The synthesis and properties of oligodeoxynucleotides (ODNs) containing 4′-C- [2-[[N-(2-aminoethyl)carbamoyl]oxy]ethyl]thymidine (3) are described. 4′R-(2-Hydroxyethyl)thymidine (4), which is a precursor for phosphoramidite 5, was synthesized using a newly developed intramolecular radical cyclization reaction at the 4′-position of thymidine derivative 7. The radical reaction of 4′ -(phenylseleno)-3′-O-(dimethylvinylsilyl)thymidine derivative 7, which was prepared from thymidine in several steps, with Bu 3 SnH and AIBN, followed by Tamao oxidation, gave either 4′R-(2-hydroxyethyl) derivative 6 or 4′R-(1-hydroxyethyl) derivative 13, respectively. With a low Bu 3 -SnH concentration, the reaction gave 6, via 6-endo-radical-cyclized product 11, as a sole product in 87% yield. The reaction of 7 in the presence of excess Bu 3 SnH gave 13 in 75% yield, via 5-exocyclized product 12, as a diastereomeric mixture. The 4′R-(2-hydroxyethyl) derivative 6 was then converted into a 4′-C-[2-[[N-(2-aminoethyl)carbamoyl]oxy]ethyl]thymidine derivative 14, which was phosphitylated to give phosphoramidite 5 in 72% yield. In this study, 3 was incorporated into a nonadecamer, d[CTGGCTCAGCTCGTCTCAT]-3′, and a heptadecamer, d[CTCGTACCATTCCGCTC]-3′, instead of T at various positions. ODNs containing 3 were more resistant to nucleolytic hydrolysis by both snake venom phosphodiesterase (a 3′-exonuclease) and DNase I (an endonuclease) than unmodified parent ODNs, although ODNs containing 3 only slightly destabilized duplex formation with both complementary DNA and RNA strands. Furthermore, the duplex formed by an ODN containing 3 and its complementary RNA was a good substrate for Escherichia coli RNase H.
A mechanistic study was performed on a novel radical ring-enlargement reaction of (3-oxa-2silacyclopentyl)methyl radicals into 4-oxa-3-silacyclohexyl radicals. Two pathways, one via a pentavalent siliconbridging radical transition state (or intermediate), the other via β-elimination to give a ring-opened silyl radical, can be postulated. The radical reactions of 1 and 2, which are precursors for a (3-oxa-2-silacyclopentyl)methyl radical C′ and a 4-oxa-3-silacyclohexyl radical D′, respectively, showed that the ring-enlargement rearrangement of C′ into D′ is irreversible. 1 H NMR analysis of the radical reactions of 8a and 8b, which have an asymmetric center at silicon, indicated that the configuration at the silicon atom is retained via a pentavalent silicon-bridging radical transition state (or intermediate) during the ring-enlargement reaction. Furthermore, examination of the radical ring-enlargement reaction with a deuterium-labeled substrate 12D showed that the ring-enlargement reaction did not involve β-elimination to give a ring-opened silyl radical. Based on these results, we conclude that the ring-enlargement reaction occurs via a pentavalent silicon-bridging radical transition state (or intermediate). This is the first experimental evidence for such a pentavalent silicon radical, which has been previously postulated to understand radical reactions of organic silicon compounds.
Recently, we developed a regio- and stereoselective method for introducing a vinyl group at the position beta to a hydroxyl group in halohydrins or alpha-phenylselenoalkanols via a radical atom-transfer cyclization reaction with a vinylsilyl group as a temporary connecting radical-acceptor tether. The synthesis of 2'-deoxy-2'-C-vinyl- and 2'-deoxy-2'-C-hydroxymethyluridines (7 and 8, respectively) and the corresponding 2'-deoxycytidine congeners (10 and 11, respectively), which were designed as potential antitumor and/or antiviral agents, was achieved using this radical atom-transfer cyclization as the key step. When the 2'-deoxy-2'-iodo-5'-O-monomethoxytrityl (MMTr) uridine derivative 19a, bearing a vinylsilyl group at the 3'-hydroxyl group, was heated with (Me(3)Sn)(2) and AIBN in benzene, the corresponding radical atom-transfer product was generated, which in turn was successively treated with tetrabutylammonium fluoride and TBSCl/imidazole to give the desired 2'-deoxy-5'-O-MMTr-3'-O-TBS-2'-C-vinyluridine (25). Compound 25 was successfully converted into the target 2'-deoxy-2'-branched pyrimidine ribonucleosides 7, 8, 10, and 11.
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