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From readily available allylamine, aldehyde and isocyanoacetamide, a three-component reaction followed by a Pummerer cyclization provided tetracyclic ring systems (6-7-5-6 and 6-6-5-6) in excellent overall yields.
An unprotected 16 residue peptide containing a C-terminal thioester and an N-terminal selenocysteine residue efficiently cyclizes in the presence of thiophenol; subsequent reduction, elimination or alkylation of the selenol yields modified cyclic peptides with alanine, dehydroalanine or a non-natural amino acid at the site of ligation.
Conformationally constrained ethylene-diamine metalloenediyne compounds exhibit alkyne termini separations that are constant and independent of metal center geometry. Ancillary chloride ligand electron donation into the Bergman cyclization reaction coordinate, however, dramatically influences the observed temperatures.
A photochemical cyclization reaction of 1-(2'-hydroxy-1'-naphthyl)-3-(1-naphthyl)-2-propen-1-one (1,1-NHC) to give a flavanone derivative took place in benzene, but did not take place in methanol and the controlling factor of the reaction was discussed based on laser transient spectroscopy and product analysis.
Juglone (7) was converted into enone 13; this underwent radical cyclization to afford 15, which was aromatized to 16 and elaborated into (+)-nocardione A (1), the enantiomer of the naturally-occurring tyrosine phosphatase inhibitor (-)-nocardione A (2).
The preference for syn- or anti-addition of an intramolecular S(N)2[prime or minute] cyclization of an alkyllithium species onto a methoxy allyl ether has been proven unequivocally to take place by a syn S(N)2[prime or minute] mechanism.
The diastereoselective total synthesis of the marine natural product (-)-dysibetaine is reported. The key steps in this venture are i) a diastereoselective nitrenium ion spirocyclization, which serves to generate the pyrrolidinone ring and quaternary stereocenter of the target, and ii) use of the 2-methoxycyclohexa-2,5-dienone ring formed during cyclization as a masked 2-amino-1,3-dicarbonyl synthon.
To provide deep insight into the polycyclization reaction of squalene, some analogs were synthesized and incubated with the cell-free homogenates of the recombinant Escherichia coli encoding the wild-type squalene cyclase. The presence of C6-Me leads to an efficient polycyclization cascade. Substitution of the C14-H and the C18-H with a methyl group halted the polycylization reaction at the tricyclic ring stage having a 6/6/6-fused ring system and the tetracycle with a 6/6/6/6-fused ring, respectively, both of which were produced according to a Markovnikov closure. Replacement of the C7-H and the C11-H with a methyl group led to no cyclization. These results, in conjunction with our previous reports, indicated that the methyl positions are important for bringing to completion of the normal polycylization reaction and further demonstrated that the precise steric bulk size at the methyl positions of squalene is critical to the correct folding and the strong binding of the substrate to the squalene cyclase.
The ternary iron(II) complex [Fe(L')(L")](PF6)3(1) as a synthetic model for the bleomycins, where L' and L" are formed from metal-mediated cyclizations of N,N'-(2-hydroxypropane-1,3-diyl)bis(pyridine-2-aldimine)(L), is synthesized and structurally characterized by X-ray crystallography. In the six-coordinate iron(ii) complex, ligands L' and L" show tetradentate and bidentate chelating modes of bonding. Ligand L' is formed from an intramolecular attack of the alcoholic OH group of L to one imine moiety leading to the formation of a stereochemically constrained five-membered ring. Ligand L" which is formed from an intermolecular reaction involving one imine moiety of L and pyridine-2-carbaldehyde has an emissive cationic imidazopyridine pendant arm. The complex binds to double-stranded DNA in the minor groove giving a Kapp value of 4.1 x 10(5) M(-1) and displays oxidative cleavage of supercoiled DNA in the presence of H2O2 following a hydroxyl radical pathway. The complex also shows photo-induced DNA cleavage activity on UV light exposure involving formation of singlet oxygen as the reactive species.
Arylhydrazines 4 and 1,3-dicarbonyl compounds 5 react to form pyrazoles by loss of water via hydrazone isomer pairs 6 and 7 which give rise to two possible regio-isomers. Occasionally, 3-hydroxy-3,4-dihydropyrazoles or hydroxy-pyrazolines 9 and 9 are observed as stable isolatable intermediates that can be fully characterized prior to loss of the second molecule of water that gives rise to pyrazoles 10 and 11. Fully characterized examples of intermediates of type 8 and 9 are relatively rare. We studied the reaction series where R = CH3, CHF2 and CF3 and Ar = Ph and 5-methanesulfonylpyridin-2-yl, (Scheme 2), and observed differences in properties between kinetic behavior and regio-isomerism depending on the degree of electron-withdrawing capability of the R and Ar substituents. The reaction conditions that caused cyclization to pyrazoles varied from direct condensation of the hydrazine and 1,3-dicarbonyl compounds, to reactions requiring catalytic quantities of sulfuric acid to sulfuric acid in excess. Unexpected regio-selectivity was observed in the case of R = CF3 that depended upon the reaction conditions.
