Hydroxymethyl Substituent Research Articles

Design and synthesis of highly potent benzodiazepine gamma-secretase inhibitors: preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide by use of an asymmetric Ireland-Claisen rearrangement.

Novel benzodiazepine-containing gamma-secretase inhibitors for potential use in Alzheimer's disease have been designed that incorporate a substituted hydrocinnamide C-3 side chain. A syn combination of alpha-alkyl or aryl and beta-hydroxy or hydroxymethyl substituents was shown to give highly potent compounds. In particular, (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)butyramide (34) demonstrated excellent in vitro potency (IC(50) = 0.06 nM). 34 could also be selectively methylated to give [(3)H]-28, which is of use in radioligand binding assays.

The effect of a 4-Formyl and Hydroxymethyl Substituent on Steroid Biotransformations by Mucor Plumbeus

Although steroids possessing a 4-formyl substituent undergo reduction on incubation with Mucor plumbeus, they do not appear to be substrates for efficient microbiological hydroxylation by this organism indicating that the structural requirements for these two enzyme systems are different.

Synthesis of hydroxymethyl branched [3.2.0]bicyclic nucleosides using a regioselective oxetane ring-formation.

Two [3.2.0]bicyclic nucleosides, 35 and 34, with one and two hydroxymethyl substituents, respectively, have been efficiently synthesized. A protected (3'-C-vinyl-beta-D-allofuranosyl)thymine derivative 28 was easily prepared from diacetone-D-glucose and the thymine moiety was protected with a BOM-group. After the introduction of a leaving group in the 2'-position, the subsequent nucleoside 31 was used as the substrate for a stereoselective dihydroxylation and a regioselective oxetane ring-formation to give after deprotection the bicyclic nucleoside 34. The surprisingly efficient formation of an oxetane was first discovered by serendipity on a corresponding methylfuranoside derivative. The allo-configured bicyclic nucleoside 34 was easily shortened to a ribo-configured analogue 35 by a diol-cleaving reaction and subsequent reduction. Both 34 and 35 are conformationally restricted in the important intermediate 04'-endo conformation.

Hyperbranched polyethers by ring‐opening polymerization: Contribution of activated monomer mechanism

AbstractPropagation in the cationic ring‐opening polymerization of cyclic ethers involves nucleophilic attack of oxygen atoms from the monomer molecules on the cationic growing species (oxonium ions). Such a mechanism is known as the active chain‐end mechanism. If hydroxyl groups containing compounds are present in the system, oxygen atoms of HO groups may compete with cyclic ether oxygen atoms of monomer molecules in reaction with oxonium ions. At the proper conditions, this reaction may dominate, and propagation may proceed by the activated monomer mechanism, that is, by subsequent addition of protonated monomer molecules to HO terminated macromolecules. Both mechanisms may contribute to the propagation in the cationic polymerization of monomers containing both functions (i.e., cyclic ether group and hydroxyl groups) within the same molecule. In this article, the mechanism of polymerization of three‐ and four‐membered cyclic ethers containing hydroxymethyl substituents is discussed in terms of competition between two possible mechanisms of propagation that governs the structure of the products—branched polyethers containing multiple terminal hydroxymethyl groups. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 457–468, 2003

Metabolic response against sulfur-containing heterocyclic compounds by the lignin-degrading basidiomycete Coriolus versicolor.

