Template-directed oligonucleotide strand ligation, covalent intramolecular DNA circularization and catenation using click chemistry

The copper-catalyzed azide-alkyne cycloaddition reaction has been used for the template-mediated chemical ligation of two oligonucleotide strands, one with a 5'-alkyne and the other with a 3'-azide, to produce a DNA strand with an unnatural backbone at the ligation point. A template-free click-ligation reaction has been used for the intramolecular circularization of a single stranded oligonucleotide which was used as a template for the synthesis of a covalently closed DNA catenane.     

Oligonucleotide conjugation to a cell-penetrating (TAT) peptide by Diels-Alder cycloaddition

Modifed oligonucleotides are routinely employed as analytical probes for use in diagnostics, e.g. in the examination of specific RNA sequences for infectious diseases, however, a major limiting factor in oligonucleotide-based diagnostics is poor cellular uptake of naked oligonucleotides. This problem can be overcome by covalent attachment of a so-called 'cell-penetrating peptide' to form an oligonucleotide peptide conjugate. Stepwise solid phase synthesis of such a conjugate is difficult and expensive due to the conflicting chemistries of oligonucleotides and peptides. A simple approach to overcome this is post-synthetic conjugation. Diels-Alder cycloaddition is an attractive methodology for oligonucleotide peptide conjugation; the reaction is fast, chemoselective and the reaction rate is greatly enhanced in aqueous media - ideal conditions for biological moieties. An oligodeoxyribonucleotide sequence has been derivatised with a series of dienes at the 5'-terminus, using a series of unique dienyl-modified phosphoramidites, and investigation into the effect of diene type on the efficiency of conjugation, using Diels-Alder cycloaddition with a maleimido-derivatised cell-penetrating (TAT) peptide, has been performed. This led to the observation that the optimal diene for conjugation was cyclohexadiene, allowing conjugation of oligodeoxyribonucleotides to a cell-penetrating peptide by Diels-Alder cycloaddition for the first time.     

A triplet mechanism for the formation of thymine-thymine (6-4) dimers in UV-irradiated DNA

The reaction pathway for the photochemical formation of thymine-thymine (6-4) dimers in DNA is explored using hybrid density functional theory techniques in gas and in bulk solvent. It is concluded that the photo-induced cycloaddition displays favorable energy barriers in the triplet excited state. The stepwise cycloaddition in the triplet excited state involves the initial formation of a diradical followed by ring closure via singlet-triplet interaction. The key geometric features and electron spin densities are also discussed. The difference in barriers of H3' transfer for the lowest-lying triplet and singlet states shows that the singlet oxetane intermediate could catch the second photon to accelerate the rate of proton transfer, leading to formation of the Dewar structure. The present results provide a rationale for the formation of thymine-thymine (6-4) dimers in the triplet excited states.     

Synthesis and biological evaluation of bile acid dimers linked with 1,2,3-triazole and bis-beta-lactam

We report herein the synthesis and biological evaluation of bile acid dimers linked through 1,2,3-triazole and bis-beta-lactam. The dimers were synthesized using 1,3-dipolar cycloaddition reaction of diazido bis-beta-lactams , and terminal alkynes derived from cholic acid/deoxycholic acid in the presence of Cu(i) catalyst (click chemistry). These novel molecules were evaluated in vitro for their antifungal and antibacterial activity. Most of the compounds exhibited significant antifungal as well as antibacterial activity against all the tested fungal and bacterial strains. Moreover, their in vitro cytotoxicities towards HEK-293 and MCF-7 cells were also established.     

Reactions of aryl chromium carbene complexes with alkoxalkyne: O-Quinonemethide formation and unusual diels-alder dimerization

Reactions of a pyrrole- and a phenyl-carbene chromium complexes with 3-alkoxy-1-ethoxy-1-butyne produced dimers through o-quinone-methide formation from the alkyne-carbene cycloaddition products and subsequent Diels-Alder dimerization.     

Catalytic opening of the diaziridine fragment in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes

Treatment of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with Lewis acids [BF₃·Et₂O or In(OTf)₃] promotes opening of the diaziridine ring, followed by formation of 1,3-dipolar cycloaddition products with N-arylmaleimides. The conversion of the initial diaziridine depends on the nature of the 6-aryl group. Diazabicyclohexanes with donor substituents react quantitatively to give (in the absence of dipolarophiles) the corresponding azomethine imine dimers, 1,2,4,5-tetrazine derivatives. The conversion of diazabicyclohexanes having acceptor substituents is poor; simultaneously, the fraction of the hydrolysis products increases. The stereoselectivity in the 1,3-dipolar cycloaddition, i.e. the ratio of the cis-and trans-adducts, depends on the catalyst and solvent. Azomethine imine dimers react with N-arylmaleimides in the presence of indium(III) trifluoromethanesulfonate to give the same 1,3-dipolar cycloaddition products as those obtained from parent 1,5-diazabicyclohexanes.     

