Intramolecular Condensation Reaction Research Articles

Synthesis of Stable and Cell-type Selective Analogues of Cyclic ADP−Ribose, a Ca2+-Mobilizing Second Messenger. Structure−Activity Relationship of the N1-Ribose Moiety1

We previously developed cyclic ADP-carbocyclic ribose (cADPcR, 2) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. A series of the N1-ribose modified cADPcR analogues, designed as novel stable mimics of cADPR, which were the 2"-deoxy analogue 3, the 3"-deoxy analogue 4, the 3"-deoxy-2"-O-(methoxymethyl) analogue 5, the 3"-O-methyl analogue 6, the 2",3"-dideoxy analogue 7, and the 2",3"-dideoxydidehydro analogue 8, were successfully synthesized using the key intramolecular condensation reaction with phenylthiophosphate-type substrates. We investigated the conformations of these analogues and of cADPR and found that steric repulsion between both the adenine and N9-ribose moieties and between the adenine and N1-ribose moieties was a determinant of the conformation. The Ca(2+)-mobilizing effects were evaluated systematically using three different biological systems, i.e., sea urchin eggs, NG108-15 neuronal cells, and Jurkat T-lymphocytes. The relative potency of Ca(2+)-mobilization by these cADPR analogues varies depending on the cell-type used: e.g., 3"-deoxy-cADPcR (4) > cADPcR (2) > cADPR (1) in sea urchin eggs; cADPR (1) >> cADPcR (2) approximately 3"-deoxy-cADPcR (4) in T-cells; and cADPcR (2) > cADPR (1) > 3"-deoxy-cADPcR (4) in neuronal cells, respectively. These indicated that the target proteins and/or the mechanism of action of cADPR in sea urchin eggs, T-cells, and neuronal cells are different. Thus, this study represents an entry to cell-type selective cADPR analogues, which can be used as biological tools and/or novel drug leads.

Solid-Phase Synthesis of Pyrroloisoquinolines via the Intramolecular N-Acyliminium Pictet−Spengler Reaction

In the present investigation, solid-phase routes toward 1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-ones via the intramolecular N-acyliminium Pictet-Spengler reaction are established. Peptide aldehydes generated from their parent N-Boc 1,3-oxazines by acidic reaction conditions undergo intramolecular condensation reactions with the amide N of a solid-supported peptide backbone, thus forming a 1:1 epimeric mixture of a cyclic 5-hydroxylactam, which in turn is in equilibrium with the corresponding intermediate N-acyliminium ion. Provided appropriate acidic reaction conditions, a second ring may be appended via Pictet-Spengler cyclization from the aromatic ring of a neighboring phenylalanine derivative in the peptide sequence. The aromatic substitution pattern of the nucleophilic benzene ring of the phenylalanine derivative and the nature of the acidic reaction media are critically important for the course of the reaction, and both Lewis and Brønsted acids may be employed to effect the cyclization process. This intramolecular reaction is under strict control of stereoselectivity, and only a single stereoisomer is detected in the crude products. A range of mono-, di-, and trisubstituted phenylalanines with diverse sets of electron-donating and electron-withdrawing substituents, pyrene, and naphthalenes have successfully been brought within the scope of the reaction, thus providing a unique scaffold for combinatorial library synthesis.

Formal total synthesis of (+)-wortmannin using catalytic asymmetric intramolecular aldol condensation reaction

A catalytic process for the synthesis of optically active C4-substituted tetrahydroindandiones using an asymmetric intramolecular aldol condensation reaction was developed. When 30 mol% of phenylalanine and 50 mol% of pyridinium p-toluenesulfonate were used under highly concentrated conditions, a variety of C4-substituted tetrahydroindandiones and octahydronaphthalenediones were obtained in high yield (up to 89% yield) and high enantiomeric excess (up to 94% ee). One of the products was successfully transformed into the key intermediate for the synthesis of the phosphatidylinositol 3-kinase inhibitor wortmannin, achieving formal total synthesis of (+)-wortmannin.

6-Chloro-2,3,4,5-tetrahydro-7,8-dimethoxy-1-(4-methoxyphenyl)-1H-3-benzazepine

The title compound, C19H22NClO3, was synthesized by an intramolecular condensation reaction of N-[2-hydroxy-2-(methoxy­phenyl)­ethyl]-2-(2-chloro-3,4-di­methoxy­phenyl)­ethyl­amine in tri­fluoro­acetic acid with 36 N H2SO4 at room temperature and obtained in 69% yield. The crystal structure determined by X-ray diffraction shows normal bond lengths and angles. The seven-membered ring adopts a half-chair conformation.

