From Synthetic Chemistry of Nucleosides to New Antiviral Agents

総  説㩷

ヌクレオシドの合成化学から抗ウイルス剤の創生へ㩷

↰ਛඳ㆏^㧝㧕㧘ᣧᎹᒄਯ^㧞㧕㧘ේญ৻ᐢ^㧝㧕㧘દ⮮૫ᴦ^㧟㧕㧘ട⮮ᕺ੺^㧠㧕㧘㩷 ᾢᧄᶈ᮸^㧝㧕㧘┄↰ ⼾^㧝㧕㧘┻↰ᘕ๋^㧡㧕㧘ፉ↰ ᄩ^㧝㧕㩷

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㪈㪀㩷 ᤘ๺ᄢቇ⮎ቇㇱ㩷⮎ຠ⵾ㅧൻቇᢎቶ㩷

㪉㪀㩷 ࡗࡑࠨ㉟ᴤᩣᑼળ␠㩷ຠ⾰଻⸽ㇱ㩷

㪊㪀㩷 ᣣᧄߚ߫ߎ↥ᬺᩣᑼળ␠㩷ක⮎✚ว⎇ⓥᚲ㩷

㪋㪀㩷 ᧲㇌ᄢቇ⮎ቇㇱ㩷⮎ൻቇᢎቶ㩷

㪌㪀㩷 ⥝๺ᩣᑼળ␠㩷ක⮎੐ᬺㇱ^㩷 㩷

ⷐ ᣦ㩷

⮎ຠ⵾ㅧൻቇᢎቶߢߎࠇ߹ߢߦ⎇ⓥߐࠇߚ࠹࡯ࡑߩਛ߆ࠄޔޟ࠿ࠢ࡟ࠝࠪ࠼ߩ࡝࠴࠙ࡓൻ෻ᔕޠ ߅ࠃ߮ޟਇ㘻๺♧࠿ࠢ࡟ࠝࠪ࠼ߩวᚑൻቇ⊛೑↪ᴺޠߦߟ޿ߡ᭎ⷰߒߚޕ㩷

࠙࡝ࠫࡦߩ㪍૏․⇣⊛࡝࠴࠙ࡓൻߪޔ㪉㩾㪃㪊㩾㪄ࠗ࠰ࡊࡠࡇ࡝࠺ࡦ⺃ዉ૕ࠍၮ⾰ߣߒ㪣㪛㪘ߢ࡝࠴࠙ࡓ ൻߔࠆߎߣߢ㆐ᚑߢ߈ߚޕᧄ෻ᔕࠍࠕࠪࠢࡠ࠿ࠢ࡟ࠝࠪ࠼ߦㆡ↪ߒߚ⎇ⓥ߆ࠄߪޔ㪟㪠㪭㪄㪈ߩჇᱺ ࠍ․⇣⊛ߦ㒖ኂߔࠆ㪟㪜㪧㪫߇⷗಴ߐࠇߚޕ㪍㪄ࠢࡠࡠࡊ࡝ࡦ࠿ࠢ࡟ࠝࠪ࠼ߩ㪣㪛㪘ߦࠃࠆ࡝࠴࠙ࡓൻ ߩㆊ⒟ߢޔࠪ࡝࡞ၮ߿ࠬ࠲࠾࡞ၮ߇Ⴎၮㇱ㪏૏߆ࠄ㪉૏ߦォ૏ߔࠆߎߣࠍ⷗಴ߒߚޕߘߩ⚿ᨐ㪉૏⟎

឵ࡊ࡝ࡦ࠿ࠢ࡟ࠝࠪ࠼ࠍวᚑߔࠆߚ߼ߩᣂߒ޿ᣇᴺࠍ㐿⊒ߔࠆߎߣ߇ߢ߈ߚޕ㩷

ࠛࡁ࡯࡞ࠛ࡯࠹࡞᭴ㅧࠍ᦭ߔࠆਇ㘻๺♧࠿ࠢ࡟ࠝࠪ࠼ࠍޔࠫࡔ࠴࡞ࠫࠝࠠࠪ࡜ࡦߢࠛࡐࠠࠪ࠼

߳ᄌ឵ߔࠆߎߣ߇ߢ߈ߚޕᓧࠄࠇߚࠛࡐࠠࠪ࠼ࠍ᦭ᯏࠪ࡝ࠦࡦ⹜⮎߿᦭ᯏࠕ࡞ࡒ࠾࠙ࡓ⹜⮎ߦࠃ ߞߡ㐿Ⅳߔࠆߎߣߢޔࠕࡁࡑ࡯૏߿㪋㩾૏ߢ὇⚛㪄὇⚛⚿วࠍᒻᚑߢ߈ࠆޕߎࠇࠄߩ෻ᔕߩᯏ᭴ࠍ᣿

ࠄ߆ߦߒߚ⚿ᨐޔ㐿Ⅳ෻ᔕߩ┙૕ൻቇࠍ೙ᓮߔࠆߎߣ߇น⢻ߦߥߞߚޕ㩷 㩷

㪢㪼㫐㩷㪮㫆㫉㪻㫊㧦㪍૏⟎឵࠙࡝ࠫࡦޔ࡝࠴࠙ࡓൻޔࠕࠪࠢࡠ࠿ࠢ࡟ࠝࠪ࠼ޔਇ㘻๺♧࠿ࠢ࡟ࠝࠪ࠼ޔ㩷 㩷 ࠛࡐࠠࠪ࠼ޔ㐿Ⅳ෻ᔕޔ┙૕ൻቇߩ೙ᓮ㩷

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ߪߓ߼ߦ

ቯᐕㅌ⡯ߔࠆߦ޽ߚߞߡ㧘ߎࠇ߹ߢߩ⎇ⓥࠍᝄ ࠅ㄰ߞߡ✚⺑㧔ᄢㇱಽߪᚒޘߩ⎇ⓥߦ㑐ߔࠆߎߣ ߥߩߢޟ✚ว⺰ᢥޠߣ๭߱߶߁߇ᱜߒ޿㧕ࠍᦠߊ ࠃ߁ߦ⸒ࠊࠇߚ㧚ᄙߊߩቇㇱቇ↢㧘ᄢቇ㒮↢㧘⡯

ຬ㧘౒ห⎇ⓥ⠪ߩ߅߆ߍߢ↢߹ࠇ⢒ߞߚ⎇ⓥ߫߆ ࠅߢ޽ࠆ߆ࠄ㧘ᧄ᧪ߔߴߡߩ⎇ⓥౝኈߦ⸅ࠇߡᗵ

⻢ߩ᳇ᜬߜࠍ⴫ߔߴ߈ߢ޽ࠆ߇㧘⚕㕙ߦ㒢ࠅ߇޽

ࠆ㧚Ყセ⊛ᄢ߈ߥ࠹࡯ࡑߦ⢒ߞߚޟ࠿ࠢ࡟ࠝࠪ࠼

ߩ࡝࠴࠙ࡓൻ෻ᔕޠߣޟਇ㘻๺♧࠿ࠢ࡟ࠝࠪ࠼ߩ วᚑൻቇ⊛೑↪ᴺޠߩੑߟߦ㒢ቯߒߡ㧘⎇ⓥߩ㐿 ᆎᤨ߿▵⋡ߦᄙᄢߥ⽸₂ࠍߒߡ޿ߚߛ޿ߚᣇޘ ߩߺࠍ౒⪺⠪ߣߔࠆ㕖␞ࠍ߅⸵ߒ޿ߚߛ߈ߚ޿㧚 ߎߩੑߟߦ⛉ߞߡߐ߃߽㧘⸅ࠇࠆߎߣ߇ߢ߈ߥ߆ ߞߚ㑐ㅪߔࠆ⎇ⓥࠍᕁ޿⿠ߎߔߣޟᄙߊߩᓐ߿ᓐ

ᅚޠߩ㗻߇ᕁ޿ᶋ߆ࠎߢ߈ߡ⢷߇∩߻㧚㩷

⎇ⓥቶߢߪޟ߅߽ߒࠈ޿⎇ⓥࠍ߿ࠈ߁ޠࠍว⸒

⪲ߦߒߡ߈ߚ߇㧘⮎ቇㇱߢวᚑൻቇࠍ߿ࠆߩߛ߆ ࠄޟวᚑߒߚᣂⷙൻว‛ߩᵴᕈࠍ⹏ଔߒࠃ߁ޠ߽

⋡ᮡߦߒߚ㧚൩⺰㧘ዋ㊂㧔ᢙࡒ࡝ࠣ࡜ࡓ㧕ߩࠨࡦ ࡊ࡞ߢࠕ࠶࠮ࠗ߇น⢻ߥ᛫࠙ࠗ࡞ࠬᵴᕈ߿ၭ㙃

⚦⢩♽ࠍ↪޿ࠆ೙ࠟࡦᵴᕈߥߤߦ㒢ࠄࠇࠆ߇㧘ᔅ ὼ⊛ߦ౒ห⎇ⓥࠍផߒㅴ߼ࠆߎߣߦߥߞߚߩߢ

࿖ౝᄖߩઁಽ㊁ߩ⎇ⓥ⠪ߣߩ੤ᵹ߇⋓ࠎߦߥߞ ߚ㧚㩷

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㧝㧚࠿ࠢ࡟ࠝࠪ࠼ߩ࡝࠴࠙ࡓൻ෻ᔕ㩷

㪈㪄㪈㧚࠙࡝ࠫࡦߩႮၮㇱ㪍૏࡝࠴࠙ࡓൻ㧦ᭂᕈォ឵㩷

੹߆ࠄ㪊㪇ᐕ߶ߤ߽೨ߩߎߣߦߥࠆ߇㧘ࠟࡦߩᴦ

≮ߦ࠴ࡒࠫࡦߩᄢ㊂ᛩਈ߇᦭ലߢ޽ࠆߣ޿߁⺑

߇޽ࠅ㧘ൻቇ⺞๧ᢱߢ޽ࠆ㪌㩾㪄㪠㪤㪧㧔߆ߟ߅▵ߩ߁

߹๧㧕ߣ㪌㩾㪄㪞㪤㪧㧔ߒ޿ߚߌߩ߁߹๧㧕ࠍ㪩㪥㪘ಽ

⸃ᴺߢ⵾ㅧߒߡ޿ࠆᣣᧄߩ޽ࠆડᬺߦ㧘☨࿖㪥㪚㪠㩷 㩿㪥㪸㫋㫀㫆㫅㪸㫃㩷㪚㪸㫅㪺㪼㫉㩷㪠㫅㫊㫋㫀㫋㫌㫋㪼㧕߆ࠄ࠴ࡒࠫࡦߩᄢ㊂ଏ

⛎ߩน⢻ᕈߦߟ޿ߡᛂ⸻߇޽ߞߚ㧚ߎߎߢ᳞߼ࠄ ࠇ ࠆ ߩ ߪ 㧘㪩㪥㪘 ಽ ⸃ ᴺ ߢ ೽ ↢ ߔ ࠆ㪌㩾㪄㪬㪤㪧 ߿

㪌㩾㪄㪚㪤㪧 ࠍ೑↪ߒߡല₸⦟ߊ࠴ࡒࠫࡦࠍวᚑߔࠆ

ߎߣߢ޽ࠆ㧚㩷

࠙࡝ࠫࡦࠍ࠴ࡒࠫࡦߦᄌ឵ߔࠆߦߪ㧘㪌૏ߦࡔ

࠴࡞ၮࠍዉ౉ߒ♧ㇱ㪉㩾૏ߩ᳓㉄ၮࠍ㒰෰ߔࠇ߫ࠃ

޿㧚ࠕ࡞ࠞ࡝ᕈ᧦ઙਅߢ㪉㩾㪃㪊㩾㪄ǘ㪄ࠗ࠰ࡊࡠࡇ࡝࠺

ࡦ࠙࡝ࠫࡦ㩷 㩿㪈㪀㩷ߩ♧ㇱ㪌㩾㪄ࠕ࡞ࠦࠠࠪ࠼߇㑐ਈߔ ࠆ࠙࡜ࠪ࡞Ⅳ㪌૏ߩ㊀᳓⚛੤឵෻ᔕ^㧝㧕߇ႎ๔ߐࠇ ߡ޿ߚߩߢ㪃ޟ㪛^㪂㩷߽㪚㪟_㪊^㪂㩷߽หߓߛࠈ߁ޠߣࡔ࠴࡞

ၮߩዉ౉ࠍ⹜ߺߚ㧚⒳ޘߩႮၮࠍ↪޿ߡ㪈ߣ࡛࠙

ൻࡔ࠴࡞ࠍ෻ᔕߐߖߚ߇㧘㪌㩾㪄ǘ㪄ࡔ࠴࡞૕߇↢ᚑ ߔࠆߛߌߛߞߚ㧚ࠕ࡞ࠦࠠࠪ࠼ߩ⺞⵾ߦ 㪣㪛㪘㩷 㩿㫃㫀㫋㪿㫀㫌㫄㩷 㪻㫀㫀㫊㫆㫇㫉㫆㫇㫐㫃㪸㫄㫀㪻㪼㪀㩷ࠍ૶↪ߔࠆߎߣ߽޽ࠆ ߩߢߎࠇ߽⹜ߒߡ⷗ߚߣߎࠈ㧘㪌૏ߢߪߥߊ㪍૏ߢ ߩࠕ࡞ࠠ࡞ൻ߇⿠ߎߞߚ㩷 㩿㪪㪺㪿㪼㫄㪼㩷㪈㪀^㧞㧕㧚ߎߩ⚿ᨐ ߪ㪣㪛㪘ߦࠃߞߡ࠙࡜ࠪ࡞Ⅳ㪍૏߇࡝࠴࠙ࡓൻߐࠇ ߚߎߣࠍ␜ߒߡ޿ࠆ㧚ࡔ࠴࡞૕㩷 㩿㪉㪀㩷ߩઁߦࠛ࠴࡞

૕㩷 㩿㪊㪀㩷߿ࠗ࠰ࡊࡠࡇ࡞૕㩷 㩿㪋㪀㩷߇೽↢ߔࠆ߇㧘࡝࠴

࠙ࡓൻ߇㪍૏ߩߺߦ⿠ߎߞߡ޿ࠆߎߣߪ㊀᳓⚛ൻ ߢ⏕⹺ߒߚ㧚㩷

࠙࡜ࠪ࡞Ⅳ㪍૏ߪ᳞ᩭ⹜⮎߇෻ᔕߔࠆㇱ૏ߢ޽

ࠆ߇㧘ߎߩ㪍૏ࠍ૏⟎․⇣⊛ߦ࡝࠴࠙ࡓൻߢ߈ߚ ߩߢ੹ᐲߪ᳞㔚ሶ⹜⮎ࠍ෻ᔕߐߖࠆߎߣ߇ߢ߈ ࠆ㧚හߜ㪍૏ߢߩᭂᕈォ឵㩷 㩿㪬㫄㫇㫆㫃㫌㫅㪾㪀^㧟㧕ߦ⋧ᒰߔ ࠆ㧚⹦ߒߊߪㅀߴߥ޿߇㧘วᚑᴺ਄ߩ೙㒢߆ࠄᭂ

߼ߡ㒢ࠄࠇߚ㪍૏⟎឵࠙࡝ࠫࡦߒ߆⍮ࠄࠇߡ޿ߥ ߆ߞߚߩߢ㪃ߎߩᣇᴺߩ৻⥸ᕈࠍታ⸽ߔࠆߎߣߦ ߒߚ㧚ൻว‛㪈ߩ࡝࠴ࠝ૕ߪ㪫㪟㪝㩷㩿㫋㪼㫋㫉㪸㪿㫐㪻㫉㫆㪽㫌㫉㪸㫅㪀㩷

߳ߩṁ⸃ᕈ߇లಽߣߪ޿߃ߥ޿ߩߢ㧘㪌㩾૏ߩ᳓㉄

ၮࠍࡔ࠻ࠠࠪࡔ࠴࡞ၮߢ଻⼔ߒߚ㪌㧔ᓟߦ 㫋㪼㫉㫋㪄ࡉ

࠴࡞ࠫࡔ࠴࡞ࠪ࡝࡞଻⼔ߩᣇ߇ఝࠇߡ޿ࠆߎߣ ߇್ߞߚ^㧠㧕㧕ࠍ↪޿ߡ㪣㪛㪘ߦࠃࠆ࡝࠴࠙ࡓൻߩᓟ ߦ᳞㔚ሶ⹜⮎ࠍ෻ᔕߐߖߚ^㧡㧕㧚㪪㪺㪿㪼㫄㪼㩷㪉ߦ␜ߒߚ ࠃ߁ߦ㧘ട߃ࠆ᳞㔚ሶ⹜⮎ࠍᄌ߃ࠆߛߌߢ߶߷છ ᗧߩ㪍૏⟎឵૕ࠍวᚑߢ߈ࠆ㧔㪍㪄ࡔ࠴࡞૕એᄖߪ ߔߴߡᣂⷙߥ㪍૏⟎឵࠙࡝ࠫࡦߢ޽ࠆ㧕㧚ૐ᷷᧦ઙ ਅߢߩ෻ᔕߥߩߢ㧘㪥㪊㪄࡝࠴ࠝߣ㪍㪄࡝࠴ࠝߩ᳞ᩭ

