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2,2-Disubstituted 4-Acylthio-3-oxobutyl Groups as Esterase- and Thermolabile Protecting Groups of Phosphodiesters

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Details

Original languageEnglish
Pages (from-to)950-959
Number of pages10
JournalJournal of Organic Chemistry
Volume78
Issue number3
DOIs
Publication statusPublished - 1 Feb 2013
Publication typeA1 Journal article-refereed

Abstract

Five different 2,2-disubstituted 4-acylthio-3-oxobutyl groups have been introduced as esterase-labile phosphodiester protecting groups that additionally are thermolabile. The phosphotriesters 1-3 were prepared to determine the rate of the enzymatic and nonenzymatic removal of such groups at 37 degrees C and pH 7.5 by HPLC-ESI-MS. Additionally, H-1 NMR spectroscopic monitoring was used for structural characterization of the intermediates and products. When treated with hog liver esterase, these groups were removed by enzymatic deacylation followed by rapid chemical cyclization to 4,4-disubstituted dihydrothiophen-3(2H)-one. The rate of the enzymatic deprotection could be tuned by the nature of the 4-acylthio substituent, the benzoyl group and acetyl groups being removed 50 and 5 times as fast as the pivaloyl group. No alkylation of glutathione could be observed upon the enzymatic deprotection. The half-life for the nonenzymatic deprotection varied from 0.57 to 35 h depending on the electronegativity of the 2-substituents and the size of the acylthio group. The acyl group evidently migrates from the sulfur atom to C3-gem-diol obtained by hydration of the keto group and the exposed mercapto group attacks on C1 resulting in departure of the protecting group as 4,4-disubstituted 3-acyloxy-4,5-dihydrothiophene with concomitant release of the desired phosphodiester.

Keywords

  • 3-(PIVALOYLOXY)PROPYL GROUPS, ENZYMATIC DEPROTECTION, DNA OLIGONUCLEOTIDES, NUCLEOTIDES, PRODRUGS, MONOPHOSPHATES, PRONUCLEOTIDES, TRIESTERS, STRATEGY, DELIVERY