8 resultados para epoxide

em QUB Research Portal - Research Directory and Institutional Repository for Queen's University Belfast


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A total synthesis of phomactin G (3), which is a central intermediate in the biosynthesis of phomactin A (5) in Phoma sp. is described. The synthesis is based on a Cr(II)/Ni(II) macrocyclisation from the aldehyde vinyl iodide 9, leading to 16, followed by sequential conversion of 16 into the -epoxide 21 and the ketone 25 which, on deprotection, led to (±)-phomactin G. Phomactin G (3) shares an interesting structural homology with phomactin D (2), the most potent PAF-antagonist metabolite in Phoma sp. It is most likely converted into phomactin A (5), by initial allylic oxidation to the transient -alcohol phomactin structure 4, known as Sch 49028, followed by spontaneous pyran ring formation.

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This study examined the effect of exogenous benzo[ a ]pyrene (BaP), an important constituent of cigarette smoke, on cultured bovine retinal pigment epithelial (RPE) cells. Evidence is presented for its metabolic conversion into benzo[ a ]pyrene diol epoxide (BPDE) and the consequent formation of potentially cytotoxic nucleobase adducts in DNA. Cultured RPE cells were treated with BaP at concentrations in the range of 0–100 µm. The presence of BaP was found to cause inhibition of cell growth and replication. BaP induced the expression of a phase I drug metabolizing enzyme which was identified as cytochrome P450 1A1 (CYP 1A1) by RT–PCR and by Western blotting. Coincident with the increased expression of CYP 1A1, covalent adducts between the mutagenic metabolite BPDE and DNA could be detected within RPE cells by immunocytochemical staining. Additional support for their formation was afforded by nuclease P1 enhanced 32P-postlabelling assays on cellular DNA. Single-cell gel electrophoresis (comet) assays showed that exposure of RPE cells to BaP rendered them markedly more susceptible to DNA damage induced by broad band UVB or blue light laser irradiation. In the case of UVB, this is consistent with the photosensitization of DNA cleavage by nucleobase adducts of BPDE. Collectively, these findings imply that BaP has a significant impact on RPE cell pathophysiology and suggest mechanisms whereby exposure to cigarette smoke might cause RPE dysfunction and cell death, thus possibly contributing to degenerative disorders of the retina.

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Epoxides and phosphites are often used as additives to stabilize the properties of polymers, including bisphenol A polycarbonate (BPA-PC). We describe density functional (DF) calculations of the reactions of cyclohexene oxide (CHO, cyclohexane epoxide) and phosphites with chain segments of BPA-PC, with the aim of identifying possible reaction paths and energy barriers. The reactions of CHO with the OH-terminated PC chains and with the carbonate group are exothermic, although there is an energy barrier in each case of more than 10 kcal/mol. A comparison of results for different CHO isomers demonstrates the importance of steric effects. The reactions between the same groups of the PC chain and the phosphites 2-[2,4-bis(tert-butyl)phenoxy]-5,5-dimethyl-1,3,2-dioxaphosphorinane] (BPDD) and trimethyl phosphite (TMP), and their phosphonate isomers are characterized by large energy barriers.

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Synthesis of the unsym. Homalium alkaloids hopromine (I, R = H, R1 = pentyl), hoprominol (I, R = OH, R1 = pentyl) and hopramalinol (I, R = OH, R1 = Ph), in diastereoisomeric mixt. form, is reported. The component eight-membered azalactams are first prepd. N-(3-halogenopropyl)-4-pentyl- and 4-heptylazetidin-2-ones are aminated and ring expanded in liq. ammonia to give, after reductive methylation, the corresponding 4-alkyl-5-methyl-1,5-diazacyclooctan-2-ones. Synthesis of the 4-(2-hydroxyheptyl)-5-methyl-1,5-diazacyclooctan-2-one required for hoprominol and hopromalinol is carried out via 4-allyl ?-lactam ring expansion to the eight-membered 4-allylazalactam, followed by methylation, epoxidn. and epoxide opening with lithium dibutylcuprate. A similar epoxidn.-cuprate sequence was carried out on the epoxypropyl ?-lactam, as its N-tert-butyldimethylsilyl deriv., and led to a convenient copper-catalyzed N- to O-migration of the protection; this migration is examd. Alkylation gave O-tert-butyldimethylsilyl-protected N-(3-chloropropyl)-4-(2-hydroxyheptyl)azetidin-2-one which could be aminated and transamidated in excellent yield, to give, after methylation, a superior sequence to the required eight-membered hydroxy azalactam. Although satisfactory for attachment of the first azalactam unit, a dibromobutane coupling system proved unreactive for the second. Couplings with unmethylated, methylated, and benzyloxycabronyl-protected azalactams were examd. using (E)-1,4-dibromobutene and (Z)-1,4-dichlorobutene as the bridging unit. Employing the latter, coupling the first N-methylated azalactam with potassium bis(trimethylsilyl)amide as the base, and then the second with bis(trimethylsilyl)amide-sodium hydride as the base system, provided a satisfactory synthetic outcome. Hydrogenation under acidic conditions gave the unsym. structures hopromine, hoprominol and hopromalinol, as well as the more simple and sym. alkaloid, homaline.

