The remarkable effect of cosolvent on a samarium(II)-mediated 4-exo-trig cyclization: further synthetic studies on pestalotiopsin A

A samarium(II)-mediated 4-exo-trig cyclization in which a remote stereocenter serves to control the facial selectivity of the cyclization is described. The apparent coordination of a tert-butyldimethylsilyl ether to the samarium center appears to give rise to the selectivity. The remarkable effect of the cosolvent, 2,2,2-trifluoroethanol, on the cyclization of this substrate, is also discussed. A stereoselective synthesis of the general class of gamma,delta-unsaturated aldehyde cyclization substrate is reported, and the utility of the cyclization is demonstrated in an approach to the fully functionalized core of pestalotiopsin A.     

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.     

Bioinspired total synthesis of agelastatin A

A one-two punch: two potentially biosynthetically relevant cyclizations of a keramadine analogue give agelastatin A. A diastereoselective C-ring formation, which proceeds through a 5-exo-trig cyclization or a Nazarov cyclization of a red-colored N-acyliminium intermediate, generates the three contiguous stereocenters of the cyclopentane core. A silica gel assisted cyclization of a nagelamide J analogue gives agelastatin A.     

A study of vinyl radical cyclization using N-alkenyl-7-bromo-substituted hexahydroindolinones

A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method utilizes an intramolecular Diels-Alder reaction of an amido-substituted furan across a tethered indole pi-bond. To apply this strategy to the synthesis of the indole alkaloid spegazzinidine, it was necessary to address the problem of assembling the final D-ring of the pentacyclic skeleton. Radical cyclization of a model N-allyl-7-bromo-3a-methylhexahydroindolinone system was found to preferentially lead to the 6-endo-trig cyclization product, with the best yield being obtained under high dilution conditions. The six-membered cyclized product is generated through two reaction pathways: (a) 6-endo-trig ring closure and (b) rearrangement of an intermediate methylene-cyclopentyl radical obtained by 5-exo-trig cyclization. A number of related 7-bromo-substituted hexahydroindolinones containing tethered olefinic groups were prepared and found to undergo efficient cyclization under both radical and palladium-mediated reaction conditions. Vinyl radical cyclization with several N-butenyl-substituted systems afforded a mixture of 6-exo and 7-endo cyclization products. A protocol to introduce an ethyl substituent into the C20-position of the aspidospermidine skeleton was also developed.     

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.     

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.     

6-Endo-dig versus 5-exo-dig: Exploring Radical Cyclization Preference with First-, Second-, and Third-row Linkers using High-level Quantum Chemical Methods

As an expansion upon Baldwin rules, the cyclization reactions of hex-5-yn-1-yl radical systems with different first-, second-, and third-row linkers are explored at the CCSD(T) level via means of the SMD(benzene)-G4(MP2) thermochemical protocol. Unlike C, O, and N linkers, systems with B, Si, P, S, Ge, As, and Se linkers are shown to favor 6-endo-dig cyclization. This offers fundamental insights into the rational synthetic design of cyclic compounds. A thorough analysis of stereoelectronic effects, cyclization barriers, and intrinsic barriers illustrates that structural changes alter the cyclization preference by mainly impacting 5-exo-dig reaction barriers. Based on the high-level computational modeling, we proceed to develop a new tool for cyclization preference prediction from the correlation between cyclization barriers and radical structural parameters (e. g., linker bond length and bond angle). A strong correlation is found between the radical attack trajectory angle and the reaction barrier heights, i. e., cyclization preference. Finally, the influence of stereoelectronic effects on the two radical cyclization pathways is further investigated in stereoisomers of hypervalent silicon system, which provides novel insight into cyclization control.     

Stereo/regio-controlled cyclization of polychlorohex-5-enoic acids into substituted cyclobutanes

A new method of synthesis was developed for functionally substituted cyclobutanecarboxylic acids based on an intramolecular cyclization of derivatives of the 2,2,4,6,6-pentachloro-3,3-dimethylhex-5-enoic acid in the presence of the copper(I) amine complexes. The cyclization proceeds both regiospecifically and stereoselectively, and the stereoisomeric composition of the products depends on the capability of the functional group in the initial polychloroalkenoic acid to coordinate to the transition metal ion. A reaction mechanism is suggested explaining the region/stereo-controlled course of the cyclization process.     

Cyclization of 2-dicyanomethylene-1,2-dihydropyridine-3-carbonitriles with amines: a mechanistic rationalization

A mechanistic rationalization for the cyclization of the 1,5-dinitrile system present in pyridines 4{1-3} with amines to lead to 1,6-naphthyridines is proposed. Three factors play an important role on the direction of cyclization: (1) the cyclization involves nucleophilic attack of an amidine onto a nitrile or amidine; (2) the attack has to fulfill strict geometrical constraints to allow the cyclization to proceed; (3) the cyclization step should involve the nucleophilic attack combined with a tautomerism to achieve the high levels of regioselectivity observed.     

Synthesis of 1H-indazole: a combination of experimental and theoretical studies

A new practical synthesis of 1H-indazole is presented. A previous mechanism for the cyclization step is proved to be nonfeasible and a hydrogen bond propelled mechanism is proposed. The new mechanism is suitable for similar cyclization, and a new reaction is predicted.     

