セラミドキナーゼ阻害剤の開発に向けたキノンテル ペノイドの合成研究
著者 光永 紫乃
URL http://hdl.handle.net/10236/3406
㸧㸥㸥㸭ᖳᗐࠈಞኃㄵᩝさ᪠
ࢬ࣐ࣚࢺ࢞ࢻ࣭ࢭ㜴ᐐࡡ㛜Ⓠ࡞ྡྷࡄࡒ࢞ࢿࣤࢷࣜ࣋ࢿࢺࡡྙᠺ◂✪
㛭こᏕ㝌ኬᏕኬᏕ㝌⌦ᕝᏕ◂✪⛁
Ꮥᑍᨯࠈົᮟ◂✪ᐄࠈකỄࠈ⣰
ࠈࠈࠈࠈࠈࠈࠈࠈࠈ
⥬ゕ 㸯ࢪࣆࣤࢥ⬙㈻ࡡㅨ࡞࠽࠷࡙㸡ࢬ࣐ࣚࢺ࢞ࢻ࣭ࢭࡢࢬ࣐ࣚࢺࢅࢬ࣐ࣚ
ࢺ ࣛࣤ㓗ንᥦࡌࡾ㓕⣪࡚࠵ࡽ㸡ࡆࡡ㓕⣪࡞ࡢᮅࡓよ᪺ࡈࡿ࡙࠷࠷㒂ฦ
ኣࡂṟࡈࡿ࡙࠷ࡾࠊ㎾ᖳ㸡ࢬ࣐ࣚࢺ࢞ࢻ࣭ࢭ㸡࣭ࣝࣜ࢟ࡡᘤࡀࡠ࡛ࡾ࣏
ࢪࢹ⣵⬂ࡡ⬲㢓⢇⌟㇗࡞ᙁࡂ㛭ࡊ࡙࠷ࡾࡆ࡛᪺ࡼ࠾࡛ࡖࡒࠊࡐࡆ࡚㸡ࡆࡡ 㓕⣪ࡡ㐽ᢝⓏ㜴ᐐࡢ㸡ࡆࡿࡼࡡ⏍మ⌟㇗ࢅ㏛㊟ࡊ㸡よᯊࡌࡾ୕࡞࠽࠷࡙ᙁງ
ࢵ࣭ࣜ࡞ࡾ࡛භ࡞㸡࣭ࣝࣜ࢟⑄ᝀ⒢ⷾ㛜Ⓠࡡᡥ࠾ࡽ࡛ࡾࡆ࡛ᙽ
ࡈࡿࡾࠊࡊ࠾ࡊࡼࡆࡿࡱ࡚࡞㸡᭯⏕ࢬ࣐ࣚࢺ࢞ࢻ࣭ࢭ㜴ᐐࡡሒ࿈ౚࡢධࡂ࠷ࠊᠻࠍࡢ࡞㸡ࢪࣆࣤࢥࢨࣤ࢞
ࢻ࣭ࢭ㜴ᐐ࡛ࡊ࡙▩ࡼࡿ࡙࠷ࡾF-12509A (1)ࡡྙᠺࢅሒ࿈ࡊ࡙࠽ࡽ㸡ྙᠺ᳠ゞࡡ㐛⛤࡞࠽࠷࡙㸡ࡐࡡ⎌మ࡚࠵ࡾK1 (2)
ࢅᚋࡒࠊࡆࡡ K1 (2)ࡡ⏍∸Ὡᛮモ㥺ࢅ⾔ࡖࡒ࡛ࡆࢀ㸡⣵⬂Ẑᛮࢅ♟ࡈࡍ㸡ࢬ࣐ࣚࢺ࢞ࢻ࣭ࢭࢅ㐽ᢝⓏ࠾ࡗᙁງ࡞㜴ᐐࡌࡾ
࡛࠷࠹⮾࠷▩ぜᚋࡼࡿࡒࠊࡆࡿࡢ㸡K1 (2)㸡⬲㢓⢇ᢒโຝᯕࢅ᭯ࡌࡾᢘ࣭ࣝࣜ࢟ⷾࡡ㛜Ⓠ࡞ࡗࡾྊ⬗ᛮࢅࡵ
ࡗࡆ࡛ࢅ♟ြࡌࡾࠊࡐࡆ࡚㸡◂✪⏕モⷾࡡ౩⤝ࢅ┘Ⓩ࡛ࡊ࡙㸡K1 (2)ࡡኬ㔖ྙᠺ࡞ྡྷࡄࡒྙᠺἪࡡ☔❟ࢅ⾔࠹࡛භ࡞㸡ࡻࡽ
ᙁງ㜴ᐐࡡ㛜Ⓠ࡞ྡྷࡄࡒㄇᑙమࡡྙᠺ᳠ゞࢅ⾔ࡖࡒࠊ
K1 (2)ࡡྙᠺ 㸯Dihydro-ș-ionone (3)࠾ࡼ㸪 ṹ㝭࡚ᚋࡼࡿࡒ Albicanal (4)࡞ᑊࡊ㸡ࢬ ࢹࢻࢺమ 5 ࡡࣛࢲ࣑ሲࢅష⏕ࡈࡎ㸡᭻
ࡳ࢜ࢴࣈࣛࣤࢡమ 6 ࢅྙᠺࡊࡒࠊ⏍ࡋࡒỀ 㓗ᇱࢅࢬࢲࣜࡊࡒᚃ㸡ࣚࢩ࢜ࣜⓏ࡞㑇 ඔࡊ㸡ྙ∸7 ࡛ᏽ㔖Ⓩ࡞ንᥦࡊࡒࠊ⤾
࠷࡙㸡ࡆࡿࢅ㓗ฌ⌦ࡌࡾࡆ࡛࡚ࢬࢹࢻ
ࢺࡡ㝎ཡࢅ⾔ࡖࡒ࡛ࡆࢀ㸡ࢹ࢛࣭ࣛࣜ 8 ᚋࡼࡿࡒࠊࡆࡿࢅ⢥⿿ࡌࡾࡆ࡛ࡂࢨࣛ࢜
ࢣࣜභᏋࡡୖ࡞᧘ᢶࡌࡾ࡛㸡✭Ẵ㓗ཬᚺ
