Simultaneous Ring Opening Research Articles

Functionalization of polymeric nanoparticles with targeting VNAR ligands using vinyl sulfone conjugation.

Actively targeted drug loaded nanoparticles represent an exciting new form of therapeutics for cancer and other diseases. These formulations are complex and in order to realize their ultimate potential, optimization of their preparation is required. In this current study, we have examined the conjugation of a model targeting ligand, conjugated in a site-specific manner using a vinyl sulfone coupling approach. A disulfide-functionalized poly(L-lactide)-b-poly(oligo(ethylene glycol) methacrylate)-stat-(bis(2-methacryloyl)oxyethyl disulfide) (PLA-b-P(OEGMA-stat-DSDMA)) diblock copolymer was synthesized by simultaneous ring opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. Subsequently, the disulfide bonds of the polymer were reduced to thiols and divinyl sulfone was attached to the polymer using thiol-ene chemistry to produce the vinyl sulfone (VS)-functionalized PLA-b-P(OEGMA-stat-VSTEMA) amphiphilic block copolymer. Single emulsion - solvent evaporation was employed using a blend of this polymer with poly(D,L-lactide-co-glycolide) (PLGA) to produce VS-functionalized polymeric nanoparticles. The ability of these novel nanoparticles to attach ligands was then exemplified using a single domain variable new antigen receptor (VNAR) with a free carboxyl terminal cysteine residue. The resulting VNAR-functionalized nanoparticles were found to maintain specific affinity to their cognate antigen (DLL4) for at least 72 h at 4 °C. The simplicity of the degradable amphiphilic block copolymer synthesis and the efficiency of VNAR conjugation to the VS-functionalized nanoparticles show the potential of this platform for therapeutic development.

Mechanism and Origins of Product Selectivity of Au‐Catalyzed Coupling Benzisoxazoles with Ynamides: A Computational Study

AbstractAu(I)‐catalyzed coupling of benzisoxazoles and ynamides was recently reported to synthesize challenging indoloquinoline core structures. In this report, we employed DFT methods to elucidate the mechanistic details of this reaction. The results reveal that the catalytic cycle involves initial coupling of ynamide with benzisoxazole, simultaneous ring opening of the isoxazole unit and attack of the dimethoxybenzene (DMOB) unit to gold carbenoid, proton transfer from the DMOB group to hydroxyl group, thioether migration, ring closure, and proton transfer. The experimentally observed ligand‐controlled product selectivity is reproduced well by the calculations. The product selectivity‐determining step is the ring opening of the isoxazole unit. The flexible P(t‐Bu)2(o‐biphenyl) ligand facilitates the approach of the DMOB group to gold carbenoid, which brings about significant C−H/π interactions in the transition state for ring opening, and thus leads to the indoloquinoline product. The rigid 1,3‐bis(diisopropylphenyl)imidazol‐2‐ylidene ligand prefers keeping the DMOB group away from the gold carbenoid, which can cause strong orbital interaction in the transition state for ring opening, and thus results in indole product.

One-Pot Photochemical Ring-Opening/Cleavage Approach for the Synthesis and Decoding of Cyclic Peptide Libraries.

A novel dual ring-opening/cleavage strategy to determine the sequence of cyclic peptides from one bead, one compound libraries is described. The approach uses a photolabile residue within the macrocycle and as a linker to allow a simultaneous ring opening and cleavage from the beads upon UV irradiation and provide linearized molecules. Cyclic peptides of five to nine residues were synthesized and the generated linear peptides successfully sequenced by tandem mass spectrometry.

Triblock Terpolymers by Simultaneous Tandem Block Polymerization (STBP).

