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[reaction: see text] Substitution of benzylic hydroxyl groups with vinyl moieties using vinylboron dihalides has been achieved. The reaction provides a novel method for preparing stereodefined alkenyl halides.
An effective, readily scalable two-step synthesis of trisubstituted (E)-vinyl bromides involving bromination of alpha,beta-unsaturated lactones followed by hydrolytic fragmentation has been developed. Several trisubstituted (E)-vinyl bromides, including multigram quantities of (+)-(E)-4-bromo-2-methyl-3-pentenol, a synthetic intermediate required for the C(8)-C(11) moieties of (+)-tedanolide (1) and (+)-13-deoxytedanolide (2), illustrate the utility of this protocol. [reaction: see text]
[reaction: see text] A Lewis acid-catalyzed formal cycloaddition of alpha,beta-unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and vinylogous silyl esters is described here.
[chemical reaction: see text]. The catalytic asymmetric Claisen rearrangement (CAC) of a highly substituted and functionalized alpha-alkoxycarbonyl-substituted allyl vinyl ether has been exploited to gain access to an advanced building block for the projected total synthesis of (-)-xeniolide F, the enantiomer of a xenicane diterpene isolated from a coral of the genus Xenia.
[reaction: see text] Imidazoindolones are present as the key structural motif in the family of antifungals, fumiquinazolines, and the antagonist asperlicin. The first example of a CuI-catalyzed tandem intramolecular amidation forming substituted imidazoindolones from readily accessible ortho gem-dibromovinylanilines is described.
[reaction: see text]. Catalytic hydrogenation of methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) in the presence of diverse aldehydes at ambient temperature and pressure using tri-2-furylphosphine-ligated rhodium catalysts enables formation of aldol products with high levels of syn-diastereoselectivity. A progressive increase in diastereoselectivity is observed upon sequential replacement of phenyl residues for 2-furyl residues (Ph3P, FurPh2P, Fur2PhP, Fur3P). Hydrogen-labile functional groups, including alkynes, alkenes, benzylic ethers, and nitroarenes, remain intact under the coupling conditions.
[reaction: see text] Cu(I)-catalyzed coupling of lactams with (E)-2-chlorovinyliodides or (E)-2-bromovinyliodides produces the corresponding beta-haloenamides in moderate to excellent yields.
[reaction: see text] Stereoselective isomerization of C-allyl glycosides into (E)-C-vinyl glycosides or (Z)-exo-glycals was carried out in the presence of the cationic iridium(I) catalyst [(Ph(2)MeP)(2)Ir(cod)PF(6)]. The products of the isomerization were affected by the relative 1,2-stereochemical relationships and by the nature of the protecting groups. These effects are discussed along with a plausible reaction mechanism.
[reaction: see text] Allylation of in situ generated beta,gamma-unsaturated aldehydes affords rapid access to vinyl halide analogues of fragment A of the cryptophycins. Three scaffolds are prepared in gram quantities by a ring-closing metathesis approach. Derivatization via a variety of cross-coupling protocols is possible, which affords novel analogues of these potent antimitotic agents.
Cross-metathesis of suitably protected 5'-deoxy-5'-methyleneadenosines with racemic and chiral N-Boc-protected six-carbon amino acids bearing a terminal double bond in the presence of the Hoveyda-Grubbs catalyst gave adenosylhomocysteine analogues with the C5'-C6' double bond. Bromination with pyridinium tribromide and dehydrobromination with DBU followed by standard deprotections yielded the 5'-(bromo)vinyl analogue. [structure: see text]
Synthesis of a C-analogue of bacterial glycolipid BbGL2 is reported using Grignard reaction of in situ generated beta-galactosyl iodide and subsequent olefin cross metathesis reaction of C-vinyl galactoside as key steps. [reaction: see text]
Catalytic hydrogenation of divinyl ketones 1a and 1e in the presence of diverse aldehydes 2a-e at ambient temperature and pressure using cationic rhodium catalysts ligated by tri-2-furyl phosphine enables formation of aldol products 3a-e and 5a-e, respectively, with high levels of syn diastereoselection. Through an assay of counterions (Rh(COD)2X), Rh(COD)2SbF6 is identified as the optimum precatalyst for reductive aldol couplings of this type. For para-substituted styryl vinyl ketones 1b-e, a progressive increase in isolated yield is observed for electron-releasing para substituents. [reaction: see text].
