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PubMed2000

Thermal-Dependent dehydration process and intramolecular cyclization of lisinopril dihydrate in the solid state.

The pathway of dehydration and intramolecular cyclization of lisinopril dihydrate in the solid state was investigated using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and a combination of thermal analyzer with Fourier transform infrared microspectroscopy (thermal FT-IR microscopic system). The results indicate that the dehydration from the solid-state lisinopril dihydrate had a two-step process from dihydrate to monohydrate at 76 degrees C and then from monohydrate to anhydrate at 99-101 approximately C, which could be clearly observed from the above three methods. Only the thermal FT-IR microscopic system could give vital information on diketopiperazine (DKP) formation via intramolecular cyclization in anhydrous lisinopril. A new peak at 1670 cm(-1) assigned to the carbonyl band of DKP formation was clearly evidenced. The water of reaction byproduct was liberated at a temperature >157 degrees C and appeared on the IR spectra near 3200-3400 cm(-1). Moreover, the peak at 1574 cm(-1) assigned to carboxylate shifted to 1552 cm(-1) due to the DKP formation. The peak at 1670 cm(-1) related to the DKP formation changed slightly in intensity from 147 degrees C and significantly near 157 degrees C. DSC and TGA methods were poor for use in supplying information on DKP formation in lisinopril. The thermal FT-IR microscopic system is useful from the view point that it can quickly and directly show the solid-state stability of drug.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

The cyclization reaction of ortho-ethynylbenzaldehyde derivatives into isoquinoline derivatives.

In order to elucidate the reaction mechanism of the cyclization between an ethynyl group and an imino group at the ortho-position on an aromatic ring to afford isoquinolines, reaction of 2-ethynylbenzaldehydes under various conditions was examined. It is concluded that reaction proceeds via an ionic process and the isoquinoline 4-hydrogen atom derives from the solvent. In addition, it was found that 2-ethynylbenzaldehyde O-methyloximes underwent cyclization in the presence of primary and secondary alcohols to give 3-substituted isoquinolines.

Benzaldehydes↗
PubMed2001

Reaction kinetics of solid-state cyclization of enalapril maleate investigated by isothermal FT-IR microscopic system.

To investigate the reaction kinetics of the solid-state degradation process of enalapril maleate, a Fourier transform infrared microspectroscope equipped with thermal analyzer (thermal FT-IR microscopic system) was used. The isothermal stability study was conducted at 120-130 degrees C for 1-2 h and changes in the three-dimensional plots of the IR spectra of enalapril maleate with respect to heating time were observed. The study indicates that the bands at 1649, 1728, and 1751 cm(-1) assigned to intact enalapril maleate gradually reduced in peak intensity with heating time. However, the peak intensities at 1672 and 1738 cm(-1) (due to enalapril diketopiperazine (DKP) formation) and at 3250 cm(-1) (corresponding to water formation) gradually increased with heating time. The solid-state diketopiperazine formation and the degradation process of enalapril maleate via intramolecular cyclization were found to be simultaneous. The isothermal decomposition curves were sigmoidal and were characterized by induction and acceleration periods, indicating the presence of autocatalytic solid-state decompositions. Moreover, the power-law equation (n = 1/4) was found to provide the best fit to the kinetics of decomposition. This isothermal FT-IR microscopic system was easily used to investigate the degradation of enalapril maleate and the concomitant formation of DKP. The solid-state reaction of enalapril maleate required an activation energy of 195+/-12 kJ/mol to undergo the processes of decomposition and intramolecular cyclization.

Algorithms↗
PubMed1995

[A stereoselective synthesis of tilivalline and its analogs utilizing a new Mannich type intramolecular cyclization].

Tilivalline (1a), a metabolite isolated from Klebsiella pneumoniae var. oxytoca, belongs to a group of pyrrolo[2,1-c][1,4]benzodiazepines, a characteristic skeleton of anthramycin-type antitumor antibiotics. We have accomplished a completely stereoselective, efficient and convenient synthesis of 1a utilizing a new Mannich type intramolecular cyclization as a key step. Further, a computational chemical analysis clarified the effect of zinc chloride on the high stereoselectivity in the tilivalline synthesis. To aim both the extension of the scope of the new Mannich type intramolecular cyclization and the studies on the structure-biological activity relationship, we further extended the method to the synthesis of tilivalline derivatives and 2-(3'-indolyl)-1,4-benzodiazepines (50). Investigation on the cytotoxicity of 1a and its analogs has revealed that 1a shows the strong cytotoxicity toward mouse leukemia L 1210 cells and the replacement of the indole function of 1a with cyano one increases the cytotoxicity of 1a about 100 times (IC50 = 0.05 microgram/ml).

