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

Synthesis of (5?S)-5?-C-Alkyl-2?-deoxynucleosides
Synthesis of (5?S)-5?-C-Alkyl-2?-deoxynucleosides
We describe the synthesis of (S'S)-5'-C-butylthymidine (5a), of the (S'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).
0018-019X
87-105
Trafelet, Huldreich
47376d04-1b85-49ea-8aac-2e0556834b82
Stulz, Eugen
9a6c04cf-32ca-442b-9281-bbf3d23c622d
Leumann, Christian
249e7dd9-7845-4a6c-ac0f-7fa09b0da4ad
Trafelet, Huldreich
47376d04-1b85-49ea-8aac-2e0556834b82
Stulz, Eugen
9a6c04cf-32ca-442b-9281-bbf3d23c622d
Leumann, Christian
249e7dd9-7845-4a6c-ac0f-7fa09b0da4ad

Trafelet, Huldreich, Stulz, Eugen and Leumann, Christian (2001) Synthesis of (5?S)-5?-C-Alkyl-2?-deoxynucleosides. Helvetica Chimica Acta, 84 (1), 87-105. (doi:10.1002/1522-2675(20010131)84:1<87::AID-HLCA87>3.0.CO;2-1).

Record type: Article

Abstract

We describe the synthesis of (S'S)-5'-C-butylthymidine (5a), of the (S'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).

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Published date: 31 January 2001

Identifiers

Local EPrints ID: 191679
URI: http://eprints.soton.ac.uk/id/eprint/191679
ISSN: 0018-019X
PURE UUID: 6cda9c9c-91c4-44f2-84f0-11e008171742
ORCID for Eugen Stulz: ORCID iD orcid.org/0000-0002-5302-2276

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Date deposited: 23 Jun 2011 13:04
Last modified: 12 Nov 2019 01:46

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