河豚毒素的合成汇总.
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H2N
2
O HO H3 N
9 10
H
4
O O
5 6 11
Kishi Synthesis (1972)
O HO H2N
10
O N 1 H 8a 4a O 7 8 H
OH
OH
AcO
O
10
O 10
H 9 H N OO 4 8a N H O H
10 9
O
5
9
O AcHN AcO
O
4 5
Baeyer-Villiger oxidation
Retrosynthetic AnalБайду номын сангаасsis
H2N
2
O HO H3 N
9 10
H
4
O O
5 6 11
Kishi Synthesis (1972)
O HO H2N
10
O N 1 H 8a 4a O 7 8 H
OH
OH
AcO
O
10
O 10
H 9 H O N O 4 8a N H O H
TTX
O
5
9
O AcHN AcO
H N
H
8a 8
O
4a
Diels-Alder
5a 6
N H O Beckmann rear rangement
N H O overman r ear r angement H
OH
H
OH r ing-opening of epoxide
Diels-Alder
Du Bois' synthesis
O methylenation HO H 2N H N H
(Isobe, M. Nagoya University)
(Du Bois, J. Stanford University)
(Isobe, M.)
About Tetrodotoxin (TTX) -2
HO 9 H2N
2
O
10
H3 N
H
4
O O O
5 6 11
N 8a 4a 1 H O 7 8 H
O
O CH3
Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217-9219. Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219-9221. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Sugiura, S.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5127-5128. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5129-5132.
O
4 5
9 4
O
OH OH
7
6
OAc
AcHN AcO
7
6
OAc
OAc
A
B
O
10
10
9 4
HO
4 4a 8a
CH3 N
8a 4a
O
9
Diel s-Alder
AcHN O
Ac O
N H
H O CH3
O
Beckmann rear rangement
O CH3
D
C
Kishi, Y. et al. J. Am. Chem. Soc. 1972, 94, 9217-9219.;ibid 1972, 94, 9219-9221. Kishi, Y. et al. Tetrahedron Lett. 1970, 59, 5127-5128.;ibid 1970, 59, 5129-5132.
OH
OH
:%*!dioxa-adamantane + #< :67,74;8+ "!/,509)< :.83-128'(pKa = 8.7%
+ < : =#''&$ )<
dioxa-adamantane
O HO O O H2 N H N N H HO OH TTX H O O O O H2N HO H N N HHO OH TTX (lactone) O H O OH O OH
8a 8 10
O
O O St er eospecif ic C-H aminat ion
HO 9 H2N
2
10
O
N H O St er eospecif ic C-H aminat ion
5 6
H3 N
H
4
O O O
5 6 11
OH
1
H
OH aldol
N 8a 4a H O 7 8 H
OH
OH
Retrosynthetic Analysis
9
O
4
OH OH
7
6
OAc int ramolecular
AcHN AcO
7
6
OAc
OAc
10
epoxide-opening cyclization
O
HO
4 4a 8a
CH3 N
8a 4a
4
O
9
Diel s-Alder
AcHN O
Ac O
N H
H O CH3
Beckmann rear rangement
OH
70) %
1909 1964-5 1970 1972 2003 2003 2004
" (Hirata-Goto, Tsuda, Woodward) (Furusaki-Tomie-Nitta)
(Kishi, Y. Harvard University )
O
O
O H2N N H N H HO
OH OH
OH
anhydr o-TTX
Kishi's synthesis
O HO H2N H N
9 8a 10
Isobe's synthesis
O HO
O O O
4a 7 5 6
Gr ignard O O
10
H
H2N
Baeyer-Villiger oxidation OH OH ring-opening of epoxide
Synthesis of Tetrodotoxin
O HO H2N H N N HHO OH H OO O OH
About Tetrodotoxin (TTX)-1
O HO H2N H N N H HO OH H O O O
7Na ,3/516-(8 7&249('59+*9(."!$#
2
O HO H3 N
9 10
H
4
O O
5 6 11
Kishi Synthesis (1972)
O HO H2N
10
O N 1 H 8a 4a O 7 8 H
OH
OH
AcO
O
10
O 10
H 9 H N OO 4 8a N H O H
10 9
O
5
9
O AcHN AcO
O
4 5
Baeyer-Villiger oxidation
Retrosynthetic AnalБайду номын сангаасsis
H2N
2
O HO H3 N
9 10
H
4
O O
5 6 11
Kishi Synthesis (1972)
O HO H2N
10
O N 1 H 8a 4a O 7 8 H
OH
OH
AcO
O
10
O 10
H 9 H O N O 4 8a N H O H
TTX
O
5
9
O AcHN AcO
H N
H
8a 8
O
4a
Diels-Alder
5a 6
N H O Beckmann rear rangement
N H O overman r ear r angement H
OH
H
OH r ing-opening of epoxide
Diels-Alder
Du Bois' synthesis
O methylenation HO H 2N H N H
(Isobe, M. Nagoya University)
(Du Bois, J. Stanford University)
(Isobe, M.)
About Tetrodotoxin (TTX) -2
HO 9 H2N
2
O
10
H3 N
H
4
O O O
5 6 11
N 8a 4a 1 H O 7 8 H
O
O CH3
Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217-9219. Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219-9221. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Sugiura, S.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5127-5128. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5129-5132.
O
4 5
9 4
O
OH OH
7
6
OAc
AcHN AcO
7
6
OAc
OAc
A
B
O
10
10
9 4
HO
4 4a 8a
CH3 N
8a 4a
O
9
Diel s-Alder
AcHN O
Ac O
N H
H O CH3
O
Beckmann rear rangement
O CH3
D
C
Kishi, Y. et al. J. Am. Chem. Soc. 1972, 94, 9217-9219.;ibid 1972, 94, 9219-9221. Kishi, Y. et al. Tetrahedron Lett. 1970, 59, 5127-5128.;ibid 1970, 59, 5129-5132.
OH
OH
:%*!dioxa-adamantane + #< :67,74;8+ "!/,509)< :.83-128'(pKa = 8.7%
+ < : =#''&$ )<
dioxa-adamantane
O HO O O H2 N H N N H HO OH TTX H O O O O H2N HO H N N HHO OH TTX (lactone) O H O OH O OH
8a 8 10
O
O O St er eospecif ic C-H aminat ion
HO 9 H2N
2
10
O
N H O St er eospecif ic C-H aminat ion
5 6
H3 N
H
4
O O O
5 6 11
OH
1
H
OH aldol
N 8a 4a H O 7 8 H
OH
OH
Retrosynthetic Analysis
9
O
4
OH OH
7
6
OAc int ramolecular
AcHN AcO
7
6
OAc
OAc
10
epoxide-opening cyclization
O
HO
4 4a 8a
CH3 N
8a 4a
4
O
9
Diel s-Alder
AcHN O
Ac O
N H
H O CH3
Beckmann rear rangement
OH
70) %
1909 1964-5 1970 1972 2003 2003 2004
" (Hirata-Goto, Tsuda, Woodward) (Furusaki-Tomie-Nitta)
(Kishi, Y. Harvard University )
O
O
O H2N N H N H HO
OH OH
OH
anhydr o-TTX
Kishi's synthesis
O HO H2N H N
9 8a 10
Isobe's synthesis
O HO
O O O
4a 7 5 6
Gr ignard O O
10
H
H2N
Baeyer-Villiger oxidation OH OH ring-opening of epoxide
Synthesis of Tetrodotoxin
O HO H2N H N N HHO OH H OO O OH
About Tetrodotoxin (TTX)-1
O HO H2N H N N H HO OH H O O O
7Na ,3/516-(8 7&249('59+*9(."!$#