Synthesis of C-Glycoside Analogs of the Immunostimulatory Glycosphingolipid, alpha-Galactosylceramide
Item
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Title
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Synthesis of C-Glycoside Analogs of the Immunostimulatory Glycosphingolipid, alpha-Galactosylceramide
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Identifier
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d_2009_2013:6d49b6ae23ad:10760
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identifier
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11020
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Creator
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Liu, Zheng,
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Contributor
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Robert Bittman
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Date
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2011
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Language
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English
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Publisher
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City University of New York.
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Subject
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Organic chemistry | Immunology | Biochemistry | Alane | alfa-Galactosylceramide | CD1d | click | NKT cell | phytosphingosine
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Abstract
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This dissertation presents the asymmetric total synthesis of immunostimulatory alpha- C-galactosylceramide (alpha-C-GalCer) glycolipids and D-ribo-phytosphingosine. Also included in this dissertation is an improved two-step synthetic route to primary allylic alcohols from aldehydes and verification of configurations of three contiguous stereogenic centers in the phytosphingosine backbone of alpha-1C-GalCer, the nonisosteric analog of alpha-C-GalCer in which the glycosidic oxygen atom linking the sugar with phytosphingosine is deleted.;Chapter 1 presents an improved two-step synthetic route to primary allylic alcohols from aldehydes. A modification of the Horner-Wadsworth-Emmons (HWE) olefination reaction in H2O/2-propanol (1:1) and a convenient protocol to prepare AlH3 in tetrahydrofuran from LiAlH4 and n-butyl bromide are the key factors in the improvement.;Chapter 2 presents an asymmetric synthesis of D- ribo-phytosphingosine. The synthesis was achieved by utilizing the ProPhenol-catalyzed alkynylation of an unsaturated aldehyde to afford an allylic propargylic alcohol followed by asymmetric epoxidation and opening of a propargylic epoxy alcohol with NaN3/NH4Cl. Deprotection and reduction of the resulting acyclic azide then gave D-ribo-phytosphingosine. The acyclic azide was also subjected to an intramolecular click reaction, generating a bicyclic triazole, whose diacetate derivative was found to have almost identical cis and trans vicinal coupling constants. The relative stereochemistry of the final product was assigned by NMR analysis of corresponding Mosher esters and amides, and confirmed by comparison of NMR spectra and specific rotations of its tetraacetate derivative with reported data. The stereochemical assignment based on comparing J values with reported data in bicyclic triazoles, generated by a copper-free intramolecular click reaction, was inconclusive. Alkynyl-azide, an efficient glycosyl acceptor in the synthesis of alpha-galactosylceramide derivatives, was also readily prepared by this route.;Chapter 3 presents (1) a modification of the first generation synthesis of alpha-1C-galactosylceramide featuring the two-step HWE olefination and alane reduction protocol described in Chapter 1 and the ProPhenol-catalyzed asymmetric alkynylation reaction, and (2) a detailed verification of the configurations of three contiguous stereogenic centers in the phytosphingosine moiety. Given the possible intramolecular participation by the 2'-O-benzyl group of the galactosyl moiety in epoxide opening by the azide anion, an attempt was made to assign the relative stereochemistry of the azide-bearing carbon through the coupling constants (J4,5 and J5,6) in a bicyclic triazole, which was obtained via an intramolecular click reaction and acetylation of diol. The cis J 4,5 and trans J5,6 displayed almost the same values, suggestive of possible retention in the opening of the epoxide; however, nOe analysis was inconclusive. Model compounds containing the same bicyclic triazole skeleton were prepared via the same reaction sequence, and their cis J4,5 and trans J 5,6 coupling constants showed similar values as to those in the sugar counterpart. According to the systematical investigation of the model compounds described in Chapter 2, the epoxide-opening reaction did indeed proceed with inversion. These results exclude intramolecular participation by the 2'- O-benzyl group and emphasize the need for caution when coupling constants alone are used to judge the relative configuration in bicyclic triazoles and related systems.;Chapter 4 presents stereocontrolled syntheses of alpha-C-GalCer and its alpha-C-acetylenic analog from 1-hexadecene and D-galactose. The key transformations include Sonogashira coupling, Sharpless asymmetric epoxidation, and Et2AlCl-catalyzed cyclization of an epoxytrichloroacetimidate to generate a protected dihydrooxazine synthon.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Chemistry
