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Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-L-lyxopyranosyl]thymine

Veerle Vanheusden, Roger Busson, Piet Herdewijn and Serge Van Calenbergh UGent (2004) JOURNAL OF ORGANIC CHEMISTRY. 69(13). p.4446-4453
abstract
Previously different types of nucleosides with a six-membered carbohydrate moiety have been evaluated for their potential antiviral and antibiotic properties and as building blocks in nucleic acid synthesis. However, a pyranose nucleoside with a 1,4-substitution pattern like 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-L-lyxopyranosyl]thymine (4) has not been studied yet. Modeling suggested that this nucleoside would show the (4)C(1) conformation in contrast to anhydrohexitol nucleosides (1) whose most stable conformation is (1)C(4). The key to the synthesis of 4 involves the stereoselective introduction of the hydroxymethyl group onto the C-4 carbon of the pyranose sugar. Attempts to achieve this via hydroboration/oxidation of a C-4'-exocyclic vinylic intermediate selectively yielded the undesired a-directed hydroxymethyl group. Therefore, we envisaged another approach in which the C-4 substituent was introduced upon treatment of 2,3-O-isopropylidene-1-O-methyl-4-O-phenoxythiocarbonyl-alpha-L-lyxopyranose with beta-tributylstannyl styrene. This allowed stereoselective beta-directed introduction of a 2-phenylethenyl group at C-4, which was converted via oxidation/reduction (OsO(4), NaIO(4)/NaBH(4)) into the desired 4-hydroxymethyl group (20). The resulting 1-O-methyl-2,3,6-tri-O-acetyl-protected sugar was coupled with silylated thymine, using SnCl(2) as Lewis acid (22). After suitable protection, Barton deoxygenation of the 2'-hydroxyl function of the obtained ribo-nucleoside yielded the desired 2'-deoxynucleoside 4, indeed showing the expected equatorial orientation of the thymine ring ((4)C(1)).
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
5-ANHYDROHEXITOL NUCLEOTIDES, 1, NUCLEOSIDES, OLIGONUCLEOTIDES, PYRIMIDINES, THYMIDINE, KINASE
journal title
JOURNAL OF ORGANIC CHEMISTRY
J. Org. Chem.
volume
69
issue
13
pages
4446 - 4453
Web of Science type
Article
Web of Science id
000222187200020
JCR category
CHEMISTRY, ORGANIC
JCR impact factor
3.462 (2004)
JCR rank
7/55 (2004)
JCR quartile
1 (2004)
ISSN
0022-3263
DOI
10.1021/jo040130g
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
297735
handle
http://hdl.handle.net/1854/LU-297735
date created
2005-01-19 16:43:00
date last changed
2014-11-07 14:36:39
@article{297735,
  abstract     = {Previously different types of nucleosides with a six-membered carbohydrate moiety have been evaluated for their potential antiviral and antibiotic properties and as building blocks in nucleic acid synthesis. However, a pyranose nucleoside with a 1,4-substitution pattern like 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-L-lyxopyranosyl]thymine (4) has not been studied yet. Modeling suggested that this nucleoside would show the (4)C(1) conformation in contrast to anhydrohexitol nucleosides (1) whose most stable conformation is (1)C(4). The key to the synthesis of 4 involves the stereoselective introduction of the hydroxymethyl group onto the C-4 carbon of the pyranose sugar. Attempts to achieve this via hydroboration/oxidation of a C-4'-exocyclic vinylic intermediate selectively yielded the undesired a-directed hydroxymethyl group. Therefore, we envisaged another approach in which the C-4 substituent was introduced upon treatment of 2,3-O-isopropylidene-1-O-methyl-4-O-phenoxythiocarbonyl-alpha-L-lyxopyranose with beta-tributylstannyl styrene. This allowed stereoselective beta-directed introduction of a 2-phenylethenyl group at C-4, which was converted via oxidation/reduction (OsO(4), NaIO(4)/NaBH(4)) into the desired 4-hydroxymethyl group (20). The resulting 1-O-methyl-2,3,6-tri-O-acetyl-protected sugar was coupled with silylated thymine, using SnCl(2) as Lewis acid (22). After suitable protection, Barton deoxygenation of the 2'-hydroxyl function of the obtained ribo-nucleoside yielded the desired 2'-deoxynucleoside 4, indeed showing the expected equatorial orientation of the thymine ring ((4)C(1)).},
  author       = {Vanheusden, Veerle and Busson, Roger and Herdewijn, Piet and Van Calenbergh, Serge},
  issn         = {0022-3263},
  journal      = {JOURNAL OF ORGANIC CHEMISTRY},
  keyword      = {5-ANHYDROHEXITOL NUCLEOTIDES,1,NUCLEOSIDES,OLIGONUCLEOTIDES,PYRIMIDINES,THYMIDINE,KINASE},
  language     = {eng},
  number       = {13},
  pages        = {4446--4453},
  title        = {Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-L-lyxopyranosyl]thymine},
  url          = {http://dx.doi.org/10.1021/jo040130g},
  volume       = {69},
  year         = {2004},
}

Chicago
Vanheusden, Veerle, Roger Busson, Piet Herdewijn, and Serge Van Calenbergh. 2004. “Synthesis and Conformational Analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-L-lyxopyranosyl]thymine.” Journal of Organic Chemistry 69 (13): 4446–4453.
APA
Vanheusden, Veerle, Busson, R., Herdewijn, P., & Van Calenbergh, S. (2004). Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-L-lyxopyranosyl]thymine. JOURNAL OF ORGANIC CHEMISTRY, 69(13), 4446–4453.
Vancouver
1.
Vanheusden V, Busson R, Herdewijn P, Van Calenbergh S. Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-L-lyxopyranosyl]thymine. JOURNAL OF ORGANIC CHEMISTRY. 2004;69(13):4446–53.
MLA
Vanheusden, Veerle, Roger Busson, Piet Herdewijn, et al. “Synthesis and Conformational Analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-L-lyxopyranosyl]thymine.” JOURNAL OF ORGANIC CHEMISTRY 69.13 (2004): 4446–4453. Print.