A route of synthesizing triblock terpolymers in a one-pot, "one-step" polymerization approach is presented. The combination of two distinct polymerization techniques through orthogonal catalyst/initiator functionalities attached to a polymeric linker furnishes novel pathways to ABC-terpolymers. Both polymerizations have to be compatible regarding mechanisms, chosen monomers, and solvents. Here, an α,ω-heterobifunctional poly(ethylene glycol) serves as poly-meric catalyst/initiator to obtain triblock terpolymers of poly(norbornene)-b-poly(ethylene glycol)-b-poly(L-lactic acid) PNB-PEG-PLLA via simultaneous ring opening metathesis poly-merization and ring opening polymerization in a fast one-pot polymerization. Structural characterization of the polymers is provided via (1)H-, DOSY-, and (1)H,(1)H-COSY-NMR, while solution and thin film self-assembly are investigated by dynamic light scattering and atomic force microscopy.

Thermal Decomposition of 2(3H) and 2(5H) Furanones: Theoretical Aspects.

The thermal decomposition reactions of 2(3H) and 2(5H) furanones and their methyl derivatives are explored. Theoretical calculations of the barriers, reaction enthalpies, and the properties of these and intermediate species are reported using the composite model chemistry CBS-QB3 and also the functional M06-2X allied to the 6-311++G(d,p) basis set. Thus, the bond dissociation enthalpies, ionization energies, and unimolecular chemical kinetic rate constants in the high-pressure limit were computed. We show that flow reactor experiments that intimated that heating the 2(3H) furanone converts it to the isomeric 2(5H) furanone occurs via a 1 → 2 H-transfer reaction to an open ring ketenoic aldehyde. The latter can then ring close to the other isomeric structure. The final products acrolein and carbon monoxide are only formed from 2(3H), and acrolein will further decompose to ethylene and CO. Comparable channels explain the interconversion of 5-methyl-2(3H) furanone to its 2(5H) isomer and to the formation of methyl vinyl ketone and CO. The influence of the methyl group at other positions on the ring is hardly of significance except in the case of 5-methyl-2(5H) furanone where a hydrogen atom transfer from the methyl group leads to the formation of a doubly unsaturated carboxylic compound, 2,4-pentadienoic acid. Studies of the UV photolysis of the parent compounds in both low-temperature inert argon matrices and in solution are broadly in accord with the thermal findings insofar as product formation is concerned and with our theoretical calculations. The dominant features of the early decomposition chemistry of these compounds are simple hydrogen transfer and simultaneous ring opening reactions, which do however result in some quite unusual species.

Reaction Mechanisms for the Formation of Mono- And Dipropylene Glycol from the Propylene Oxide Hydrolysis over ZSM-5 Zeolite

Stepwise and concerted mechanisms for the formation of mono- and dipropylene glycol over ZSM-5 zeolite were investigated. For the calculations, a T128 cluster model of zeolite was used with a QM/QM scheme to investigate the reaction mechanism. The active inner part of zeolite was represented by a T8 model and was treated at the DFT (BP86) level, including D3 Grimme dispersion, and the outer part of the zeolite was treated at the DFTB level. The solvent effects were taken into account by including explicitly water molecules in the cavity of the zeolite. The Gibbs energies were calculated for both mechanisms at 70 °C. In the case of the stepwise mechanism for the monopropylene glycol formation, the rate-limiting step is the opening of the epoxide ring. The activation energy for this process is 35.5 kcal mol–1, while in the case of the concerted mechanism the rate-limiting step is the simultaneous ring opening of the epoxide and the attack by a water molecule. This process has an activation energy of 27.4 kcal mol–1. In the case of the stepwise mechanism of the dipropylene glycol formation, the activation energy for the rate-limiting step is the same as for the monopropylene glycol formation, and in the case of the concerted mechanism, the activation energy for the rate-limiting step is 30.8 kcal mol–1. In both cases (mono- and dipropylene glycol formation), the concerted mechanism should be dominant over the stepwise one. The barrier for monopropylene glycol formation is lower than that for dipropylene glycol formation. Consequently, our results show that the formation of the monopropylene glycol is faster, although the formation of dipropylene glycol as a byproduct cannot be avoided using this zeolite.

