Tetrahydropyranyl Derivatives Research Articles

Terminal Cyclopropylsilyl Alcohols as Useful Key Units to Access 2,3,4,6-Tetrasubstituted Tetrahydropyran Scaffolds by Stereocontrolled Prins Cyclization.

In this study, the use of terminal cyclopropylsilyl alcohols in Prins cyclization is reported as a very efficient methodology for the preparation of polysubstituted tetrahydropyrans, in which three new stereogenic centers have been created in a single pot. The reaction is general for a wide variety of aldehydes (alkylic, vinylic, aromatic, or dialdehydes), different types of alcohols, and halogenation agents providing high yields and excellent diastereoselectivity 2,3,4,6-tetrasubstituted tetrahydropyranyl frameworks. Interestingly, diastereomeric alcohols provide the same tetrahydropyranyl derivatives, showing that the reaction mechanism proceeds through common intermediates.

Tetrahydropyranyl protection and deprotection of alcohols using a niobium-based Brønsted acid catalyst

Solid niobium oxide treated with phosphoric acid (NbP) was used as a heterogeneous catalyst in the protection of a series of aliphatic alcohols as tetrahydropyranyl (THP) derivatives. Protection of primary alcohols using this material with strong Brønsted acid sites was achieved in good yields (75%–94%), while moderate values were obtained in the protection of secondary and tertiary alcohols (50%–84%), largely dependent on the steric hindrance in the proximity of the hydroxyl moiety. NbP also catalyzed deprotection of THP ethers derived from primary alcohols and phenol with moderate yields (65%–99%).

ChemInform Abstract: Synthesis and Characterization of para‐Substituted N,N′‐Dihydroxybenzamidines and Their Derivatives as Model Compounds for a Class of Prodrugs.

A synthetic strategy for previously unknown para-substituted N,N′-dihydroxybenzamidines and their O-monosubstituted and O,O′-disubstituted methyl, benzyl, and tetrahydropyranyl derivatives is described. The procedure starts with the corresponding hydroxamic acid chlorides, which after dehydrohalogenation give nitrile oxides. These intermediates in turn react with O-substituted hydroxylamines to afford the desired N,N′-dihydroxybenzamidines after workup. This new class of potential prodrugs was characterized by 15N NMR spectroscopy. The chemical shifts show significant correlations with Hammett σ values, especially for the oxime-type nitrogen with r2 > 0.99. The Hammett σ parameter reliably correlates with electron density in molecules. The presented results thus allow predictions relating to π-electron density and basicity in this functional group, and these are important parameters for the discussion of substrate enzyme interactions.

Synthesis and Characterization of para‐Substituted N,N′‐Dihydroxybenzamidines and Their Derivatives as Model Compounds for a Class of Prodrugs

AbstractA synthetic strategy for previously unknown para‐substituted N,N′‐dihydroxybenzamidines and their O‐monosubstituted and O,O′‐disubstituted methyl, benzyl, and tetrahydropyranyl derivatives is described. The procedure starts with the corresponding hydroxamic acid chlorides, which after dehydrohalogenation give nitrile oxides. These intermediates in turn react with O‐substituted hydroxylamines to afford the desired N,N′‐dihydroxybenzamidines after workup. This new class of potential prodrugs was characterized by 15N NMR spectroscopy. The chemical shifts show significant correlations with Hammett σ values, especially for the oxime‐type nitrogen with r2 > 0.99. The Hammett σ parameter reliably correlates with electron density in molecules. The presented results thus allow predictions relating to π‐electron density and basicity in this functional group, and these are important parameters for the discussion of substrate enzyme interactions.

Diastereoselective syntheses via Prins cyclization, crystal structures determination and theoretical studies of cis-2,6-diphenyl-4-hydroxytetrahydropyran and analogues

We report in this article the diastereoselective syntheses of tetrahydropyranyl derivatives 1–5, its cis configurational ascertainment by spectroscopy and finally the crystal structures determination that unequivocally shows the 1–5 configurations and its crystals packing features. Besides that, we have developed a theoretical study using density functional theory (M06-2X/6-311++G**) to obtain the 1–5 optimized molecular geometries in gas phase.

