河豚毒素的合成
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6 OH
H
OH
Retrosynthetic Analysis
Kishi Synthesis (1972)
H2N
O
HO 9 10
2
H N
3
H
4
O O
O
1
N H
8a
O
4a 8
7
5 11
6 OH
H
OH
H2N
O
HO 10
H N N
9 8a
HO 4 OO
5
HO
OH
H
OH
AcO
9
O AcHN AcO
7
O
10
O
4
O 10
Baey er-V i lli ger ox id at ion 9
5
AcHN
6
OAc
OAc int ramolecular
epoxi d e-opening cy cli zation
AcO
O
4
6
7O
OAc
10
94
O
AcHN
O
10
9
4
Ac N 4a H
OH 8a
O
CH3
Diel s-Alder
Synthesis of Tetrodotoxin
O
HO
H2N
H
H
O O
N
O
N
HHO
OH
OH
About Tetrodotoxin (TTX)-1
O
HO
H2N
H
H
O O
N
O
7Na ,3/516-(8 7&249('59+*9(."!$#
N
H HO
OH 70) %
OH
Beckmann rear rangement
HO
CH3
N
8a
4a
O
O
CH3
Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217-9219. Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219-9221. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Sugiura, S.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5127-5128. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5129-5132.
OH
ri ng-opening of epoxide
Isobe's synthesis
O
Gr ignard
HO
10
H2N
H
H
O O
N
8a
O
5a
N H
O
4a 8
6
overman
H
OH
r ear r angement
Diels-Ald er
OH
r ing-opening of epoxide
Du Bois' synthesis
HO
CH3
N
8a
4a
O
O
CH3 D
SnCl4 CH3CN
rt
83%
OH
N
H3C O
4a
H
1. MsCl, Et3N, quant.
1909 " 1964-5 (Hirata-Goto, Tsuda, Woodward) 1970 (Furusaki-Tomie-Nitta) 1972
(Kishi, Y. Harvard University ) 2003
(Isobe, M. Nagoya University) 2003
6 OH
H
OH
O 10
9
AcHN AcO
O
4
6
7O B
OAc
10
94
O
AcHN
O
10
9
4
Ac N OH
4a 8a
H O
CH3 C
Diel s-Alder
Beckmann rear rangement
HO
CH3
N
8a
4a
O
O
CH3 D
Kishi, Y. et al. J. Am. Chem. Soc. 1972, 94, 9217-9219.;ibid 1972, 94, 9219-9221. Kishi, Y. et al. Tetrahedron Lett. 1970, 59, 5127-5128.;ibid 1970, 59, 5129-5132.
:67,74;8+ "!/,509)<
O
O
:.83-128'(pKa = 8.7%
+ <
: =#''&$ )<
dioxa-adamantane
O O
O
H2N
N
O
H
N
H HO
H2 N OH
HO H N N HHO
O
H
O O
O
H2N OH
O
HO
H
H
OH O
N
O
methylenation HO
10
H2N
H N
8a
N
H
O O
O
5
HO
8
6
H St er eospecif ic
OH
C-H aminat ion
ald ol
St er eospecif ic C-H aminat ion
OH
H2N
O
HO 9 10
2
H N
3
H
4
O O
O
1
N H
8a
O
4a 8wenku.baidu.com
7
5 11
O
N
HHO
OH
OH
OH
OH
anhydr o-TTX
TTX
TTX (lactone)
Kishi's synthesis
O
H2N
HO
H9 N
8a
N HO
10
H
O O
O
5
4a
6
7
Beckmann
H
OH
rear rangement
Di el s-Al der
Baey er-V i lli ger ox id at ion
Retrosynthetic Analysis
Kishi Synthesis (1972)
O
AcO O
HO 10
H2N
H N N
9 8a
HO 4 OO
5
HO
OH
10 9
O O
4
AcHN
5
AcO
76
OAc
H
OH
OAc
TTX
A
H2N
O
HO 9 10
2
H N
3
H
4
O O
O
1
N H
8a
O
4a 8
7
5 11
(Du Bois, J. Stanford University) 2004
(Isobe, M.)
