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Studies towards a method for incorporation of 3'-deoxy-3'-C-methylenephosphonate linkages into oligonucleotides
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
3'-deoxy-3'-C-methylenephosphonate linkages (English)
Abstract [en]

Synthetic strategies towards 3’-deoxy-3’-C-methylenephosphinate building blocks were explored. The key transformations involved stereoselective hydroboration of 1-[2-O-(tert-butyldimethylsilyl-5-O-(4-methoxytrityl)-3-deoxy-3-C-methylene- ß -D-erythro-pentofuranosyl]uracil to give the corresponding 3’-deoxy-3’-C- hydroxymethyl derivative with ribo-configuration, as well as the further conversion into a precursor with a suitable leaving group, e. g., triflate, for subsequent substitution with the phosphinic acid synthon bis(trimethylsilyl)hypophosphite. Improvements of these steps enabled synthesis of 2’-O-(tert-butyldimethylsilyl-5’-O-( 4-methoxytrityl)-3’-deoxy-3’-C-methylenephosphinate uridine in a respectable overall yield of 40% over 6 steps, from the corresponding 2’-O-(tert-butyldimethylsilyl- 5’-O-(4-methoxytrityl)uridine.

For the introduction of internucleosidic 3’-deoxy-3’-C-methylenephosphonate linkages into oligonucleotides, a preparatory study of the elongation steps, i. e., coupling of the phosphinate building block to the 5’-hydroxyl function of a nucleoside derivative and subsequent oxidation, was performed. Of several coupling reagents studied for the activation of the phosphinate building block prior to coupling, the most promising proved to be N,N-bis(2-oxo-3-oxazolidin-1-yl)phosphinic chloride. The oxidation of the resulting 3’-deoxy-3’-C-methylenephosphinate ester to the corresponding 3’-deoxy-3’-C-methylenephosphonate linkage was achieved using iodine in pyridine-water, in the presence of a catalyst, i. e., either a base (triethylamine) or an acid (pyridinium salt).

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2002. , 50 p.
Keyword [sv]
Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-142874ISBN: 91-7265-402-3 (print)OAI: oai:DiVA.org:su-142874DiVA: diva2:1093207
Public defence
2002-01-31, 14:00 (English)
Opponent
Note

Härtill 4 uppsatser

Stockholms universitetsbiblioteks retrospektiva digitalisering. Avhandlingar 1906-2003.

Available from: 2017-05-05 Created: 2017-05-05 Last updated: 2017-07-18Bibliographically approved

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