ᕈߩᏅ߇ߺߏߣߦ෻ᤋߐࠇߡ㧘㪥㪊૏ߢ෻ᔕߒߚ↢

ᚑ‛ߪోߊᓧࠄࠇߥ޿㧚㩷

ᒰೋ㪌㩾㪄ࠕ࡞ࠦࠠࠪ࠼ߩ㓞ធၮ㑐ਈࠍ߽ߊࠈࠎ ߢ↪޿ߚࠗ࠰ࡊࡠࡇ࡝࠺ࡦ଻⼔ၮߢ޽ࠆ߇㧔㪉㩾㧘 㪊㩾૏ߩ᳓㉄ၮࠍ੖ຬⅣ⁁ߦ଻⼔ߔࠆߣ㧘࠙࡜ࠪ࡞

Ⴎၮߣ㪌㩾㪄᳓㉄ၮ߇ធㄭߔࠆ㧕㧘ߎߩ࡝࠴࠙ࡓൻ෻

ᔕߢߪ㪍૏ߩ๟࿐ߦⓨ㑆ࠍ૞ࠅ಴ߒߡ㪣㪛㪘ߩធㄭ ࠍኈᤃߦߒߡ޿ࠆ㧚੐ታ㧘࠙࡝ࠫࡦߩߔߴߡߩ᳓

㉄ၮࠍ 㫋㪼㫉㫋㪄ࡉ࠴࡞ࠫࡔ࠴࡞ࠪ࡝࡞ၮߢ଻⼔ߔࠆ

ߣ㧘㪍૏ㄭற߇ㆤ⭁ߐࠇߡ㪣㪛㪘ߦࠃࠆ࡝࠴࠙ࡓൻ ߪోߊ⿠ߎࠄߥߊߥࠆ^㧢㧕㧚ᓟߦߎߩߎߣࠍ೑↪ߒ ߡ㧘㪌૏ࠍㆬᛯ⊛ߦ࡝࠴࠙ࡓൻߔࠆߎߣߦ߽ᚑഞ ߒߚ^㧣㧕㧚㩷

ᄤὼߦሽ࿷ߔࠆࡇ࡝ࡒࠫࡦ࠿ࠢ࡟ࠝࠪ࠼߅ࠃ

߮ߘߩ㪌૏⟎឵૕ߪ㧘ࠣ࡝ࠦࠪ࡞⚿ว࿁ࠅߩ㈩ᐳ ߇ࠕࡦ࠴㧔Ⴎၮㇱ㪉૏ࠞ࡞ࡏ࠾࡞߇࡝ࡏ࡯ࠬⅣߩ ᄖ஥ߦ޽ࠆ㧕ߢ޽ࠆߎߣ߇⍮ࠄࠇߡ޿ࠆ㧚ߎࠇߦ ኻߒߡ㪍૏ߦ⟎឵ၮ߇ሽ࿷ߔࠆߣ㧘㪉૏ࠞ࡞ࡏ࠾࡞

߇ ࡝ ࡏ ࡯ ࠬ Ⅳ ౝ ߦ ૏ ⟎ ߔ ࠆ ࠪ ࡦ ㈩ ᐳ ࠍ ข ࠆ 㧔㪪㪺㪿㪼㫄㪼㩷㪈ߩൻว‛㪈߇ࠕࡦ࠴㧘㪉㪄㪋߇ࠪࡦ㈩ᐳߢ޽

ࠆ㧕㧚ޟࠠ࠽࡯࠯ߪߎߩ㈩ᐳߩ㆑޿ࠍ⹺⼂ߔࠆߩߢ㧘 㪍૏⟎឵૕ߪ㉂⚛ߩၮ⾰ߣߥࠄߕ㧔࡝ࡦ㉄ൻߐࠇ ߕ㧕↢ℂᵴᕈߩὐߢᦼᓙߢ߈ߥ޿ޠߣ޿߁⠨߃߇ ᡰ㈩⊛ߢ޽ߞߚ㧚ߒ߆ߒߥ߇ࠄ㧘วᚑߒߚ㪍૏⟎

឵࠙࡝ࠫࡦߩਛߢ㪍㪄࡛࡯࠼૕߅ࠃ߮㪍㪄ࡈࠚ࠾࡞࠴㩷

O

NH N O

O

O

Scheme 1. Reaction of 2',3'-O-isopropylideneuridine (1) with CH₃I in the presence of LDA.

O

HO in THF, 78 ^oC

2) CH₃I 1

O HN

N O

O O

HO O R

2 R = CH₃ 3 R = CH₂CH₃ 4 R = CH(CH₃)₂

2' 3'

5 5' 6

N Li (LDA) 1)

㩷 㩷

O

NH N O

O

O

Scheme 2. Synthesis of various types of 6-substituted uridines based on LDA-lithiation.

O O

5 O

N N O

O Rf

Li Li

Rf = 2,3-O-isopropylidene-5-O-methoxy- methyl-E-D-ribofuranosyl

LDA THF, 78 ^oC

HN N O

O R

R-I (inverse addition) R = alkyl Rf

HN N O

O C

Rf R OH

R HN

N O

O C

Rf R

H OH

HN N O

O CHO

Rf HN

N O

O C

Rf O R

HN N O

O Rf HN OH

N O

O X

Rf HN

N O

O X

Rf

R = CMe₃, Ph, OEt

X = I, SiMe₃ X = S, Se

RCOR

RCHO

HCO₂Et

RCOCl

I₂ or Me₃SiCl (PhX)₂

O

㩷 㩷

ࠝ૕ߦࡑ࠙ࠬ⊕ⴊ∛⚦⢩ߩჇᱺࠍᛥ೙ߔࠆᵴᕈ ߇⹺߼ࠄࠇߚ㧚ߘߎߢ㪌૏ߦࡔ࠴࡞ၮ߿ࡂࡠࠥࡦ ࠍ᦭ߔࠆ࠙࡝ࠫࡦ⺃ዉ૕ࠍ↪޿ߡ㪃ኻᔕߔࠆ㪍૏⟎

឵૕ࠍวᚑߔࠆߎߣߦߒߚ㧚ߎߩㆊ⒟ߢ㪍૏࡝࠴

࠙ࡓൻߩല₸߇㪌૏⟎឵ၮߩ㔚ሶ⊛ലᨐߦࠃߞߡ ᄢ߈ߥᓇ㗀ࠍฃߌߡ޿ࠆߎߣ߇᣿ࠄ߆ߦߥߞߚ㧚

วᚑߒߚൻว‛ߩ᭴ㅧᑼߣᵴᕈ࠺࡯࠲ࠍ 㪫㪸㪹㫃㪼㩷 㪈 ߦ߹ߣ߼ߡ޽ࠆ^㧤㧕㧚⒟ᐲߩᏅߪ޽ࠆ߇޿ߕࠇߩൻ ว‛߽ᵴᕈࠍ␜ߒ㧘ਛߢ߽㪌㪄ࡈ࡞ࠝࡠ㪄㪍㪄࡛࡯࠼

૕ߩᵴᕈߪ೙ࠟࡦ೷㪌㪄ࡈ࡞ࠝࡠ࠙࡜ࠪ࡞ࠍ⿧߃ ࠆ߽ߩߢ޽ߞߚ㧚㩷

Table 1. Antileukemic activity of 6-phenylthio- and 6-iodouridine derivatives.

O HN

N O

HO OH

HO O X

R

R X EC₅₀ (Pg/mL)^a)

H SPh

Me F Cl Br I H Me

F Cl Br I

SPh SPh SPh SPh SPh I I I I I I

70 60 30 8.0 20 40 8.0 4.0 0.02 55 52 55

5-fluorouracil 0.1

a) Effective concentration of compound required to achieve 50% suppression of proliferation of mouse leukemia L5178Y cells in culture. 㩷

㩷 㪈㪄㪉㧚㪍㪄ࡈࠚ࠾࡞࠴ࠝ࠙࡝ࠫࡦߩ㪌૏࡝࠴࠙ࡓൻ㧦

⣕⎫⊛ࠬ࠲࠾࡞ൻߣߩ಴ળ޿㩷

ฦ⒳ߩ㪍૏⟎឵࠙࡝ࠫࡦࠍวᚑߢ߈ࠆࠃ߁ߦߥ ߞߚ㩷 㩿㪪㪺㪿㪼㫄㪼㩷 㪉㪀ߩߢ㧘ᒰೋߩ⋡⊛ߢ޽ߞߚ㪌૏ࡔ

࠴࡞ൻߩᬌ⸛ࠍౣ㐿ߒߚ㧚෼₸⦟ߊวᚑߢ߈ࠆ㪍㪄 ࡈࠚ࠾࡞࠴ࠝ૕㩷 㩿㪍㪀㩷ߩ㪌૏ࠍ࡝࠴࠙ࡓൻ⚻↱ߢࡔ

࠴࡞ൻߒ㧘ߘߩᓟߦࡈࠚ࠾࡞࠴ࠝၮࠍ㒰෰ߒࠃ߁ ߣ޿߁⸘↹ߢ޽ࠆ㧚㩷

㊀ ᳓ ⚛ ൻ ታ 㛎 ߩ ⚿ ᨐ 㧘࡝ ࠴ ࠙ ࡓ ൻ ೷ ߣ ߒ ߡ 㪣㪫㪤㪧㩷 㩿㫃㫀㫋㪿㫀㫌㫄㩷 㪉㪃㪉㪃㪍㪃㪍㪄㫋㪼㫋㫉㪸㫄㪼㫋㪿㫐㫃㫇㫀㫇㪼㫉㫀㪻㫀㪻㪼㪀㩷ࠍ↪

޿ࠆߣ㪍ߩ㪌૏߇ቯ㊂⊛ߦ࡝࠴࠙ࡓൻߐࠇࠆߎߣ ߇ಽ߆ߞߚ㩷 㩿㪪㪺㪿㪼㫄㪼㩷㪊㪀㧚࡛࠙ൻࡔ࠴࡞ࠍ෻ᔕߐߖ ࠆߣᅢ෼₸ߢ㪌㪄ࡔ࠴࡞૕㩷 㩿㪎㪀㩷߇ᓧࠄࠇࠆ߇㧘ࡈࠚ

࠾࡞࠴ࠝၮࠍ㒰෰ߔࠆᎿ⒟ߢ⧰ഭࠍߒߚ㧚⣕⎫෻

ᔕ ߦ૶ ↪ߐࠇ ࠆࠕ ࡞ࡒ࠾ ࠙ࡓ ࠕࡑ࡞ ࠟࡓ ߿࡜

ࡀ࡯࠾࠶ࠤ࡞ߣ㪎ߣߩ෻ᔕߢߪ㪌㪃㪍㪄ੑ㊀⚿วߩㆶ ర߇ఝవ⊛ߦ⿠ߎࠆ㧚ᄙߊߩᄬᢌࠍ㊀ߨߚ߇㧘࠻

࡝ࡉ࠴࡞ࠬ࠭࡜ࠫࠞ࡞ߣ㪎ࠍ෻ᔕߐߖࠆߣࡈࠚ࠾

࡞࠴ࠝၮ߇⟎឵ߐࠇ㪍㪄࠻࡝ࡉ࠴࡞ࠬ࠲࠾࡞૕㪏߇

߶߷ቯ㊂⊛ߦ↢ᚑߔࠆߎߣࠍ⷗಴ߒߚ㧚ൻว‛㪏 ࠍ㉄ᕈ᧦ઙߢಣℂߔࠆߣ㧘♧ㇱ᳓㉄ၮߩ⣕଻⼔ߣ หᤨߦࠬ࠲࠾࡞ၮߩࡊࡠ࠻ࡁ࡝ࠪࠬ߇⿠ߎࠅ⋡

⊛ߣߔࠆ㪌㪄ࡔ࠴࡞࠙࡝ࠫࡦ㩷 㩿㪐㪀㩷ࠍᓧࠆߎߣ߇ߢ ߈ߚ^㧥㧕㧚㩷

਄⸥ߩ㪎߆ࠄ㪏ߦ⥋ࠆ෻ᔕߪࠬ࠭࡜ࠫࠞ࡞ߦࠃ ࠆࠕ࡝࡯࡞࠴ࠝၮߩ⋥ធ⊛ߥ⟎឵ߢ޽ࠆ㧚ੑ㊀⚿

วߩࠪࡈ࠻ࠍ઻߁ࠕ࡝࡯࡞࠴ࠝၮߣࠬ࠭࡜ࠫࠞ

࡞ߩ⟎឵෻ᔕ㧔㪪_㪟㩾㩷ᯏ᭴㧕ߪႎ๔ߐࠇߡ޿ߚ߇^㪈㪇㧕㧘

⪺⠪ࠄߩ⍮ࠆ㒢ࠅߎߩࠃ߁ߥ⋥ធ⟎឵ߩ෻ᔕ଀

ߪߥ߆ߞߚ㧚ߎߩޟ⣕⎫⊛ࠬ࠲࠾࡞ൻޠߩ෻ᔕᯏ

᭴ߦ㑐ߒߡߪ⃻࿷߽⎇ⓥࠍ⛯ߌߡ޿ࠆ߇㧘ߎߩᓟ ㆡ↪▸࿐ࠍࡆ࠾࡞ࠬ࡞ࡎࡦ╬ߩࠬ࠲࠾࡞ൻߦ߽

᜛ᒛߢ߈ߚߩߢ㧘࠿ࠢ࡟ࠝࠪ࠼ߩ♧ㇱಽ㧔὇⚛Ⅳ ߥߤߩᡆૃ♧߽฽߻㧕ߩᄌ឵෻ᔕߣߒߡᄢ޿ߦᓎ

┙ߞߡ޿ࠆ^㪈㪈㧕㧚㩷

ߎߩ▵ߩᦨᓟߦ㧘਄⸥วᚑ⎇ⓥߩㆊ⒟ߢⷰኤߐ ࠇߚ㪍૏ࡈࠚ࠾࡞࠴ࠝၮߩ┙૕᭴ㅧߩᄌൻ㧔㈩ᐳ ߩᄌൻ㧕ߦߟ޿ߡ⸅ࠇߡ߅ߊ㧚㪫㪸㪹㫃㪼㩷㪉ߦߪൻว‛

㪌ߣ㪍㧘߅ࠃ߮㪍ߩ࡝࠴࠙ࡓൻࠍ⚻ߡวᚑߒߚ㪌૏⟎

឵㪄㪍㪄ࡈࠚ࠾࡞࠴ࠝ૕㩷 㩿㪎㪃㪈㪇㪃㪈㪈㪀ߩࠗ࠰ࡊࡠࡇ࡝࠺

ࡦࡔ࠴࡞ၮߩൻቇࠪࡈ࠻ࠍ⸥タߒߚ㧚⴫ߩ⣉ᵈߦ

޽ࠆࠃ߁ߦ㧘㪍㪄ࡈࠚ࠾࡞࠴ࠝ૕㪍ߩ㪟㪄㪌ߪ㪌ߩߘࠇ ࠃࠅ߽⚂㪇㪅㪏㩷 㫇㫇㫄 㜞⏛႐ߦࠪࡈ࠻ߒߡ޿ࠆ㧚ߎࠇ ߪࡌࡦ࠯ࡦⅣߩ⏛᳇⇣ᣇᕈലᨐߦࠃࠆ߽ߩߢ㪃㩷ߎ㩷

O

O

Scheme 3. Synthesis of 5-methyluridine (9) from the 6-phenylthiouridine derivative 6.