Intramolecular condensation reactions in protonated dipeptides: carbon monoxide, water, and ammonia losses in competition

The elimination of carbon monoxide and water from a series of protonated dipeptides, [XxxYyy + H] +, is investigated by tandem mass spectrometry experiments and density functional theory. The combined results show that CO loss occurs on the a 1-y 1 pathway, which begins by rearrangement of the added proton to the amide N-atom and creates the proton-bound dimer of an amino acid (Yyy) and an imine (that from Xxx residue). The loss of H 2O is initiated from a tautomer in which the added proton has migrated to the hydroxyl group of the C-terminus, thereby promoting the formation of an ion with protonated oxazolone structure (a nominal b 2 ion). The highest yields of [XxxYyy + H − CO] + and [XxxYyy + H − H 2O] + are observed at threshold energies. As the internal energy of the protonated dipeptides increases, these primary products are depleted by consecutive dissociations yielding mostly backbone fragments. Specifically, [XxxYyy + H − CO] + decomposes to y 1 (protonated Yyy) and a 1 (immonium ion of Xxx residue), while [XxxYyy + H − H 2O] + produces a 2 and the immonium ions of residues Xxx (a 1) and Yyy (“internal” immonium ion). Water loss takes place more efficiently when the more basic residue is at the C-terminal position. Increasing the basicity of the N-terminal residue enhances the extent of CO versus H 2O loss and introduces the competitive elimination of NH 3. The dissociations leading to eliminations of small neutrals (CO, H 2O, etc.) generally proceed over transition states that lie higher in energy than the corresponding dissociation products. The excess energy is disposed of either in translational or rovibrational modes of the products, depending on the stability of the incipient noncovalent assemblies emerging during the cleavage of the small neutrals.

Titania-Doped Silica Fibers Prepared by Electrospinning and Sol-Gel Process

Titania-doped silica fibers were prepared by electrospinning of the sol of silica containing titania. The electrospun fibers had ribbon type morphology. The fibers had significant quantities of hydroxyl groups of Si—OH and Ti—OH. The fibers did not have crystalline structure. Diameters of the fibers were reduced by solvent evaporation and calcination. The hydroxyl groups on the fibers disappeared by calcination. The hydroxyl groups, M—OH (M≡Si, Ti) were changed to M—O—M by intermolecular and intramolecular condensation reactions.

Intramolecular condensation reactions in protonated dipeptides: carbon monoxide, water, and ammonia losses in competition*1

Intramolecular condensation reactions in protonated dipeptides: carbon monoxide, water, and ammonia losses in competition*1

Synthesis of N‐Oxydihydropyrrole Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Novel and Efficient Macrolactonization of ω‐Hydroxycarboxylic Acids Using 2‐Methyl‐6‐nitrobenzoic Anhydride (MNBA).

AbstractFor Abstract see ChemInform Abstract in Full Text.

Thermal degradation and melting point determination of diclofenac

The thermal behaviour of Diclofenac was investigated using Differential Scanning Calorimetry, Hot Stage Microscopy, and Thermogravimetric Analysis. A discrepancy was observed between the melting point values recorded under dynamic flow of either dry nitrogen (180°C) or air (160°C). By means of High Performance Liquid Chromatography/Mass Spectrometric analyses, it has been possible to ascribe this difference in melting points to the formation of three degradation products as a result of intramolecular cyclization and condensation reactions during the heating process in an oxidative atmosphere.

A novel and efficient macrolactonization of ω-hydroxycarboxylic acids using 2-methyl-6-nitrobenzoic anhydride (MNBA)

A variety of lactones were prepared in high yields at room temperature from the corresponding ω-hydroxycarboxylic acids using 2-methyl-6-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction also occurs with triethylamine when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for the intramolecular condensation reaction. These methods were successfully applied to the synthesis of erythro-aleuritic acid lactone and the efficiency of the cyclizations is compared to those of other reported mixed anhydride methods.

Unimolecular Rearrangement Reactions in SilylpyrazolonesA Theoretical Approach

Due to the easy migration of silyl groups, the chemistry of silylpyrazolones exhibits various unimolecular reaction channels not encountered in conventional pyrazolone chemistry. The unimolecular rearrangement process starting from the CH form of N-(trimethylsilyl)-pyrazolone (which is primarily formed in the intramolecular condensation reaction of silylhydrazones) is investigated by density functional (B3LYP) and ab initio (MP2) calculations. The transition states are discussed in detail. First, the organosilyl group migrates from the nitrogen atom to the oxygen atom (1,3-Si shift). The second and third steps consist of two consecutive 1,2-H shifts from the carbon to the nitrogen atom. The barriers for the hydrogen migrations determine the overall classical barrier. In comparison to the reactant CH form, the most stable isomer O-silylpyrazolone is lower in energy by 5 kcal mol - 1 . This finding is in agreement with the experimental result. The calculated structure of this isomer is compared with X-ray diffraction data. The OH and NH forms of N-(trimethylsilyl)-pyrazolone are slightly higher in energy than the CH form.

Polydentate ligand construction: intramolecular condensation reactions in the synthesis of imine-containing ligands

Intramolecular condensation reactions between coordinated polyamines and 2-ketoacids have been examined as part of a route to the synthesis of polydentate amino acid complexes. Imine-containing products have been isolated, and eight of these have been characterised by X-ray crystallographic techniques. In most cases, only a single product is isolated from these reactions. This selectivity can be attributed largely to the geometric constraints that are placed on a system by formation of the imine group. Reaction between a coordinated primary amine and a 2-ketoacid ligand appears to be a quite general route to polydentate iminoacid complexes.

