DIALOG(R)File 35: Dissertation Abs Online
`(c) 2007 ProQuest Info&Learning. All rights reserved.
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`0956748 ORDER NO: AAD87-13295
`SYNTHESIS AND EVALUATION OF AMMONIUM ANALOGS OF CARBOCATIONIC INTERMEDIATES IN
`SQUALENE BIOSYNTHESIS
`
`Author: CAPSON, TODD LEO
`Degree: PH.D.
`Year: 1987
`Corporate Source/Institution: THE UNIVERSITY OF UTAH ( 0240)
`Source: Volume 4803B of Dissertations Abstracts International.
`PAGE 757 . 157 PAGES
`Descriptors: CHEMISTRY, ORGANIC
`Descriptor Codes: 0490
`
`The syntheses of primary amine, N- 2- 4,8-dimethyl-3, 7-(3E)-nonadienyl -2-methyl-3- 2,6,10-trimethyl-
`1,5,9-(1E,5E)-undecatrienyl -trans-1,2-trans-1,3-cyclopropylamine (35) and secondary amine, N- 2- 4,8-
`dimethyl-3,7-(3E}-nonadienyl -2-methyl-3- 2,6,10..,trimethyl-l,5,9-(lE,SE)-undecatrienyl -1,2-trans-1,3-
`cyclopropylamino -N-propyl-3-phosphonophosphate (80) are described. Both amines were converted to their
`ammonium forms and tested as inhibitors of squalene synthetase.
`Both amines were synthesized from presqualene alcohol (38), which was oxidized to aldehyde 62 by a
`Swem oxidation and then to acid 37 with tertabutylammonium permanganate or sodium chlorite. Acid 37 was
`converted to the isocyanate, which was treated with 2-trimethylsilylethanol to afford carbamate 63.
`Treatment of 63 with tetrabutylammonium fluoride afforded primary amine 35. Reaction of 63 with potassium
`hydride and then with diethyl (3-p-toluenesulfonyloxy}propyl phosphonate afforded N-alkylated
`phosphonocarbamate 83. Hydrolysis of 83 afforded phosphonic acid 100, which was treated sequentially with
`carbonyldiimidazole, tetrabutylammonium dihydrogen phosphonate, and tetrabutylammonium fluoride to
`afford 80.
`Radioactive substrates of squalene synthetase were prepared for enzymatic studies. 1-('3)H Farnesyl
`pyrophosphate ( 1-('3)H farnesyl)PP, l-{'3)H 9) was synthesized from 1-('3}H farnesyl bromide { 1-('3)H 41)
`and tris-tetrabutylammonium pyrophosphate. 1-('3)H Presqualene pyrophosphate ( 1-('3)H presqualene PP, 1
`-('3)H 13) was synthesized from presqualene alcohol ( 1-('3)H 38), bis-triethylammonium phosphate, and
`trichloro-acetonitrile.
`Squalene synthesis from farnesyl PP was unaffected in the presence 33 (20 (mu)M) in the absence of
`inorganic pyrophospate (PP{,i)). In the presence of 2 mM PP(,i), synthesis of squalene from farnesyl PP was
`inhibited 75%. In the absence of PP(,i), 33 inhibited the conversion of presqualene PP to squalene by 34%. In
`the presence of 1 mM PP(,i), synthesis of squalene from presqualene PP was inhibited by 73%.
`Secondary ammonium compound 79 inhibited squalene synthetase in the absence of PP(,i). In the
`presence of 18 (mu)M 79, squalene synthesis from farnesyl PP and presqualene PP was inhibited by 80% and
`90%, respectively. The proton release assay was used to measure the conversion of farnesyl PP to
`presqualene PP. When proton release and squalene synthesis were measured simultaneously in the same
`assay, presqualene PP and squalene production from farnesyl PP was inhibited to virtually the same degree {
`56%). Inhibition of squalene synthetase by 33 and 79 was interpreted as evidence for the existence for
`carbocationic intermediates that exist as ion pairs with PP(,i) during the exzymatic rearrangement of
`presqualene PP to squalene.
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`PENN EX. 2176
`CFAD V. UPENN
`IPR2015-01836