O O

O HN

N O

O SPh

6

(LTMP) 1)

in THF, 78 ^oC 2) CH₃I

O

O O

O

O HN

N O

O SPh

CH₃

O

O O

O

O HN

N O

O SnBu₃

CH₃

O

NH N O

O

HO OH

HO H₃C

Bu₃SnH/AIBN benzene, reflux

50% CF₃CO₂H

7 (81%)

9 (79% from 7) 8

NLi

㩷 㩷

㩷 ߩࡈࠚ࠾࡞࠴ࠝၮ߇࠙࡜ࠪ࡞Ⴎၮߦ⋥ⴕߔࠆ㈩

ᐳࠍขࠅ㪟㪄㪌߇ࡌࡦ࠯ࡦⅣߩ߶߷⌀਄ߦ૏⟎ߒߡ

޿ࠆߎߣࠍ␜ߒߡ޿ࠆ㧚ਔൻว‛ߩࠛࠠ࠰߅ࠃ߮

ࠛࡦ࠼ࡔ࠴࡞ၮߩൻቇࠪࡈ࠻ߦᏅ߇ߥ޿੐ታߪ㧘 ߎࠇࠍᡰᜬߒߡ޿ࠆ㧚৻ᣇ㪎߆ࠄ㪈㪈ߢߪ㧘㪌૏⟎឵

ၮ߇߆ߐ㜞ߊߥࠆߦᓥߞߡࠛࠠ࠰߅ࠃ߮ࠛࡦ࠼

ࡔ࠴࡞ၮ߇㜞⏛႐ߦ⒖ⴕߔࠆ㧚ߎߩ࠺࡯࠲ߪ㧘ߎ ࠇࠄߩൻว‛ߩ㪍૏ࡈࠚ࠾࡞࠴ࠝၮ߇㪌૏⟎឵ၮ ߣߩ┙૕㓚ኂࠍㆱߌࠆߴߊ㈩ᐳࠍᄌൻߐߖߡ㧘ࠗ

࠰ࡊࡠࡇ࡝࠺ࡦၮߦㄭߠߊࠃ߁ߦߥߞߚߎߣࠍ

␜ߒߡ޿ࠆ㧚㩷 㩷

㪈㪄㪊㧚࠿ࠢ࡟ࠝࠪ࠼ߩൻቇ߆ࠄ↢߹ࠇߚ㕖࠿ࠢ࡟

ࠝࠪ࠼♽㪟㪠㪭ㅒォ౮㉂⚛㒖ኂ೷㪟㪜㪧㪫㩷 㩷 ᚒޘ߇࠙࡝ࠫࡦߩ࡝࠴࠙ࡓൻ෻ᔕߦ㑐ߔࠆ⎇

ⓥࠍㅴ߼ߡ޿ߚᒰᤨ㧘㪟㪠㪭㩷㩿㪟㫌㫄㪸㫅㩷㪠㫄㫄㫌㫅㫆㪻㪼㪽㫀㪺㫀㪼㫅㪺㫐㩷 㪭㫀㫉㫌㫊㪀㩷ߦࠃߞߡᗵᨴߔࠆࠛࠗ࠭㩷 㩿㪘㪠㪛㪪㪑㩷 㪘㪺㫈㫌㫀㫉㪼㪻㩷 㪠㫄㫄㫌㫅㪼㩷㪛㪼㪽㫀㪺㫀㪼㫅㪺㫐㩷㪪㫐㫅㪻㫉㫆㫄㪼㪀㩷߇਎⇇⊛ߥ໧㗴ߦߥ ߞߡ޿ߚ㧚൩⺰㪘㪱㪫㩷 㩿㪊㩾㪄㪸㫑㫀㪻㫆㪄㪊㩾㪄㪻㪼㫆㫏㫐㫋㪿㫐㫄㫀㪻㫀㫅㪼㪀 ࠍೋ߼ߣߔࠆ࠿ࠢ࡟ࠝࠪ࠼⺃ዉ૕߇ᴦ≮⮎ߣߒ

ߡ૶↪ߐࠇߡ޿ߚ߇㧘㛽㜑ᛥ೙ߥߤߩ೽૞↪߿⠴

ᕈ㪟㪠㪭ߩ಴⃻߇޽ࠅᣂߒ޿ᴦ≮⮎ߩ⊓႐߇ᓙߚࠇ ߡ޿ߚ㧚৻ᣇ㧘᛫࠙ࠗ࡞ࠬ⮎ࠕࠪࠢࡠࡆ࡞ߩᚑഞ ߦೝỗߐࠇߡ㧘ࠕࠪࠢࡠ࠿ࠢ࡟ࠝࠪ࠼㧔♧ㇱಽ߇ 㕖Ⅳ⁁᭴ㅧߦߥߞߚᡆૃ࠿ࠢ࡟ࠝࠪ࠼㧕ߩวᚑ߇

⋓ࠎߦⴕࠊࠇ⤘ᄢߥᢙߩൻว‛߇ႎ๔ߐࠇߡ޿

ߚ㧚޽ࠅߣ޽ࠄࠁࠆࠕࠪࠢࡠ࠿ࠢ࡟ࠝࠪ࠼߇ᣢߦ วᚑߐࠇߚߣᕁߞߡ޿ߚ߇㧘ᢥ₂ࠍᬌ⚝ߒߡߺࠆ ߣᩭ㉄Ⴎၮߣߒߡ㪍૏⟎឵ࡇ࡝ࡒࠫࡦࠍ᦭ߔࠆ߽

ߩߪ㪍㪄ࡔ࠴࡞࠙࡜ࠪ࡞ߣ㪍㪄ࡔ࠴࡞ࠪ࠻ࠪࡦߩ⺃

ዉ૕ߩߺߢ޽ߞߚ㧚㩷

ߎߩࠃ߁ߥ⢛᥊߆ࠄ㧘࠙࡝ࠫࡦߩ࡝࠴࠙ࡓൻ෻

ᔕࠍㆡ↪ߒߡ㪍૏⟎឵ࠕࠪࠢࡠ࠙࡝ࠫࡦࠍวᚑߒ㧘 ߘߩ᛫㪟㪠㪭ᵴᕈࠍ⹏ଔߔࠆߎߣߦߒߚ㧚ࠕࠪࠢࡠ

᭴ㅧߣߒߡߪ㧘ࠕࠪࠢࡠࡆ࡞ߣหߓࡅ࠼ࡠࠠࠪࠛ

࠻ࠠࠪࡔ࠴࡞ࠍㆬᛯߒߚ㧚ᣢߦㅀߴߚࠃ߁ߦ㪍૏

⟎឵࠙࡝ࠫࡦߢߪ㪍㪄࡛࡯࠼૕ߣ㪍㪄ࡈࠚ࠾࡞࠴ࠝ

૕ߦࡑ࠙ࠬ⊕ⴊ∛⚦⢩ߩჇᱺᛥ೙૞↪߇⹺߼ࠄ ࠇߡ޿ߚߩߢ㩷 㩿╙㪈▵ߩ㪫㪸㪹㫃㪼㩷㪈ෳᾖ㪀㧘ߎࠇࠄߦኻ ᔕߔࠆࠕࠪࠢࡠ࠙࡝ࠫࡦࠍ࠺ࠩࠗࡦߒ㪈㪇୘ߩൻ㩷

Table 2. Chemical shifts of the two isopropylidene methyl groups (exo and endo) of compounds 5, 6, 7, 10, and 11 in CDCl₃.

6 R = H 7 R = Me 10 R = Et 11 R = SiMe₃

Compd. at C5 at C6 Exo Endo

5^a) 6^a) 7 10 11

H H

H SPh

Me SPh

Et SPh

SiMe₃ SPh

1.36 1.59

1.35 1.58

1.23 1.46

1.18 1.40

1.10 1.34

substituent G (ppm) of isopropylidene methyl

a) Chemical shifts of H-5 are 5.70 ppm for 5 and 4.93 ppm for 6.

O

O O

O

O HN

N O

O SPh

R

Me Me

exo endo

㩷 㩷

Table 3. Inhibitionof HIV-1 replication in MT-4 cells by acyclouridines (12-21).

Compd. EC₅₀ (PM)^a) CC₅₀ (PM)^b)

12 13 (HEPT) 14 15

H

Me SPh

SPh SPh SPh

>500 1850

7.0 740

>100 288

>30 100

>20 44

a) Effective concentration of compound required to achieve 50% protection of MT-4 cells against the cytopathic effect of HIV-1.

HO O

HN N

O

O X

R

16 17 18 19 20 21

R X

SPh

F Cl Br

b) Cytotoxic concentrationof compound required to reduce the viability of mock-infected MT-4 cells by 50%.

c) Selectivity index: ratio of CC₅₀/EC₅₀.

SI^c)

<3.7 106

<2.9

<3.4

<2.2 H

Me F Cl Br

I I I I I

>30 75 <2.5

>80 400 <5

>15 32 <2.1

>6 13 <2.2

>5 11.5 <2.3

AZT 0.016 20 1250

㩷 㩷

ว‛ࠍวᚑߒߚ㩷 㩿㪫㪸㪹㫃㪼㩷㪊㪀^㪈㪉㧕㧚᛫㪟㪠㪭ᵴᕈߩ⹏ଔߪ㪃

⍮ੱߢ޽ࠆ㪮㪸㫃㫂㪼㫉ᢎ᝼㩷 㩿㪙㫀㫉㫄㫀㫅㪾㪿㪸㫄㩷 㪬㫅㫀㫍㪼㫉㫊㫀㫋㫐㧘

㪬㫅㫀㫋㪼㪻㩷 㪢㫀㫅㪾㪻㫆㫄㪀㩷ࠍㅢߓߡ᛫࠙ࠗ࡞ࠬ೷ߩ⎇ⓥߢ

⪺ ฬ ߥ 㪛㪼㩷 㪚㫃㪼㫉㪺㫈 ᢎ ᝼㩷 㩿㪢㪸㫋㪿㫆㫃㫀㪼㫂㪼㩷 㪬㫅㫀㫍㪼㫉㫊㫀㫋㪼㫀㫋㩷

㪣㪼㫌㫍㪼㫅㧘㪙㪼㫃㪾㫀㫌㫄㪀㩷ߦ߅㗿޿ߒߚ㧚ࠕ࠶࠮ࠗߪᒰᤨ

ࡌ࡞ࠡ࡯ߦ⇐ቇਛߛߞߚ㚍႐ᢎ᝼㧔⃻㣮ఽፉᄢ ቇ㧕߇ᜂᒰߒߚ㧚㩷

㪫㪸㪹㫃㪼㩷 㪊 ߦ ␜ ߒ ߚ ࠃ ߁ ߦ 㪈㪊㩷 㩿㪟㪜㪧㪫㪑㩷 㪉㪄㩷 㪿㫐㪻㫉㫆㫏㫐㪼㫋㪿㫆㫏㫐㫄㪼㫋㪿㫐㫃㪄㪍㪄㫇㪿㪼㫅㫐㫃㫋㪿㫀㫆㫋㪿㫐㫄㫀㫅㪼㪀㩷 ߦ ᛫ 㪟㪠㪭㪄㪈㩷 㩿㪟㪠㪭㩷 㫋㫐㫇㪼㩷 㪈㪀㩷ᵴᕈ߇⹺߼ࠄࠇߚ㧚㪟㪜㪧㪫ߩ

ᵴᕈ㩷 㩿㪜㪚_㪌㪇㩷 㪎㪅㪇Ǵ㪤㪀㩷ߪ㪘㪱㪫ߦᲧセߔࠆߣ㪋㪇㪇ಽߩ

㪈⒟ᐲߢ޽ࠆ߇㧘ߘߩ᛫࠙ࠗ࡞ࠬ૞↪ߪ㪟㪠㪭㪄㪈ߦ․

⇣⊛ߢ޽ࠆ㧚㪟㪠㪭㪄㪉ࠍ฽߻ઁߩ޿߆ߥࠆ࠙ࠗ࡞ࠬ

ߩჇᱺ߽㒖ኂߒߥ޿ߣ޿߁ὐߢᭂ߼ߡ࡙࠾࡯ࠢ

ߢ޽ࠅ㧘㪘㪱㪫ߥߤߩ࠿ࠢ࡟ࠝࠪ࠼♽᛫㪟㪠㪭⮎ߣߪ ᄢ޿ߦ⇣ߥࠆ᜼േࠍ␜ߔ^㪈㪊㧕㧚㪟㪜㪧㪫 ࠍ࡝࡯࠼ൻว

‛ߣߒߡ㧘ࠃࠅᵴᕈߩ㜞޿⺃ዉ૕ࠍวᚑߔࠆߎߣ ߇ᕆോߦߥߞߚ㧚㪫㪸㪹㫃㪼㩷㪊ߦ޽ࠆࠃ߁ߦ㧘㪟㪜㪧㪫ߩ㪌

૏ࡔ࠴࡞ၮ߇ᰳᅤߒߚ㪈㪉ߪᵴᕈࠍ␜ߐߥ޿㧚ߎߩ

੐ታߪ㧘࠙࡝ࠫࡦ⺃ዉ૕ߢᣢߦⷰኤߐࠇߡ޿ߚ㪌

૏⟎឵ၮߦࠃࠆ㪍૏ࡈࠚ࠾࡞࠴ࠝၮߩ┙૕㈩ᐳᄌ ൻ㧔╙㪉▵ᓟඨࠍෳᾖ㧕ࠍᕁ޿⿠ߎߐߖߚ㧚ᓥߞ

ߡ⋥ߜߦޟ᛫㪟㪠㪭㪄㪈ᵴᕈߩ⊒⃻ߦߪ㪌૏⟎឵ၮߩሽ

࿷߇ᔅⷐߢ޽ࠅ㧘ࡔ࠴࡞ၮࠃࠅ߽߆ߐ㜞޿ࠕ࡞ࠠ

࡞ၮࠍ㪌૏ߦዉ౉ߔࠆߎߣ߇ᵴᕈߩᡷༀߦ❬߇ࠆ ߢ޽ࠈ߁ޠߣផ᷹ߔࠆߎߣ߇ߢ߈ߚ㧚߹ߚޟ㪟㪜㪧㪫 ߪ㪍૏⟎឵ࡇ࡝ࡒࠫࡦࠕࠪࠢࡠ࠿ࠢ࡟ࠝࠪ࠼ߢ޽

ࠆ߆ࠄ㧘ࠠ࠽࡯࠯ߦࠃࠆ࡝ࡦ㉄ൻࠍฃߌߥ޿ߩߢ ߪߥ޿ߛࠈ߁߆ޠߛߣߔࠇ߫ޟ᳓㉄ၮࠍ㒰෰ߒߚ

࠺ࠝࠠࠪ⺃ዉ૕߽᛫ 㪟㪠㪭㪄㪈ᵴᕈࠍ␜ߔߪߕߢ޽

ࠆޠߣ޿߁૞ᬺ઒⺑߽┙ߡߚ㧚ߎࠇࠄ㪉ߟߩ⠨߃ ࠍၮߦޔડᬺߩදജࠍᓧߡ⺃ዉ૕ߩวᚑࠍㅴ߼ߚ㧚㩷

ߎߩ㪉ߟߩ⠨߃߇⊛ࠍ኿ߚ߽ߩߢ޽ࠆߎߣߪ㧘 วᚑߒߚൻว‛ߩ᛫㪟㪠㪭ᵴᕈ߇ᄢ᏷ߦᡷༀߐࠇߚ ߎߣߢ⸽᣿ߐࠇߚ^{㪈㪋㧘㪈㪌㧕}㧚㪫㪸㪹㫃㪼㩷 㪋ߦ␜ߒߚࠃ߁ߦ㧘 ߎߎߢวᚑߐࠇߚൻว‛ߩਛߦߪ㧘㪜㪚_㪌㪇୯ޔ㪪㪠୯ ߩ޿ߕࠇߦ߅޿ߡ߽ 㪘㪱㪫 ࠍಒ㚧ߔࠆ߽ߩ߇⷗಴

ߐࠇߚ㧚㩷

㪟㪜㪧㪫 ⺃ ዉ ૕ ߇ 㪟㪠㪭㪄㪈ߩ ㅒ ォ ౮ ㉂ ⚛㩷 㩿㪩㪫㪑㩷 㫉㪼㫍㪼㫉㫊㪼㩷 㫋㫉㪸㫅㫊㪺㫉㫀㫇㫋㪸㫊㪼㪀㩷ࠍ․⇣⊛ߦ㒖ኂߔࠆߎߣߪ ߎߎߦ⥋ࠆ߹ߢߩ⎇ⓥߢ᣿ࠄ߆ߦߐࠇߡ޿ߚ߇㧘 ಽሶ࡟ࡌ࡞ߢߩ㒖ኂᯏ᭴ࠍ⸃᣿ߔࠆߚ߼ߦ 㪪㫋㫌㪸㫉㫋 ᢎ᝼㩷 㩿㪦㫏㪽㫆㫉㪻㩷 㪬㫅㫀㫍㪼㫉㫊㫀㫋㫐㧘㪬㫅㫀㫋㪼㪻㩷 㪢㫀㫅㪾㪻㫆㫄㪀㩷ߩදജ

