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Total Synthesis of Isotope-Labeled Isolevuglandins

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Total Synthesis of Isotope-Labeled Isolevuglandins TOTAL SYNTHESIS OF ISOTOPE-LABELED ISOLEVUGLANDINS by YUNFENG XU Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Thesis Advisor: Dr. Robert G. Salomon Department of Chemistry CASE WESTERN RESERVE UNIVERSITY Augest 2012 i CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Yunfeng Xu candidate for the Doctor of Philosophy degree *. (signed) Dr. Michael Zagorski (chair of the committee) Dr. Anthony Pearson Dr. Gregory Tochtrop Dr. Irina Pikuleva Dr. Robert Salomon (date) 06/28/2012 * We also certify that written approval has been obtained for any propriety material contained therein. ii This thesis is dedicated to my parents and my aunt. iii TABLE OF CONTENTS Table of Contents .......................................................................................... iv List of Tables ................................................................................................. vi List of Figures ............................................................................................... vi List of Schemes ............................................................................................ xii Acknowledgements ..................................................................................... xiv List of Abbreviations and Acronyms ........................................................ xvi Abstract........................................................................................................ xix Total Synthesis of Isotope-labeled Isolevuglandins Chapter 1 Introduction ................................................................................. 1 1.1 Enzymatic pathways ................................................................................................2 1.2 The free radical pathway and nomenclature of isolevuglandins ........................5 1.3 Isolevuglandins covalently modify biomolecules ...................................................7 1.4 A new strategy of preparation of quantification internal standards .................10 1.5 The synthesis of isoLGs ..........................................................................................11 1.6 References ...............................................................................................................14 Chapter 2 Total Synthesis of Deuterium-labeled iso[4]LGE2-d6 ............ 21 2.1 Background .............................................................................................................22 2.2 Results and discussion ............................................................................................23 2.2.1 An Improved synthesis of iso[4]LGE2 ...........................................................23 2.2.2 Synthetic design of deuterium-labeled iso[4]LGE2-d6..................................26 2.2.3 Ring opening of THF-d8 ..................................................................................28 2.2.4 Alkylation of diethyl phosphonoacetone .......................................................29 iv 2.2.5 Formation of the top chain: TBDMS deprotection, oxidation and esterification ....................................................................................................30 2.2.6 Construction of iso[4]LGE2-d6 carbon skeleton ...........................................32 2.2.7 Generationof iso[4]LGE2-d6 acetal: deprotection of the TBDMS silyl ether and hydrolysis of the methyl ester ................................................34 2.2.8 Generation of iso[4]LGE2-d6 ..........................................................................35 2.3 Conclusions .............................................................................................................37 2.4 Experimental ...........................................................................................................38 2.5 References ...............................................................................................................51 Chapter 3 Total Synthesis of Deuterium-labeled isoLGE2-d6 ................. 