The fungal conversions of sulfur-containing heterocyclic compounds were investigated using the lignin-degrading basidiomycete Coriolus versicolor. The fungus metabolized a series of sulfur compounds--25 structurally related thiophene derivatives--via several different pathways. Under primary metabolic conditions, C. versicolor utilized thiophenes, such as 2-hydroxymethyl-, 2-formyl-, and 2-carboxyl-thiophenes, as a nutrient sulfur source for growth; thus, the fungus degraded these compounds more effectively in a non-sulfur-containing medium than in conventional medium. The product analysis revealed that several redox reactions, decarboxylation reactions, and C-S cleavage reactions were involved in the fungal conversion of non-aromatic thiophenes. On the other hand, benzothiophene (BT) and dibenzothiophene (DBT) skeletons were converted to water-soluble products. All the products and metabolic intermediates were more hydrophilic than the starting substrates. These metabolic actions seemed to be a chemical stress response against exogenously added xenobiotics. These metabolic reactions were optimized under ligninolytic conditions, also suggesting the occurrence of a fungal xenobiotic response. Furthermore, the fungus converted a series of BTs and DBTs via several different pathways, which seemed to be controlled by the chemical structure of the substrates. DBT, 4-methylDBT, 4, 6-dimethylDBT, 2-methylBT, and 7-methylBT were immediately oxidized to their S-oxides. BTs and DBTs with the hydroxymethyl substituent were converted to their xylosides without S-oxidation. Those with carboxyl and formyl substituents were reduced to form a hydroxymethyl group, then xylosidated. These observations strongly suggested the involvement of a fungal substrate-recognition and metabolic response mechanism in the metabolism of sulfur-containing heterocyclic compounds by C. versicolor.

Construction of Supported Organometallics Using Cycloplatinated Arylamine Ligands

The preparation of ortho-chelating aminoaryl ligands ([C6H3(CH2NMe2)-2-R-4]-, abbreviated as C,N) containing a pendant hydroxymethyl group is described. These ligands have been cycloplatinated with cis-PtCl2(DMSO)2, yielding the corresponding C,N-platinum(II) complexes. The pendant hydroxymethyl substituent is a versatile group for attachment of the organometallic moiety to macromolecules, which has been demonstrated by attaching the C,N-platinum complexes to a dendritic wedge and to C60.

Syntheses of diazadithiacrown ethers containing two 8-hydroxyquinoline side arms

Ten new diazadithiacrown ethers containing two 8-hydroxyquinoline (HQ) sidearms attached through the HQ 7-positions and four new diazadithiacrown ethers containing two HQ sidearms attached through the HQ 2-positions have been prepared. Some of these new ligands also contain a hydroxymethyl substituent. The starting macrocyclic diazadithiacrown ethers were obtained by treatment of a bis(α-chloroamide) with the appropriate dimercaptan using K2CO3 as the base followed by reduction of the resulting macrocyclic dithiadiamide by BH3-THF or by NaBH4 in the presence of BF3-ether as a catalyst. HQ-containing ligands 23-32 were synthesized by a Mannich reaction of the secondary macrocyclic diamines with the substituted-8- hydroxyquinoline. HQ-containing ligands 33-36 were prepared by reductive amination of the secondary macrocyclic diamines with 8-hydroxyquinoline-2-carbaldehyde. The HQ-containing diazadithiacrown ethers which also contain a hydroxymethyl group on the macroring 23-29, 33, and 35 are more soluble in polar solvents than those without the hydroxymethyl group.

Synthesis and antiviral activity of fluoro-substituted apio dideoxynucleosides.

Novel fluoro-substituted apio dideoxynucleosides ((+/-)-3a and (+/-)-3b) were efficiently synthesized starting from 1,3-dihydroxyacetone via Horner-Emmons olefination as a key step. Cyclization of fluoro ester (+/-)-6 under acidic conditions to the fluorolactone was smoothly proceeded in favor of trans-fluorolactone due to the favorable transition state with equatorial hydroxymethyl substituent. Unfortunately, the final nucleosides (+/-)-3a and (+/-)-3b were found to be inactive against several viruses such as HIV-1, HSV-1, HSV-2 and HCMV.