Novel Cytokinin Derivatives Do Not Show Negative Effects on Root Growth and Proliferation in Submicromolar Range

BackgroundWhen applied to a nutrition solution or agar media, the non-substituted aromatic cytokinins caused thickening and shortening of the primary root, had an inhibitory effect on lateral root branching, and even showed some negative effects on development of the aerial part at as low as a 10 nanomolar concentration. Novel analogues of aromatic cytokinins ranking among topolins substituted on N9-atom of adenine by tetrahydropyranyl or 4-chlorobutyl group have been prepared and tested in standardized cytokinin bioassays [1]. Those showing comparable activities with N6-benzylaminopurine were further tested in planta.Methodology/Principal FindingsThe main aim of the study was to explain molecular mechanism of function of novel cytokinin derivatives on plant development. Precise quantification of cytokinin content and profiling of genes involved in cytokinin metabolism and perception in treated plants revealed several aspects of different action of m-methoxytopolin base and its substituted derivative on plant development. In contrast to standard cytokinins, N9- tetrahydropyranyl derivative of m-topolin and its methoxy-counterpart showed the negative effects on root development only at three orders of magnitude higher concentrations. Moreover, the methoxy-derivative demonstrates a positive effect on lateral root branching and leaf emerging in a nanomolar range of concentrations, in comparison with untreated plants.Conclusions/SignificanceTetrahydropyranyl substitution at N9-position of cytokinin purine ring significantly enhances acropetal transport of a given cytokinins. Together with the methoxy-substitution, impedes accumulation of non-active cytokinin glucoside forms in roots, allows gradual release of the active base, and has a significant effect on the distribution and amount of endogenous isoprenoid cytokinins in different plant tissues. The utilization of novel aromatic cytokinin derivatives can distinctively improve expected hormonal effects in plant propagation techniques in the future.

Discovery and SAR of Methylated Tetrahydropyranyl Derivatives as Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase (ICMT)

A series of tetrahydropyranyl (THP) derivatives has been developed as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) for use as anticancer agents. Structural modification of the submicromolar hit compound 3 led to the potent 3-methoxy substituted analogue 27. Further SAR development around the THP ring resulted in an additional 10-fold increase in potency, exemplified by analogue 75 with an IC(50) of 1.3 nM. Active and potent compounds demonstrated a dose-dependent increase in Ras cytosolic protein. Potent ICMT inhibitors also reduced cell viability in several cancer cell lines with growth inhibition (GI(50)) values ranging from 0.3 to >100 μM. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor.

ChemInform Abstract: A Versatile Ruthenium Catalyst for the Tetrahydropyranylation of Alcohols and Phenols.

Abstract The tetrahydropyranyl derivatives of alcohols and phenols are efficiently prepared in the presence of catalytic amounts of [Ru(CH 3 CN) 3 (triphos)](OTf) 2 (triphos = CH 3 C(CH 2 PPh 2 ) 3 ) under mild conditions, in good to excellent yields.

Synthesis and Enantioselectivity of Cyclopropavir Phosphates for Cellular GMP Kinase

Enantiomeric cyclopropavir phosphates (+)-9 and (−)-9 were synthesized and investigated as substrates for GMP kinase. N2-Isobutyryl-di-O-acetylcyclopropavir (11) was converted to (+)-monoacetate 12 using hydrolysis catalyzed by porcine liver esterase. Phosphorylation via phosphite 13 gave after deacylation, phosphate (+)-9. Acid-catalyzed tetrahydropyranylation of (+)-monoacetate 12 gave, after deacylation, tetrahydropyranyl derivative 14. Phosphorylation via phosphite 15 furnished, after deprotection, enantiomeric phosphate (-)-9. Racemic diphosphate 16 was also synthesized. The phosphate (+)-9 is a relatively good substrate for GMP kinase with a KM value of 57 μM that is similar to that of the natural substrates GMP (61 μM) and dGMP (82 μM). In contrast, the enantiomer (−)-9 is not a good substrate (KM 1200 μM) indicating a significant enantioselectivity for the GMP kinase catalyzed reaction of monophosphate to diphosphate.

The Use of Basic Resin in the Preparation of Tetrahydropyranyl Derivatives of Alcohols and Phenols.

A quick and efficient method for the preparation of tetrahydropyranyl (THP) derivatives of phenols and alcohols using a basic resin IRA-400 (iodide) is described.

Nitrogen versus Oxygen Group Protection in Hydroxypropylbenzimidazoles

In order to convert 1′H-benzimidazol-2′-ylpropanols into aryl ethers using Mitsunobu coupling, it was necessary to protect the benzimidazole nitrogen in the starting alcohols. Selective protection at nitrogen was achieved through N-benzyl derivatives, but attempts to protect the nitrogen directly through tert-butoxycarbonyl, acetyl, trityl, or tetrahydropyranyl derivatives were complicated either by selective reactions at oxygen or by the formation of bis-protected compounds. Transformations of some oxygen-protected derivatives are discussed, and in particular the conversion of the acetates of 1′H-benzimidazol-2′-ylpropanols to N-tetrahydropyranyl derivatives is described. Mitsunobu coupling involving the N-benzyl and N-tetrahydropyranyl derivatives and methyl 4-hydroxybenzoate were achieved, and thus afforded synthetic routes to the desired propylbenzimidazole aryl ethers.