ࠍᓧߡ㪟㪠㪭㪄㪈㩷㪩㪫ߣߩⶄว૕ߩ㪯✢⚿᥏⸃ᨆߦ㑐

ߔࠆ⎇ⓥࠍㅴ߼ߚ㧚ߘߩ⚿ᨐ㧘㪟㪜㪧㪫⺃ዉ૕ߪ㪩㪫 ߩ⸅ᇦㇱ૏߆ࠄᢙචࠝࡦࠣࠬ࠻ࡠ࡯ࡓ㔌ࠇߚࠕ ࡠࠬ࠹࡝࠶ࠢㇱ૏ߦ⚿วߔࠆߎߣߦࠃߞߡ㪩㪫 ߩ

┙૕᭴ㅧߦᄌൻࠍ߽ߚࠄߒ㧘ㅒォ౮ࠍ㒖ኂߒߡ޿

ࠆߎߣ߇᣿ࠄ߆ߦߥߞߚ^㪈㪍㧕㧚㪟㪜㪧㪫 ߩ⊒⷗ᓟߦห

᭽ߩ㒖ኂᯏ᭴ߢ௛ߊᄙߊߩ 㪟㪠㪭㪄㪈․⇣⊛㪩㪫 㒖ኂ

೷߇ႎ๔ߐࠇ㧘ߎࠇࠄߩൻว‛ߪ㕖࠿ࠢ࡟ࠝࠪ࠼

♽ ㅒ ォ ౮ ㉂ ⚛ 㒖 ኂ ೷㩷 㩿㪥㪥㪩㪫㪠㫊㪑㩷 㪥㫆㫅㪄㪥㫌㪺㫃㪼㫆㫊㫀㪻㪼㩷 㪩㪼㫍㪼㫉㫊㪼㩷 㪫㫉㪸㫅㫊㪺㫉㫀㫇㫋㪸㫊㪼㩷 㪠㫅㪿㫀㪹㫀㫋㫆㫉㫊㪀㩷ߣ๭߫ࠇࠆࠃ߁ ߦߥߞߚ㧚ᓥߞߡ㪟㪜㪧㪫ߪޟ࠿ࠢ࡟ࠝࠪ࠼ߩൻቇ ߆ࠄ↢߹ࠇߚ㕖࠿ࠢ࡟ࠝࠪ࠼♽ㅒォ౮㉂⚛㒖ኂ

೷ޠߣ⸒߁ߎߣ߇ߢ߈ࠆ㧚੹ᐕߦߥߞߡ㪛㪼㩷㪚㫃㪼㫉㪺㫈 ᢎ᝼߇᛫࠙ࠗ࡞ࠬ೷ߦ㑐ߔࠆ࿁㘈㍳⊛ߥ✚⺑^㪈㪎㧕ࠍ

⊒⴫ߒߚ߇㧘ߘߩਛߢޟᝄࠅ㄰ߞߡߺࠆߣ 㪟㪜㪧㪫 ߇਎⇇ߢᦨೋߩ㪥㪥㪩㪫㪠ߢ޽ߞߚޠߣㅀᙬߒߡ޿ࠆ㧚㩷 㩷

㩷

㪈㪄㪋㧚࠿ࠢ࡟ࠝࠪ࠼ߩ࡝࠴࠙ࡓൻ෻ᔕߦ߅ߌࠆᣂ ዷ㐿㧦ࠪ࡝࡞ၮ߿ࠬ࠲࠾࡞ၮߩォ૏㩷 㩷

࡝࠴࠙ࡓൻߦ㑐ߒߡߪߎࠇ߹ߢㅀߴߡ߈ߚએ ᄖߦ߽ᄙߊߩ⎇ⓥࠍⴕߞߚ߇㧘ೋᦼߩ઀੐ߩ৻ߟ ߦ㪍㪄ࠢࡠࡠࡊ࡝ࡦ࠿ࠢ࡟ࠝࠪ࠼ߩ㪏૏࡝࠴࠙ࡓൻ ߇޽ߞߚ^㪈㪏㧕㧚ߎߩ⎇ⓥߩㆊ⒟ߢਇᕁ⼏ߥ⚿ᨐ߇ᓧ ࠄࠇߡ޿ߚߩߢ㧘ߘࠇࠍ⸃᣿ߔߴߊ⎇ⓥࠍౣ㐿ߒ ߚ㧚ਇᕁ⼏ߥ⚿ᨐߣߪᰴߩࠃ߁ߥߎߣߢ޽ࠆ㧚㩷

᳓㉄ၮࠍࠪ࡝࡞଻⼔ߒߚ㪍㪄ࠢࡠࡠࡊ࡝ࡦ࠿ࠢ

࡟ࠝࠪ࠼㪉㪉㩷㩿㪝㫀㪾㫌㫉㪼㩷㪈㪀㩷ߣ㪣㪛㪘߹ߚߪ㪣㪫㪤㪧ࠍ෻ᔕ ߐߖࠆߣ㧘㪏૏ߩߺ߇ല₸⦟ߊ࡝࠴࠙ࡓൻߐࠇࠆ㧚 ߎߩߎߣߪ㊀᳓⚛ൻታ㛎ߦࠃߞߡ߽⏕⹺ߒߚߒ㧘

࡛࠙⚛ࠍ෻ᔕߐߖࠆߣ㪏㪄࡛࡯࠼૕㩿㪉㪊㪀߇㜞෼₸ߢ ᓧࠄࠇࠆߩߢ㑆㆑޿ߪߥ޿㧚ߣߎࠈ߇࡝࠴࠙ࡓൻ ߩᓟߦ᳞㔚ሶ⹜⮎ߣߒߡ㪤㪼_㪊㪪㫀㪚㫃ࠍ෻ᔕߐߖࠆߣ㧘

੍ᦼߦ෻ߒߡ㪏૏⟎឵૕㪉㪋ߩ෼₸ߪૐߊ㪊㪇㪄㪋㪇㩼߽

ߩ㪉㪉߇࿁෼ߐࠇࠆ߁߃ߦ㧘࡝࠴࠙ࡓൻߐࠇߡ޿ߥ

޿ߪߕߩ㪉૏ߦࠪ࡝࡞ၮ߇ዉ౉ߐࠇߚ㪉㪌߿㪉㪍߇↢

ᚑߔࠆ㧚㩷

ߎࠇߪ৻૕ߥߗߛࠈ߁㧫㪣㪛㪘 ࠍ↪޿ࠆߣ㪍૏ߢ ߩ᳞ᩭ⟎឵෻ᔕ߽૬⊒ߒߡ↢ᚑ‛ߩಽᏓ߇ⶄ㔀 ߦߥࠆߩߢ㧘࡝࠴࠙ࡓൻ೷ߣߒߡ߆ߐ㜞޿㪣㪫㪤㪧 ࠍ↪޿ߚߣߎࠈ↢ᚑ‛ߪ㪉㪋㪄㪉㪍ߛߌߦߥߞߚ^㪈㪐㧕㧚㩷

න㔌ߒߚ㪏㪄ࠪ࡝࡞૕㩿㪉㪋㪀ࠍ 㪣㪫㪤㪧 ߢ࡝࠴࠙ࡓൻ ߔࠆߣ㧘⣕ࠪ࡝࡞ൻߐࠇߚ㪉㪉ߣߣ߽ߦ㪉㪃㪏㪄ࡆࠬࠪ

࡝࡞૕㩿㪉㪌㪀߅ࠃ߮㪉㪄ࠪ࡝࡞૕㩿㪉㪍㪀ߩ↢ᚑ߇⹺߼ࠄ ࠇߚ㧚ߎߩ෻ᔕ᧦ઙਅߢ㪉㪄ࠪ࡝࡞૕㩷 㩿㪉㪍㪀ߪ቟ቯߢ ᄌൻߒߥ޿ߎߣ߽⏕⹺ߒߚ㧚߹ߚ࡝࠴࠙ࡓൻߒߚ 㪉㪉ߦ╬ࡕ࡞ߩ㪉㪃㪏㪄ࡆࠬࠪ࡝࡞૕㩿㪉㪌㪀ࠍ෻ᔕߐߖࠆ ߣ㪎㪉㩼ߩ෼₸ߢ㪉㪄ࠪ࡝࡞૕㩿㪉㪍㪀߇↢ᚑߒߚ㧚ߎߩ෼

₸ߪ㪉㪉ߣ㪉㪌ࠍวࠊߖߚࡕ࡞ᢙߦၮߠ޿ߡ▚಴ߒ

ߚ߽ߩߥߩߢ㧘㪉㪍ߩ෼₸߇㪌㪇㩼ࠍ⿧߃ߚߣ޿߁੐

ታߪޟනߦ㪉㪌ߩ㪏૏⣕ࠪ࡝࡞ൻ߇⿠ߎߞߚߛߌߢ ߪߥߊ㧘㪉㪉ߦ߅޿ߡࠪ࡝࡞ၮߩ㪏૏߆ࠄ㪉૏߳ߩォ

૏߇⿠ߎߞߡ㪉㪍߇↢ᚑߒߚޠߎߣࠍ␜ໂߒߡ޿ࠆ㧚 ߎ ࠇ ࠄ ߩ ታ 㛎 ੐ ታ ߆ ࠄ ផ ቯ ߒ ߚ ෻ ᔕ ᯏ ᭴ ࠍ 㪪㪺㪿㪼㫄㪼㩷㪋ߦ␜ߒߚ㧚㩷

ᧄ෻ᔕߪ᳞㔚ሶ⹜⮎ߣߒߡ 㪤㪼_㪊㪪㫀㪚㫃ߩઍࠊࠅߦ 㪙㫌_㪊㪪㫅㪚㫃 ࠍ↪޿ߡ߽ㅴⴕߔࠆ㧚↢ᚑ‛ߢ޽ࠆ㪉㪄ࠬ

࠲࠾࡞૕ߪኈᤃߦࡂࡠࠥࡦൻࠍฃߌࠆߒ㧘ࡄ࡜ࠫ

࠙ࡓ⸅ᇦሽ࿷ਅߢߩࠞ࠶ࡊ࡝ࡦࠣ෻ᔕߦࠃߞߡ㩷

Table 4. Inhibitionof HIV-1 replication in MT-4 cells by highly active HEPT analogues.

EC₅₀ (PM)^a) CC₅₀ (PM)^b)

Me Ph

0.0062 >100

0.0049 30

a) Effective concentration of compound required to achieve 50% protection of MT-4 cells against the cytopathic effect of HIV-1.

R² O HN

N O

O X

R¹

HEPT

R¹ R²

Et Et

b) Cytotoxic concentrationof compound required to reduce the viability of mock-infected MT-4 cells by 50%.

c) Selectivity index: ratio of CC₅₀/EC₅₀.

SI^c)

>16100 6100 Et

i-Pr

i-Pr i-Pr Me

Me CH₂OH Me Me CH₂OH

0.0022 249 113000

0.0027 128 47400

0.006 43 72000

0.0042 186 44000

AZT 0.016 20 1250

7.0 740 106

X

SPh CH₂Ph

CH₂-(2,4-di-Me)Ph S-(2,4-di-Me)Ph CH₂-(2,4-di-Me)Ph SPh

S-(2,4-di-Me)Ph

㩷 㩷

Figure 1. Structures of compounds 22-26.

22

N N N N

Cl

23 N

N Cl

N N

I

25 X = SiMe₃ N

N Cl

N N

SiMe₃

Rf = 2,3,5-tris-O-(tert-butyldimethyl- silyl)-E-D-ribofuranosyl

Rf Rf

24

26 X = H N N N N

Cl

Rf X

SiMe₃ O

O O

O

Si Si

Si

2 8

6

㩷 㩷

ฦ⒳὇⚛⟎឵ၮࠍዉ౉ߔࠆ⋡⊛ߦ߽૶↪ߢ߈ࠆ ߩߢ㧘วᚑൻቇ⊛ߥଔ୯߇ᄢ޿ߦ㜞߹ߞߚ㧚߹ߚ 㪍૏ࠢࡠ࡞ේሶߩ᳞ᩭ⟎឵෻ᔕࠍ⚵ߺวࠊߖࠆߎ ߣ߽น⢻ߥߩߢ㧘ࠕ࠺ࡁࠪࡦ㧘ࠗࡁࠪࡦ㧘㪍㪄࠴ࠝ

ࠗࡁࠪࡦߥߤߩ㪉૏⟎឵૕ߩวᚑߦ߽ㆡ↪ߢ߈ࠆ㧚 ߎߎߢㅀߴߚ㪪㫀㪤㪼_㪊߿㪪㫅㪙㫌_㪊ߩォ૏෻ᔕߦߪ㧘ࡊ࡝

ࡦⅣ㪍૏ࠢࡠ࡞ේሶߩ㔚ሶ᳞ᒁᕈ߇㊀ⷐߢ޽ࠅ㧘

㪥㪃㪥㪄ࠫࡔ࠴࡞ࠕ࠺ࡁࠪࡦߩ႐วߦߪනߦ㪏૏߇⟎

឵ߐࠇࠆߛߌߢ޽ࠆ㧚㩷

㪪㪺㪿㪼㫄㪼㩷㪋ߩ෻ᔕ⚻〝ߦߪ㧘㪉૏߇࡝࠴࠙ࡓൻߐࠇ

ߚ㪏㪄ࠪ࡝࡞૕㪉㪋㪸 ߇฽߹ࠇߡ޿ࠆ㧚ߎߩ෻ᔕߢߪ 㪉㪋㪸 ߪ⋥ߜߦ㪉㪌ߦᄌ឵ߐࠇࠆ߇㧘߽ߞߣ߆ߐ㜞޿

ࠪ࡝࡞ၮࠍ㪉㪋ߩ㪏૏ߦዉ౉ߒߡ߅ߌ߫㪉૏߳ߩォ

૏ߪ⿠ߎࠄߕ㧘ߎࠇ߹ߢߦႎ๔଀ߩߥ޿ࡊ࡝ࡦߩ 㪉㪄࡝࠴ࠝ૕ࠍ⊒↢ߐߖߡ⒳ޘߩ᳞㔚ሶ⹜⮎ࠍ෻

ᔕߐߖࠆߎߣ߇น⢻ߦߥࠆ㧚⚕㕙ߩㇺวߢ⹦ߒ޿

⺑᣿ߪ⋭ߊ߇㧘Ⴎၮㇱ㪏૏ߦ࠻࡝ࠗ࠰ࡊࡠࡇ࡞ࠪ

࡝࡞ၮࠍ᦭ߔࠆ㪉㪎㩿㪝㫀㪾㫌㫉㪼㩷 㪉㪀ࠍ↪޿ߡ⋡⊛ࠍ㆐ߒ ߚ^㪉㪇㧕㧚♧ㇱಽࠍ㪉㪉㩿㪝㫀㪾㫌㫉㪼㩷㪈㪀ߣหߓ㫋㪼㫉㫋㪄ࡉ࠴࡞ࠫࡔ

࠴࡞ࠪ࡝࡞଻⼔ߦߔࠆߣ㧘࡝࠴࠙ࡓൻߩᲑ㓏ߢ

㫋㪼㫉㫋㪄ࡉ࠴࡞ࠫࡔ࠴࡞ࠪ࡝࡞ၮ߇Ⴎၮㇱ㪉૏ߦォ૏

ߒߚ೽↢ᚑ‛߇ᓧࠄࠇࠆ㧚ൻว‛㪉㪎ࠍ㪣㪫㪤㪧ߢ࡝

࠴࠙ࡓൻߒ㧘⒳ޘߩ᳞㔚ሶ⹜⮎ߣ෻ᔕߐߖࠆߣฦ

⒳㪉૏⟎឵૕㪉㪏߇↢ᚑߔࠆ㧚ൻว‛㪉㪏ࠍࡔ࠲ࡁ࡯

࡞ᕈࠕࡦࡕ࠾ࠕߢಣℂߔࠆߣ㧘৻Ბ㓏ߢ㪏૏ߩ⣕

ࠪ࡝࡞ൻߣ㪍૏ߢߩ᳞ᩭ⟎឵෻ᔕ߇⿠ߎࠆߩߢ㧘㪉

૏⟎឵ࠕ࠺ࡁࠪࡦ㪉㪐ߩᣂߚߥวᚑᣇᴺࠍ㐿⊒ߔ ࠆߎߣ߇ߢ߈ߚ㧚㩷

㩷 㩷 㩷 㩷

Scheme 4. Lithiation-mediated transfer of Me₃Si group from the C8 to C2-position of 22.

22 N N N N

Cl

Rf = 2,3,5-tris-O-(tert-butyldimethylsilyl)-E-D-ribofuranosyl Rf

LTMP (LDA)

N N N N

Cl

Rf

Li Me₃SiCl N

N Cl

N N

SiMe₃ Rf

24

N N Cl

N N

SiMe₃ Rf

Li 22a

22a 22

or LTMP (LDA)

24a 24

22a N

N N N

Cl

Rf Me₃Si

SiMe₃ 25

N N N N

Cl

Rf Li

SiMe₃ 26a

22a 24

㩷 㩷

㩷

Figure 2. Structures of compounds 27-29.