The role of human cytochrome P-450 IIE1 (P-450 IIE1) in the oxidation of a number of suspect carcinogens was examined by using a variety of approaches, including (1) selective inhibition of catalytic activity in human liver microsomes by diethyldithiocarbamate, which was found to be a selective mechanism-based inactivator of P-450 IIE1, (2) correlation of rates of different catalytic activities with each other and with chlorzoxazone 6-hydroxylation, an indicator of P-450 IIE1, in human liver microsomes, (3) demonstration of catalytic activity in reconstituted systems containing purified human P-450 IIE1, and (4) immunoinhibition of catalytic activity in human liver microsomes with rabbit anti-human P-450 IIE1. The results collectively indicate that P-450 IIE1 is a major catalyst of the oxidation of benzene, styrene, CCl4, CHCl3, CH2Cl2, CH3Cl, CH3CCl3, 1,2-dichloropropane, ethylene dichloride, ethylene dibromide, vinyl chloride, vinyl bromide, acrylonitrile, vinyl carbamate, ethyl carbamate, and trichloroethylene. Levels of P-450 IIE1 can vary considerably among individual humans--the availability of chlorzoxazone as a noninvasive probe of human P-450 IIE1 and of disulfiram (oxidized diethyldithiocarbamate) as an inhibitor may facilitate discernment of the in vivo significance of human P-450 IIE1 as a factor in the bioactivation and detoxication of these cancer suspects. Further, many investigations with diethyldithiocarbamate, disulfiram, and ethanol in humans and experimental animals may be interpreted in light of mechanisms involving P-450 IIE1.
Etheno adducts are formed after exposure to a number of carcinogens, including vinyl chloride, as well as endogenously as a result of lipid peroxidation. A sensitive and selective assay for N(2), 3-ethenoguanine (epsilonGua) was developed using immunoaffinity (IA) columns made with polyclonal antibodies to epsilonGua followed by gas chromatography/electron capture negative chemical ionization/high-resolution mass spectrometry (GC/ECNCI/HRMS) analysis of its pentafluorobenzyl derivative. These IA columns were specific for epsilonGua and did not bind guanine, deoxyguanosine, 1, N(6)-ethenoadenine, or 1,N(2)-ethenoguanine. The level of recovery of standards from the IA columns was 107 +/- 7% and throughout the entire method (using nucleoside enzymatic digestion) with or without DNA was 72 +/- 6%. Four different hydrolysis/digestion procedures were compared, nucleoside enzymatic (EZ), neutral thermal hydrolysis (NT), formic acid hydrolysis (FA), and HCl hydrolysis. All hydrolysis methods with subsequent IA chromatography produced linear standard curves with r(2) values of 0.999 or better. The level of epsilonGua in chloroethylene oxide-treated calf thymus DNA (CEO-ctDNA) was 38 +/- 2, 42 +/- 3, and 49 +/- 2 fmol of epsilonGua/microg of DNA using EZ, NT, and FA, respectively. These numbers remained consistent when the amount of DNA processed was doubled or tripled. These numbers were comparable to the previously published value of 55 +/- 8 fmol of epsilonGua/micrograms of DNA for the same DNA using HCl hydrolysis, cation exchange cleanup, and LC/MS analysis [Yen, T. Y., et al. (1996) J. Mass Spectrom. 31, 1271-1276]. Additionally, HCl hydrolysis of rat liver DNA from control and vinyl fluoride-exposed rats gave similar epsilonGua results when compared to those from enzymatic digestion using this method. This method gave a detection limit of 5 epsilonGua adducts/10(8) normal dGuo nucleosides in 150 micrograms of DNA using EZ and somewhat lower detection limits using NT and HCl hydrolysis. The method is more sensitive and selective than previously used methods for the quantitation of this adduct.