Thermolysis of 3,3,5,5‐Tetramethyl‐1,2,4‐trithiolane 1‐Oxide: First Matrix Isolation of the HOSS· Radical

AbstractFlash vacuum pyrolysis of 3,3,5,5‐tetramethyl‐1,2,4‐trithiolane 1‐oxide performed at 700 °C yields the 1‐oxatrisulfan‐3‐yl radical (HOSS·) along with disulfur monoxide (S2O) and diisopropyl sulfide, which were isolated in argon matrices at 10 K. Upon irradiation with UV light, the 1‐oxatrisulfan‐3‐yl radical undergoes isomerization to the 1‐oxatrisulfan‐1‐yl radical (HSSO·). Both radicals were identified by comparison of their computed and experimental IR and UV/Vis spectra. In addition, density functional theory (DFT) computations offer a plausible explanation of the most likely reaction mechanism, suggesting that the initial step is a 1,3‐H shift with simultaneous ring opening. A 1‐oxatrisulfane derivative formed thereby undergoes fragmentations via a radical and a competitive concerted pathway leading to the observed final products. The same mechanism also governs the thermal fragmentation of di‐tert‐butyl disulfide S‐oxide. Its pyrolysis at 700 °C affords an analogous set of products, including the 1‐oxatrisulfan‐3‐yl radical (HOSS·) as the key intermediate.

1,4]Dithiepino[2,3‐b]furans from Oxiranecarbaldimines and Lithiated 1,3‐Dithiane: A Series of Rearrangement Reactions in One Pot

AbstractOxiranecarbaldimines 1, which are easily accessible in a two‐step procedure, were converted into [1,4]dithiepino[2,3‐b]furans 5 by the addition of lithiated 1,3‐dithiane and subsequent aqueous workup under acidic conditions. In case of bis(imine) 6, the isolation of the intermediate bis(aziridinyl alcohol) 7 was possible and resulted from an aza‐Payne rearrangement. Acid treatment of 7 led to the bis(furan) 8. According to quantum chemical calculations, the key step of the acid‐catalyzed step is the ring expansion of the 1,3‐dithiane with simultaneous ring opening of the aziridine. Several [1,4]dithiepino[2,3‐b]furan derivatives 5 and 8 were characterized by X‐ray diffraction.

Synthesis of new polyesters with methacrylate pendant groups

A catalytic process for synthesis of new polyesters with methacrylate pendant groups is presented. Thus, zinc succinate catalyzed reaction of succinic anhydride with glycidyl methacrylate (GMA) in dimethoxyethane gives linear oligoesters with low molecular weights (1380-2400 Da). The polyester formation takes place via simultaneous ring opening of the cyclic anhydride and oxirane units.

Forgotten monomers: free radical polymerization behavior of norbornadiene derivatives in comparison with methyl methacrylate

The free radical polymerization behavior of three norbornadiene derivatives was studied as a function of their structure. The compounds examined were 3-ethoxycarbonyl-tricyclo[3.2.1.0 2,4]oct-6-ene 1 (liquid), 2-carbethoxybicyclo[2.2.1]-2,5-heptadiene 2 (liquid) and 2-carboxybicyclo[2.2.1]-2,5-heptadiene 3 (solid). They were polymerized in bulk and in benzene solutions. The tricyclic compound 1 was the least reactive monomer whereas the bicyclic derivatives 2 and 3 readily polymerized radically to high conversions. The corresponding polymers were isolated and their structure were determined by means of IR- and NMR spectroscopy. The polymerization of 3-ethoxycarbonyl-tricyclo[3.2.1.0 2,4]oct-6-ene 1 is supposed to proceed through a simultaneous ring opening–ring closing mechanism. The corresponding polymer poly- 1 shows low molecular weights. The polymerization results were compared with those obtained for a conventional solution polymerization of methyl methacrylate.

Hydrophobic ‐ Hydrophilic Copolymers from Functional Organosiloxane Oligomers

AbstractHydrophobic ‐ hydrophilic siloxane containing copolymers were synthesized by two different methods, namely a) radical polymerization of methacrylic acid or N‐vinylpyrrolidone initiated by azo containing polydimethylsiloxanes, and b) radical polymerization of methacrylic acid in the presence of glycidoxypropyl functional polydimethylsiloxanes with simultaneous ring opening reaction by the carboxylic groups.

