Yoshinari Honda - Academia.edu (original) (raw)
Papers by Yoshinari Honda
ulosyl]thymine with nitromethane anion (to give the corresponding 3'-C-nitromethyl-oxylo derivati... more ulosyl]thymine with nitromethane anion (to give the corresponding 3'-C-nitromethyl-oxylo derivative), with subsequent dehydration [giving the 3'-(nitromethylene) derivative] and NaBH 4 reduction. Our lack of success is ascribed to the absence of a 2'-hydroxy group; in the 2'-deoxy structure, nitromethane anion may abstract the 2'-hydrogen preferentially to give the C-2' carbanion, which is then converted into glycal 4 with the loss of a thymine fragment. We searched for an alternative route for 1 not utilizing a 3'-oxo compound as the starting material. Branchaud and co-workers reported [24-28] a CC bond formation reaction using of cobaloxime-mediated radical alkyl-alkenyl or alkyl-nitroalkyl cross coupling. These authors transformed 3-deoxy-l,2;5,6-di-O-isopropylidene-3-iodo-D-glucofuranose into the Com(dmgH)2py complex (dmgH = dimethylglyoxime monoanion) by treatment with [Co~(dmgH)2py]-[24,27], and the complex was treated with nitromethane anion under photolysis. Cross coupling occurred [28] to give 3-deoxy-1,2;5,6-di-O-isopropylidene-3-C-(nitromethyl)-D-gluco-furanoses and-allo-furanoses (1 : 1, 48% isolated yield). We attempted to apply their procedure to our case. 3'-Deoxy-3'-iodothymidine (5) [29-31] was converted into its 5'-O-(tert-butyldimethylsilyl) derivative 6 and this was treated with Na+[CoI(dmgH)2py]-according to the procedure of Branchaud and co-workers [24,27]. The orange-colored Co complex 7 was isolated in 30% yield after flash column chromatography, along with the 3'-eno 8, 2'-eno 9 [32,33], and 3'-deoxy derivatives 10 [34], in the ratio of 1 : 1.15 : 1.4 according to NMR analysis of the product mixture. When, however, this reaction was performed with the 5'-hydroxy compound 5, complex formation similar to 7 was minor, and a mixture of the known 3'-eno [35], 2'-eno [17,36], and 3'-deoxy [6,29,30,32,34-37] derivatives were the major products. The structure of 7 was determined by NMR analysis. High-field resonances of H-3' (6 1.80 in CD2CIe), and C-3' (6 37.3, broad, in CDC13) in the ~H and 13C NMR spectra, respectively, indicate that Co is attached to C-3'. The 3'S absolute configuration (that is, Co approaches C-3' from the a-face) was determined by 1H NOE difference spectroscopy (saturation of H-6 showed 0.8% signal enhancement of H-3') as well as by phase-sensitive 1H NOESY, where cross peaks were observed between H-6 and H-3', and between H-3' and H-5'a. All of the other functional groups present in 7 including pyridine, were confirmed by the 1H and 13C NMR spectra. Cross coupling of 7 with nitromethane anion was then carried out under visible light in 3 : 1 ethanol-water at 10-20°C, essentially according to the method of Branchaud and co-workers [26,28]. The desired (3'R)-3'-(nitromethyl) derivative 11 was produced in 47% yield, together with 8 and 9 and without formation of the 3'S-isomer of 11. Exclusive formation of the 3'R-isomer 11 may be ascribed to the presence of the bulky thymine and tert-butyldimethylsilyl groups on the E-face. Raising or lowering the reaction temperature, or scale-up of the preparation (more than 100 mg at one time) markedly decreased the yield of 11. It is noteworthy that the 3'-deoxy compound 10 was not produced in this reaction. Final deprotection by acidic cleavage of the silyl group afforded 1. Compound 1 was inactive in an in vitro anti-HIV test, using HIV-1 infected T4 lymphocytes (CEM cell line).
ulosyl]thymine with nitromethane anion (to give the corresponding 3'-C-nitromethyl-oxylo derivati... more ulosyl]thymine with nitromethane anion (to give the corresponding 3'-C-nitromethyl-oxylo derivative), with subsequent dehydration [giving the 3'-(nitromethylene) derivative] and NaBH 4 reduction. Our lack of success is ascribed to the absence of a 2'-hydroxy group; in the 2'-deoxy structure, nitromethane anion may abstract the 2'-hydrogen preferentially to give the C-2' carbanion, which is then converted into glycal 4 with the loss of a thymine fragment. We searched for an alternative route for 1 not utilizing a 3'-oxo compound as the starting material. Branchaud and co-workers reported [24-28] a CC bond formation reaction using of cobaloxime-mediated radical alkyl-alkenyl or alkyl-nitroalkyl cross coupling. These authors transformed 3-deoxy-l,2;5,6-di-O-isopropylidene-3-iodo-D-glucofuranose into the Com(dmgH)2py complex (dmgH = dimethylglyoxime monoanion) by treatment with [Co~(dmgH)2py]-[24,27], and the complex was treated with nitromethane anion under photolysis. Cross coupling occurred [28] to give 3-deoxy-1,2;5,6-di-O-isopropylidene-3-C-(nitromethyl)-D-gluco-furanoses and-allo-furanoses (1 : 1, 48% isolated yield). We attempted to apply their procedure to our case. 3'-Deoxy-3'-iodothymidine (5) [29-31] was converted into its 5'-O-(tert-butyldimethylsilyl) derivative 6 and this was treated with Na+[CoI(dmgH)2py]-according to the procedure of Branchaud and co-workers [24,27]. The orange-colored Co complex 7 was isolated in 30% yield after flash column chromatography, along with the 3'-eno 8, 2'-eno 9 [32,33], and 3'-deoxy derivatives 10 [34], in the ratio of 1 : 1.15 : 1.4 according to NMR analysis of the product mixture. When, however, this reaction was performed with the 5'-hydroxy compound 5, complex formation similar to 7 was minor, and a mixture of the known 3'-eno [35], 2'-eno [17,36], and 3'-deoxy [6,29,30,32,34-37] derivatives were the major products. The structure of 7 was determined by NMR analysis. High-field resonances of H-3' (6 1.80 in CD2CIe), and C-3' (6 37.3, broad, in CDC13) in the ~H and 13C NMR spectra, respectively, indicate that Co is attached to C-3'. The 3'S absolute configuration (that is, Co approaches C-3' from the a-face) was determined by 1H NOE difference spectroscopy (saturation of H-6 showed 0.8% signal enhancement of H-3') as well as by phase-sensitive 1H NOESY, where cross peaks were observed between H-6 and H-3', and between H-3' and H-5'a. All of the other functional groups present in 7 including pyridine, were confirmed by the 1H and 13C NMR spectra. Cross coupling of 7 with nitromethane anion was then carried out under visible light in 3 : 1 ethanol-water at 10-20°C, essentially according to the method of Branchaud and co-workers [26,28]. The desired (3'R)-3'-(nitromethyl) derivative 11 was produced in 47% yield, together with 8 and 9 and without formation of the 3'S-isomer of 11. Exclusive formation of the 3'R-isomer 11 may be ascribed to the presence of the bulky thymine and tert-butyldimethylsilyl groups on the E-face. Raising or lowering the reaction temperature, or scale-up of the preparation (more than 100 mg at one time) markedly decreased the yield of 11. It is noteworthy that the 3'-deoxy compound 10 was not produced in this reaction. Final deprotection by acidic cleavage of the silyl group afforded 1. Compound 1 was inactive in an in vitro anti-HIV test, using HIV-1 infected T4 lymphocytes (CEM cell line).