PURPOSE: To measure solid-state features of amorphous molecular dispersions of indomethacin and various molecular weight grades of poly(vinylpyrrolidone), PVP, and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA, in relation to isothermal crystallization of indomethacin at 30 degrees C. METHODS: The glass transition temperatures (Tg) of molecular dispersions were measured using differential scanning calorimetry (DSC). FT-IR spectroscopy was used to investigate possible differences in interactions between indomethacin and polymer in the various dispersions. The enthalpy relaxation of 5%w/w and 30%w/w polymer dispersions was determined following various aging times. Quantitative isothermal crystallization studies were carried out with pure indomethacin and 5%w/w polymers in drug as physical mixtures and molecular dispersions. RESULTS: All coprecipitated mixtures exhibited a single glass transition temperature. All polymers interacted with indomethacin in the solid state through hydrogen bonding and in the process eliminated the hydrogen bonding associated with the carboxylic acid dimers of indomethacin. Molecular mobility at 16.5 degrees C below Tg was reduced relative to indomethacin alone, at the 5%w/w and 30%w/w polymer level. No crystallization of indomethacin at 30 degrees C was observed in any of the 5%w/w polymer molecular dispersions over a period of 20 weeks. Indomethacin alone and in physical mixtures with various polymers completely crystallized to the y form at this level within 2 weeks. CONCLUSIONS: The major basis for crystal inhibition of indomethacin at 30 degrees C at the 5%w/w polymer level in molecular dispersions is not related to polymer molecular weight and to the glass transition temperature, and is more likely related to the ability to hydrogen bond with indomethacin and to inhibit the formation of carboxylic acid dimers that are required for nucleation and growth to the gamma crystal form of indomethacin.
PURPOSE: To measure the water vapor absorption behavior of sucrose-poly(vinyl pyrrolidone) (PVP) and sucrose-poly(vinyl pyrrolidone co-vinyl acetate) (PVP/VA) mixtures, prepared as amorphous solid solutions and as physical mixtures, and the effect of absorbed water on the amorphous properties, i.e., crystallization and glass transition temperature, Tg, of these systems. METHODS: Mixtures of sucrose and polymer were prepared by co-lyophilization of aqueous sucrose-polymer solutions and by physically mixing amorphous sucrose and polymer. Absorption isotherms for the individual components and their mixtures were determined gravimetrically at 30 degrees C as a function of relative humidity. Following the absorption experiments, mixtures were analyzed for evidence of crystallization using X-ray powder diffraction. For co-lyophilized mixtures showing no evidence of crystalline sucrose, Tg was determined as a function of water content using differential scanning calorimetry. RESULTS: The absorption of water vapor was the same for co-lyophilized and physically mixed samples under the same conditions and equal to the weighted sums of the individual isotherms where no sucrose crystallization was observed. The crystallization of sucrose in the mixtures was reduced relative to sucrose alone only when sucrose was molecularly dispersed (co-lyophilized) with the polymers. In particular, when co-lyophilized with sucrose at a concentration of 50%, PVP was able to maintain sucrose in the amorphous state for up to three months, even when the Tg was reduced well below the storage temperature by the absorbed water. CONCLUSIONS: The water vapor absorption isotherms for co-lyophilized and physically mixed amorphous sucrose-PVP and sucrose-PVPNA mixtures at 30 degrees C are similar despite interactions between sugar and polymer which are formed when the components are molecularly dispersed with one another. In the presence of absorbed water the crystallization of sucrose was reduced only by the formation of a solid-solution, with PVP having a much more pronounced effect than PVP/VA. The effectiveness of PVP in preventing sucrose crystallization when significant levels of absorbed water are present was attributed to the molecular interactions between sucrose, PVP and water.
An artificial phosphotriesterase (PTE) was constructed by co-polymerization of 4(5)-vinylimidazole-Zn(2+)-methacrylic acid cluster with a divinylbenzene polymer. Compared with the spontaneous hydrolysis, the resulting polymer catalyst caused 105-fold rate acceleration towards the hydrolysis of diethyl p-nitrophenyl phosphate (Paraoxon). The catalytic activity of the polymer catalyst could be enhanced for 30% using molecular imprinting technique and the molecularly-imprinted catalyst (MIC) showed a turnover rate of 7.4 x 10(-2) s(-1) towards the hydrolysis of Paraoxon. The MIC also hydrolyzed thiophosphates and phosphorothiolate triester pesticides. Construction of an amperometric sensor employing the MIC as catalyst achieved a detection limit of 0.1 mM Paraoxon.
An efficient synthesis of polymerizable 3'- and 5'-O-acyl-nucleoside derivatives has been developed from inosine and 2'-deoxyuridine by enzyme-catalyzed regioselective acylation with divinyl dicarboxylates. In acetone, Lipozyme (immobilized lipase from Mucor miehei) gave 5'-O-acyl-nucleoside products, and PPL (lipase from porcine pancreas) provided 3'-O-acyl-nucleoside products.