Hydroxymethyl-Functionalised 9,10-Bis(1,3-dithiol-2-ylidene)-9,10-Dihydroanthracene π-Electron Donors as Synthetic Intermediates for Supramolecular Structures

The synthesis of new derivatives of 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene is reported. 1H NMR studies on compound 4 are consistent with two conformers of the saddle-shaped molecule which interconvert by a boat−boat flipping of the central ring at high temperature. The hydroxymethyl substituent of 4 is readily esterified to yield the benzoyl and 2-naphthaloyl ester derivatives 5a and 5b, respectively, and the dimer and the trimer structures 6 and 7, respectively, by reaction with benzoyl chloride, 2-naphthaloyl chloride, 1,4-benzenedicarbonyl chloride and 1,3,5-benzenetricarbonyl chloride. Deprotonation of 9-(4,5-dimethyl-1,3-dithiol-2-ylidene)-10-(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene (8) using lithium bis(trimethylsilyl) amide (LHMDS) followed by in situ quenching of the lithiated intermediate with methylchloroformate gave the diester derivative 10 (96% yield), whereas using LDA gave the monoester 9 as the major product (32% yield). Diester 10 was reduced to the di(hydroxymethyl) derivative 11. The solution electrochemistry of these new compounds has been studied by cyclic voltammetry: the ester substituents of 9 and 10 are conjugated to the π-framework, causing a positive shift of Eox. The X-ray crystal structures of compounds 4, 5a, 5b·CH2Cl2, 10 and 11 are reported. The molecules adopt a saddle-like conformation; the bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene system is U-shaped due to the boat conformation of the central quinodimethane ring and folding of both the 1,3-dithiole rings. Each compound displays a dimeric packing motif which is most pronounced for 5a and 5b·CH2Cl2. Both these structures contain “oligomeric” acceptor···donor stacks: 4-layer ADDA in 5a and 6-layer DADDAD in 5b (D = dithiole; A = benzoyl and naphthoyl, respectively) but neither contains infinite stacks.

13C NMR Studies of Hyaluronan. 2. Dependence of Conformational Dynamics on Chain Length and Solvent

The conformational dynamics of low molecular weight hyaluronan (HA) polymer and oligosaccharides have been assayed by 13C NMR T1 relaxation time measurements. For polymeric HA in aqueous solution, the average relaxation time for ring carbons was not significantly affected by changing the ionic strength or by changing counterion type. The average relaxation time of HA was found to be similar to that for chondroitin 4-sulfate or chondroitin 6-sulfate in aqueous solution. As has been observed previously for other polysaccharides, the segmental motions of HA chains studied at room temperature in aqueous solution appear to be dominated by viscous damping of the chain motions. Within a chain structure, there are variations in observed T1 that correspond to differences in relative mobility. The hydroxymethyl substituent group shows a difference in relaxation rate relative to the ring to which it is attached, depending on the ring configuration (glucose vs galactose). These differences correlate with relative rotational isomerization rates measured by ultrasonic relaxation. In short HA chains, the nonreducing and reducing terminal residues show much greater mobility than penultimate residues, and these are in turn more mobile than interior residues. In contrast, the more rigid hydrogen-bonded conformation of an HA tetrasaccharide in dimethyl sulfoxide solution shows less position-dependent variation in T1. These data are in accord with the dynamic nature of conformation-stabilizing hydrogen bonds for HA chains in aqueous solution.

New Crown Annelated Tetrathiafulvalenes: Synthesis, Electrochemistry, Self-Assembly of Thiol Derivatives, and Metal Cation Recognition