55 3.1 Background .............................................................................................................56 3.2 Results and discussion ............................................................................................57 3.2.1 Alkylation of propargyl alcohol .....................................................................59 3.2.2 Acetylation of alkylated propargyl alcohol (3.1) ..........................................61 3.2.3 Generation of 3.3: deprotection, oxidation and esterification of 3.2 ...........62 3.2.4 Selective hydrogenation of the triple bond to a cis double bond using P-2 nickel boride ....................................................................................63 3.2.5 The Appel reaction: bromination of 3.4 to generate the top side chain precursor 3.5 .........................................................................................64 3.2.6 Generation of enone-d6 (3.7) ...........................................................................64 3.2.7 Elaboration of isoLGE2-d6 (3.12) from enone-d6 3.7 ....................................65 3.3 Conclusions .............................................................................................................67 3.4 Experimental ...........................................................................................................68 3.5 References ...............................................................................................................83 Appendix ....................................................................................................... 86 Bibliography ............................................................................................... 142 v LIST OF TABLES Table 2.1 The yield of alkylation of propargyl alcohol with 2.1 using different 61 bases LIST OF FIGURES Fig. 1.1 The origin of "levuglandin" 4 Fig. 1.2 Strategy for isotope-labeling in previous studies of iso[4]LGE2 10 modification Fig. 1.3 Phospholipase cleavage sites. An enzyme that displays both PLA1 11 and PLA2 activities is called a Phospholipase B (PLB). 1 2 13 Fig 2.1 H, H and C NMR spectra of TBDMS protected 4-iodobutyl-d8 29 alcohol Fig 2.2 Determination of the ratio of cis- and trans- isomers of enone-d6 2.5 33 by 1H-NMR Fig 2.3 Estimation of the yield of hydrolysis of acetal 2.10 to generate 36 iso[4]LGE2-d6 1 Fig. A1 H-NMR spectrum of tert-butyl(1,1,2,2,3,3,4,4-d8-4- 87 iodobutoxy)dimethylsilane (2.1) 2 Fig. A2 H-NMR spectrum of tert-butyl(1,1,2,2,3,3,4,4-d8-4- 88 iodobutoxy)dimethylsilane (2.1) 13 Fig. A3 C-NMR spectrum of tert-butyl(1,1,2,2,3,3,4,4-d8-4- 89 vi iodobutoxy)dimethylsilane (2.1) 1 Fig. A4 H-NMR spectrum of diethyl(4,4,5,5,6,6,7,7-d8-7-((tert- 90 butyldimethylsilyl)oxy)-2-oxoheptan-3-yl)phosphonate (2.2) 2 Fig. A5 H-NMR spectrum of diethyl(4,4,5,5,6,6,7,7-d8-7-((tert- 91 butyldimethylsilyl)oxy)-2-oxoheptan-3-yl)phosphonate (2.2) 13 Fig. A6 C-NMR spectrum of diethyl(4,4,5,5,6,6,7,7-d8-7-((tert- 92 butyldimethylsilyl)oxy)-2-oxoheptan-3-yl)phosphonate (2.2) 1 Fig. A7 H-NMR spectrum ofdiethyl(4,4,5,5,6,6,7,7-d8-7-hydroxy-2- 93 oxoheptan-3-yl)phosphonate (2.3) 2 Fig. A8 H-NMR spectrum ofdiethyl(4,4,5,5,6,6,7,7-d8-7-hydroxy-2- 94 oxoheptan-3-yl)phosphonate (2.3) 13 Fig. A9 C-NMR spectrum ofdiethyl(4,4,5,5,6,6,7,7-d8-7-hydroxy-2- 95 oxoheptan-3-yl)phosphonate (2.3) 1 Fig. A10 H-NMR spectrum of methyl 2,2,3,3,4,4-d6-5-(diethoxyphosphono)- 96 6-oxoheptanoate (2.4) 2 Fig. A11 H-NMR spectrum of methyl 2,2,3,3,4,4-d6-5-(diethoxyphosphono)- 97 6-oxoheptanoate (2.4) 13 Fig. A12 C-NMR spectrum of methyl 2,2,3,3,4,4-d6-5-(diethoxyphosphono)- 98 6-oxoheptanoate (2.4) 1 Fig. A13 H-NMR spectrum of methyl 2,2,3,3,4,4-d6-5-acetyl-7,7- 99 dimethoxyhept-5-enoate(2.5) 2 Fig. A14 H-NMR spectrum of methyl 2,2,3,3,4,4-d6-5-acetyl-7,7- 100 dimethoxyhept-5-enoate(2.5) vii 13 Fig. A15 C-NMR spectrum of methyl 2,2,3,3,4,4-d6-5-acetyl-7,7- 101 dimethoxyhept-5-enoate(2.5) 1 Fig. A16 H-NMR spectrum of (7E,11Z)-methyl 2,2,3,3,4,4-d6-5-acetyl-9- 102 (tert-butyldimethylsilyloxy)-6-(dimethoxymethyl)heptadeca-7,11- dienoate (2.8) 2 Fig. A17 H-NMR spectrum of (7E,11Z)-methyl 2,2,3,3,4,4-d6-5-acetyl-9- 103 (tert-butyldimethylsilyloxy)-6-(dimethoxymethyl)heptadeca-7,11- dienoate (2.8) 1 Fig. A18 H-NMR spectrum of (7E,11Z)-methyl 2,2,3,3,4,4-d6-5-acetyl-6- 104 (dimethoxymethyl)-9-hydroxyheptadeca-7,11-dienoate (2.9u) 2 Fig. A19 H-NMR spectrum of (7E,11Z)-methyl 2,2,3,3,4,4-d6-5-acetyl-6- 105 (dimethoxymethyl)-9-hydroxyheptadeca-7,11-dienoate (2.9u) 1 Fig. A20 H-NMR spectrum of (7E,11Z)-methyl 2,2,3,3,4,4-d6-5-acetyl-6- 106 (dimethoxymethyl)-9-hydroxyheptadeca-7,11-dienoate (2.9l) 2 Fig. A21 H-NMR spectrum of (7E,11Z)-methyl 2,2,3,3,4,4-d6-5-acetyl-6- 107 (dimethoxymethyl)-9-hydroxyheptadeca-7,11-dienoate (2.9l) 1 Fig. A22 H-NMR spectrum of (7E,11Z)-2,2,3,3,4,4-d6-5-acetyl-6- 108 (dimethoxymethyl)-9-hydroxyheptadeca-7,11-dienoic acid (2.10) 2 Fig. A23 H-NMR spectrum of (7E,11Z)-2,2,3,3,4,4-d6-5-acetyl-6- 109 (dimethoxymethyl)-9-hydroxyheptadeca-7,11-dienoic acid (2.10) 1 Fig. A24 H-NMR spectrum of (7E,11Z)-2,2,3,3,4,4-d6-5-acetyl-6-formyl-9- 110 hydroxyheptadeca-7,11-dienoic acid (2.11) 2 Fig. A25 H-NMR spectrum of (7E,11Z)-2,2,3,3,4,4-d6-5-acetyl-6-formyl-9- 111 viii hydroxyheptadeca-7,11-dienoic acid (2.11) 1 Fig. A26 H-NMR spectrum of 4,4,5,5,6,6,7,7-d8-7-((tert- 112 butyldimethylsilyl)oxy)hept-2-yn-1-ol (3.1) 2 Fig. A27 H-NMR spectrum of 4,4,5,5,6,6,7,7-d8-7-((tert- 113 butyldimethylsilyl)oxy)hept-2-yn-1-ol
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