Synthesis and reactivity of cyclam-based enediynes

Cyclam-based enediynes 1-3 have been synthesized for the first time either by direct bis- or tetra-alkylation of the cyclam or via double alkylation of the 1,8-bis-sulfonyl derivative. The enediyne 1 readily forms a complex with Ni(II), which also lowered the onset temperature for Bergman cyclization of the parent enediyne by 60 °C. In the presence of a co-oxidant, MMPP, the Ni-complex can cleave ds-DNA into the nicked relaxed form at micromolar concentrations.     

Synthesis and photoactivated insecticidal activity of tetraethynylsilanes

A series of tetraethynylsilanes (TETS) have been synthesized by reaction of silicon tetrachloride (SiCl₄) with Ar–CCLi, which was prepared in situ by treatment of Ar–CCH with n-BuLi. For these TETS thus prepared, their photoactivated insecticidal activities against the 4th-instar larvae of Aedes albopictus (Skuse) were evaluated to enrich the structure–activity relationship. In particular, compound 8 exhibited excellent photoactivated insecticidal activity, the LC₅₀ value was 0.1346 mg L^?1 under UV light treatment and the irradiation-generated enhancement in the activity was more than 69.58-fold, thus could be exploitable as ideal analog candidates in the search for new photoactivated insecticide leads.     

Synthesis of selectively deuterated fulvenes and indenes from enediynes

A facile enediyne--> fulvene--> indene transformation provides a route to all possible isotopomers of substituted fulvenes and indenes.     

Synthesis of 13C-labelled,bicyclic mimetics of natural enediynes

Using a versatile synthesis with 13CH3PPh3I and CH(3)13CO2Et as 13C sources, the first examples of nine-membered chromophores which have been differentially labelled with 13C in their carbocyclic enediyne cores are described.     

Synthesis and photochemical properties of photoactivated antitumor prodrugs releasing 5-fluorouracil

A new family of antitumor prodrugs (1-3) of 5-fluorouracil (5-FU) possessing photolabile 2-nitrobenzyl chromophores have been designed and synthesized to investigate the efficiency and mechanism of photoactivated 5-FU release upon UV-irradiation at lambda(ex)= 365 nm. The photoactivated prodrug 3 derived from conjugation of 2 with a tumor-homing cyclic peptide Cys-Asn-Gly-Arg-Cys (CNGRC) was so designed as to manifest a tumor-targeting function.     

Synthesis of conjugated enediynes via palladium catalyzed cross-coupling reactions of potassium alkynyltrifluoroborates

An efficient synthesis of cross-conjugated enediynes has been developed utilizing the palladium catalyzed cross-coupling reactions of 1,1-dibromo-1-alkenes with potassium alkynyltrifluoroborates under mild conditions.     

Synthesis of polyphenylenes through bergman cyclization of enediynes with long chain alkyl groups

Several new enediynes with long chain alkyl groups were synthesized through Sonogashira coupling reactions between long chain alkynes and(Z)-1,2-dichloroethene. These enediynes(1) were then subjected to thermal Bergman cyclization in a refluxing diphenyl ether bath under vacuum to obtain conjugated polyphenylenes with the weight-average molecular weights up to 4.9 × 103 g·mol·1. The occurrence of Bergman cyclization was confirmed by 1H-NMR, 13C-NMR, and IR spectroscopic analysis. These polyphenylenes are fully soluble in common organic solvents and exhibit good thermal stability. The optical properties of the polyphenylenes were investigated by UV-Vis absorption and photoluminescence(PL) spectroscopies. A blue emission was observed for all these polyphenylenes.     

Design strategy of enediynes and enyne-allenes

The review summarizes synthetic approaches to enediynes and enyne-allenes that are responsible for a Bergman and Myers-Saito cycloaromatizations resulting in the formation of benzene, β-substituted naphthalene, and acene derivatives. Cycloaromatization paths leading to fulvene and indene systems in the presence of radical and ionic initiators, as well as of metal catalysts, are discussed. Practical importance of the syntheses is noted.     

Palladium-catalyzed cycloaromatization polymerization of enediynes

Bergman cyclization has shown great promise in constructing conjugated polymers.However,the application of this reaction in polymer science is still limited due to the harsh reaction condition and ill-defined structure of the achieved polymers.To this end,the cycloaromatization polymerization of enediynes catalyzed by a series of transition metal catalysts is investigated in this work,by taking advantage of the coordination chemistry of the enediyne with the transition metal complexes.According to the nuclear magnetic resonance (NMR),Fourier transform infrared (FTIR),ultraviolet-visble (UV-Vis) spectroscopies and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis,the cycloaromatization polymerization of enediynes proceeds under milder conditions and in a more controlled manner in the presence of palladium(Ⅱ) complexes,giving structurally regulated conjugated polymers in high yields.     