The synthesis of new S(2)O(4)-crown annelated tetrathiafulvalene (TTF) derivatives substituted with one terminal thiol group is described. Self-assembled monolayers (SAMs) of these compounds have been assembled on gold and platinum surfaces, the latter substrate giving improved quality films. SAMs of TTF derivative 16b are the most stable of those we have studied. Electrochemical data for SAMs of 5a, 5b, 8, 16a, and 16b in acetonitrile reveal two reversible one-electron waves, typical of the TTF system; the current increased linearly with scan rate, indicating a surface wave response. SAMs of 8, 16a, and 16b exhibited an electrochemical response in aqueous electrolytes, which was observed between 50 and 100 cycles. Moreover, if the potential scanned was limited to the first TTF oxidation, the cyclic voltammetry response was observed for at least 1000 cycles. Metal complexation by the crown ionophore of the SAMs in acetonitrile has been monitored by a positive shift in the first oxidation potential of the TTF unit (maximum DeltaE(1)(1/2) = 80 mV for Ag(+)). We also report the X-ray crystal structure of TTF-crown derivative 21 bearing two hydroxymethyl substituents, synthesized during the course of this work. The structure is characterized by infinite chains of molecules linked by strong intrachain hydrogen bonds between the terminal hydroxy groups.

Preparation of functionalized, conformationally constrained DTPA analogues from L- or D-serine and trans-4-hydroxy-L-proline. Hydroxymethyl substituents on the central acetic acid and on the backbone.

The enantio- and diastereospecific syntheses of conformationally constrained diethylenetriaminepentaacetic acid (DTPA) analogues that are functionalized with a hydroxymethyl linker substituent on the central acetic acid or on the backbone are described. Key synthetic steps include (i) displacement of the 4-hydroxyl group of N-BOC-trans-4-hydroxy-L-proline benzyl ester, via activation as the triflate, with suitable amines derived from L- or D-serine, (ii) the low-temperature alkylation of diethylenetriamines with the triflate of benzyl glycolate, thereby minimizing competitive lactamization, to give DTPA pentabenzyl esters, and (iii) deprotection to afford the corresponding DTPA analogues under very mild hydrogenolysis conditions.

A method for syn-dihydroxylation of double bonds cis to a hydroxymethyl substituent

A method for syn-dihydroxylation of double bonds cis to a hydroxymethyl substituent

Stereocontrolled Preparation of Stereocomplementary Regioisomeric Tricarbonyliron Complexes in Enantiopure Form

The use of ultrasound to form ferralactone complexes from an enantiomerically pure allylic epoxide with an adjacent hydroxymethyl substituent affords a pair of stereocomplementary isomers that offer a regioconvergent route to the same chiral pentadienyliron complex. The enantiomeric purity, CD properties, and absolute configurations of intermediate η 4-diene complexes are reported, and X-ray diffraction analysis of a pair of rearranged ferralactone complexes establishes their relative stereochemistries, and confirms their absolute stereochemistries.

Copper(II) complexes of 6-hydroxymethyl-substituted tris(2-pyridylmethyl)amine ligands †

Three potentially tripodal, tris(2-pyridylmethyl)amine (tpa) ligands with hydroxymethyl substituents, [6-(hydroxymethyl)-2-pyridylmethyl]bis(2-pyridylmethyl)amine (HL1), bis[6-(hydroxymethyl)-2-pyridylmethyl]2-(pyridylmethyl)amine (H2L2), tris[6-(hydroxymethyl)-2-pyridylmethyl]amine (H3L3), have been prepared in good yields. From these ligands, the copper(II) co-ordination complexes [Cu(HL1)Cl]Cl 1, [Cu(H2L2)Cl]X (X = Cl 2 or p-toluenesulfonate 3), [Cu(L2BF2)][BF4] 4 a complex of a novel macrocyclic anion with a tpa core, [Cu(H3L3)Br0.43Cl0.57]2[Cu(Br0.43Cl0.57)2(Br0.97Cl0.03)2] 5 with compositionally disordered bromo and chloro co-ligands, [Cu(H3L3)Br]Br 6 and the unusual trimer [Cu3{H3(L3)2}Br][BF4]27 have been synthesized and their spectroscopic and redox properties and crystal structures obtained.