27 N N

Cl

N N

Si O

O O

O C

Rf = 2,3-O-isopropylidene-5-O-trityl-E-D-ribofuranosyl N

N Cl

N N

Si

Rf R

R = Me, Et, CH(OH)Me₂, CHO, CO₂Me 28

N N N N

NH2

Rf

R

29

㩷 㩷

㧞㧚ਇ㘻๺♧࠿ࠢ࡟ࠝࠪ࠼ߩวᚑൻቇ⊛೑↪ᴺ㩷

♧ㇱಽߦੑ㊀⚿วࠍ᦭ߔࠆਇ㘻๺♧࠿ࠢ࡟ࠝ

ࠪ࠼ߪ὇⚛㪄὇⚛⚿วᒻᚑߦᕸᅢߩၮ⾰ߣ⠨߃ࠄ ࠇࠆ߇㪃น⢻ߥ㪋ߟߩ࠲ࠗࡊߩ߁ߜߢ㪉㩾㪃㪊㩾㪄ਇ㘻๺

૕ࠍ㒰޿ߚ㪊⒳ߪ޿ߕࠇ߽ੑ㊀⚿ว߇ࠛࡁ࡯࡞

ࠛ࡯࠹࡞ࠍ᭴ᚑߔࠆߣ޿߁․⇣ߥ᭴ㅧࠍᜬߟ㧚ᓥ ߞߡߎࠇࠄߩਇ㘻๺♧࠿ࠢ࡟ࠝࠪ࠼ߦኻߔࠆ෻

ᔕߣߒߡႎ๔ߐࠇߡ޿ࠆ߽ߩߪ㧘᳞㔚ሶઃടߦࠃ ࠆࡋ࠹ࡠቭ⢻ၮߩዉ౉߿ធ⸅ㆶరߦ㒢ቯߐࠇߡ

޿ߚ㧚㩷

ࠛࡁ࡯࡞ࠛ࡯࠹࡞᭴ㅧࠍ᦭ߔࠆ㪊⒳㘃ߩਇ㘻๺

♧࠿ࠢ࡟ࠝࠪ࠼ࠍၮ⾰ߣߒߡ↪޿ࠆ὇⚛㪄὇⚛⚿

วᒻᚑ෻ᔕߦߟ޿ߡએਅߦㅀߴࠆ߇㧘಴⊒‛⾰ߢ

޽ࠆߎࠇࠄߩൻว‛ߩ⺞⵾ߦ㑐ߒߡ߽㧘࠮࡟࠾࠼

ࠕ࠾ࠝࡦߦࠃࠆࠕࡦࡅ࠼ࡠ࠿ࠢ࡟ࠝࠪ࠼ߩ㐿ⵚ

෻ᔕߣ㉄ൻ⊛ࠪࡦ⣕㔌ࠍ⚵ߺวࠊߖߚࠕࡊࡠ࡯

࠴ࠍ㐿⊒ߒߚ^㪉㪈㧕㧚㩷 㩷

㪉㪄㪈㧚㪈㵭㪃㪉㵭㪄ਇ㘻๺࠿ࠢ࡟ࠝࠪ࠼ࠍ↪޿ࠆࠕࡁࡑ࡯

૏ߢߩ὇⚛㪄὇⚛⚿วᒻᚑ෻ᔕ㩷

࠿ࠢ࡟ࠝࠪ࠼ߩൻቇࠍ⎇ⓥߒߡ޿ࠆ⠪ߦߣߞ ߡ㧘ࠕࡁࡑ࡯૏㩷 㩿㪸㫅㫆㫄㪼㫉㫀㪺㩷㫇㫆㫊㫀㫋㫀㫆㫅㪑㩷㪈㩾૏㪀ߣ޿߁⸒

⪲ߪ૗߆․೎ߥ㗀߈ࠍᜬߞߡ޿ࠆ㧚ߣᗵߓࠆߩߪ

⑳ߛߌߥߩߛࠈ߁߆㧫ዋߥߊߣ߽⑳ߦߣߞߡ㧘ࠕ ࡁࡑ࡯૏ߢߩ὇⚛㪄὇⚛⚿วᒻᚑ෻ᔕߪߣߡ߽㝯 ജ⊛ߥ⎇ⓥ࠹࡯ࡑߛߞߚ㧚ᩭ㉄Ⴎၮߣ♧ߩ❗ว෻

ᔕߢࠕࡁࡑ࡯૏ߦ὇⚛㎮ߩಽጘߒߚ࠿ࠢ࡟ࠝࠪ

࠼߇วᚑߐࠇߡ޿ߚ߇㧘࠿ࠢ࡟ࠝࠪ࠼࡟ࡌ࡞ߩ෻㩷㩷

Scheme 5. Synthesis of the 1'-branched nucleosides 32 from 30 (P = tert-butyldimethylsilyl).

30 O

PO PO

N NH O

O

31 O

PO PO

NH N O

O

Br O C

O

32 O

PO PO

NH N O

O Br R

R = CH₂CH=CH₂, CN, CH₂COPh, CH₂COMe, Me, Et, C CSiMe₃ NBS

pivalic acid/Et₃N Et₂O

1' 2'

nucleophile

㩷 㩷

ᔕߢࠕࡁࡑ࡯૏ߦ὇⚛⟎឵ၮࠍዉ౉ߒߚ଀ߪ⊝

ήߢ޽ߞߚ㧚㩷

ਇ㘻๺♧࠿ࠢ࡟ࠝࠪ࠼㪊㪇ߦǪ㕙ㆬᛯ⊛᳞㔚ሶ

ઃട෻ᔕࠍⴕ޿㧘ࠕࡁࡑ࡯૏ߦ⣕㔌ၮߣߒߡ௛ߊ ࡇࡃࡠࠗ࡞ࠝࠠࠪၮࠍዉ౉ߒߚ㩷 㩿㪪㪺㪿㪼㫄㪼㩷㪌㪀㧚ൻว

‛㪊㪈ߦኻߒߡ᦭ᯏࠕ࡞ࡒ࠾࠙ࡓ⹜⮎߹ߚߪ࡞ࠗ

ࠬ㉄ሽ࿷ਅߩ᦭ᯏࠪ࡝ࠦࡦ⹜⮎ࠍ෻ᔕߐߖࠆߎ ߣߦࠃߞߡ㧘ೋ߼ߡࠕࡁࡑ࡯૏ߢߩ὇⚛㪄὇⚛⚿

วᒻᚑ߇น⢻ߦߥߞߚ^㪉㪉㧕㧚ߎߩ᳞ᩭ⟎឵෻ᔕߪ㧘 㪉㩾૏⥇⚛ේሶߩ㓞ធၮ㑐ਈߦࠃߞߡቢోߦ┙૕଻

ᜬߢㅴⴕߔࠆ㧚㩷

ߎߩ⎇ⓥߩㆊ⒟ߢ㪊㪈ߩ㪉㩾૏⥇⚛ේሶࠍ㒰෰ߔߴ ߊ㪙㫌_㪊㪪㫅㪟ࠍ↪޿ࠆ࡜ࠫࠞ࡞ㆶరࠍⴕߞߚߣߎࠈ㧘 ࡇࡃࡠࠗ࡞ࠝࠠࠪၮߩ㪈㪃㪉㪄ォ૏ߦࠃࠅࠕࡁࡑ࡯૏

ߦ࡜ࠫࠞ࡞߇↢ᚑߔࠆߎߣࠍ⷗಴ߒߚ㧚߹ߚ㪊㪇߇ Ⴎၮߩሽ࿷ਅߢ㪧㪿㪪㪟 ߩ᳞ᩭઃടࠍฃߌࠆߎߣ߽

᣿ࠄ߆ߦߒ㧘ઃട‛߆ࠄࠕࡁࡔ࡝࠶ࠢ࡜ࠫࠞ࡞ࠍ

⊒↢ߐߖࠆ࡞࡯࠻߽㐿⊒ߒߚ㧚ߎࠇࠄߩࠕࡁࡔ࡝

࠶ࠢ࡜ࠫࠞ࡞ࠍ೑↪ߔࠆ὇⚛㪄὇⚛⚿วᒻᚑ෻ᔕ ߦߟ޿ߡ߽⎇ⓥߒߚ߇^{㪉㪊㧘㪉㪋㧕}ߎߎߢߪ⋭⇛ߐߖߡ

޿ߚߛߊ㧚㩷

㪪㪺㪿㪼㫄㪼㩷 㪌ߩ࡞࡯࠻ߢวᚑߒߚ㪊㪉߆ࠄ㪉㩾㪄࠺ࠝࠠ

ࠪ૕߿ࠕ࡜ࡆࡁࡈ࡜ࡁࠪ࡞૕߳⺃ዉߒߚ߇㧘࡝ࡏ ࡈ࡜ࡁࠪ࡞૕ࠍᓧࠆߎߣߪߢ߈ߥ߆ߞߚ㧚৻ᣇ㧘

㪪㪺㪿㪼㫄㪼㩷㪍ߩࠃ߁ߦ♧ㇱ㪈㵭㧘㪉㵭㪄ੑ㊀⚿วࠍࠛࡐࠠࠪ

ൻߒߡǩ㪄ࠛࡐࠠࠪ࠼ࠍ┙૕ㆬᛯ⊛ߦᓧࠆߎߣ߇ ߢ߈ࠇ߫㧘᦭ᯏࠕ࡞ࡒ࠾࠙ࡓ⹜⮎㩷 㩿㪘㫃㪩_㪊㪀ߣߩ෻ᔕ ߢ㐿Ⅳߒ㪉㩾㪄㪦㪄ࠕ࡞ࡒࡀ࡯࠻ਛ㑆૕߇↢ᚑߔࠆ㧚 ߎߩࠕ࡞ࡒࡀ࡯࠻߆ࠄ㪩߇ࠕࡁࡑ࡯૏ߦ᳞ᩭ᡹᠄

ߔࠆߣ㧘࡝ࡏࡈ࡜ࡁࠪ࡞૕߇วᚑߢ߈ࠆ㧚㩷

ࠛࡁ࡯࡞ࠛ࡯࠹࡞㧔߹ߚߪࠣ࡝ࠞ࡯࡞㧕᭴ㅧࠍ

᦭ߔࠆ㪈㵭㪃㪉㵭㪄ਇ㘻๺࠿ࠢ࡟ࠝࠪ࠼ߩࠛࡐࠠࠪൻߦ ߪ㪃ㆊ㉄߿ࡊࡠ࠻ࡦᕈߩṁᇦߪ૶↪ߢ߈ߥ޿㧚ࠕ࠮

࠻ࡦṁᇦਛߢࠫࡔ࠴࡞ࠫࠝࠠࠪ࡜ࡦߦࠃࠆ㪈㵭㪃㪉㵭㪄 ਇ㘻๺࠙࡝ࠫࡦߩࠛࡐࠠࠪൻߦ߅ߌࠆ㕙ㆬᛯᕈ ࠍ⺞ߴߚߣߎࠈ㧘᳓㉄ၮࠍⅣ⁁ࠪ࡝࡞଻⼔ߒߚ㪊㪊㩷 㩿㪝㫀㪾㫌㫉㪼㩷 㪊㪀ߩ႐วߦǩ㪄ࠛࡐࠠࠪ࠼ߩߺ߇↢ᚑߔࠆ ߎߣࠍ⷗಴ߒߚ㧚ฦ⒳ߩ㪘㫃㪩_㪊ࠍ෻ᔕߐߖߡ⋡⊛‛

ߢ޽ࠆ㪊㪋ࠍวᚑߢ߈ߚ߇㧘૗᡿߆ 㪘㫃㪧㪿_㪊ߣߩ෻ᔕ એᄖߢߪᏱߦǩ㪄ࠕࡁࡑ࡯ߩ೽↢߇ⷰኤߐࠇߚ㧚 ߎߩ੐ታߪవߦ㪪㪺㪿㪼㫄㪼㩷 㪍ߢផቯߒߚ㪉㩾㪄㪦㪄ࠕ࡞ࡒ ࡀ࡯࠻ਛ㑆૕ߩႮၮㇱ㪉૏ࠞ࡞ࡏ࠾࡞ၮߦ㧘߽߁㪈 ಽሶߩ㪘㫃㪩_㪊߇㈩૏ߒߚ㪊㪌㩷 㩿㪝㫀㪾㫌㫉㪼㩷 㪊㪀߇ታ㓙ߩਛ㑆

૕ߢ޽ࠆߎߣࠍ␜ໂߒߡ޿ࠆ㧚Ⴎၮㇱಽߦ㈩૏ߒ ߚࠕ࡞ࡒࡀ࡯࠻ߩ㪩߇෻ᔕߔࠆߣ㧘㪥㪈㪄㪚㪈㩾⚿ว࿁

ࠅߩࠦࡦࡎࡔ࡯࡚ࠪࡦߦଐሽߒߡ޿ߕࠇߩࠕࡁ ࡑ࡯ࠍ߽ਈ߃ᓧࠆ߆ࠄߢ޽ࠆ㧔߆ߐ㜞޿ 㪘㫃㪧㪿_㪊ߩ ႐วߦߪႮၮㇱߦ㈩૏ߢ߈ߥ޿ߣ⠨߃ࠄࠇࠆ㧕㧚㩷

ߘߎߢ㪥㪊૏ߦ଻⼔ၮࠍዉ౉ߒ㧘ߘߩ┙૕㓚ኂߦ

ࠃߞߡ 㪘㫃㪩_㪊ߩ㪉૏ࠞ࡞ࡏ࠾࡞ၮ߳ߩ㈩૏ࠍ㒐ߋߎ ߣࠍ⠨߃ߚ㧚ࡌࡦ࠱ࠗ࡞ၮ߿ࡌࡦࠫ࡞ࠝࠠࠪࡔ࠴

࡞ၮߢ଻⼔ߒߚ㪊㪍㩷 㩿㪝㫀㪾㫌㫉㪼㩷 㪊㪀ࠍ↪޿ߡࠫࡔ࠴࡞ࠫ

ࠝࠠࠪ࡜ࡦߦᒁ߈⛯߈ 㪘㫃㪩_㪊ࠍ෻ᔕߐߖߚߣߎࠈ㧘

෻ᔕߩ┙૕ൻቇߪ⷗੐ߦ೙ᓮߐࠇߡኻᔕߔࠆǪ㪄 ࠕࡁࡑ࡯ߩߺ߇↢ᚑߒߡ߈ߚ^㪉㪌㧕㧚ᧄ෻ᔕߪࠕ࠺ࡁ

ࠪࡦ⺃ዉ૕ߩวᚑߦ߽ㆡ↪ߢ߈ߚ㧚㩷

㩷 㩷

Scheme 6. Synthetic plan for 1'-branched uridine derivatives (P = protecting group).

O

PO PO

NH N O

O

O

AlR₃

O

PO

PO N

N OAlR₂

O Al R

R R + O

O

PO PO

NH N O

O

OH R

2'-O-aluminate 1',2'-D-epoxide

㩷 㩷

33 P = H O

O O

N O N

O

Figure 3. Structures of 33-36.

Si

34 O

O O Si

NH N O

O

OH R

R = Me, Et, i-Bu, CH=CH₂, C CH, Ph

35 O

O O

N N O

OAlR₂ Si

+

OAlR₃ Al + R

R R

P

36 P = Bz or CH₂OBn

㩷 㩷

O

Figure 4. Structures of compounds 37-41 (P = silyl protecting group, Piv = pivaloyl).