Polydentate ligand construction: preparation of oxime–imine complexes via intramolecular condensation reactions

Complexes of tridentate ligands containing oxime, imine and amine donor groups have been prepared both by complexation of the preformed ligands and by condensation reactions between added dionemonoxime ligands and coordinated amine ligands. Higher yields of the bis(tridentate) complexes result from the former method, while the latter method produces other complexes that may prove synthetically useful as well. Many of the complexes have been characterised by X-ray crystallographic techniques.

Synthesis of N-Oxydihydropyrrole Derivatives

N-Oxydihydropyrrole derivatives were synthesized through an intramolecular Claisen condensation reaction. The N-acylation of hindered hydroxylamines played a key role in providing the useful intermediates, which could be converted to a variety of N-oxydihydropyrrole derivatives.

Polydentate ligand construction: a re-examination of an intramolecular condensation reactionElectronic supplementary information (ESI) available: crystal data tables. See http://www.rsc.org/suppdata/dt/b1/b104976n/

The intramolecular condensation reaction of coordinated aminoacetaldehyde and 1,4,7,10-tetraazadecane (trien) has been reinvestigated. The structure of the product, an imine-containing cobalt(III) complex, has been corrected, and this, together with the isolation and characterisation of carbinolamine intermediates, has allowed a modified mechanism to be proposed for the reaction. The isolated carbinolamines result from condensation of the aldehyde with the most acidic coordinated amine (trans to the chloride ligand). The carbinolamines are unable to dehydrate to form an imine product until after they have undergone a rearrangement of the coordination sphere to a geometry that will allow a planar imine to form.

Synthesis of Benzofuran Analogue of Go6976, an Isoform‐Selective Protein Kinase C Inhibitor

AbstractBased on the structure of Go6976, a known isoform‐selective protein kinase C inhibitor, a benzofuran analogue (1) was designed. This analogue was synthesized by coupling of benzofuran 3‐acetic acid and 8‐oxo‐tryptamine and subsequent intramolecular Dieckmann condensation, alkylation, oxidative photocydization and cyanation reaction of mesylate.

Structural Basis for the Function of Pyridoxine 5′-Phosphate Synthase

Background: Pyridoxal 5′-phosphate is the active form of vitamin B 6 that acts as an essential, ubiquitous coenzyme in amino acid metabolism. In Escherichia coli, the pathway of the de novo biosynthesis of vitamin B 6 results in the formation of pyridoxine 5′-phosphate (PNP), which can be regarded as the first synthesized B 6 vitamer. PNP synthase (commonly referred to as PdxJ) is a homooctameric enzyme that catalyzes the final step in this pathway, a complex intramolecular condensation reaction between 1-deoxy-D-xylulose-5′-phosphate and 1-amino-acetone-3-phosphate. Results: The crystal structure of E. coli PNP synthase was solved by single isomorphous replacement with anomalous scattering and refined at a resolution of 2.0 Å. The monomer of PNP synthase consists of one compact domain that adopts the abundant TIM barrel fold. Intersubunit contacts are mediated by three additional helices, respective to the classical TIM barrel helices, generating a tetramer of symmetric dimers with 422 symmetry. In the shared active sites of the active dimers, Arg20 is directly involved in substrate binding of the partner monomer. Furthermore, the structure of PNP synthase with its physiological products, PNP and P i, was determined at 2.3 Å resolution, which provides insight into the dynamic action of the enzyme and allows us to identify amino acids critical for enzymatic function. Conclusion: The high-resolution structures of the free enzyme and the enzyme–product complex of E. coli PNP synthase suggest essentials of the enzymatic mechanism. The main catalytic features are active site closure upon substrate binding by rearrangement of one C-terminal loop of the TIM barrel, charge–charge stabilization of the protonated Schiff-base intermediate, the presence of two phosphate binding sites, and a water channel that penetrates the β barrel and allows the release of water molecules in the closed state. All related PNP synthases are predicted to fold into a similar TIM barrel pattern and have comparable active site architecture. Thus, a common mechanism can be anticipated.

A One-Pot, One-Operation

Enantiomerically pure 2,1-benzothiazines are readily prepared by a one-pot, one-operation procedure consisting of a palladium-catalyzed aryl amination of an ortho-bromobenzaldehyde with a sulfoximine followed by an intramolecular condensation reaction [Eq. (1)]. BINAP=1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane).

Synthesis of 18-Demethyltaxoid via Stereoselective Allylation and Intramolecular Aldol Condensation Reactions

Abstract Optically active novel 18-demethyltaxiods were successfully synthesized from 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy-1α-(p-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans-bicyclo[6.4.0]dodecan-9-one (2) which corresponds to the BC ring system of Taxol by stereoselective allylation and intramolecular aldol condensation reactions.