A triplet mechanism for the formation of cyclobutane pyrimidine dimers in UV-irradiated DNA

The reaction pathways for the photochemical formation of cyclobutane thymine dimers in DNA are explored using hybrid density functional theory techniques. It is concluded that the thymine-thymine [2 + 2] cycloaddition displays favorable energy barriers and reaction energies in both the triplet and the singlet excited states. The stepwise cycloaddition in the triplet excited state involves the initial formation of a diradical followed by ring closure via singlet-triplet interaction. The triplet mechanism is thus completely different from the concerted singlet state cycloaddition processes. The key geometric features and electron spin densities are also discussed. Bulk solvation has a major effect by reducing the barriers and increasing the diradical stabilities. The present results provide a rationale for the faster cycloreaction observed in the singlet excited states than in the triplet excited states.     

A new approach to oligonucleotide labelling using Diels-Alder cycloadditions and detection by SERRS

Diels-Alder cycloaddition has been used to add a benzotriazole azo dye to a diene tagged oligonucleotide to generate unique SERRS signals at 10 attomoles.     

Duplex‐forming Oligonucleotide of Triazole‐linked RNA

An oligonucleotide of triazole‐linked RNA (^TLRNA) was synthesized by performing consecutive copper‐catalyzed azide‐alkyne cycloaddition reactions for elongation. The reaction conditions that had been optimized for the synthesis of 3‐mer ^TLRNA were found to be inappropriate for longer oligonucleotides, and the conditions were reoptimized for the solid‐phase synthesis of an 11‐mer ^TLRNA oligonucleotide. Duplex formation of the 11‐mer ^TLRNA oligonucleotide was examined with the complementary oligonucleotide of natural RNA to reveal the effects of the 2′‐OH groups on the duplex stability.     

CuCl-mediated tandem CO insertion and annulation of 1,4-dilithio-1,3-dienes: formation of multiply substituted cyclopentadienones and/or their head-to-head dimers

Mediated by CuCl, 1,4-dilithio-1,3-dienes reacted with carbon monoxide (CO) to generate multi-substituted cyclopentadienones and/or their head-to-head dimers, via tandem CO insertion and intra/intermolecular cycloaddition of organocopper compounds.     

Dimerization of α-ethylenic dithioesters

Methyl propenedithioate and three methyl 2-butenedithioates were prepared and all but one of these hetero-dienes gave dimers resulting from a [4 + 2] cycloaddition. Formation of a 1,5-dithiocin ring was also observed from the propenedithioate.     

Synthesis of 1,1'-binaphthyl-based enantiopure C(60) dimers

The first enantiomerically pure and soluble C(60) dimers have been synthesized from suitably functionalized 1,1'-binaphthyl derivatives by 1,3-dipolar cycloaddition of the respective in situ generated diazo compounds to C(60). These systems exhibit optical and electrochemical activity.     

In situ photochemical conversion from cinnamoyl-functionalized liquid-crystalline monomers to liquid-crystalline dimers

Liquid-crystalline (LC) monomers, which were functionalized with a cinnamoyl group on their extremity, were synthesized and irradiated with UV light in their LC phases. In the presence of a triplet sensitizer, most LC monomers were converted into the corresponding dimers, which were produced by the cycloaddition reaction of the cinnamoyl group. The photodimerization reaction could proceed while the LC phases were maintained, because the dimers showed LC phases whose temperature ranges were wider than those of the corresponding monomers. A ¹H NMR study of the LC dimers indicated that the cyclobutane unit dominantly had an anti-head-to-head configuration, that is, δ-truxinate. As the LC monomers, which had a phenyl biphenyl-4-carboxylate moiety as a mesogen, showed smectic A phases and the corresponding dimers also exhibited smectic A phases, we estimated the smectic layer distances by X-ray diffraction analysis and found that the dimers adopted the structure in which the two mesogens aligned laterally and existed in the same smectic layer in the LC phases.     