38 O

OP PO

N N N N

NHPiv

PO O

O

OP

N N N N

NHPiv

Y OH X

39 X = CH₂OP, Y = Me

37 40 X = Me, Y = CH₂OP

N N N N

NHPiv

OP

O

OP

N N N N

NH₂

BzO 41 PO

3' 4'

㩷 㩷

㪉㪄㪉㧚㪊㩾㪃㪋㩾㪄ਇ㘻๺࠿ࠢ࡟ࠝࠪ࠼߆ࠄ㪋㩾૏⟎឵૕߳㩷 ೨ㅀߩ࠙࡝ࠫࡦ㪈㵭㪃㪉㵭㪄ࠛࡐࠠࠪ࠼ߣ㪘㫃㪩_㪊ߣߩ෻

ᔕߢߪ㧘↢ᚑ‛ߦ߅޿ߡࠛࡐࠠࠪ࠼↱᧪ߩ᳓㉄ၮ ߣዉ౉ߐࠇߚ㪩߇ࠪࡦߩ㑐ଥߦߥࠆ㧚ߎߩࠃ߁ߥ

┙૕ൻቇߦߥࠆߎߣߪࠣ࡝ࠞ࡯࡞ࠛࡐࠠࠪ࠼ߩ

෻ᔕߢႎ๔ߐࠇߡ޿ߚ^㪉㪍㧕㧚ࠫࡔ࠴࡞ࠫࠝࠠࠪ࡜ࡦ ߦࠃߞߡ㪊㩾㪃㪋㩾㪄ਇ㘻๺ࠕ࠺ࡁࠪࡦ㩿㪊㪎㧘㪝㫀㪾㫌㫉㪼㩷 㪋㪀߆ ࠄ↢ᚑߔࠆࠛࡐࠠࠪ࠼㪊㪏ߣ 㪘㫃㪤㪼_㪊ߣߩ෻ᔕࠍ⹦⚦

ߦᬌ⸛ߒߚ⚿ᨐ㧘㐿Ⅳ෻ᔕߩ┙૕ൻቇ㧔ࠪࡦ߹ߚ ߪࠕࡦ࠴㧕߇ṁᇦ߅ࠃ᷷߮ᐲ㧘㪘㫃㪤㪼_㪊ߩᒰ㊂ᢙ߅ ࠃ߮Ớᐲ㧘ࠪ࡝࡞଻⼔ၮߩ㆑޿ߥߤߦࠃߞߡᓇ㗀

ࠍฃߌࠆߎߣࠍ᣿ࠄ߆ߦߒߚ㧚ߎߩ⚿ᨐࠍၮߦ෻

ᔕ᧦ઙࠍ⸳ቯߔࠆߎߣߢ㧘ᄤὼဳߢ޽ࠆࠕࡦ࠴㐿

Ⅳ૕㩿㪊㪐㪀ࠍല₸ࠃߊ㩿㪊㪐㪆㪋㪇㩷㪔㩷㪌㪇㪆㪈㪀วᚑߔࠆߎߣ߇ น⢻ߦߥߞߚ㧚߹ߚࠕ࠺࠾ࡦႮၮߩሽ࿷߇ᧄ෻ᔕ ߩ┙૕ൻቇߦᄢ߈ߥᓇ㗀ࠍ෸߷ߔ࿃ሶߢ޽ࠆߎ ߣࠍ␜ߔ෻ᔕᯏ᭴ࠍឭ໒ߒ㧘ታ㛎⊛ߦ⸽᣿ߔࠆߎ ߣ߽ߢ߈ߚ^㪉㪎㧕㧚㩷

߹ߚ৻ᣇߢߪ㧘㪊㪎ߦኻߔࠆ᳞㔚ሶઃട෻ᔕࠍ⚻

↱ ߒ ߡ 㧘 ᛫ ↢ ‛ ⾰ ߢ ޽ ࠆ ࠦ ࡞ ࠫ ࠮ ࡇ ࡦ㩷 㩿㪺㫆㫉㪻㫐㪺㪼㫇㫀㫅㪑㩷 㪊㩾㪄㪻㪼㫆㫏㫐㪸㪻㪼㫅㫆㫊㫀㫅㪼㪀ߩ㪋㩾૏ߦ⣕㔌ၮߣ ߒߡ௛ߊࡌࡦ࠱ࠗ࡞ࠝࠠࠪၮࠍዉ౉ߒߚ㩷 㩿㪋㪈㧘

㪝㫀㪾㫌㫉㪼㩷㪋㪀㧚ൻว‛㪋㪈ߦ㪪㫅㪚㫃_㪋ߩሽ࿷ਅߢ᦭ᯏࠪ࡝ࠦ

ࡦ⹜⮎ࠍ෻ᔕߐߖࠆߣ㧘㪋㩾૏ߦࠕ࡝࡞ၮ߿ࠪࠕࡁ ၮࠍዉ౉ߢ߈ࠆ^㪉㪏㪀㧚ൻว‛㪋㪈߅ࠃ߮ߘߩ㪋㩾㪄ࠛࡇ ࡑ࡯ߣ 㪘㫃㪤㪼_㪊ߣߩ෻ᔕߢߪ㧘ࡌࡦ࠱ࠗ࡞ࠝࠠࠪၮ ߩ⣕㔌ߦࠃߞߡ↢ᚑߔࠆࠕ࡞ࡒࡀ࡯࠻ߣ♧ㇱࠝ

ࠠ࠰࠾࠙ࡓࠗࠝࡦߣ߇㕖ᭂᕈṁᇦਛߢᒝ࿕ߥࠗ

ࠝ ࡦ ࡍ ࠕ ࡯ ࠍ ᒻ ᚑ ߔ ࠆ ߚ ߼ ߦ 㧘 ෻ ᔕ ߪ 㪪_㪥㫀㩷 㩿㫊㫌㪹㫊㫋㫀㫋㫌㫋㫀㫆㫅㩷㫅㫌㪺㫃㪼㫆㫇㪿㫀㫃㫀㪺㩷㫀㫅㫋㪼㫉㫅㪸㫃㪀ᯏ᭴ߢㅴⴕߒ㧘ࡔ

࠴࡞ၮ߇┙૕଻ᜬߢዉ౉ߐࠇࠆߎߣࠍ᣿ࠄ߆ߦ ߒߚ^㪉㪐㧕㧚㩷

㩷

㪉㪄㪊㧚㪋㩾㪃㪌㩾㪄ਇ㘻๺૕߆ࠄ㪋㩾૏⟎឵࠴ࡒࠫࡦ⺃ዉ૕ߩ วᚑ㧦ᣂⷙ᛫㪟㪠㪭࠿ࠢ࡟ࠝࠪ࠼ߩ⊒⷗㩷

᛫㪟㪠㪭ᵴᕈࠍ᦭ߔࠆᄙߊߩࠢ࡟ࠝࠪ࠼⺃ዉ૕ߪ㧘

㪊㩾૏᳓㉄ၮࠍᜬߞߡ޿ߥ޿㧚ᓥߞߡ࠻࡝࡝ࡦ㉄ࠍ

⚻↱ߒߡࡊࡠ࠙ࠗ࡞ࠬ㪛㪥㪘ߩ㪊㩾㪄ᧃ┵ߦขࠅㄟ߹

ࠇߚᓟߦ㧘ߘߩ㎮િ㐳ࠍ஗ᱛߔࠆ㧚Ყセ⊛ᦨㄭߦ

ߥߞߡ㧘㪋㩾㪄ࠕࠫ࠼࠴ࡒࠫࡦߩࠃ߁ߦ㪊㩾૏᳓㉄ၮࠍ

ᜬߟߦ߽߆߆ࠊࠄߕᒝ޿᛫ 㪟㪠㪭 ᵴᕈࠍ␜ߔ㪋㩾㪄⟎

឵࠿ࠢ࡟ࠝࠪ࠼߇ႎ๔ߐࠇߡᵈ⋡ࠍᶎ߮ߡ޿ࠆ^㪊㪇㧕㧚 㪋㩾㪄ࠕࠫ࠼࠴ࡒࠫࡦߩ᭴ㅧᵴᕈ⋧㑐ߦ㑐ߔࠆ⎇ⓥ

ߢ㧘㪊㩾૏᳓㉄ၮࠍ㒰෰ߒߚࠫࡅ࠼ࡠ૕߅ࠃ߮ߘߩ 㪉㩾㪃㪊㩾૏ߦੑ㊀⚿วࠍᜬߟ⺃ዉ૕ߢߪᵴᕈ߇ᶖᄬߔ ࠆߣႎ๔ߐࠇߡ޿ࠆ^㪊㪈㧕㧚ߘࠇ᡿㧘߽ߞ߬ࠄ㪊㩾૏ߦ

᳓㉄ၮࠍᜬߟ㪉㩾㪄࠺ࠝࠠࠪ࠿ࠢ࡟ࠝࠪ࠼ߩ㪋㩾㪄⟎឵

૕߇วᚑߐࠇߡ޿ߚ㧚㩷

ࠫࡔ࠴࡞ࠫࠝࠠࠪ࡜ࡦߣ㪋㩾㪃㪌㩾㪄ਇ㘻๺࠴ࡒࡦ࠿

ࠢ࡟ࠝࠪ࠼㪋㪉ߩ෻ᔕߢߪ㧘ࠛࡐࠠࠪ࠼㪋㪊߇ᓧࠄࠇ ߚ㩷 㩿㪝㫀㪾㫌㫉㪼㩷 㪌㪀㧚ൻว‛㪋㪊ߣ᦭ᯏࠪ࡝ࠦࡦ⹜⮎ߣߩ

෻ᔕࠍ 㪪㫅㪚㫃_㪋ሽ࿷ਅߢⴕ޿㧘ฦ⒳ߩ㪋㩾㪄⟎឵૕㪋㪋ࠍ วᚑߒߚ㧚࠙࡝ࠫࡦ⺃ዉ૕ࠍၮ⾰ߦ↪޿ߚ෻ᔕߩ

⚿ᨐ^㪊㪉㧕߆ࠄ㧘ᧄ෻ᔕߩਛ㑆૕ߪႮ⚛ේሶ߇ᡆࠕࠠ

ࠪࡖ࡞⚿วࠍขࠆ㪋㩾㪄ࠢࡠࡠ૕㪋㪌ߢ޽ࠈ߁ߣផቯ ߒߡ޿ࠆ㧚㩷

৻ᣇࠛࡐࠠࠪ࠼㪋㪊ߣ 㪘㫃㪤㪼_㪊ߣߩ෻ᔕߢߪ㕖ᄤὼ

ဳߩ㪋㩾㪄ࡔ࠴࡞૕㪋㪍߇ਥ↢ᚑ‛ߢ޽ߞߚ㩷 㩿㪪㪺㪿㪼㫄㪼㩷 㪎㪀㧚㩷

ߎࠇߪޔ㐿Ⅳߒߚࠝࠠ࠰࠾࠙ࡓਛ㑆૕ߦ߅޿ߡ

㪊㩾㪄㪦㪧 ߣ㪌㩾㪄㪦㪄ࠕ࡞ࡒࡀ࡯࠻ߩ┙૕෻⊒ࠍㆱߌࠆ

ߎߣ߇ߢ߈ࠆฝ஥ߩࠦࡦࡎࡔ࡯࡚ࠪࡦ߇ఝ૏ߦ ߥࠆߚ߼ߢ޽ࠆߣផቯߒߚ㧚ߘߎߢ㪊㩾㪄㪦㪧ߩ┙૕

㈩⟎ࠍ෻ォߐߖߚ㪋㩾㪃㪌㩾㪄ਇ㘻๺⺃ዉ૕߆ࠄࠛࡐࠠ

ࠪ࠼㪋㪎㩷㩿㪝㫀㪾㫌㫉㪼㩷㪍㪀ࠍ⺞⵾ߒ㪘㫃㪤㪼_㪊ߣ෻ᔕߐߖߚߣߎ ࠈ㧘㪋㪏߇න৻ߩ↢ᚑ‛ߣߒߡᓧࠄࠇߚ㧚ઁߩ᦭ᯏ ࠕ࡞ࡒ࠾࠙ࡓ⹜⮎ࠍ↪޿ߡࡆ࠾࡞૕㩷 㩿㪋㪐㪀߿ࠛ࠴

࠾࡞૕㩷 㩿㪌㪇㪀߽วᚑߒߚ߇㪃ߎࠇࠄߩൻว‛ߩ㪊㩾૏

᳓㉄ၮࠍ෻ォߐߖߡ㪋㩾㪄⟎឵࠴ࡒࠫࡦ߳⺃ዉߔࠆ

⹜ߺߪᄬᢌߦ⚳ࠊߞߚ㧚଀߃߫㧘㪊㩾㪄㪦㪄ࠬ࡞ࡎࡀ࡯

࠻ߣ 㪚㫊㪦㪘㪺 ࠍ↪޿ߚ႐วߩਥߚࠆ෻ᔕ⚻〝ߪ⣕

㔌෻ᔕߢ޽ࠅ㧘᛫㪟㪠㪭⮎ߢ޽ࠆ㫊㫋㪸㫍㫌㪻㫀㫅㪼㩷㩿㪻㪋㪫㪑㩷㪌㪈㪀 ߩ㪋㩾㪄⟎឵૕㪌㪉㪄㪌㪋߇ᓧࠄࠇߚ㧚㩷

ߎߩ⎇ⓥߩᢙᐕ೨ߦࡅࡘ࡯ࡑࡦࠨࠗࠛࡦࠬᝄ

⥝⽷࿅࿖㓙⎇ⓥࠣ࡜ࡦ࠻੐ᬺ߆ࠄߩេഥࠍ޿ߚ ߛ޿ߡ 㪚㪿㪼㫅㪾 ᢎ᝼㩷 㩿㪰㪸㫃㪼㩷 㪬㫅㫀㫍㪼㫉㫊㫀㫋㫐㧘㪬㪪㪘㪀㧘㚍႐ ᢎ᝼㧔㣮ఽፉᄢቇ㧕㧘ߣᚒޘߩ㪊ᯏ㑐ߩ౒หߢޟࠛ

ࠗ࠭ක⮎ຠ╬㐿⊒⎇ⓥޠ߇ࠬ࠲࡯࠻ߒߡ޿ߚ㧚వ ߦㅀߴߚࠃ߁ߦ㧘㪋㩾㪄ࠕࠫ࠼࠴ࡒࠫࡦߩ႐วߦߪ

㪉㩾㪃㪊㩾૏ߦੑ㊀⚿วࠍዉ౉ߔࠆߣ᛫㪟㪠㪭ᵴᕈߪᶖᄬ

ߔࠆߣႎ๔ߐࠇߡ޿ߚ߇㧘ߣ߽߆ߊ㪌㪉㪄㪌㪋ߩᵴᕈ ࠍ⹏ଔߒߡߺࠆߎߣߦߒߚ㧚㛳޿ߚߎߣߦ㧘㪋㩾㪄 ࠕࠫ࠼૕ߩ႐วߣߪ⇣ߥࠅ㧘ੑ㊀⚿วࠍ᦭ߔࠆ㪋㩾㪄

ࠛ࠴࠾࡞㪄㪻㪋㪫㩷㩿㪌㪋㪀ߦᲣൻว‛ߢ޽ࠆ㪻㪋㪫㩷㩿㪌㪈㪀ߩ⚂

㪈㪇୚ߩᵴᕈ߇⹺߼ࠄࠇߚ^㪊㪊㧕㧚ᧄൻว‛ߪ⒳ޘߩ⚦

⢩ߦኻߔࠆᲥᕈ߇㪻㪋㪫ࠃࠅ߽ૐ޿㧘㪻㪋㪫ߣߪ⇣ߥ ࠅࡒ࠻ࠦࡦ࠼࡝ࠕߩ 㪛㪥㪘 วᚑࠍ㒖ኂߒߥ޿㧘ࠠ

࠽࡯࠯ߩ⦟޿ၮ⾰ߦߥࠆ㧘㉂⚛ߦࠃࠆട࡝ࡦ㉄ಽ

⸃ߦᛶ᛫ߔࠆ㧘ㅒォ౮㉂⚛ߦ㪢㪈㪇㪊㪥ߩᄌ⇣߇⿠ߎ ߞߚᄙ೷⠴ᕈ㪟㪠㪭ࡒࡘ࡯࠲ࡦ࠻ߦ߽Ⴧᱺ㒖ኂᵴᕈ ࠍ␜ߔ㧘ߥߤߩ․ᓽࠍᜬߟ^㪊㪋㧕㧚ߘߩᓟ㧘㘃✼૕ߩ วᚑ^㪊㪌㧕߿ᄢ㊂วᚑࠍⷞ㊁ߦ౉ࠇߚ㪌㪋ߩᡷ⦟วᚑᴺ ߩ㐿⊒^㪊㪍㧕߽ⴕߞߚ㧚ᧄൻว‛ߪࡈࠚࠬ࠹ࠖ࠽ࡆ࡞㩷 㩿㪝㪼㫊㫋㫀㫅㪸㫍㫀㫉㪀ߣ⸒߁৻⥸ฬߢ⥃ᐥ⹜㛎ਛߢ޽ࠆ㧚㩷

⚿ ⺆

⮎ຠ⵾ㅧൻቇᢎቶߣ޿߁ฬ೨ߩߚ߼߆㧘ᵴᕈൻ ว‛ࠍ᳞߼ߡวᚑࠍߒߡ޿ࠆࠃ߁ߦ⷗ࠄࠇࠆࠃ ߁ߛ߇㧘޽ߊ߹ߢ߽ޟ߅߽ߒࠈ޿⎇ⓥޠࠍว⸒⪲

ߦ⎇ⓥࠍㅴ߼ߡ᧪ߚ㧚ޟߥߗ㧫ޠ߇⸃ߌߚᤨߣ㧘 ߘߩ⎇ⓥ߇⹏ଔߐࠇߚᤨߩ༑߮ߪ૗‛ߦ߽ઍ߃ 㔍޿㧚⎇ⓥߩ㝷ജߢ޽ࠈ߁㧚ߎߩ⺰ᢥߢขࠅ਄ߍ ߚ㪟㪜㪧㪫߿ࡈࠚࠬ࠹ࠖ࠽ࡆ࡞ߩࠃ߁ߥ࡙࠾࡯ࠢߥ

૞↪ࠍᜬߟ᛫࠙ࠗ࡞ࠬൻว‛ߦㆣㆄߢ߈ߚߩ߽㧘㩷

Figure 5. Structures of compounds 42-45 (P = tert-butyldimethylsilyl).