Two-photon excitation of substituted enediynes

Electronic spectroscopy of nine benzannelated enediynes and a related fulvene was studied under one-photon and two-photon excitation conditions. We utilize measured absorbance and emission spectra and time-resolved fluorescence decays of these molecules to calculate their radiative lifetimes and fluorescence quantum yields. The fluorescence quantum yields for the other compounds were referenced to the fluorescence quantum yield of compound 3 and used to determine relative two-photon absorption cross-sections. Further insight into experimental studies has been achieved using time-dependent density functional (TD-DFT) computations. The probability of two-photon absorption (TPA) increases noticeably for excitation to the higher excited states. The photophysical properties of benzannelated enediynes are sensitive to substitutions at both the core and the periphery of the enediyne chromophore. Considerably enhanced two-photon absorption is observed in an enediyne with donor substitution in the middle and acceptor substitution at the termini. Excited states with B symmetry are not active in TPA spectra. From a practical point of view, this study extends the range of wavelengths applicable for activation of the enediyne moiety from 350 to 600 nm and provides a rational basis for future studies in this field. Our theoretical computations confirmed that lowest energy TPA in benzannelated enediynes involves different orbitals than lowest energy one-photon absorbance and provided further support to the notion that introduction of donor and acceptor substituents at different ends of a molecule increases TPA.     

Synthesis and properties of 1-methylthiopropargylammonium salts and their use as key precursors to sulfur-containing enediynes

1-methylthiopropargylammonium salts were synthesized in a highly efficient manner by reaction of alkynyl S,N-acetals with methyl triflate. Reactions of the 1-methylthiopropargylammonium salts with Grignard reagents gave propargyl sulfides or allenyl sulfides, whereas the reaction with organocopper reagents led to exclusive formation of allenyl sulfides regardless of the nature of substituents on the acetylenic carbon. The salts undergo self-dimerization reactions when treated with organolithium and lithium amide bases.     

Synthesis and structural characterization of porphyrinic enediynes: geometric and electronic effects on thermal and photochemical reactivity

We report the preparation of [5,10,15,20-tetraphenyl-2,3,7,8,12,13,17,18-octakis(phenylethynyl)porphinato] complexes of Ni(II), H(2), Zn(II), Mg(II), and Cu(II), as well as select trimethylsilanylethynyl derivatives. The X-ray structures of the octakis(phenylethynyl) compounds show systematic deviations from planarity (Ni(II), 0.2851 A; Zn(II), 0.0304 A) as a function of the central cation. These geometric distortions are reflected in bathochromic shifts of the Soret and Q bands (Ni(II), 497, 604, and 650 nm; Mg(II), 515, 595, 642, and 705 nm) which loosely correlate with increasing planarity of the structure. Similarly, vibrational modes involving the octasubstituted porphyrin core exhibit shifts to lower frequency as a function of increasing planarity in the solution-state resonance Raman spectra (lambda(exc) = 501.7 nm) of these compounds. Analogous trends are also observed in their solid-state electronic and resonance Raman spectra, indicating that the structural distortions within the octakis(phenylethynyl) series are preserved in solution. Comparison of the saddle distortion of the octasubstituted Ni(II) compound with the ruffle/saddle distortions of the pentakis and hexakis Ni(II) derivatives reveals some influence of asymmetric peripheryl substitution on geometric structure. These Ni(II) derivatives also exhibit systematic red shifts in their electronic spectra as a function of the number of conjugated alkyne units ( approximately 13 nm/alkyne), revealing participation of the enediyne units in the electronic ground and excited states. The solid-state Bergman cyclization temperatures of the phenylethynyl compounds vary markedly as a function of planarity, and correlate loosely with alkyne termini separation (Ni(PA)(8), 4.00 A, 281 degrees C; MgP(PA)(8), 3.77 A, 244 degrees C). In solution, both thermal and photochemical activation of the free-base octakis(phenylethynyl) compound lead to formal reduction of the porphyrin backbone via H-atom addition at opposing meso-positions. Generation of a common product suggests that both thermal and photochemical pathways to Bergman cyclization in solution contain significant activation barriers to formation of the 1,4-phenyl diradical intermediate, and under these solution conditions, alternate reaction channels are more thermodynamically favorable.     

Synthesis of chiral polyphenylenes through Bergman cyclization of enediynes with pendant chiral amino ester groups

Chiral enediynes with pendant chiral amino ester groups are synthesized through Sonogashira reactions and subjected to thermal triggered Bergman cyclization at elevated temperatures either in bulk or in solvents to produce chiral polyphenylenes. The disappearance of enediyne monomers are evidenced by FTIR and NMR spectroscopies. The formation of polyphenylenes is further confirmed by UV-Vis and MALDI-TOF mass spectroscopies(MS). Isotope pattern analysis of the MS spectra shows that the polymers prepared in solvents are terminated by the solvent molecules, whereas the chain ends of the polymers prepared in bulk consist of considerable amount of unmasked free radicals, which is further confirmed by EPR analysis. Circular dichroism(CD) spectra of the chiral polymers show blue shifts of the Cotton peaks, indicating the occurrence of the cycloaromatization reaction. A new set of peaks mirrored at the horizontal axis show up in the long wavelength range, which are assigned to main chain chirality of the polyphenylenes.     