THE SYNTHESIS AND THE ANTI-INFLAMMATORY AND ANTIULCER ACTIVITIES OF A NUMBER OF 2-SUBSTITUTED DERIVATIVES OF BETULONIC ACID, METHYLBETULONE, AND LUPENONE

In previous reports, we have described the synthesis and hepatoprotective activity of a variety of esters – 2-arylidene derivatives of betuline, lupol, and methylbetulonate [1, 2]. The present report presents data on the synthesis and study of the anti-inflammatory and antiulcer activities of 2-methylideneureido derivatives of betulonic acid, methylbetulonate, and lupenone. 2-Hydroxymethylene derivatives (IIa – IIc) were prepared by reaction of betulonic acid (Ia), methylbetulonate (Ib), and lupenone (Ic) with ethyl formiate in the presence of sodium methylate, with yields of 89 – 95%. Interaction of these compounds with urea and thiourea leads to the formation of 2-methylideneureido (IIIa – IIIc) and thioureido (IIId – IIIf) derivatives. The structures of these compounds were confirmed by IR, UV, and NMR spectra (see Tables 1, 2) and by comparison with published data for lupane triterpenoids [3 – 5]. The IR spectra of compounds IIa – IIc included, along with absorption peaks typical of these triterpenoids, bands in the region 3160 – 3150 cm –1 , due to the appearance of OH groups on the hydroxymethylene fragment [6]. In the 13 C NMR spectrum, the C-3 signal showed strongfield shifts compared with the signals in the initial 3-ketotriterpenoids, and also contained new signals corresponding to the C-1 atoms at 188.8 – 188.9 ppm, while the 1 H NMR spectra acquired weakfield signals at 8.52 – 8.60 ppm and 14.65 – 14.85 ppm corresponding to protons in =CH–OH and =CH–OH hydroxymethyl substituents. Analogous signals were also seen in the spectra of the formyl derivative of oleanolic acid [7]. The 13 C NMR spectra of compounds IIIa – IIIf showed resonating C-1 carbon atoms at 139.9 – 140.0 and 141.5 – 141.7 ppm, along with signals from the carbon atoms in the ureide fragments C=O and C=S at 155.3 – 155.5 and 182.4 – 182.6 ppm respectively. In addition, the 1 H NMR spectra of 2-methylideneureido (IIIa – IIIc) and thioureido (IIId – IIIf) derivatives showed interaction of the protons of these fragments in the form of doublets at 7.17 – 7.25 and 7.65 – 7.70 ppm, and 11.35 – 11.45 and 11.68 – 11.75 ppm.

Synthesis, physicochemical characterization, and biological evaluation of 2-(1'-hydroxyalkyl)-3-hydroxypyridin-4-ones: novel iron chelators with enhanced pFe(3+) values.

The synthesis of a range of 2-(1'-hydroxyalkyl)-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pK(a) values of the ligands and the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of a 1'-hydroxyalkyl group at the 2-position leads to a significant improvement in the pFe(3+) values. Such an effect was found to be greater with the hydroxyethyl substituent than with the hydroxymethyl substituent, particularly in the cases of 1-ethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.4) and 1,6-dimethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.5) where an enhancement on pFe(3+) values in the region of two orders of magnitude is observed, as compared with Deferiprone (1, 2-dimethyl-3-hydroxypyridin-4-one) (pFe(3+) = 19.4). The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a [(59)Fe]ferritin-loaded rat model. Chelators and prodrug chelators possessing high pFe(3+) values show great promise in their ability to remove iron under in vivo conditions.

Thermochemistry and structures of Na + coordinated mono- and disaccharide stereoisomers

