Synthesis of Oligodeoxynucleotides Containing 5-(β-D-Glucopyranosyloxymethyl)-2′-deoxyuridine, a Modified Nucleoside in the DNA ofTrypanosoma Brucei

Abstract

The synthesis of the recently discovered modified DNA base 5‐(β‐D‐glucopyranosyloxymethyl)‐2′‐deoxyuridine (β‐dJ, 1) is described. TMSOTf mediated β‐glucosylation of 5‐hydroxymethyl‐2′‐deoxyuridine (5‐HMdU) derivative 10 (obtained in 20% from 2′‐deoxyuridine) with trichloroacetimidate 12 gave dimer 13 in 47% yield. On the other hand, condensation of 12with N3‐POM‐protected derivative 20, readily available from thymidine in 48%, afforded the fully protected nucleoside 22 in 96% yield. The latter compound was converted into phosphoramidite 3 which was applied in the automated solid phase synthesis of several biological interesting β‐dJ containing DNA fragments.

Preparation of 5‐Hydroxymethyl‐pyrimidine Based Nucleosides: A Reinvestigation

“…Compared to other described procedures, except a paper by Feng, [26] which describes its achievement with 65 % yield by the radical bromination pathway, most of the studies mention yields between 24 and 40 % for this compound. [25,49,50] Indeed, as previously mentioned, in our hands, the radical bromination was poorly efficient when the N 3 is unprotected, an observation that was already reported by others. Glc-5hmdU was obtained by glycosylation reaction of acceptor 3',5'-TBDMS-protected 5hmdU 12 using the 2,3,4,6tetra-O-benzoyl-α-D-glucopyranosyl trichloroacetimidate in the presence of trimethylsilyl triflate (TMSOTf) as promoter.…”

“…The 3’,5’‐di‐ t ‐butyldimethylsilyl‐5‐acetyloxymethyl‐2’‐deoxyuridine 13 , a useful precursor for the synthesis of 5hmdC derivatives, was obtained from 12 with an overall yield of 59 %. Compared to other described procedures, except a paper by Feng, [26] which describes its achievement with 65 % yield by the radical bromination pathway, most of the studies mention yields between 24 and 40 % for this compound [25,49,50] . Indeed, as previously mentioned, in our hands, the radical bromination was poorly efficient when the N 3 is unprotected, an observation that was already reported by others.…”

Chemical and Enzymatic Synthesis of DNA Fragments Containing 5-(β-D-Glucopyranosyloxymethyl)-2′-deoxycytidine − a Modified Nucleoside in T4 Phage DNA

“…NH 4 OH, 60 °C, 60 h) required for complete removal of the cyanoethyl group was an incentive for replacing the cyanoethyl group with an acetyl moiety and for using thymidine as the starting material. The synthesis of target compound 4 is presented in Scheme and commences with radical bromination15 of the known13a bis‐silylated thymidine derivative 6 . Substitution of the resulting crude allylic bromide with cesium acetate in DMF afforded 5‐HMdU derivative 7 , which was transformed into 5‐HMdC 8 by the following three‐step sequence.…”

“…An alternative route to the 5‐GlcMdC derivative 5 would entail transformation of the known13a glucosylated 5‐HMdU building block 15 (Scheme ). Surprisingly, subjection of the benzoylated gluconucleoside 15 to the same conditions as used for the synthesis of 8 did not produce the expected intermediate triazolide 16 .…”

“…It did, however, prove possible to obtain 16 , in a poor yield (29%), by prolonged treatment of 15 with excess POCl 3 and 1,2,4‐triazole at elevated temperature. Alternatively, treatment of the tetra‐ O ‐acetyl derivative 18 , easily accessible by conversion of N 3 ‐pivaloyloxymethyl (POM)‐protected 17 ,13a could readily be converted under the originally applied mild conditions (cf. 7 → 9 ) into the requisite triazolide 19 , in 86% yield.…”