Bis [Trinitratocerium (IV)] Chromate [Ce(No3)2 Cro4] and tris-[Trinitratocerium (IV)] Paraperiodate [(No3)3Ce]3 H2IO6. Two Mild and Efficient Catalysts for Tetrahydropyranylation of Alcohols.

The tetrahydropyranyl derivatives of variety of alcohols are efficiently prepared in the presence of catalytic amounts of [Ce(NO3)2Cro4] and [(NO3)3 Ce]3 H2IO6 in mild condition in good to excellent yields. *Chemistry & Chemical Engineering Research Center of Iran. P.O. Box: 14335—186 Tehran.Iran. Department of Chemistry Alzahra University, Tehran,Iran.

A convergent synthesis of an LTD 4 antagonist, RG12525

An efficient, convergent synthesis of an LTD 4 antagonist, RG12525 ( 1) has been achieved through the alkylation of the (2-quinolinylmethoxy)phenol ( 2) with either a triphenylmethyl protected tetrazole synthon ( 4a) or with a tetrahydropyranyl derivative ( 4b). Preparation of synthons 4a and 4b, as well as novel preparation of 2 is described.

Polyhydroxyoligothiophenes. 2. Hydrogen-Bonding-Oriented Solid State Conformation of 3,3'-Bis(2-hydroxyethyl)-2,2'-bithiophene and Regioselective Synthesis of the Corresponding Head-to-Head/Tail-to-Tail Quater- and Sexithiophene.

This paper reports the X-ray structure of 3,3'-bis(2-hydroxyethyl)-2,2'-bithiophene (1), which is the building block for the synthesis of head-to-head/tail-to-tail 2-hydroxyethyl-substituted oligothiophenes. Contrary to all the bithiophenes reported so far, 1 exhibits a noncoplanar anti conformation and an inter-ring twist angle (67.5 degrees ) which is the largest ever measured for adjacent rings of alpha-conjugated oligothiophenes. This unusual conformation appears to be dictated by intermolecular hydrogen-bonding interactions involving the OH groups, which bind the molecule in close packed layers. The paper also describes the regioselective synthesis of the dimer and the trimer of 1, namely of 3,3',4",3"'-tetrakis(2-hydroxyethyl)-2,2':5',2":5",2"'-quaterthiophene (3c) and of 3,3',4",3"',4"",3""'-hexakis(2-hydroxyethyl)-2,2':5',2":5",2"':5"',2"":5"",2""'-sexithiophene (4b). 3c And 4b were obtained through palladium(0)-catalyzed coupling of the mono- and distannanes of the tetrahydropyranyl derivative of 1 with the appropriate monobromo compound (Stille's reaction). Finally, the paper reports force-field calculations which suggest that the low lambda(max) values measured for 1, 3c, and 4b are also the result of intramolecular hydrogen-bonding interactions which favor highly twisted conformations in solution.

A large scale synthesis of 3‐chloro‐5‐methoxypyridazine

AbstractA large scale synthesis of 3‐chloro‐5‐methoxypyridazine was developed (18 moles) that relies on the protection of the pyridazinone nitrogen of 4,5‐dichloro‐3(2H)‐pyridazinone as the tetrahydropyranyl derivative 2. The 5‐chloro position of the protected pyridazinone was selectively displaced with methoxide to give 3 followed by catalytic hydrogenation of the 4‐chloro group to give 4. Removal of the protecting group with acid followed by phosphorous oxychloride treatment gave the target compound 6 in good yield. This route is superior to the previously described synthesis of this compound.

Antitumor antibiotics discovered and studied at the Institute of Microbial Chemistry.

In 1951, we were pioneers in initiating screening of antitumor agents from microbial metabolites. We discovered bleomycin in 1962 and aclacinomycin in 1975. Peplomycin, a derivative of bleomycin, and pirarubicin, a tetrahydropyranyl derivative of doxorubicin, were also studied. All of them have been clinically used for the treatment of cancer. Using new screening methods, we isolated spergualin in 1982. This agent exhibited immunosuppressive activity as well as antitumor activity. Deoxyspergualin, a derivative of spergualin, is now clinically used for the treatment of acute rejection after kidney transplantation. Bestatin was screened as an inhibitor of aminopeptidase B in 1976. It binds to the aminopeptidases located on the cell membrane of immunocompetent cells and modulates immune responses. It is now used for the treatment of acute non-lymphocytic leukemia. Microbial metabolites will become more important as a source of anticancer drugs in the future.