The Na + affinities of several mono- and disaccharide stereoisomers are determined in the gas phase based on the dissociations of Na +-bound heterodimers [saccharide + B i ]Na +, where B i represents a reference base of known Na + affinity (kinetic method). The compounds investigated include the pentoses arabinose, xylose, and ribose; the hexoses glucose, galactose, and mannose; and the disaccharides melibiose, gentiobiose, and lactose. The decompositions of [saccharide + B i ]Na + are assessed as a function of internal energy, to thereby obtain both absolute Na + affinities as well as relative entropies of Na + attachment. The Na + affinities measured are consistent with multidentate coordination of sodium ion by the oxygen sites of the saccharides. In general, hexoses bind Na + stronger than pentoses, suggesting that the hydroxymethyl substituent equips them with more conformational flexibility and larger inductive effects for complexing Na +. The latter properties are further enhanced in the disaccharides, which also carry more basic substituents; as a result, disaccharides form even stronger bonds to Na +. The entropies of Na + attachment are found to rise in the order pentose < hexose < disaccharide, pointing to an increase in this direction of the rotational flexibility lost after attachment of Na +. The favored [monosaccharide + Na] + structures predicted computationally contain pyranose rings in chair or boat conformations that permit tri- or tetradentate Na + coordination and hydrogen bonds between the hydroxyl ligands; the most stable disaccharide complexes are tetradentate and involve chair forms. In the calculated structures, the pyranose O atom and the hydroxymethyl group(s) generally participate in the Na + binding, in agreement with the experimental trends. Small changes in the saccharide stereochemistry alter the optimum Na + coordination possible and, therefore, the Na + affinity; as a result, the latter thermochemical property is ideally suitable for the distinction of stereoisomeric saccharides.

New 1alpha,25-dihydroxy-19-norvitamin D3 compounds of high biological activity: synthesis and biological evaluation of 2-hydroxymethyl, 2-methyl, and 2-methylene analogues.

New highly active isomers of the natural hormone 1alpha, 25-dihydroxyvitamin D3 possessing an exomethylene group at the 2-position were prepared in a convergent manner, starting with (-)-quinic acid and the corresponding (20R)- and (20S)-25-hydroxy Grundmann ketones. These 2-methylene-19-norvitamins were efficiently converted to the 2-methyl and 2-hydroxymethyl derivatives, some of which exhibited pronounced in vivo biological activity. Configurations of the A-ring substituents were determined by 1H NOE difference spectroscopy as well as by spin decoupling experiments. It was established that the bulky methyl and hydroxymethyl substituents at C-2, due to their large conformational free energies, occupy mainly equatorial positions. Additionally, hydroxylation of the C(10)-C(19) double bond in 1alpha,25-(OH)2D3 was performed, resulting in 1alpha,19,25-trihydroxy-10,19-dihydrovitamin D3 derivatives in which the hydroxymethyl substituent at C-10, for steric reasons, is forced to occupy an axial position. In consequence, the vitamin D3 analogues were synthesized in which the 1alpha-hydroxy group, required for biological activity, is almost exclusively axially or equatorially oriented because of stabilization of the single A-ring chair conformations. The relative ability of the synthesized analogues to bind the porcine intestinal vitamin D receptor was assessed and compared with that of the natural hormone. It was established that vitamins possessing the axial orientation of the 1alpha-hydroxy substituent exhibit a significantly increased receptor binding affinity. Compounds with a 2-methylene substituent showed selective calcemic activity profiles, being extremely effective on bone calcium mobilization. 2alpha-Methyl-substituted vitamins proved to be much more active in vivo than the corresponding epimers with 2beta-configuration. All of the 2-substituted vitamins exhibited pronounced HL-60 differentiating activity, those 2alpha-substituted in the 20S-series being especially potent. The present studies imply that the axial orientation of the 1alpha-hydroxy group is necessary for biological activity of vitamin D compounds.

Chilocorine C: a new "dimeric" alkaloid from a coccinellid beetle, Chilocorus cacti.

A new hexacyclic alkaloid, chilocorine C (4), has been isolated from Chilocorus cacti and characterized on the basis of its IR, UV, MS, and NMR data. Although its structure is closely related to that of exochomine (1) (isolated from Exochomus quadripustulatus) and to chilocorine A (2) and B (3) (obtained previously from C. cacti), the presence of a hydroxymethyl substituent on the saturated tricyclic moiety represents an unexpected structural variation on the dimeric alkaloid theme.