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Herein we describe our application of the O-directed free radical hydrostannation of disubstituted alkyl-acetylenes (with Ph3SnH and Et3B) to the (+)-pumiliotoxin B total synthesis problem. Specifically, we report on the use of this method in the synthesis of the Overman alkyne 8, and thereby demonstrate the great utility of this process in a complex natural product total synthesis setting for the very first time. We also report here on a new, stereocontrolled, and highly practical enantioselective pathway to Overman's pyrrolidine epoxide partner 9 for 8, which overcomes the previous requirement for use of preparative HPLC to separate the 1:1 mixture of diastereomeric epoxides that was obtained in the original synthesis of 9.

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An increasing number of publications on the dried blood spot (DBS) sampling approach for the quantification of drugs and metabolites have been spurred on by the inherent advantages of this sampling technique. In the present research, a selective and sensitive high-performance liquid chromatography method for the concurrent determination of multiple antiepileptic drugs (AEDs) [levetiracetam (LVT), lamotrigine (LTG), phenobarbital (PHB)], carbamazepine (CBZ) and its active metabolite carbamazepine-10,11 epoxide (CBZE)] in a single DBS has been developed and validated. Whole blood was spotted onto Guthrie cards and dried. Using a standard punch (6. mm diameter), a circular disc was punched from the card and extracted with methanol: acetonitrile (3:1, v/v) containing hexobarbital (Internal Standard) and sonicated prior to evaporation. The extract was then dissolved in water and vortex mixed before undergoing solid phase extraction using HLB cartridges. Chromatographic separation of the AEDs was achieved using Waters XBridge™ C18 column with a gradient system. The developed method was linear over the concentration ranges studied with r=0.995 for all compounds. The lower limits of quantification (LLOQs) were 2, 1, 2, 0.5 and 1. µg/mL for LVT, LTG, PHB, CBZE and CBZ, respectively. Accuracy (%RE) and precision (%CV) values for within and between day were

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Biotransformation of acridine, dictamnine and 4-chlorofuro[2,3-b]quinolone, using whole cells of Sphingomonas yanoikuyae B8/36, yielded five enantiopure cyclic cis-dihydrodiols, from biphenyl dioxygenase-catalysed dihydroxylation of the carbocyclic rings. cis-Dihydroxylation of the furan ring in dictamnine and 4-chlorofuro[2,3-b] quinoline, followed by ring opening and reduction, yielded two exocyclic diols. The structures and absolute configurations of metabolites have been determined by spectroscopy and stereochemical correlation methods. Enantiopure arene oxide metabolites of acridine and dictamnine have been synthesised, from the corresponding cis-dihydrodiols. The achiral furoquinoline alkaloids robustine, gamma-fagarine, haplopine, isohaplopine-3,3'-dimethylallylether and pteleine have been obtained, from either cis-dihydrodiol, catechol or arene oxide metabolites of dictamnine.

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Monocyclic allylic cis-1,2-diols reacted with sulfuryl chloride at 0 °C in a regio- and stereo-selective manner to give 2-chloro-1-sulfochloridates, which were hydrolysed to yield the corresponding trans-1,2-chlorohydrins. At −78 °C, with very slow addition of sulfuryl chloride, cyclic sulfates were formed in good yields, proved to be very reactive with nucleophiles and rapidly decomposed on attempted storage. Reaction of a cyclic sulfate with sodium azide yielded a trans-azidohydrin without evidence of allylic rearrangement occurring. An enantiopure bicyclic cis-1,2-diol reacted with sulfuryl chloride to give, exclusively, a trans-1,2-dichloride enantiomer with retention of configuration at the benzylic centre and inversion at the non-benzylic centre; a mechanism is presented to rationalise the observation.