O

PO 42

O

PO 43

O O

PO 44

Cl Cl₃SnO O

PO

45 R

HO

R = allyl, CN, N₃ NH

N

Me O

O

NH N

Me O

O

NH N

Me O

O NH

N

Me O

O

4' 5'

㩷 㩷

Scheme 7. Reaction between 43 and AlMe₃ forming 46 (P = tert-butyldimethylsilyl).

O

PO

46 O

PO Me NH

N

Me O

O

NH N

Me O

O

Me₃AlO HO

+

O

PO

NH N

Me O

+ O O

Al

Me Me

Me

㩷 㩷

Figure 6. Structures of compounds 47-54 (P = tert-butyldimethylsilyl).

47 O

NH N

Me O

O OP

O O

NH N

Me O

O OP

R HO

48 R = Me 49 R = CH=CH₂ 50 R = C CH

O

NH N

Me O

O R

HO

52 R = Me 53 R = CH=CH₂ 54 R = C CH 51 R = H

㩷 㩷

㩷

ᣢ⍮ߩᵴᕈൻว‛ࠍᗧ⼂ߔࠆߎߣߥߊ⥄↱ᅁ

᡼ߦ⎇ⓥࠍᭉߒࠎߛߎߣ߇ᐘ޿ߒߡ޿ࠆࠃ߁ߦ ᕁ߁㧚ޟߪߓ߼ߦޠߩਛߢㅀߴߚࠃ߁ߦ㧘ߔߴߡ ߩ⎇ⓥߦ⸅ࠇࠆߎߣ߇ߢ߈ߥ߆ߞߚߩ߇ᱷᔨߢ

޽ࠅ㧘ᄙߊߩතᬺ↢ߦኻߒߡ↳ߒ⸶ߥߊᕁ߁㧚৻

✜ߦ⎇ⓥ↢ᵴࠍㅍߞߚතᬺ↢ߩᄙߊߪ੹߇௛߈

⋓ࠅߢ㧘␠ળߩਛၷߤߎࠈߣߒߡᄢ޿ߦᵴべߒߡ

޿ࠆ㧚੹ᓟߩ⋉ޘߩᵴべࠍ␨ᔨߔࠆߣหᤨߦ㧘ታ 㛎ߦᖱᾲࠍᵈ޿ߢㆊߏߒߚ㕍ᤐࠍ޿ߟ߹ߢ߽ᔓ ࠇߕߦ޿ߡߊࠇࠆࠃ߁ߦ㗿ߞߡ޿ࠆ㧚㩷

ᢥ ₂

㪈㪀㩷 㪪㪸㫅㫋㫀㪃㩷㪛㪅㩷㪭㪅㩷㪸㫅㪻㩷㪙㫉㪼㫎㪼㫉㪃㩷㪚㪅㩷㪝㪅㩷㪑㩷㪤㫆㪻㪼㫃㩷㫊㫋㫌㪻㫀㪼㫊㩷㫆㪽㩷 㫋㪿㫐㫄㫀㪻㫐㫃㪸㫋㪼㩷 㫊㫐㫅㫋㪿㪼㫋㪸㫊㪼㪅㩷 㪥㪼㫀㪾㪿㪹㫆㫉㫀㫅㪾㪄㪾㫉㫆㫌㫇㩷 㪽㪸㪺㫀㫃㫀㫋㪸㫋㫀㫆㫅㩷㫆㪽㩷 㪼㫃㪼㪺㫋㫉㫆㫇㪿㫀㫃㫀㪺㩷㫊㫌㪹㫊㫋㫀㫋㫌㫋㫀㫆㫅㩷㫉㪼㪸㪺㫋㫀㫆㫅㫊㩷 㫆㪽㩷 㫌㫉㪸㪺㫀㫃㩷 㪽㫌㫉㪸㫅㫆㫊㫀㪻㪼㫊㪅㪃㩷 㪡㪅㩷 㪘㫄㪅㩷 㪚㪿㪼㫄㪅㩷 㪪㫆㪺㪅㪃㩷 㪐㪇㪃㩷 㪍㪉㪊㪍㩷 㩿㪈㪐㪍㪏㪀㪅㩷 㩷

㪉㪀㩷 㪫㪸㫅㪸㫂㪸㪃㩷 㪟㪅㪃㩷 㪥㪸㫊㫌㪃㩷 㪠㪅㩷 㪸㫅㪻㩷 㪤㫀㫐㪸㫊㪸㫂㪸㪃㩷 㪫㪅㩷 㪑㩷 㪩㪼㪾㫀㫆㫊㫇㪼㪺㫀㪽㫀㪺㩷 㪚㪄㪸㫃㫂㫐㫃㪸㫋㫀㫆㫅㩷 㫆㪽㩷 㫌㫉㫀㪻㫀㫅㪼㪅㩷 㪘㩷 㫊㫀㫄㫇㫃㪼㩷 㫉㫆㫌㫋㪼㩷㫋㫆㩷 㪍㪄㪸㫃㫂㫐㫃㫌㫉㫀㪻㫀㫅㪼㫊㪅㪃㩷㪫㪼㫋㫉㪸㪿㪼㪻㫉㫆㫅㩷㪣㪼㫋㫋㪅㪃㩷㪉㪇㪃㩷 㪋㪎㪌㪌㩷㩿㪈㪐㪎㪐㪀㪅㩷 㩷

㪊㪀㩷 㪪㪼㪼㪹㪸㪺㪿㪃㩷㪛㪅㩷㪸㫅㪻㩷㪜㫅㪻㪼㫉㫊㪃㩷㪛㪅㩷㪑㩷㪬㫄㫇㫆㫃㫌㫅㪾㩷㫆㪽㩷㪸㫄㫀㫅㪼㩷

㫉㪼㪸㪺㫋㫀㫍㫀㫋㫐㪅㩷㪥㫌㪺㫃㪼㫆㫇㪿㫀㫃㫀㪺㩷ǩ㪄㩿㫊㪼㪺㫆㫅㪻㪸㫉㫐㩷㪸㫄㫀㫅㫆㪀㩷㪄㩷 㪸㫃㫂㫐㫃㪸㫋㫀㫆㫅㩷 㫍㫀㪸㩷 㫄㪼㫋㪸㫃㪸㫋㪼㪻㩷 㫅㫀㫋㫉㫆㫊㪸㫄㫀㫅㪼㫊㪅㪃㩷 㪘㫅㪾㪼㫎㪅㩷 㪚㪿㪼㫄㪅㩷㪠㫅㫋㪅㩷㪜㪻㪅㩷㪜㫅㪾㫃㪅㪃㩷㪈㪋㪃㩷㪈㪌㩷㩿㪈㪐㪎㪌㪀㪅㩷 㩷 㩷

㪋㪀㩷 㪫㪸㫅㪸㫂㪸㪃㩷 㪟㪅㪃㩷 㪟㪸㫐㪸㫂㪸㫎㪸㪃㩷 㪟㪅㪃㩷 㪪㪿㫀㪹㪸㫋㪸㪃㩷 㪪㪅㩷 㪼㫋㩷 㪸㫃㪅㩷 㪑㩷 㪪㫐㫅㫋㪿㪼㫊㫀㫊㩷 㫆㪽㩷 㪍㪄㫄㪼㫋㪿㫐㫃㫌㫉㫀㪻㫀㫅㪼㩷 㫍㫀㪸㩷 㫇㪸㫃㫃㪸㪻㫀㫌㫄㪄㩷 㪺㪸㫋㪸㫃㫐㫑㪼㪻㩷㪺㫉㫆㫊㫊㪄㪺㫆㫌㫇㫃㫀㫅㪾㩷㪹㪼㫋㫎㪼㪼㫅㩷㪸㩷㪍㪄㫀㫆㪻㫆㫌㫉㫀㪻㫀㫅㪼㩷 㪻㪼㫉㫀㫍㪸㫋㫀㫍㪼㩷 㪸㫅㪻㩷 㫋㪼㫋㫉㪸㫄㪼㫋㪿㫐㫃㫊㫋㪸㫅㫅㪸㫅㪼㪅㪃㩷 㪥㫌㪺㫃㪼㫆㫊㫀㪻㪼㫊㩷 㪥㫌㪺㫃㪼㫆㫋㫀㪻㪼㫊㪃㩷㪈㪈㪃㩷㪊㪈㪐㩷㩿㪈㪐㪐㪉㪀㪅㩷 㩷

㪌㪀㩷 㩿㪸㪀㩷㪫㪸㫅㪸㫂㪸㪃㩷㪟㪅㪃㩷㪟㪸㫐㪸㫂㪸㫎㪸㪃㩷㪟㪅㩷㪸㫅㪻㩷㪤㫀㫐㪸㫊㪸㫂㪸㪃㩷㪫㪅㩷㪑㩷 㪪㫐㫅㫋㪿㪼㫊㫀㫊㩷 㫆㪽㩷 㪍㪄㪸㫉㫆㫐㫃㫌㫉㫀㪻㫀㫅㪼㩷 㪽㫉㫆㫄㩷 㫌㫉㫀㪻㫀㫅㪼㩷 㫍㫀㪸㩷 㫉㪼㪾㫀㫆㫊㫇㪼㪺㫀㪽㫀㪺㩷㫃㫀㫋㪿㫀㪸㫋㫀㫆㫅㪅㪃㩷㪚㪿㪼㫄㪅㩷㪧㪿㪸㫉㫄㪅㩷㪙㫌㫃㫃㪅㪃㩷㪉㪐㪃㩷 㪊㪌㪍㪌㩷㩿㪈㪐㪏㪈㪀㪅㩷㩿㪹㪀㩷㪫㪸㫅㪸㫂㪸㪃㩷㪟㪅㪃㩷㪟㪸㫐㪸㫂㪸㫎㪸㪃㩷㪟㪅㩷㪸㫅㪻㩷 㪤㫀㫐㪸㫊㪸㫂㪸㪃㩷㪫㪅㩷㪑㩷㩹㪬㫄㫇㫆㫃㫌㫅㪾㩹㩷㫆㪽㩷㫉㪼㪸㪺㫋㫀㫍㫀㫋㫐㩷㪸㫋㩷㫋㪿㪼㩷 㪚㪄㪍㩷 㫇㫆㫊㫀㫋㫀㫆㫅㩷 㫆㪽㩷 㫌㫉㫀㪻㫀㫅㪼㪅㩷 㪘㩷 㫊㫀㫄㫇㫃㪼㩷 㪸㫅㪻㩷 㪾㪼㫅㪼㫉㪸㫃㩷 㫄㪼㫋㪿㫆㪻㩷㪽㫆㫉㩷㪍㪄㫊㫌㪹㫊㫋㫀㫋㫌㫋㪼㪻㩷㫌㫉㫀㪻㫀㫅㪼㫊㪅㪃㩷㪫㪼㫋㫉㪸㪿㪼㪻㫉㫆㫅㪃㩷 㪊㪏㪃㩷㪉㪍㪊㪌㩷㩿㪈㪐㪏㪉㪀㪅㩷 㩷

㪍㪀㩷 㪟㪸㫐㪸㫂㪸㫎㪸㪃㩷㪟㪅㪃㩷㪫㪸㫅㪸㫂㪸㪃㩷㪟㪅㪃㩷㪤㪸㫉㫌㫐㪸㫄㪸㪃㩷㪰㪅㩷㪼㫋㩷㪸㫃㪑㩷 㪩㪼㪾㫀㫆㫊㪼㫃㪼㪺㫋㫀㫍㫀㫋㫐㩷 㫀㫅㩷 㫋㪿㪼㩷 㫃㫀㫋㪿㫀㪸㫋㫀㫆㫅㩷 㫆㪽㩷 㫌㫉㫀㪻㫀㫅㪼㪅㩷 㪜㪽㪽㪼㪺㫋㩷 㫆㪽㩷 㫋㪿㪼㩷 㫊㫌㪾㪸㫉㩷 㫇㫉㫆㫋㪼㪺㫋㫀㫅㪾㩷 㪾㫉㫆㫌㫇㫊㪅㪃㩷 㪚㪿㪼㫄㪅㩷 㪣㪼㫋㫋㪅㪃㩷㪈㪋㪃㩷㪈㪋㪇㪈㩷㩿㪈㪐㪏㪌㪀㪅㩷 㩷

㪎㪀㩷 㪟㪸㫐㪸㫂㪸㫎㪸㪃㩷 㪟㪅㪃㩷 㪫㪸㫅㪸㫂㪸㪃㩷 㪟㪅㪃㩷 㪦㪹㫀㪃㩷 㪢㪅㩷 㪼㫋㩷 㪸㫃㪅㩷 㪑㩷 㪘㩷 㫊㫀㫄㫇㫃㪼㩷 㪸㫅㪻㩷 㪾㪼㫅㪼㫉㪸㫃㩷 㪼㫅㫋㫉㫐㩷 㫋㫆㩷 㪌㪄㫊㫌㪹㫊㫋㫀㫋㫌㫋㪼㪻㩷 㫌㫉㫀㪻㫀㫅㪼㫊㩷 㪹㪸㫊㪼㪻㩷 㫆㫅㩷 㫋㪿㪼㩷 㫉㪼㪾㫀㫆㫊㪼㫃㪼㪺㫋㫀㫍㪼㩷 㫃㫀㫋㪿㫀㪸㫋㫀㫆㫅㩷 㪺㫆㫅㫋㫉㫆㫃㫃㪼㪻㩷 㪹㫐㩷 㪸㩷 㫇㫉㫆㫋㪼㪺㫋㫀㫅㪾㩷 㪾㫉㫆㫌㫇㩷 㫀㫅㩷 㫋㪿㪼㩷 㫊㫌㪾㪸㫉㩷 㫄㫆㫀㪼㫋㫐㪅㪃㩷㪫㪼㫋㫉㪸㪿㪼㪻㫉㫆㫅㩷㪣㪼㫋㫋㪅㪃㩷㪉㪏㪃㩷㪏㪎㩷㩿㪈㪐㪏㪎㪀㪅㩷 㩷 㪏㪀㩷 㪫㪸㫅㪸㫂㪸㪃㩷 㪟㪅㪃㩷 㪤㪸㫋㫊㫌㪻㪸㪃㩷 㪘㪅㪃㩷 㪠㫀㫁㫀㫄㪸㪃㩷 㪪㪅㩷 㪼㫋㩷 㪸㫃㪅㩷 㪑㩷

㪪㫐㫅㫋㪿㪼㫊㫀㫊㩷 㪸㫅㪻㩷 㪹㫀㫆㫃㫆㪾㫀㪺㪸㫃㩷 㪸㪺㫋㫀㫍㫀㫋㫀㪼㫊㩷 㫆㪽㩷 㪌㪄㫊㫌㪹㫊㫋㫀㫋㫌㫋㪼㪻㩷 㪍㪄㫇㪿㪼㫅㫐㫃㫋㪿㫀㫆㩷 㪸㫅㪻㩷 㪍㪄㫀㫆㪻㫆㫌㫉㫀㪻㫀㫅㪼㫊㪃㩷 㪸㩷㫅㪼㫎㩷㪺㫃㪸㫊㫊㩷㫆㪽㩷㪸㫅㫋㫀㫃㪼㫌㫂㪼㫄㫀㪺㩷㫅㫌㪺㫃㪼㫆㫊㫀㪻㪼㫊㪅㪃㩷㪚㪿㪼㫄㪅㩷 㪧㪿㪸㫉㫄㪅㩷㪙㫌㫃㫃㪅㪃㩷㪊㪈㪃㩷㪉㪈㪍㪋㩷㩿㪈㪐㪏㪊㪀㪅㩷 㩷 㩷

