intermediate derived from cyclization onto the terminal pi-bond was trapped with p-TsOH from the least hindered face, opposite the angular carbomethoxy and methyl groups. Related cyclization cascades were also found to occur with systems containing tethered indole rings.     

Dearomatizing cyclization of arylsulfonylalkoxymethyl lithiums: a route to the podophyllotoxin skeleton

[reaction: see text] The phenylsulfonyl group promotes the dearomatizing cyclization of tethered organolithiums onto aromatic rings. With an ether tether, the cyclizations create a new tetrahydrofuran ring, and both cyclization and subsequent electrophilic quenches proceed with high levels of diastereoselectivity. The sulfonyl group can be removed from the cyclized products oxidatively or reductively. The dearomatizing cyclization of a naphthyl sulfone was used in the synthesis of a close structural analogue of podophyllotoxin.