ಀ㐅ࡈࡿ㸡K1 (2)ࢅ㸧ṹ㝭㸭㸩㸚ࡡ⋙
࡚ᚋࡾࡆ࡛࡚ࡀࡒࠊ
8-epi ࠽ࡻࡦ Pyran ㄇᑙమࡡྙᠺ 㸯හ㒂࢛
ࣝࣆࣤࢅࡵࡗࣜࢸࣃࢺ 9 ࡛ࢬࢹࢻ
ࢺ 5 ࡡ࢜ࢴࣈࣛࣤࢡࢅ⾔࠷ྙ∸ 10 ࡛ࡊ ࡒࠊࡆࡿ࡞ᑊࡊ㸡㓗ฌ⌦㸡⤾ࡂࢨࣛ࢜ࢣࣜ
ࢅ⏕࠷ࡒ✭Ẵ㓗ࢅ⾔࠹ࡆ࡛࡚㸡ࢩࢪࢷ
࢛࣏࣭ࣝΊྙ∸࡛ࡊ࡙ Pyran ㄇᑙమ (11)ࢅ
ᚋࡒࠊࡱࡒ㸡ྙ∸ 10 ࠾ࡼࡡ⎌ࢅ⾔࠹
ࡆ࡛࡚cis⦨⎌ྙ∸࡚࠵ࡾ8-epiㄇᑙమࢅ
ᚋࡾࡆ࡛࡞ᠺຉࡊࡒࠊ
CHO
H rac-Albicanal (4)
1)Ac2O, DMAP, pyridine 2)Li, liq.NH3
O O O
OH
H
SiO2, air
K1 (2)
5 n-BuLi,
Dihydro-β-ionone (3) CH3 O
O HO
OH
H
OH
O O O O
H 6
8 Scheme 1
O O O O
H 7
77%
quant. for 2 steps
84% for 2 steps
HO
TFA 41% for 5 steps
O O O O
(H2O)
CHO
H
O O O
OH
H O
O O O HO
9 H
5
n-BuLi, 1)TFA, (H2O)
Pyran derivative (11)
+ O
O O
OH
H 12 10
Scheme 2
69% 82% for 2 steps
O O O O
H 13
K1 (2) O
O O
OH
H
8-epi derivative (14) + 2)SiO2, air
1)NHMDS, CS2, MeI 2)Bu3SnH, AIBN
2)SiO2, air 84% for 2 steps quant. for 2 steps
1)TFA, (H2O)
O O O
OH
H K1 (2) O
O
OH HO
H F-12509A (1) Fig.1 F-12509A (1)とK1 (2)
Oxepene ㄇᑙమࡡྙᠺ 㸯ྙ∸㸬࡞ᑊࡊ㸡ࣃࢺࣞ࣌⣪࠽ࡻࡦ࣒ࢨࣜࢅ⾔࠷㸡ྙ∸ 15 ࡛ࡊࡒࠊࡆࡿ࡞㸡ࣈࣞࣂࣤ
