Synthesis of (5' S )-5'- C -Alkyl-2'-deoxynucleosides

Trafelet, H. U.; Stulz, E.; Leumann, Christian (2001). Synthesis of (5' S )-5'- C -Alkyl-2'-deoxynucleosides. Helvetica chimica acta, 84(1), pp. 87-105. Verlag Helvetica Chimica Acta 10.1002/1522-2675(20010131)84:1<87::AID-HLCA87>3.0.CO;2-1

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We describe the synthesis of (5 S )-5- C -butylthymidine ( 5a ), of the (5 S )-5- C -butyl- and the (5 S )-5- C -isopentyl derivatives 16a and 16b of 2-deoxy-5-methylcytidine, as well as of the corresponding cyanoethyl phosphoramidites 9a , b and 14a , b , respectively. Starting from thymidin-5-al 1 , the alkyl chain at C(5) is introduced via Wittig chemistry to selectively yield the ( Z )-olefin derivatives 3a and 3b ( Scheme 2 ). The secondary OH function at C(5) is then introduced by epoxidation followed by regioselective reduction of the epoxy derivatives 4a and 4b with diisobutylaluminium hydride. In the latter step, a kinetic resolution of the diastereoisomer mixture 4a and 4b occurs, yielding the alkylated nucleoside 2a and 2b , respectively, with (5 S )-configuration in high diastereoisomer purity (de=94%). The corresponding 2-deoxy-5-methylcytidine derivatives are obtained from the protected 5-alkylated thymidine derivatives 7a and 7b via known base interconversion processes in excellent yields ( Scheme 3 ). Application of the same strategy to the purine nucleoside 2-deoxyadenine to obtain 5- C -butyl-2-deoxyadenosine 25 proved to be difficult due to the sensitivity of the purine base to hydride-based reducing agents ( Scheme 4 ).

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Leumann, Christian

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0018-019X

Publisher:

Verlag Helvetica Chimica Acta

Language:

English

Submitter:

Christian Leumann

Date Deposited:

19 May 2015 14:32

Last Modified:

19 May 2015 14:32

Publisher DOI:

10.1002/1522-2675(20010131)84:1<87::AID-HLCA87>3.0.CO;2-1

Uncontrolled Keywords:

alkyl base chemistry kinetic nucleoside phosphoramidite purine reduction synthesis thymidine

BORIS DOI:

10.7892/boris.68585

URI:

https://boris.unibe.ch/id/eprint/68585

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