About Tetrodotoxin (TTX) -2
H2N
O
HO 9 10
2
H N
3
H
4
O O
O
1
N H
8a
O
4a 8
7
5 11
6 OH
H
OH
:%*!dioxa-adamantane + #<
H
OH
Retrosynthetic Analysis
Kishi Synthesis (1972)
H2N
O
HO 9 10
2
H N
3
H
4
O O
O
1
N H
8a
O
4a 8
7
5 11
6 OH
H
OH
H2N
O
HO 10
H N N
9 8a
HO 4 OO
5
HO
OH
H
OH
AcO
9
O AcHN AcO
7
O
10
O
4
O 10
Baey er-V i lli ger ox id at ion 9
5
AcHN
6
OAc
OAc int ramolecular
epoxi d e-opening cy cli zation
AcO
O
4
6
7O
OAc
10
94
O
AcHN
O
10
9
4
Ac N 4a H
OH 8a
O
CH3
Diel s-Alder
Synthesis of Tetrodotoxin
O
HO
H2N
H
H
O O
N
O
N
HHO
OH
OH
About Tetrodotoxin (TTX)-1
O
HO
H2N
H
H
O O
N
O
7Na ,3/516-(8 7&249('59+*9(."!$#
N
H HO
OH 70) %
OH
Beckmann rear rangement
HO
CH3
N
8a
4a
O
O
CH3
Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217-9219. Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219-9221. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Sugiura, S.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5127-5128. Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Kakoi, H. Tetrahedron Lett. 1970, 59, 5129-5132.
OH
ri ng-opening of epoxide
Isobe's synthesis
O
Gr ignard
HO
10
H2N
H
H
O O
N
8a
O
5a
N H
O
4a 8
6
overman
H
OH
r ear r angement
Diels-Ald er
OH
r ing-opening of epoxide
Du Bois' synthesis
HO
CH3
N
8a
4a
O
O
CH3 D
SnCl4 CH3CN
rt
83%
OH
N
H3C O
4a
H
1. MsCl, Et3N, quant.
1909 " 1964-5 (Hirata-Goto, Tsuda, Woodward) 1970 (Furusaki-Tomie-Nitta) 1972
(Kishi, Y. Harvard University ) 2003
(Isobe, M. Nagoya University) 2003
6 OH
H
OH
O 10
9
AcHN AcO
O
4
6
7O B
OAc
10
94
O
AcHN
O
10
9
4
Ac N OH
4a 8a
H O
CH3 C
Diel s-Alder
Beckmann rear rangement
HO
CH3
N
8a
4a
O
O
CH3 D
Kishi, Y. et al. J. Am. Chem. Soc. 1972, 94, 9217-9219.;ibid 1972, 94, 9219-9221. Kishi, Y. et al. Tetrahedron Lett. 1970, 59, 5127-5128.;ibid 1970, 59, 5129-5132.
:67,74;8+ "!/,509)<
O
O
:.83-128'(pKa = 8.7%
+ <
: =#''&$ )<
dioxa-adamantane
O O
O
H2N
N
O
H
N
H HO
H2 N OH
HO H N N HHO
O
H
O O
O
H2N OH
O
HO
H
H
OH O
N
O
methylenation HO
10
H2N
H N
8a
N
H
O O
O
5
HO
8
6
H St er eospecif ic
OH
C-H aminat ion
ald ol
St er eospecif ic C-H aminat ion
OH
H2N
O
HO 9 10
2
H N
3
H
4
O O
O
1
N H
8a
O
4a 8wenku.baidu.com
7
5 11
O
N
HHO
OH
OH
OH
OH
anhydr o-TTX
TTX
TTX (lactone)
Kishi's synthesis
O
H2N
HO
H9 N
8a
N HO
10
H
O O
O
5
4a
6
7
Beckmann
H
OH
rear rangement
Di el s-Al der
Baey er-V i lli ger ox id at ion
Retrosynthetic Analysis
Kishi Synthesis (1972)
O
AcO O
HO 10
H2N
H N N
9 8a
HO 4 OO
5
HO
OH
10 9
O O
4
AcHN
5
AcO
76
OAc
H
OH
OAc
TTX
A
H2N
O
HO 9 10
2
H N
3
H
4
O O
O
1
N H
8a
O
4a 8
7
5 11
(Du Bois, J. Stanford University) 2004
(Isobe, M.)
About Tetrodotoxin (TTX) -2
H2N
O
HO 9 10
2
H N
3
H
4
O O
O
1
N H
8a
O
4a 8
7
5 11
6 OH
H
OH
:%*!dioxa-adamantane + #<