Affordable Access

Enhanced stereoselectivity in internucleotidic bond formation by the use of the chiral ribose moiety of thymidine.

Authors
  • Seio, Kohji
  • Kumura, Kou
  • Bologna, Jean-Charles
  • Sekine, Mitsuo
Type
Published Article
Journal
The Journal of organic chemistry
Publication Date
May 16, 2003
Volume
68
Issue
10
Pages
3849–3859
Identifiers
PMID: 12737563
Source
Medline
License
Unknown

Abstract

This paper deals with the synthesis of new cyclic thymidine 3'-phosphoramidite building blocks having a covalent linker between the trityl type 5'-hydroxyl protecting group and the phosphorus atom attached to the 3'-hydroxyl group of thymidine. The ring structures were designed to reduce the conformational freedom around the phosphorus center so that the stereoselectivity in the internucleotide linkage formation would be improved. The linkers were also designed to be removed readily by treatment with aqueous ammonia. These building blocks were synthesized in good yield by one-pot cyclization of the diol precursors with dichloro(N,N-diisopropylamino)phosphine, despite their large-membered ring. Various activators having 1H-tetrazole, imidazole, and triazole structures were investigated to find the best selectivity in the synthesis of thymidylyl(5'-3')thymidine phosphorothioate. It turned out that our cyclic phosphoramidites gave preferentially the R(p) diastereoisomer in high coupling yield applicable to the solid-phase synthesis of oligodeoxynucleotides. It should be noted that high stereoselectivity was achieved without any chiral sources other than the 2'-deoxyribose moiety itself. The mechanistic studies revealed the importance of the steric bulk and the acidity of the activators. It was also found that the steric bulk of the alcoholic nucleophile was an important factor that determined the stereoselectivity in our systems.

Report this publication

Statistics

Seen <100 times