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초록
영어
Racemic synthesis of novel 5',5'-difluoro-2'-methyl-apiose nucleoside phosphonic acid analogs was achieved as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2 and HCMV revealed that the pyrimidine analogs (cytosine, uracil, and thymine) have weak anti-HIV or HCMV activity.
목차
Abstract
1. Introduction
2. Experimental Section
2.1. (rel)-(3S,4S)-Dihydro-4-(hydroxymethyl)-3-methylfuran-2(3H)-one (7)
2.2. (rel)-(3S,4S)-Dihydro-4-(t-butyldimethylsilyloxymethyl)-3-methylfuran-2(3H)-one (8)
2.3. (rel)-(4R,3S,2R/S)-Tetrahydro-4-(t-butyldimethylsilyloxymethyl)-3-methylfuran-2-ol (9)
2.4. (rel)-(3R,4S,5R/S)-[(4-Methyl-tetrahydro-5-methoxyfuran-3-yl)methoxy](t-butyl)dimethylsilane(10)
2.5. (rel)-(3S,4S,5R/S)-(4-Methyl-tetrahydro-5-methoxyfuran-3-yl)methanol (11)
2.6. (rel)-(3R,4S,5R/S)-(4-Methyl-tetrahydro-5-methoxyfuran-3-yl)methyl trifluoromethanesulfonate (12)
2.7. (rel)-Diethyl 1,1-difluoro-2-[(3S,4S,5R/S)-4-methyl-tetrahydro-5-methoxyfuran-3-yl] ethylphosphonate(13)
2.8. (rel)-Diethyl 2-[(3S,4S,5R/S)-5-acetoxy-4-methyl-tetrahydrofuran-3-yl]-1,1-difluoroethylphosphonate(14)
2.9. (rel)-Diethyl 4-[(1S,2S,3S)-1-(6-chloro-9H-purin-9-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphonate(15α) an
2.10. (rel)-Diethyl 4-[(1R,2S,3S)-1-(6-amino-9Hpurin-9-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphonate (16)
2.11. (rel)-4-[(1R,2S,3S)-1-(6-Amino-9H-purin-9-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethylphosphonicacid sodium salt (17)
2.12. (rel)-Diethyl 4-[(1S,2S,3S)-1-(2-fluoro-6-chloro-9H-purin-9-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphona
2.13. (rel)-Diethyl 4-[(1R,2S,3S)-1-(2-fluoro-6-amino-9H-purin-9-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphonate (19) and (rel)-diethyl 4-[(1R,2S,3S)-1-(2-amino-6-chloro-9H-purin-9-yl)-2-methyltetrahydrofuran-3-yl]-5,5-difluoroethylphosphona
2.14. (rel)-4-[(1R,2S,3S)-1-(2-Amino-6-oxo-9Hpurin-9-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethyl-phosphonic acid sodium salt (21)
2.15. (rel)-Diethyl 4-[(1S,2S,3S)-1-(N4-benzoylamino-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-di
2.16. (rel)-Diethyl 4-[(1R,2S,3S)-1-(4-amino-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphonate (23)
2.17. (rel)-4-[(1R,2S,3S)-1-(4-Amino-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethyl-phosphonic acid sodiumsalt (24)
2.18. (rel)-Diethyl 4-[(1S,2S,3S)-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylp
2.19. (rel)-Diethyl 4-[(1S,2S,3S)-1-(2,4-dioxo-5-methyl-3,4-dihydropyrimidin-1(2H)-yl)-2-methyltetrahydrofuran-3-yl]-5,5-difluo
2.20. (rel)-4-[(1R,2S,3S)-1-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethyl-phosphonic acid sodium salt (27)
2.21. (rel)-4-[(1R,2S,3S)-1-(2,4-Dioxo-5-methyl-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethyl-phosphonic acid sodiumsalt (28)
3. Results and Discussion
3.1. Biological Activity Evaluation
4. Conclusion
Acknowledgment
References
1. Introduction
2. Experimental Section
2.1. (rel)-(3S,4S)-Dihydro-4-(hydroxymethyl)-3-methylfuran-2(3H)-one (7)
2.2. (rel)-(3S,4S)-Dihydro-4-(t-butyldimethylsilyloxymethyl)-3-methylfuran-2(3H)-one (8)
2.3. (rel)-(4R,3S,2R/S)-Tetrahydro-4-(t-butyldimethylsilyloxymethyl)-3-methylfuran-2-ol (9)
2.4. (rel)-(3R,4S,5R/S)-[(4-Methyl-tetrahydro-5-methoxyfuran-3-yl)methoxy](t-butyl)dimethylsilane(10)
2.5. (rel)-(3S,4S,5R/S)-(4-Methyl-tetrahydro-5-methoxyfuran-3-yl)methanol (11)
2.6. (rel)-(3R,4S,5R/S)-(4-Methyl-tetrahydro-5-methoxyfuran-3-yl)methyl trifluoromethanesulfonate (12)
2.7. (rel)-Diethyl 1,1-difluoro-2-[(3S,4S,5R/S)-4-methyl-tetrahydro-5-methoxyfuran-3-yl] ethylphosphonate(13)
2.8. (rel)-Diethyl 2-[(3S,4S,5R/S)-5-acetoxy-4-methyl-tetrahydrofuran-3-yl]-1,1-difluoroethylphosphonate(14)
2.9. (rel)-Diethyl 4-[(1S,2S,3S)-1-(6-chloro-9H-purin-9-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphonate(15α) an
2.10. (rel)-Diethyl 4-[(1R,2S,3S)-1-(6-amino-9Hpurin-9-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphonate (16)
2.11. (rel)-4-[(1R,2S,3S)-1-(6-Amino-9H-purin-9-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethylphosphonicacid sodium salt (17)
2.12. (rel)-Diethyl 4-[(1S,2S,3S)-1-(2-fluoro-6-chloro-9H-purin-9-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphona
2.13. (rel)-Diethyl 4-[(1R,2S,3S)-1-(2-fluoro-6-amino-9H-purin-9-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphonate (19) and (rel)-diethyl 4-[(1R,2S,3S)-1-(2-amino-6-chloro-9H-purin-9-yl)-2-methyltetrahydrofuran-3-yl]-5,5-difluoroethylphosphona
2.14. (rel)-4-[(1R,2S,3S)-1-(2-Amino-6-oxo-9Hpurin-9-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethyl-phosphonic acid sodium salt (21)
2.15. (rel)-Diethyl 4-[(1S,2S,3S)-1-(N4-benzoylamino-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-di
2.16. (rel)-Diethyl 4-[(1R,2S,3S)-1-(4-amino-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylphosphonate (23)
2.17. (rel)-4-[(1R,2S,3S)-1-(4-Amino-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethyl-phosphonic acid sodiumsalt (24)
2.18. (rel)-Diethyl 4-[(1S,2S,3S)-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methyl-tetrahydrofuran-3-yl]-5,5-difluoroethylp
2.19. (rel)-Diethyl 4-[(1S,2S,3S)-1-(2,4-dioxo-5-methyl-3,4-dihydropyrimidin-1(2H)-yl)-2-methyltetrahydrofuran-3-yl]-5,5-difluo
2.20. (rel)-4-[(1R,2S,3S)-1-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethyl-phosphonic acid sodium salt (27)
2.21. (rel)-4-[(1R,2S,3S)-1-(2,4-Dioxo-5-methyl-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl]-2-methyl-5,5-difluoroethyl-phosphonic acid sodiumsalt (28)
3. Results and Discussion
3.1. Biological Activity Evaluation
4. Conclusion
Acknowledgment
References
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