Animals↗
PubMed1989

An unexpected intramolecular cyclization of isothiouronium teicoplanins. II. Reaction mechanism and biological activity.

N15-Isothiouronium derivatives of teicoplanin and its aglycone submitted to alkaline condition give rise to an intramolecular cyclization. The structures of the new gamma-lactam derivatives were determined by using 1H NMR, IR and fast atom bombardment mass spectra. The cyclization mechanism was interpreted on the basis of the identification of the intermediate structure. The poor in vitro antibacterial activity of the new cyclic compounds and the negligible affinity for the synthetic peptidoglycan model Ac2-L-Lys-D-Ala-D-Ala is probably due to the lack of the N-17 amidic proton and to the lack of the basic character of the nitrogen in position 15.

Anti-Bacterial Agents↗
PubMed2001

Single-step formation of structurally defined bicyclic peptides via S(N)Ar cyclization.

[structure: see text]. A solid-phase methodology for macrocyclization via an S(N)Ar reaction has been developed for the unambiguous formation of bicyclic peptidic compounds in a single cyclization step. The cyclization strategy involves the reaction of a 3,5-dihydroxybenzoyl group with two nitrofluorobenzoyl moieties. The symmetry of the dihydroxy aromatic ring results in a single product, and the remaining nitro groups are subsequently reduced to anilines and acylated.

Bridged Bicyclo Compounds↗
PubMed1993

Proofreading and the evolution of a methyl donor function. Cyclization of methionine to S-methyl homocysteine thiolactone by Escherichia coli methionyl-tRNA synthetase.

A cyclic sulfonium compound, S-methyl homocysteine thiolactone (SMHT), is formed from methionine during in vitro tRNA aminoacylation catalyzed by Escherichia coli methionyl-tRNA synthetase. The mechanism of SMHT formation involves enzymatic deacylation of Met-tRNA (k = 0.06 s-1) and, to a lesser extent, Met-AMP (k = 0.02 s-1). Cyclization of methionine, reminiscent of cyclization of homocysteine during editing, illustrates the limited ability of methionyl-tRNA synthetase to discriminate against the cognate methionine at the editing site designed for the noncognate homocysteine. In early stages of biotic evolution, SMHT, a sulfonium compound, may have fulfilled the present day methyl donor function of S-adenosylmethionine. Existing homologies between methionyl-tRNA synthetase and S-adenosylmethionine synthetase indicate evolutionary relatedness of the two proteins.

Acylation↗
PubMedDate not supplied

Synthesis of a novel side-chain to side-chain cyclized enkephalin analogue containing a carbonyl bridge.

A novel type of cyclic opioid peptide analogue, cyclo[N epsilon,N epsilon'-carbonyl-D-Lys2,Lys5]enkephalinamide, was prepared from a linear precursor peptide. The peptide was synthesized on the Merrified resin and also by a combination of the solid-phase technique and the classical method in solution. In both cases the cyclization was performed by reaction of bis(4-nitrophenyl)carbonate with the free side-chain amino groups of the two lysine residues. The described method permits the convenient preparation of novel peptide analogues cyclized via a ureido group incorporating the side-chain amino groups of two alpha, omega-diamino acid residues. The cyclic enkephalin analogue containing a 21-membered ring structure showed preference for mu over delta opioid receptors in opioid bioassays in vitro.

Animals↗
PubMed1999

Solid-phase synthesis and cyclization of a large branched peptide from IgG Fc with affinity for Fc gammaRI.

A solid phase approach has been used to synthesize a large branched disulphide peptide from IgG Fc, Ac-F-C*-A-K-V-N-N-K-D-L-P-A-P-I-E-K(Ac-E-L-L-G-G-P-S-V-F)-C*-I-NH2. This peptide combines the lower hinge region of IgG and a proximal beta-hairpin loop, both implicated in binding to Fc gammaRI. Solid phase Tl(tfa)3 cyclization of the linear branched peptide resulted in a poor yield of cyclic hinge-loop peptide (11%) most likely due to steric hindrance caused by the branch. However, if addition of the branch was preceded by solid phase Tl(tfa)3 cyclization of the loop, the yield was excellent at 75%. Cyclic hinge-loop peptide was active in displacing IgG2a from Fc gammaRI expressed on monocyte cell lines with an IC50 of 40 microM, whereas the linear form of this peptide was inactive. The Fc hinge-loop peptide demonstrates the potential for a non-mAb high affinity, immunomodulatory ligand for Fc gammaRI.