Tetracyclic phenothiazines. VII. Electron impact promoted mass spectral fragmentation of some pyrido[3,2,1‐kl]phenothiazines

AbstractThe mass spectral fragmentation pattern of a series of pyrido[3,2,1‐kl]phenothiazines is reported. The major fragments are derived from the breakdown of the pyrido ring and substituents thereon. The 1,2‐/2,3‐unsaturated, unsubstituted and most of the 3‐substituted compounds show the molecular ion as the base peak indicative of their relative stability toward electron impact. The genesis of the base peaks from the molecular ions of the 2,2‐dithiophenyl substituted compounds probably involves a concerted expulsion of a neutral diphenyldisulfide molecule and hydrogen atom transfer from the 1‐position to the 2‐position in the pyrido ring. On the other hand, 2‐thiophenyl substituted molecular ions lead to base peaks involving simultaneous ring opening of the pyrido ring, cleavage of phenylthiomethylene moiety as a radical and contractive ring closure to the pyrrole system. These two mechanisms appear to be diagnostic for distinguishing 2,3‐ versus 2,2‐positional isomers. The McLafferty rearrangement takes place in the 2‐thiophenyl and 2,2‐dithiophenyl substituted compounds. The retro‐Diels‐Alder fragmentation of the pyrido ring occurs in varying degrees depending on the nature of the 2‐ and 3‐ substituents and also the presence or absence of unsaturation in the pyrido ring. In the 2‐thiophenyl‐3‐keto compounds, thiophenyl group participation with 3‐carbonyl carbon and oxygen atoms is observed in the genesis of some interesting ion fragments. The detection of metastable ions in the spectra of 1,2‐dihydro‐2‐thiophenyl‐, 1,2‐dihydro‐2,2‐dithiophenyl‐3‐hydroxy‐, and 1,2‐dihydro‐2,2‐dithiophenyl‐3‐keto‐3H‐pyrido[3,2,1‐kl]phenothiazines; and spectra of 1,2‐dihydro‐3‐methyl‐, 1,2‐dihydro‐2‐carbethoxy‐3‐keto‐ and 1,2‐dihydro‐2‐thiophenyl‐3‐keto‐3H‐pyrido[3,2,1‐kl]pheno‐thiazines at low voltage support major fragmentation pathways.

Reactions of group IV organometallic compounds XXV. Preparations and reactions of tetramethylene-[(α-trimethylsilyl- or α-trimethylstannyl)phenacyl]sulphonium salts and ylides

Tetramethylene[(α-trimethylsilyl- and α-trimethylstannyl)phenacyl]sulphonium salts [(CH 2) 4S +CH(MMe 3)COPh]Cl - (M = Si and Sn) have been prepared by the reaction of tetramethylenesulphonium phenacyclide (I) with the relevant Me 3MCl. The thermal rearrangement of tetramethylene[(α-trimethylsilyl)phenacyl]sulphonium chloride (II) unexpectedly afforded Cl(CH 2) 4SCHC(OSiMe 3)Ph (III) by a 1,3-migration of the trimethylsilyl group to the oxygen atom accompanied by simultaneous ring-opening. Tetramethylene[(α-trimethylstannyl)phenacyl]sulphonium chloride (IV) gave the corresponding ylide (VI) by reaction with n-butyllithium.

Synthesis of pyridazine derivatives—XXVIII : Tetrazolo-azido isomerizations in some fused tetrazolopyridazines

It has been found that in certain cases azidotetrazolopyridazines can isomerize. 6-Azido-7-methyltetrazolo[1·5- b]pyridazine isomerizes into 6-azido-8-methyltetrazolo[1·5- b]pyridazine by simultaneous ring opening of the tetrazolo ring and cyclization of the azido group. Similarly, 6-azidopyrido-[3·2- d]tetrazolo[5·1- b]pyridazine isomerizes to the thermodynamically more stable 6-azidopyrido[2·3- d]tetrazolo[5·1-b]pyridazine.