A one-pot glycosylation of tetrahydropyranyl (THP) ether intermediates

Tetrahydropyranyl (THP) derivatives of alcohols are converted in one-pot and in stereoselective manner into the corresponding 1- O-alkyl-2,3,5-tri- O-benzoyl-β-D-ribofuranosides on treatment with 1- O-acetyl-2,3,5-tri- O-benzoyl-β-D-ribofuranose and trimethylsilyl triflate (TMSOTf). The same protocol was also applyed on 1- O-acetyl-2,3,4,6-tetra- O-benzyl-glucopyranoside (α/β 9:1) to give, by reaction with 1- O-methyl-2,3,4-tri- O-benzyl-6-THP-α-D-glucopyranoside, the corresponding disaccaride (α/β 3:1). The reaction is high yielding and proceeds rapidly at very mild conditions (−30°C) on easily available starting materials.

ChemInform Abstract: The Efficient Deprotection of Acetals and Tetrahydropyranyl Derivatives of Phenols Using (Ru(CH3CN)3(triphos))(OTf)2 as a Catalyst.

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Synthesis of deuterated cyclopropene fatty esters structurally related to palmitic and myristic acids

AbstractTo develop a synthesis of tritiated cyclopropene fatty acids (CPFA), compounds that should prove useful for affinity labeling of desaturases in insect pheromone biosynthetic studies, a series of novel, selectively deuterated CPFA analogues was prepared and characterized. In methyl [16‐2H]12,13‐methylene‐12‐hexadecenoate, the incorporation of deuterium was achieved by treatment of the corresponding ω‐chloro derivative with sodium borodeuteride in dimethylsulfoxide at 70°C for 24 h (67% yield) following conventional procedures. Alkylation of the tetrahydropyranyl derivative of 13‐tridecynol in the presence of lithium diisopropylamide in tetrahydrofuran at −20°C with 1‐chloro‐3‐iodopropane in hexamethylphosphoramide, followed by Jones oxidation of the crude product, yielded 16‐chloro‐12‐hexadecynoic acid (54%), which was esterified to the corresponding methyl ester by treatment with potassium carbonate and methyl iodide in dimethylformamide. Treatment of this acetylenic ester with ethyldiazoacetate in the presence of activated copper‐bronze as catalyst followed by hydrolysis in KOH solution at room temperature yielded 16‐chloro‐12,13‐(carboxymethylene)‐12‐hexadecenoic acid. This diacid was treated with excess oxalyl chloride to give the corresponding diacyl chloride, which was decarbonylated in a diethyl ether solution with zinc chloride, and the cyclopropenium ions thus formed were added at −40°C to a methanolic sodium hydroxide solution of sodium borohydride to give methyl 16‐chloro‐12,13‐methylene‐12‐hexadecenoate. Analogous procedures were followed to prepare methyl [17‐2H]10,11‐methylene‐10‐hexadecenoate, methyl [17‐2H]11,12‐methylene‐11‐hexadecenoate and methyl [17‐2H]12,13‐methylene‐12‐hexadecenoate from the corresponding diacids using sodium borodeuteride in the reduction of the cyclopropenium ions. Alternatively, methyl [2,2,3,3‐2H4]hexadecynoate, prepared by reaction of methyl 2,11‐hexadecadiynoate with magnesium in deuterated methanol at room temperature, was submitted to the above cyclopropenylation and reductive decarbonylation sequence to give methyl [2,2,3,3,17‐2H5]‐11,12‐methylene‐11‐hexadecenoate. In summary, complementary methods for the selective incorporation of one to five deuterium atoms into cyclopropene fatty acids, at different sites, in moderate to high yields have been developed. The methods should easily be applicable to the preparation of the corresponding tritiated analogues.

The efficient deprotection of acetals and tetrahydropyranyl derivatives of phenols using [Ru(CH 3CN) 3(triphos)](OTf) 2 as a catalyst

Acetals and tetrahydropyranyl derivatives of phenols are efficiently and highly chemoselectively deprotected in the presence of catalytic amounts of [Ru(CH 3CN) 3(triphos)]-(OTf) 2 (triphos = CH 3C(CH 2PPh 2) 3), under mild condition, in good to excellent yields.