㪐㪀㩷 㩿㪸㪀㩷㪫㪸㫅㪸㫂㪸㪃㩷㪟㪅㪃㩷㪟㪸㫐㪸㫂㪸㫎㪸㪃㩷㪟㪅㪃㩷㪦㪹㫀㪃㩷㪢㪅㩷㪼㫋㩷㪸㫃㪅㩷㪑㩷 㪛㪼㫊㫌㫃㪽㫌㫉㫀㫑㪸㫋㫀㫍㪼㩷㫊㫋㪸㫅㫅㫐㫃㪸㫋㫀㫆㫅㩷㫆㪽㩷㫌㫉㪸㪺㫀㫃㩷㪻㪼㫉㫀㫍㪸㫋㫀㫍㪼㫊㪅㪃㩷 㪫㪼㫋㫉㪸㪿㪼㪻㫉㫆㫅㩷㪣㪼㫋㫋㪅㪃㩷㪉㪍㪃㩷㪍㪉㪉㪐㩷㩿㪈㪐㪏㪌㪀㪅㩷㩿㪹㪀㩷㪫㪸㫅㪸㫂㪸㪃㩷 㪟㪅㪃㩷 㪟㪸㫐㪸㫂㪸㫎㪸㪃㩷 㪟㪅㪃㩷 㪦㪹㫀㪃㩷 㪢㪅㩷 㪼㫋㩷 㪸㫃㪅㩷 㪑㩷 㪪㫐㫅㫋㪿㪼㫋㫀㪺㩷 㫉㫆㫌㫋㪼㩷㫋㫆㩷㪌㪄㫊㫌㪹㫊㫋㫀㫋㫌㫋㪼㪻㩷㫌㫉㫀㪻㫀㫅㪼㫊㩷㫍㫀㪸㩷㪸㩷㫅㪼㫎㩷㫋㫐㫇㪼㩷㫆㪽㩷 㪻㪼㫊㫌㫃㪽㫌㫉㫀㫑㪸㫋㫀㫍㪼㩷 㫊㫋㪸㫅㫅㫐㫃㪸㫋㫀㫆㫅㪅㪃㩷 㪫㪼㫋㫉㪸㪿㪼㪻㫉㫆㫅㪃㩷 㪋㪉㪃㩷 㪋㪈㪏㪎㩷㩿㪈㪐㪏㪍㪀㪅㩷 㩷

㪈㪇㪀㩷 㪬㪼㫅㫆㪃㩷 㪰㪅㩷 㪸㫅㪻㩷 㪦㫂㪸㫎㪸㫉㪸㪃㩷 㪤㪅㩷 㪑㩷 㪛㪼㫊㫌㫃㪽㫌㫉㫀㫑㪸㫋㫀㫍㪼㩷 㫊㫋㪸㫅㫅㫐㫃㪸㫋㫀㫆㫅㩷㫆㪽㩷㫇㫉㫆㫇㪸㫉㪾㫐㫃㫀㪺㩷㫆㫉㩷㪸㫃㫃㫐㫃㫀㪺㩷㫊㫌㫃㪽㫀㪻㪼㫊㩷㫍㫀㪸㩷 㪸㫅㩷㪪_㪟㩾㩷㫇㫉㫆㪺㪼㫊㫊㪅㪃㩷㪡㪅㩷㪘㫄㪅㩷㪚㪿㪼㫄㪅㩷㪪㫆㪺㪅㪃㩷㪈㪇㪈㪃㩷㪈㪏㪐㪊㩷 㩿㪈㪐㪎㪐㪀㪅㩷 㩷

㪈㪈㪀㩷 㩿㪸㪀㩷㪦㫅㫌㫄㪸㪃㩷㪪㪅㪃㩷㪢㫌㫄㪸㫄㫆㫋㫆㪃㩷㪟㪅㪃㩷㪢㪸㫎㪸㫋㫆㪃㩷㪤㪅㩷㪼㫋㩷㪸㫃㪅㩷㪑㩷㪘㩷 㫍㪼㫉㫊㪸㫋㫀㫃㪼㩷 㫀㫅㫋㪼㫉㫄㪼㪻㫀㪸㫋㪼㩷 㪽㫆㫉㩷 㫋㪿㪼㩷 㫊㫐㫅㫋㪿㪼㫊㫀㫊㩷 㫆㪽㩷 㪊㩾㪄㫊㫌㪹㫊㫋㫀㫋㫌㫋㪼㪻㩷 㪉㩾㪃㪊㩾㪄㪻㫀㪻㪼㪿㫐㪻㫉㫆㪄㪉㩾㪃㪊㩾㪄㩷 㪻㫀㪻㪼㫆㫏㫐㪸㪻㪼㫅㫆㫊㫀㫅㪼㩷 㩿㪻㪋㪘㪀㪅㩷 㪧㫉㪼㫇㪸㫉㪸㫋㫀㫆㫅㩷 㫆㪽㩷 㪊㩷 㩾㪄㩷 㪚㩷 㪄㩷 㫊㫋㪸㫅㫅㫐㫃㪄㪻㪋㪘㩷 㫍㫀㪸㩷 㫉㪸㪻㫀㪺㪸㫃㪄㫄㪼㪻㫀㪸㫋㪼㪻㩷 㪻㪼㫊㫌㫃㪽㫆㫅㫐㫃㪸㫋㫀㫍㪼㩷 㫊㫋㪸㫅㫅㫐㫃㪸㫋㫀㫆㫅㪅㪃㩷 㪫㪼㫋㫉㪸㪿㪼㪻㫉㫆㫅㪃㩷㪌㪏㪃㩷㪉㪋㪐㪎㩷㩿㪉㪇㪇㪉㪀㪅㩷㩿㪹㪀㩷㪢㫌㫄㪸㫄㫆㫋㫆㪃㩷㪟㪅㪃㩷 㪦㫅㫌㫄㪸㪃㩷㪪㪅㩷㪸㫅㪻㩷㪫㪸㫅㪸㫂㪸㪃㩷㪟㪅㩷㪑㩷㪪㫌㫃㪽㫌㫉㩷㪼㫏㫋㫉㫌㫊㫀㫆㫅㩷㫎㫀㫋㪿㩷 㫋㫀㫅㩷 㫉㪸㪻㫀㪺㪸㫃㪅㩷 㪪㫐㫅㫋㪿㪼㫊㫀㫊㩷 㫆㪽㩷 㪋㩾㪃㩷 㪌㩾㪄㪻㫀㪻㪼㪿㫐㪻㫉㫆㪄㩷 㪌㩾㪄㪻㪼㫆㫏㫐㪄㪌㩾㪄㩿㫋㫉㫀㪹㫌㫋㫐㫃㫊㫋㪸㫅㫅㫐㫃㪀㪸㪻㪼㫅㫆㫊㫀㫅㪼㪃㩷 㪸㫅㩷 㫀㫅㫋㪼㫉㫄㪼㪻㫀㪸㫋㪼㩷 㪽㫆㫉㩷 㫇㫆㫋㪼㫅㫋㫀㪸㫃㩷 㫀㫅㪿㫀㪹㫀㫋㫆㫉㫊㩷 㪸㪾㪸㫀㫅㫊㫋㩷 㪪㪄㪸㪻㪼㫅㫆㫊㫐㫃㩷 㪿㫆㫄㫆㪺㫐㫊㫋㪼㫀㫅㪼㩷 㪿㫐㪻㫉㫆㫃㪸㫊㪼㪅㪃㩷 㪡㪅㩷 㪦㫉㪾㪅㩷 㪚㪿㪼㫄㪅㪃㩷 㪍㪐㪃㩷 㪎㪉㩷 㩿㪉㪇㪇㪋㪀㪅㩷㩿㪺㪀㩷㪢㫌㫄㪸㫄㫆㫋㫆㪃㩷㪟㪅㪃㩷㪛㪼㪾㫌㪺㪿㫀㪃㩷㪢㪅㪃㩷㪮㪸㪾㪸㫋㪸㪃㩷㪫㪅㩷 㪼㫋㩷 㪸㫃㪅㩷 㪑㩷 㪩㪸㪻㫀㪺㪸㫃㪄㫄㪼㪻㫀㪸㫋㪼㪻㩷 㫊㫋㪸㫅㫅㫐㫃㪸㫋㫀㫆㫅㩷 㫆㪽㩷 㫍㫀㫅㫐㫃㩷 㫊㫌㫃㪽㫆㫅㪼㫊㪅㩷㪘㪺㪺㪼㫊㫊㩷㫋㫆㩷㫅㫆㫍㪼㫃㩷㪋㩾㪄㫄㫆㪻㫀㪽㫀㪼㪻㩷㫅㪼㫇㫃㪸㫅㫆㪺㫀㫅㩷㪘㩷 㪸㫅㪸㫃㫆㪾㫌㪼㫊㪅㪃㩷㪫㪼㫋㫉㪸㪿㪼㪻㫉㫆㫅㪃㩷㪍㪌㪃㩷㪏㪇㪇㪎㩷㩿㪉㪇㪇㪐㪀㪅㩷 㩷

㪈㪉㪀㩷 㪤㫀㫐㪸㫊㪸㫂㪸㪃㩷 㪫㪅㪃㩷 㪫㪸㫅㪸㫂㪸㪃㩷 㪟㪅㪃㩷 㪙㪸㪹㪸㪃㩷 㪤㪅㩷 㪼㫋㩷 㪸㫃㪅㩷 㪑㩷 㪘㩷 㫅㫆㫍㪼㫃㩷 㫃㪼㪸㪻㩷 㪽㫆㫉㩷 㫊㫇㪼㪺㫀㪽㫀㪺㩷 㪸㫅㫋㫀㪄㪟㪠㪭㪄㪈㩷 㪸㪾㪼㫅㫋㫊㪅㩷 㪈㪄㪲㩿㪉㪄㪟㫐㪻㫉㫆㫏㫐㪼㫋㪿㫆㫏㫐㪀㫄㪼㫋㪿㫐㫃㪴㪄㩷 㪍㪄㩿㫇㪿㪼㫅㫐㫃㫋㪿㫀㫆㪀㪄㩷 㫋㪿㫐㫄㫀㫅㪼㪅㪃㩷㪡㪅㩷㪤㪼㪻㪅㩷㪚㪿㪼㫄㪅㪃㩷㪊㪉㪃㩷㪉㪌㪇㪎㩷㩿㪈㪐㪏㪎㪀㪅㩷 㩷 㪈㪊㪀㩷 㪙㪸㪹㪸㪃㩷 㪤㪅㪃㩷 㪫㪸㫅㪸㫂㪸㪃㩷 㪟㪅㪃㩷 㪛㪼㩷 㪚㫃㪼㫉㪺㫈㪃㩷 㪜㪅㩷 㪼㫋㩷 㪸㫃㪑㩷

㪟㫀㪾㪿㫃㫐㩷 㫊㫇㪼㪺㫀㪽㫀㪺㩷 㫀㫅㪿㫀㪹㫀㫋㫀㫆㫅㩷 㫆㪽㩷 㪿㫌㫄㪸㫅㩷 㫀㫄㫄㫌㫅㫆㪻㪼㪽㫀㪺㫀㪼㫅㪺㫐㩷 㫍㫀㫉㫌㫊㩷 㫋㫐㫇㪼㩷 㪈㩷 㪹㫐㩷 㪸㩷 㫅㫆㫍㪼㫃㩷 㪍㪄㫊㫌㪹㫊㫋㫀㫋㫌㫋㪼㪻㩷 㪸㪺㫐㪺㫃㫆㫌㫉㫀㪻㫀㫅㪼㩷 㪻㪼㫉㫀㫍㪸㫋㫀㫍㪼㪅㪃㩷 㪙㫀㫆㪺㪿㪼㫄㪅㩷 㪙㫀㫆㫇㪿㫐㫊㪅㩷 㪩㪼㫊㪅㩷 㪚㫆㫄㫄㫌㫅㪅㪃㩷 㪈㪍㪌㪃㩷 㪈㪊㪎㪌㩷 㩿㪈㪐㪏㪐㪀㪅㩷 㩷

㪈㪋㪀㩷 㩿㪸㪀㩷㪙㪸㪹㪸㪃㩷㪤㪅㪃㩷㪛㪼㩷㪚㫃㪼㫉㪺㫈㪃㩷㪜㪅㪃㩷㪫㪸㫅㪸㫂㪸㪃㩷㪟㪅㩷㪼㫋㩷㪸㫃㪅㩷㪑㩷 㪧㫆㫋㪼㫅㫋㩷 㪸㫅㪻㩷 㫊㪼㫃㪼㪺㫋㫀㫍㪼㩷 㫀㫅㪿㫀㪹㫀㫋㫀㫆㫅㩷 㫆㪽㩷 㪿㫌㫄㪸㫅㩷 㫀㫄㫄㫌㫅㫆㪻㪼㪽㫀㪺㫀㪼㫅㪺㫐㩷 㫍㫀㫉㫌㫊㩷 㫋㫐㫇㪼㩷 㪈㩷 㩿㪟㪠㪭㪄㪈㪀㩷 㪹㫐㩷 㪌㪄㪼㫋㪿㫐㫃㪄㪍㪄㫇㪿㪼㫅㫐㫃㫋㪿㫀㫆㫌㫉㪸㪺㫀㫃㩷 㪻㪼㫉㫀㫍㪸㫋㫀㫍㪼㫊㩷 㫋㪿㫉㫆㫌㪾㪿㩷 㫋㪿㪼㫀㫉㩷 㫀㫅㫋㪼㫉㪸㪺㫋㫀㫆㫅㩷 㫎㫀㫋㪿㩷 㫋㪿㪼㩷 㪟㪠㪭㪄㪈㩷 㫉㪼㫍㪼㫉㫊㪼㩷 㫋㫉㪸㫅㫊㪺㫉㫀㫇㫋㪸㫊㪼㪅㪃㩷㪧㫉㫆㪺㪅㩷㪥㪸㫋㫃㪅㩷㪘㪺㪸㪻㪅㩷㪪㪺㫀㪅㩷㪬㪪㪘㪃㩷㪏㪏㪃㩷 㪉㪊㪌㪍㩷 㩿㪈㪐㪐㪈㪀㪅㩷 㩿㪹㪀㩷 㪫㪸㫅㪸㫂㪸㪃㩷 㪟㪅㪃㩷 㪫㪸㫂㪸㫊㪿㫀㫄㪸㪃㩷 㪟㪅㪃㩷 㪬㪹㪸㫊㪸㫎㪸㪃㩷 㪤㪅㩷 㪼㫋㩷 㪸㫃㪅㩷 㪑㩷 㪪㫋㫉㫌㪺㫋㫌㫉㪼㪄㪸㪺㫋㫀㫍㫀㫋㫐㩷 㫉㪼㫃㪸㫋㫀㫆㫅㫊㪿㫀㫇㫊㩷㫆㪽㩷㪈㪄㪲㩿㪉㪄㪿㫐㪻㫉㫆㫏㫐㪼㫋㪿㫆㫏㫐㪀㪄㩷㫄㪼㫋㪿㫐㫃㪴㪄㩷 㪍㪄㩿㫇㪿㪼㫅㫐㫃㫋㪿㫀㫆㪀㫋㪿㫐㫄㫀㫅㪼㩷 㪸㫅㪸㫃㫆㪾㫌㪼㫊㪅㩷 㪜㪽㪽㪼㪺㫋㩷 㫆㪽㩷 㫊㫌㪹㫊㫋㫀㫋㫌㫋㫀㫆㫅㫊㩷㪸㫋㩷㫋㪿㪼㩷㪚㪄㪍㩷㫇㪿㪼㫅㫐㫃㩷㫉㫀㫅㪾㩷㪸㫅㪻㩷㪸㫋㩷㫋㪿㪼㩷 㪚㪄㪌㩷 㫇㫆㫊㫀㫋㫀㫆㫅㩷 㫆㫅㩷 㪸㫅㫋㫀㪄㪟㪠㪭㪄㪈㩷 㪸㪺㫋㫀㫍㫀㫋㫐㪅㪃㩷 㪡㪅㩷 㪤㪼㪻㪅㩷 㪚㪿㪼㫄㪅㪃㩷㪊㪌㪃㩷㪊㪊㪎㩷㩿㪈㪐㪐㪉㪀㪅㩷 㩷

㪈㪌㪀㩷 㪫㪸㫅㪸㫂㪸㪃㩷㪟㪅㪃㩷㪙㪸㪹㪸㪃㩷㪤㪅㪃㩷㪪㪸㫀㫋㫆㪃㩷㪪㪅㩷㪼㫋㩷㪸㫃㪅㩷㪑㩷㪪㫇㪼㪺㫀㪽㫀㪺㩷 㪸㫅㫋㫀㪄㪟㪠㪭㪄㪈㩷 㩹㪸㪺㫐㪺㫃㫆㫅㫌㪺㫃㪼㫆㫊㫀㪻㪼㫊㩹㩷 㫎㪿㫀㪺㪿㩷 㪺㪸㫅㫅㫆㫋㩷 㪹㪼㩷 㫇㪿㫆㫊㫇㪿㫆㫉㫐㫃㪸㫋㪼㪻㪅㩷 㪪㫐㫅㫋㪿㪼㫊㫀㫊㩷 㫆㪽㩷 㫊㫆㫄㪼㩷 㪻㪼㫆㫏㫐㩷