Amino Acid Sequence↗
PubMed2000

A valence bond study of the Bergman cyclization: geometric features, resonance energy, and nucleus-independent chemical shift (NICS) values

The Bergman cyclization of (Z)-hex-3-ene-1,5-diynes (1, enediynes), which produces pharmacologically important DNA-cleaving biradicals (1,4-benzyne, 2), was studied by using Hartree-Fock (HF) and density-functional theory (DFT) based valence bond (VB) methods (VB-HF and VB-DFT, respectively). We found that only three VB configurations are needed to arrive at results not too far from complete active space [CASSCF(6 x 6)] computations, while the quality of VB-DTF utilizing the same three configurations improves upon CASSCF(6 x 6) analogous to CASPT2. The dominant VB configuration in 1 contributes little to 2, while the most important biradical configuration in 2 plays a negligible role in 1. The avoided crossing of the energy curves of these two configurations along the reaction coordinate leads to the transition state (TS). As a consequence of the shape and position of the crossing section, the changes in geometry and in the electronic wavefunction along the reaction coordinate are non-synchronous; the TS is geometrically approximately 80% product-like and electronically approximately 70% reactant-like. While the pi resonance in the TS is very small, it is large (64.4 kcal mol(-1)) for 2 (cf. benzene=61.5 kcal mol(-1)). As a consequence, substituents operating on the sigma electrons should be much more effective in changing the Bergman reaction cyclization barrier. Furthermore, additional sigma resonance in 2 results in unusually high values for the nucleus-independent chemical shift (NICS, a direct measure for aromaticity). Similarly, the high NICS value of the TS is due mostly to sigma resonance to which the NICS procedure is relatively sensitive.

Journal Article↗
PubMed2002

Synthesis of functionalized 2-alkylidenetetrahydrofurans by cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with epoxides.

The Lewis acid mediated cyclization of epoxides with 1,3-bis(trimethylsilyloxy)-1,3-butadienes, electroneutral equivalents of 1,3-dicarbonyl dianions, results in the formation of 2-alkylidenetetrahydrofurans with a great variety of substitution patterns and functional groups. This includes the synthesis of 2,3'-bifuranylidenes and 7-oxabicyclo[4.3.0]nonanes. The cyclization of dienes with functionalized epoxides containing base-labile groups proceeds with good chemoselectivity. In all reactions, good regio- and E diastereoselectivities are observed. Based on the stereoselectivities observed for reactions of 1,2-disubstituted epoxides, a working hypothesis for the mechanism of the reaction is suggested.

Journal Article↗
PubMed2003

Reaction of enol ethers with alkynes catalyzed by transition metals: 5-exo-dig versus 6-endo-dig cyclizations via cyclopropyl platinum or gold carbene complexes.

The intramolecular reaction of enol ethers with alkynes in methanol is catalyzed by electrophilic Pt(II), Pd(II), and Au(III) chlorides and by a Cu(I) complex to give five- or six-membered rings bearing dimethyl acetals. The reaction takes place by an anti addition of the enol ether and the metal to the alkyne. The possible involvement of vinylidene complexes in this reaction is excluded. In addition to the usual 5-exo-dig (or 6-exo-dig) pathways, a 6-endo-dig pathway has also been found to take place with certain enynes. One case of 5-endo-dig cyclization has also been found. A general scheme for the alkoxycyclization of enynes catalyzed by transition metals based on DFT calculation of PtCl(2) and AuCl(3) complexes that includes exo and endo cyclizations is presented.

Journal Article↗
PubMed2004

Synthesis of phthalide derivatives using nickel-catalyzed cyclization of o-haloesters with aldehydes.