ࢩ࢛࣭ࣜᏋᅹୖ࡚ TMSOTf ࢅష⏕ࡈࡎࢬࢹࢻࢺࡡ㝎ཡࢅ⾔ࡖࡒ࡛ࡆࢀ㸡✭Ẵ㓗ࢅఔ࠷ࢩࣃࢺࣞ࢞ࢿࣤ 16 ᚋࡼࡿ
ࡒࠊࡈࡼ࡞㸡ࡆࡿࢅDBU࡚ฌ⌦ࡌࡾࡆ࡛࡞ࡻࡽ㸡㸨㸪㸚࡛⋙࡚ࡢ࠵ࡾ㸡Oxepene ㄇᑙమ (13)ࡡྙᠺ࡞ᠺຉࡊࡒࠊ
Methyl ether࠽ࡻࡦGlycineㄇᑙమࡡྙᠺ 㸯ྙ∸K1 (2)ࢅ
ࢩࢯ࣒ࢰ࡚ࣤฌ⌦ࡊ㸡Methyl ether ㄇᑙమ (9)࡛ንᥦࡊ ࡒࠊࡈࡼ࡞㸡ࡆࡿ࡞ᑊࡊ㸡ࢹ࢙ࣛࢲ࣐ࣜࣤᏋᅹୖ࡚Glycine
ࢅష⏕ࡈࡎ㸡ᐄῺ࡚㸪㛣᧘ᢶࡌࡾࡆ࡛࡚㸡Glycine ㄇᑙమ (10)ࡡྙᠺࢅ㧏⋙࡚㐡ᠺࡊࡒࠊ
Monoterpene ㄇᑙమ࠽ࡻࡦDiterpeneㄇᑙమࡡྙᠺ 㸯ș-Cyclocitral (20)ࢅཋᩩ࡛ࡊ㸡Scheme 2࡛ྜྷᵕࡡᡥ㡨࡚ࢹ࢛࣭ࣛࣜ21
ࢅᚋࡒࠊࡈࡼ࡞㸡ྙ∸21 ࡞ᑊࡊ Ề⣪῟ຊࢅ⾔࠹ࡆ࡛࡚ࢩࢪࢷࣝ
࢛࣏࣭Ίྙ∸࡚ࡢ࠵ࡾ㸡ࢂࡍ࠾
㸩ṹ㝭࡚ Monoterpene ㄇᑙమ (22)
ࢅྙᠺࡌࡾࡆ࡛ฝᮮࡒࠊࡱࡒ㸡 Dihydro-ș-ionone (3)ࡻࡽᚋࡼࡿࡒ 㸨⎌ᛮࣜࢸࣃࢺ 24 ࢅ Scheme 1
࡛ྜྷᵕࡡᡥ㡨࡚ฌ⌦ࡌࡾࡆ࡛࡚㸡 Diterpeneㄇᑙమ (25)ࢅྙᠺࡊࡒࠊ
⏍∸Ὡᛮモ㥺࠽ࡻࡦ㓗㑇ඔ㞹నࡡῼᏽ㸯ࠈFig.2 ࡞ࢴࢬ
⤎ᯕࢅ♟ࡌࠊFig.2 ࢅぜ࡙ࡵ᪺ࡼ࠾ࡻ࠹࡞㸡Monoterpene ㄇᑙమ࡛ྙ∸ 26 ྙ∸K㸦࡛ྜྷ⛤ᗐࡡ㜴ᐐຝᯕࢅ♟ࡊ
࡙࠷ࡾࡡ࡞ᑊࡊ㸡cis ⦨⎌ࡊࡒྙ∸ 23 ࡢ࡛ࢆ㜴ᐐຝ ᯕࢅ♟ࡈ࠾ࡖࡒࠊࡱࡒ㸡ྙ∸ K㸦࡞Ẓ Oxepene ㄇᑙ మࡡ㜴ᐐຝᯕࡢᙁງ࡚࠵ࡾࡆ࡛ࡢ᪺ࡼ࠾࡚࠵ࡾࠊK㸦࡛
Oxepene ㄇᑙమࡢẒ㍉Ⓩజࡒࢤࣤࣆ࢚࣒࣭ࢨࣘࣤࢅᣚࡖ࡙
࠷ࡾ࡞ࡵ㛭ࢂࡼࡍ㜴ᐐຝᯕ࡞㢟ⴥᕣ࠵ࡽ, ࡆࡿࡢ㟸ᖏ
࡞⮾࠷⤎ᯕ࡚࠵ࡾࠊࡱࡒ㸡 ᚋࡼࡿࡒ࢞ࢿࣤྙ∸ࡡ㑇 ඔ㞹నࡡῼᏽࢅ⾔ࡖࡒ࡛ࡆࢀ㸡K㸦࡞Ẓ Pyran ㄇᑙమ࠽ࡻ
ࡦ Oxepene ㄇᑙమࡡ㓗ງᙁ࠷ࡆ࡛᪺ࡼ࠾࡛ࡖࡒࠊ
⏍∸Ὡᛮモ㥺ࡢᮅࡓୌ㒂ࡡྙ∸࡞ࡗ࠷࡙ࡊ࠾⾔ࡖ࡙࠷
࠷ࡒࡴ㸡ࢬ࣐ࣚࢺ࢞ࢻ࣭ࢭ㜴ᐐຝᯕ࡛㑇ඔ㞹న࡞┞㛭࠵