Photoinduced Bergman cycloaromatization of imidazole-fused enediynes

A series of 4,5-bis-(alkyn-1-yl)imidazoles—‘imidazole-fused’ enediynes—were synthesized and their reactivities in photoinduced Bergman cycloaromatization reactions were determined. The more conformationally rigid analogues gave cycloaromatized products in good yields upon irradiation (450 W low-pressure mercury lamp, ambient temperature). A bicyclic analogue (3) was shown to cleave supercoiled plasmid DNA.     

Synthesis of angularly fused aromatic compounds from alkenyl enediynes by a tandem radical cyclization process

Let's get radical: A general synthetic route toward angularly ortho-fused polyaromatic [4]helicenes starting from aryl alkenyl N-substituted cyclic enediynes is described (see scheme; DMSO=dimethyl sulfoxide, Ns=4-nitrobenzenesulfonyl). The process involved a Bergman cyclization (BC) as the key step of an unprecedented tandem radical reaction.     

Pd-catalyzed borylative polycyclization of enediynes to allylboronates

Pd-catalyzed dicyclization of 6-ene-1,11-diynes with bis(pinacolato)diboron affords synthetically useful allylboronates under smooth conditions. Two new C-C and one C-B bonds are stereospecifically formed in a single operation. The stereochemical outcome depends on the starting alkene configuration. The reaction is general and has been applied to differently substituted enediynes. Isolation of intermediate 1,3-dienes suggests a regioselective beta-hydrogen elimination along the reaction pathway.     

Pd-catalyzed borylative polycyclization of enediynes to alkylboronates

Pd-catalyzed bicyclization of 1-ene-6,11-diynes with bis(pinacolato)diboron smoothly affords synthetically useful homoallylic alkylboronates under mild conditions, avoiding the use of highly nucleophilic or basic reagents. One C-B bond and two new C-C bonds are created, and two new stereogenic centers are stereospecifically formed in a single tandem operation. The obtained products suggest a cascade reaction in which the last step is the transmetalation of bis(pinacolato)diboron, this being faster than a possible β-hydride elimination process. The reaction is general and has been applied to enediynes with different substituents on the alkene unit, the bridging groups, and the alkyne moiety. The bicyclized alkylboronates thus obtained can be functionalized by oxidation to alcohols, formation of trifluoroborate salts, or by Suzuki coupling reactions.     

Conformational properties of simple monocyclic conjugated enediynes

An investigation employing the AM1 semi-empirical SCF MO method to calculate structure optimization and conformational interconversion pathways for Z-cyclonona-3-ene-1,5-diyne (1), Z-cyclodeca-3-ene-l,5-diyne (2), and Z-cycloundeca-3-ene-1, 5-diyne (3) has been undertaken. The plane-symmetrical half-chair conformation of 1 is calculated to be 23.8 kJ mol⁻¹ more stable than the planar C_2v transition-state geometry. Compound 2 has two energy-minimum conformations with the twistboat (C₂) form being 31.1 kJ mol⁻¹ more stable than the twist (C₁) geometry. The calculated energy barrier for interconversion of C₂ and C₁ conformations is 37.4 kJ mol⁻¹. The unsymmetrical twist-boat form of 3 is calculated to be the most stable conformation. The twist-boat geometry can undergo two degenerate processes to achieve a time-averaged symmetry of C_2v.     

A synthetic photoactivated protein to generate local or global Ca(2+) signals

Ca(2+) signals regulate diverse physiological processes through tightly regulated fluxes varying in location, time, frequency, and amplitude. Here, we developed LOVS1K, a genetically encoded and photoactivated synthetic protein to generate local or global Ca(2+) signals. With 300?ms blue light exposure, LOVS1K translocated to Orai1, a plasma membrane Ca(2+) channel, within seconds, generating a local Ca(2+) signal on the plasma membrane, and returning to the cytoplasm after tens of seconds. With repeated photoactivation, global Ca(2+) signals in the cytoplasm were generated to modulate engineered Ca(2+)-inducible proteins. Although Orai1 is typically associated with global store-operated Ca(2+) entry, we demonstrate that Orai1 can also generate local Ca(2+) influx on the plasma membrane. Our photoactivation system can be used to generate spatially and temporally precise Ca(2+) signals and to engineer synthetic proteins that respond to specific Ca(2+) signals.