The reaction of o-bromobenzoate (1 b) with benzaldehyde (2 a) in the presence of [NiBr(2)(dppe)] (dppe=1,2-bis(diphenylphosphino)ethane) and zinc powder in THF (24 hours, reflux temperature), afforded 3-phenyl-3H-isobenzofuran-1-one (3 a) in an 86 % yield. Similarly, o-iodobenzoate reacts with 2 a to give 3 a, but in a lower yield (50 %). A series of substituted aromatic and aliphatic aldehydes (2 b, 4-MeC(6)H(4)CHO; 2 c, 4-MeOC(6)H(4)CHO; 2 d, 3-MeOC(6)H(4)CHO; 2 e, 2-MeOC(6)H(4)CHO; 2 f, 4-CNC(6)H(4)CHO; 2 g, 4-(Me)(3)CC(6)H(4)CHO; 2 h, 4-C(6)H(5)C(6)H(4)CHO; 2 i, 4-ClC(6)H(4)CHO; 2 j, 4-CF(3)C(6)H(4)CHO; 2 k, CH(3)(CH(2))(5)CHO; 2 l, CH(3)(CH(2))(2)CHO) also underwent cyclization with o-bromobenzoate (1 b) producing the corresponding phthalide derivatives in moderate to excellent yields and with high chemoselectivity. Like 1 b, methyl 2-bromo-4,5-dimethoxybenzoate (1 c) reacts with tolualdehyde (2 b) to give the corresponding substituted phthalide 3 m in a 71 % yield. The methodology can be further applied to the synthesis of six-membered lactones. The reaction of methyl 2-(2-bromophenyl)acetate (1 d) with benzaldehyde under similar reaction conditions afforded six-membered lactone 3 o in a 68 % yield. A possible catalytic mechanism for this cyclization is also proposed.

Journal Article↗
PubMed2006

Gold(I)-catalyzed cyclizations of 1,6-enynes: alkoxycyclizations and exo/endo skeletal rearrangements.

Gold(I) complexes are the most active catalysts for alkoxy- or hydroxycyclization and for skeletal rearrangement reactions of 1,6-enynes. Intramolecular alkoxycyclizations also proceed efficiently in the presence of gold(I) catalysts. The first examples of the skeletal rearrangement of enynes by the endocyclic cyclization pathway are also documented. Iron(III) is also able to catalyze exo and endo skeletal rearrangements of 1,6-enynes, although the scope of this transformation is more limited. The gold(I)-catalyzed endocyclic cyclization proceeds by a mechanism different from those followed in the presence of PdII, HgII, or RhI catalysts.

Journal Article↗
PubMed2007

Studies on Pd(0)-catalyzed cyclization of N-3,4-alkadienyl toluenesulfonamides with organic halides: selective synthesis of 2,3-dihydropyrroles, 1,2,3,6-tetrahydropyrridines, and azetidines.

The palladium-catalyzed coupling-cyclization of beta-amino allenes with organic halides ranging from aryl halide to 1-alkenyl halide was studied. 2,3-Dihydro-1H-pyrroles were obtained by reaction of 3-substituted-5-unsubstituted-3,4-allenyl amides under conditions A, while the reaction of 5-substituted-3,4-allenyl amides afforded 1,2,5,6-tetrahydropyridines and/or azetidines with high de under conditions B or C. The skeleton and relative configuration of the six-membered products were established by the X-ray diffraction studies of 10 ka. Allenyl amide 4 q reacted with 1,4-diiodobenzene 6 r to afford double cyclization product 15. The structure of its major stereoisomer was also determined by the X-ray diffraction study.

Journal Article↗
PubMed2006

Diastereomeric discrimination in the lifetimes of Norrish Type II triplet 1,4-biradicals and stereocontrolled partitioning of their reactivity (Yang cyclization versus Type II fragmentation).

The stereochemistry at C2 and C3 carbons controls the partitioning of triplet 1,4-biradicals of ketones 2 among various pathways. Differences in the major reaction pathways, for example, cyclization (syn) and fragmentation (anti), adopted by the diastereomeric 1,4-radicals of ketones 2 have permitted unprecedented diastereomeric discrimination in their lifetimes to be observed by nanosecond laser flash photolysis. From quantum yield measurements and transient lifetime data, the absolute rate constants for cyclization and fragmentation of a pair of diastereomeric triplet 1,4-biradicals have been determined for the first time.

Journal Article↗
PubMedDate not supplied

Solution versus solid-phase cyclization strategies for large sidechain lactam-bridged peptides: a comparative study.

A 22-residue peptide with a sidechain lactam bridge involving 18 residues (60-atom cycle) has been synthesized. Three different protection schemes using Fmoc/tBu/cyclohexyl, Fmoc/tBu/allyl or Boc/Bzl/ fluorenylmethyl protecting group combinations have been explored for the solid phase of the linear precursors, which have been subsequently cyclized in solution or in the solid phase. Cyclization yields in solution have been consistently better than on solid phase; however, the solid-phase strategy requires fewer purification steps and therefore global yields are comparable.

Amino Acid Sequence↗