ࡾ࠾࠹࠾ࡢ᪺࡚࠵ࡾࠊࡊ࠾ࡊࡼ㸡ኣࡂࡡ࢞ࢿࣤྙ∸ࡐࡡ㓗㑇ඔཬᚺ≁ᛮࢅฺ⏕ࡊ࡙⏍మහࡡᵕࠍ㇗࡞
㛭ࡊ࡙࠷ࡾࡆ࡛࠾ࡼ㸡ᚃ㸡ࡆࡿࡼࡡ⤎ᯕࡡ㛣࡞㛭㏻ᛮぜฝࡎࡾࡡ࡚ࡢ࠷࠾࡛ᙽࡈࡿࡾࠊ
Scheme 4 K1 (2)
O O O
H
CO2H HN
Glycine derivative (19) O
O O
OMe
H
Methyl ether derivative (18) CH2N2
AcOEt 79 %
Glycine, Et3N MeOH
76 % O
O O O
OMs
H
1)TMSOTf, HS SH
OMs O O
OH
OH O
O O HO
H DBU
H Oxepene derivative (17)
7
16 1) BH3-SMe2,
then 2N NaOH aq., H2O2 2)MsCl, Et3N
Scheme 3 15
69% for 2 steps
2)air
68% for 2 steps
35%
CHO
β-Cyclocitral (20)
O
O O
OH OH
OH OH O
21 Monoterpene derivative (22)
Pd-C/H2
O
O O
OH 23
+ 64% for 4 steps
Diterpene derivative (25) O
O O
OH H
H H
Scheme 5
CHO H
H 24 Dihydro-β-ionone (3)
13% for 11 steps 51% for 5 steps SiO2, air
2 steps
●
●
●
●
▲
▲
■
■ ■
■
◆ ◆
◆
◆
●
▲
▲
▲ 120 100 80 60 40 20
0
10 20 30 40 50
0
Compound (µM) C er K a ct iv it y (% o f co nt ro l)
O O O
OH
O O O
HO
H H
K1 Oxepene derivative
۔
ڷ ۋ ڦ
Monoterpene derivative O
O O
OH
O
O O
OH O
O OH O
26 23
Fig.2
