A novel radical method for the stereoselective introduction of an ethynyl group has been developed. When a solution of ethynyldimethylsilyl (EDMS) or [2-(trimethylsilyl)ethynyl]dimethylsilyl (TEDMS) ethers of trans-2-iodoindanol was treated with Et(3)B followed by tetrabutylammonium fluoride in toluene, atom transfer 5-exo-cyclization and subsequent elimination occurred to give cis-2-ethynylindanol in high yield. The method was shown to be useful in the introduction of an ethynyl group in various five- and six-membered-ring iodohydrins. Furthermore, 2'-deoxy-2'-C-ethynyluridine (6) and -cytidine (7), which were designed as novel antimetabolites, were readily synthesized by using this method as the key step. This would be the first example in which a radical reaction was used for introducing an ethynyl group.
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.
A strategy is presented that uses dynamic equlibria to assemble in situ composite DNA polymerase primers, having lengths of 14 or 16 nt, from DNA fragments that are 6 or 8 nt in length. In this implementation, the fragments are transiently joined under conditions of dynamic equilibrium by an imine linker, which has a dissociation constant of ∼1 μM. If a polymerase is able to extend the composite, but not the fragments, it is possible to prime the synthesis of a target DNA molecule under conditions where two useful specificities are combined: (i) single nucleotide discrimination that is characteristic of short oligonucleotide duplexes (four to six nucleobase pairs in length), which effectively excludes single mismatches, and (ii) an overall specificity of priming that is characteristic of long (14 to 16mers) oligonucleotides, potentially unique within a genome. We report here the screening of a series of polymerases that combine an ability not to accept short primer fragments with an ability to accept the long composite primer held together by an unnatural imine linkage. Several polymerases were found that achieve this combination, permitting the implementation of the dynamic combinatorial chemical strategy.
Atom‐transfer 5‐exo cyclization and subsequent elimination occur when ethynyldimethylsilyl ethers of iodohydrins are treated with Et3B followed by tetrabutylammonium fluoride (TBAF) to give the corresponding cis‐configured α‐hydroxy ethynyl compounds in high yield (see scheme). This is the first example of the use of a radical reaction to introduce an ethynyl group.
Radical reactions
Radical reactions O 0195Nucleosides and Nucleotides. Part 219. The First Radical Method for the Introduction of an Ethynyl Group Using a Silicon Tether and Its Application to the Synthesis of 2'-Deoxy-2'-C-ethynylnucleosides. -The ethynyl group is stereoselectively introduced into various five-and six-membered ring systems by treatment of the corresponding ethynyldimethylsilyl or [2-(trimethylsilyl)ethynyl]dimethylsilyl ethers with Et 3 B followed by Bu 4 NF. Atom-transfer 5-exo-radical cyclization and subsequent fluoride ion promoted elimination reaction occurs. Uridine and cytidine derivatives (XVII) are prepared using this method as key step. -(SUKEDA, M.; ICHIKAWA, S.; MATSUDA, A.; SHUTO*, S.; J. Org. Chem. 68 (2003) 9, 3465-3475; Grad. Sch. Pharm. Sci., Hokkaido Univ., Sapporo 060, Japan; Eng.) -Klein 35-026 2003 Radical reactions
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