Stereoselective furan-iminium cation cyclization in the construction of the core structure of manzamine A

[reaction: see text] A new type of furan-iminium cation cyclization was developed and used to construct the ABC ring of manzamine A. The cyclization proceeded at the 2-position with complete regio- and stereoselectivity to give a spiro-center. The product was efficiently converted to the highly substituted core structure of manzamine A.     

Progress toward a biomimetic synthesis of phomoidride B

[reaction: see text]. An intramolecular cyclization strategy for effecting a biomimetic synthesis of the core structure of the fungal secondary metabolites phomoidrides A and B is described. The cyclization substrate 20 is prepared in eight steps from dibromide 10. Treatment of 20 with triethylamine in acetonitrile results in a rapid cyclization to give 21 and 22 in good yield.     

Sortase A-catalyzed peptide cyclization for the synthesis of macrocyclic peptides and glycopeptides

A chemoenzymatic method was developed for the synthesis of macrocyclic peptides and glycopeptides. Sortase A was found to mediate either head to tail cyclization or oligomerization and then head to tail cyclization of peptides and glycopeptides, depending on the peptide length, to produce 15-mer or higher cyclic peptides and glycopeptides.     

Dependence of the cyclization behavior of multifunctional network molecules on molecular size

The tendency for cyclization of nonlinear network molecules is quantitatively expressed by the cyclization probability, defined as the ratio of cyclization to total reaction rate. In contrast to branching, the rate of cyclization depends on the configurational statistical mechanics of segments joining functional groups. Direct integration of the joint configurational probability density in the subspace of encounters yields the distribution of the number of configurationally formed intramolecular functional group encounters (nearest neighbors). Statistically independent network segments are assumed to obey the Gaussian statistics. A recursive relationship for the distribution of chain lengths is developed, and it is shown that for large molecular sizes this relationship tends to a limiting distribution. Corresponding average and standard deviation follow power law dependence on degree of polymerization (DP). With these results, cyclization probabilities are explicitly expressed as functions of DP. When segmental diffusion is the rate controlling factor, cyclization is similar to short range (or primary) cyclization. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 861–870, 2005     

An Efficient and Convenient Cyclization Method for the Synthesis of Flavans

Flavansrefertoalargegroupofnaturallyoccurringcompoundspossessinga2-phenyl-chromannucleus.Naturallyoccurringflavansexhibitanumberofimportantbiologicalactivitieswhichifexploitedproperly,mayleadtovaluablenewdrugsoragrochemicals'.Inflavansynthesis,thekeystepistoconstructthe3,4-dihydrobenzopyranring-Variousmethodshavebeendevelopedfortheringformation,butmostoftheminvolvemultiplestepsandgivelowoverallyields2.Inthispaper,BF3wasusedforthefirsttimeasanefficientcatalysttoformthepyranringfroml,3-diaryIp…     

Triflic acid-catalyzed cascade cyclization of arenyl enynes via acetylene-cation cyclization and Friedel-Crafts type reaction

A novel triflic acid-catalyzed cascade cyclization of arenyl 1,7-enynes through acetylene-cation cyclization followed by Friedel-Crafts reaction has been described. Various fused poly carbocycles can be obtained in good to high yields under mild reaction conditions.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Asymmetric cyclization of omega-formyl-1,3-dienes catalyzed by a zerovalent nickel complex in the presence of silanes

A nickel(0)-catalyzed asymmetric cyclization of omega-formyl-1,3-diene in the presence of silanes in which five- or six-membered carbocycles or pyrrolidine derivatives were afforded up to 86% ee by the use of (2R,5R)-2,5-dimethyl-1-phenylphospholane as a monodentate chiral ligand was investigated. The reaction course of this asymmetric cyclization can be explained for by two possible mechanisms: one in which the cyclization proceeds via a pi-allylnickel intermediate to produce a cyclized product having an internal olefin in the side chain, and one in which the cyclization proceeds via a sigma bond metathesis of silane and the nickel-oxygen bond of oxanickelacycle to produce a cyclized compound having a terminal olefin and/or an internal olefin in the side chain. It was speculated that both of these mechanisms operate in this asymmetric cyclization depending upon the nature of silanes and the reaction conditions.     

Development of palladium(II)-catalyzed oxidative cyclization of olefinic keto and/or lactone esters

A highly efficient palladium-catalyzed oxidative cyclization of olefinic keto and/or lactone esters, which features a catalytic cyclization employing one atmosphere of oxygen as a reoxidizing agent, is developed.     

Synthesis of fused polycyclic nitrogen-containing heterocycles via cascade cyclization

A novel strategy for the synthesis of fused polycyclic-nitrogen containing heterocycles via cascade cyclization is described. The methodology involves condensation of 1-(2-aminophenyl)-9H-β-carboline-3-carboxylic acid amide with isothiocyanates followed by in situ treatment of the resulting thioureas with HgCl₂ for 1 h at rt. The one-pot cascade cyclization leads to interesting changes in molecular structure and an increase in molecular complexity. A mechanistic rationale for the cascade cyclization is discussed.