Synthesis of Certain 5‐Substituted 2′‐Deoxytubercidin Derivatives

Abstract

The synthesis of the 7-deaza-2'-deoxy-adenine derivatives 7 b d with chloro, bromo, or methyl substituents at C(S) is described. Glycosylation of the 5-substituted 4-chloropyrrolo[2,3-d]pyrimidines 4 W with 2-deoxy-3,s-di-O-(4-toluoyl)-a -D-erythro-pentofuranosyl chloride (3) gave the -o-nucleosides 5 M , exclusively. They were deblocked ( + 6 M ) and converted into the tubercidin derivatives 7 M .The 5-methyl group of 2'-deoxyribosylthymine ( = 2'-deoxythymidine; T,) has a major impact on the DNA duplex structure. Oligonucleotides containing 2'-deoxyuridine (U,) in place of T, form less stable duplexes [l]. On the other hand, the isosteric replacement of T, by BrW, containing a 5-substituent of the same size but different electronegativity influences base-pairing pattern and causes mutagenesis. The inspection of the DNA duplex structure suggests that a Me group introduced at the 7-position of purines has considerable steric freedom but hydrophobizes the major groove in a similar manner as observed for the Me group of T,. However, the introduction of a 7-Me group into purines generates a positive charge which can be compensated by deprotonation of the six-membered ring yielding a zwitterionic structure. Ionic structures can be circum-

Synthesis of 9‐Halogenated 9‐Deazaguanine N7‐(2′‐Deoxyribonucleosides).

“…Estimation of syn-and anti-conformer populations according to [20] gave an anti-rotamer population of 55% for 1a, 65% for 1b, and 75% for 1c. This is in line with earlier findings reported for 7-deazapurine 2'-deoxyribonucleosides [22] [23].…”

7-Deazaadenine-DNA: Bulky 7-Iodo Substituents or Hydrophobic 7-Hexynyl Chains Are Well Accommodated in the Major Groove of Oligonucleotide Duplexes

“…This is different from the 8substituents of purine residues, which unlike the 7-substituents interfere with the sugar ± phosphate backbone. Furthermore, the halogen and the alkynyl 7-substituents reduce the basicity of nitrogen 1 of the 7-deazaadenine moiety (pK a values: c 7 A d 5.3, [38] I 7 c 7 A d 4.5, hxy 7 c 7 A d 4.3). At the same time, the 6-amino group can become a better proton donor.…”

“…At the same time, the 6-amino group can become a better proton donor. With regard to these properties, compounds 1 and 2 are closer analogues of dA (pK a 3.8 [38] ) than the nonsubstituted 7-deaza-2'-deoxyadenosine (c 7 A d ).…”

Advances in the Synthesis of 7-Deazapurine - Pyrrolo[2,3-d]pyrimidine 2-Deoxyribonucleosides Including D- and L-Enantiomers, Fluoro Derivatives and 2,3-Dideoxyribonucleosides

“…Nucleobase-anion glycosylation of 32a-d [59] or 32e [60] with halogenose 6 performed in MeCN in the presence of KOH and TDA-1 afforded the toluoylprotected -D-nucleosides 33a-e in 65-81% yields (Scheme 19) [51b, 56,61,62]. Compounds 33a-e were converted to the 2'-deoxytubercidin derivatives 13a-e using conc.…”