Exposure of 1-alkynyl[p-(trifluoromethyl)phenyl](tetrafluoroborato)-lambda3-bromanes to 2-mercaptobenzimidazole or benzothiazole in dichloromethane at 0 degrees C under argon resulted in a domino Michael addition-carbene rearrangement-cyclization reaction to produce directly tricyclic heterocycles in high yields, whereas the reaction with 2-mercaptobenzoxazole afforded 1-alkynyl sulfides.
A novel and facile method for the Zn-mediated intramolecular cyclization of beta-porphyrin radicals has been developed for the convenient and effective construction of newly fused five-membered porphyrin systems from readily available beta-bromotetraarylporphyrins.
Prins cyclization using an electron-rich benzaldehyde and a homoallylic alcohol efficiently delivered the fully substituted C-aryl tetrahydropyranoside of kendomycin.
The interweaving of two identical acyclic positively charged anion recognizing units around a chloride anion template leads to the formation of an orthogonal supramolecular ensemble which upon subsequent double ring cyclization gives a chloride selective [2]catenane in very high yield.
The analysis of a candidate biosynthetic gene cluster (97 kbp) for the polyether ionophore monensin from Streptomyces cinnamonensis has revealed a modular polyketide synthase composed of eight separate multienzyme subunits housing a total of 12 extension modules, and flanked by numerous other genes for which a plausible function in monensin biosynthesis can be ascribed. Deletion of essentially all these clustered genes specifically abolished monensin production, while overexpression in S. cinnamonensis of the putative pathway-specific regulatory gene monR led to a fivefold increase in monensin production. Experimental support is presented for a recently-proposed mechanism, for oxidative cyclization of a linear polyketide intermediate, involving four enzymes, the products of monBI, monBII, monCI and monCII. In frame deletion of either of the individual genes monCII (encoding a putative cyclase) or monBII (encoding a putative novel isomerase) specifically abolished monensin production. Also, heterologous expression of monCI, encoding a flavin-linked epoxidase, in S. coelicolor was shown to significantly increase the ability of S. coelicolor to epoxidize linalool, a model substrate for the presumed linear polyketide intermediate in monensin biosynthesis.
Catalytic tandem conjugate addition-enolate trapping represents an effective strategy for the design of catalytic transformations that enable formation of multiple C-C bonds. Recently, using enantioselective rhodium-catalyzed conjugate addition methodology, we developed a catalytic tandem conjugate addition-aldol cyclization of keto-enones. Here, we report related desymmetrizations and parallel kinetic resolutions involving the use of diones as terminal electrophiles. The Rh-enolate generated on enone carbometallation effectively discriminates among four diastereotopic pi-faces of the appendant dione, ultimately providing products that embody four contiguous stereocenters, including two adjacent quaternary centers, with quantitative diastereoselection and high levels of enantiomeric excess. This methodology allows concise entry to optically enriched seco-B ring steroids possessing a 14-hydroxy cis-fused C-D ring junction, as found in naturally occurring cardiotonic steroids derived from digitalis.
Pyrroloindoline and bispyrroloindoline are a subclass of alkaloid structural motifs that commonly exhibit biological activity. An enantioselective organocatalytic approach to the synthesis of pyrroloindoline architecture is described. The addition-cyclization of tryptamines with alpha,beta-unsaturated aldehydes in the presence of imidazolidinone catalysts 1 and 8 provides pyrroloindoline adducts in high yield and excellent enantioselectivities. This transformation is successful for a wide range of tryptamine and alpha,beta-unsaturated aldehyde substrates. This amine-catalyzed sequence has been extended to the enantioselective construction of furanoindoline frameworks. Application of this pyrroloindoline-forming reaction to natural product synthesis has been accomplished in the context of the enantioselective synthesis of (-)-flustramine B.
A mechanism of noncooperative (isodesmic) assembly coupled with preferential cyclization of long polymers is proposed to explain the previously posed question of how a single-stranded filament of the bacterial cell-division protein FtsZ can assemble in an apparently cooperative manner. This proposal is based on results of GTP-mediated assembly of FtsZ from Escherichia coli that was studied under physiologically relevant steady-state solution conditions by a combination of methods including measurement of sedimentation velocity, atomic force and electron microscopy, and precipitation assays. Sedimentation-velocity experiments carried out at multiple protein concentrations reveal an essentially bimodal distribution of slowly sedimenting species and a relatively narrow distribution of rapidly sedimenting species that appears only above an apparent "critical concentration" of protein. In a precipitation assay, the amount of protein that pellets, which correlates with the fraction of rapidly sedimenting species observed in sedimentation-velocity experiments, increases linearly with the total concentration of protein in excess of the critical concentration. Sedimentation coefficients of the rapidly sedimenting fraction are qualitatively consistent with the presence of single-stranded cyclic oligomers with a size range of approximately 50-150 protomers, similar to polymeric single-stranded rings observed in atomic force and electron micrographs. The proposed model is in accord with the results obtained from our experimental observations.