The Addition of Nitriles to a Molecular Digermene: Reversible Addition and Comparison to Surface Reactivity

The addition of acetonitrile, propionitrile, and acrylonitrile to tetramesityldigermene was investigated and compared to the addition of acetonitrile and acrylonitrile to germanium dimers on the Ge(100)‐2×1 surface. In each case, a 1,2,3‐azadigermetine was formed as the major product. As on the surface, the addition of nitriles to digermenes was found to be reversible, providing the first example of a reversible cycloaddition of a ditetrelene. No evidence for a six‐membered cyclic ketenimine was observed as noted in the surface chemistry, suggesting that the surface ketenimine might only form between two adjacent dimers rather than on a single dimer. The comparative chemistry provides important insights that are not possible by the independent study of each system.     

Detection of DNA probes using Diels Alder cycloaddition and SERRS

A number of methods for detecting specific DNA sequences have been used to provide data for use in diagnosis of disease states and examination of gene expression. This study shows how the use of labelled oligonucleotides created by Diels Alder cycloaddition can be used as surface enhanced resonance Raman scattering (SERRS) active probes that provide easily identifiable signals at low concentrations in a mixture. The probes were produced by first tagging the oligonucleotides with a furan residue at the 5'-terminus to act as the diene. Three specifically designed benzotriazole azo maleimide dyes were then used as dienophiles to undergo cycloaddition with the furan modified oligonucleotide to generate SERRS active probes. These probes gave excellent SERRS signals from a silver-PVA film. Surface mapping of the silver PVA film indicated that the distribution of the dyes was uniform and that the number of moles of probe detected at any one time was approximately in the attomole region.     

Design, synthesis, and micellar properties of bile acid dimers and oligomers linked with a 1,2,3-triazole ring

1,3-Dipolar cycloaddition of propargyl esters of bile acids to azide group attached at different positions of bile acids gave dimers, trimer, and tetramer linked with 1,2,3-triazole. These dimeric and oligomeric structures were able to solubilize hydrophilic dye—cresol red, in nonpolar solvent.     

Oxyfadichalcones A–C: three chalcone dimers fused through a cyclobutane ring from Tibetan medicine Oxytropis falcata Bunge

Oxyfadichalcones A and B, two unprecedented chalcone dimers fused through a cyclobutane ring by head-to-tail [2+2] cycloaddition of two chalcones that had never been found previously in nature, along with oxyfadichalcone C, a new head-to-head [2+2] cyclized chalcone dimer, were simultaneously obtained from Oxytropis falcata. Structural elucidation was succeeded by spectroscopic and single-crystal synchrotron radiation analysis. Additionally, the photosynthesis of the chalcone dimers was performed and the plausible biosynthesis was discussed.     

Density-functional study of the cycloaddition of acrylonitrile on the Si(100) surface

Using a density functional approach, we have explored the cycloaddition of acrylonitrile on the Si(100) surface. The buckling of the surface dimers characteristic for the (2x1) reconstructed surface is shown to favor structures with a dipolar moment such as the resonant form of acrylonitrile with cumulative double bonds. The bond of acrylonitrile via a single C atom is a possible intermediate leading to the nitrile structure of the adsorbed molecule.     

In situ photochemical conversion from cinnamoyl‐functionalized liquid‐crystalline monomers to liquid‐crystalline dimers

Liquid‐crystalline (LC) monomers, which were functionalized with a cinnamoyl group on their extremity, were synthesized and irradiated with UV light in their LC phases. In the presence of a triplet sensitizer, most LC monomers were converted into the corresponding dimers, which were produced by the cycloaddition reaction of the cinnamoyl group. The photodimerization reaction could proceed while the LC phases were maintained, because the dimers showed LC phases whose temperature ranges were wider than those of the corresponding monomers. A ¹H NMR study of the LC dimers indicated that the cyclobutane unit dominantly had an anti‐head‐to‐head configuration, that is, δ‐truxinate. As the LC monomers, which had a phenyl biphenyl‐4‐carboxylate moiety as a mesogen, showed smectic A phases and the corresponding dimers also exhibited smectic A phases, we estimated the smectic layer distances by X‐ray diffraction analysis and found that the dimers adopted the structure in which the two mesogens aligned laterally and existed in the same smectic layer in the LC phases.     

Novel solid-state synthesis of dimeric 4-aryl-1,4-dihydropyridines

On irradiation in the solid state the 4-aryl-1,4-dihydroypridines 1 undergo [2+2] cycloadditon to centrosymmetric head-to-tail dimers 3 and 4a . The almost exclusive formation of the cage dimers 3 via the C₂-symmetric syn-dimers 2 takes place in nearly quantitative yields, in contrast with the cycloaddition reaction of the anti-dimer 4a , which is accompanied by photooxidation to pyridine 5a .