![Page 1: Total Synthesis of Zoanthamine Alkaloids 郭蕊 2012.03.31 Miyashita, M., et al. Acc. Chem. Res., 2012, ASAP. Stoltz, B.M., et al. Angew. Chem. Int. Ed. 2008,](https://reader036.vdocuments.pub/reader036/viewer/2022062722/56649f285503460f94c406fd/html5/thumbnails/1.jpg)
Total Synthesis of Zoanthamine Alkaloids
郭蕊2012.03.31
Miyashita, M., et al. Acc. Chem. Res., 2012, ASAP.Stoltz, B.M., et al. Angew. Chem. Int. Ed. 2008, 47, 2365
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Natural Products Isolated from the Zoanthids
Zoanthoxanthin
PGA2
Zoanthoxanthin
H
HMe
O
MeO
N
O
Me
H
O O
Me
Zoanthamine
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Zoanthamine Alkaloids: Isolation andBiological Activity
Zoanthamine: Isolation: Rao and Faulker, 1984 off the coast of India Biological activity: Inhibits ear inflammation in mice
Norzoanthamine: Isolation: Uemura, 1995 from the coast of islands south of Japan Biological activity: Prevents osteoporosis in vivo in ovarieoctimized mice Cytoxicity against P388 murine leucemia cells Inhibits human platelet aggregation
Zoanthenol: Isolation: Norte, 1996 in the Canary Islands Biological activity: Inhibits human platelet aggregation
H
HMe
O
MeO
N
O
Me
H
O O
RH
R=H NorzoanthamineR=Me Zoanthamine
MeMe
O
N
O
Me
H
O O
Me
Zoanthenol
OH
Rao, C. B.; Faulkner, D. J., et al. J. Am. Chem. Soc. 1984, 106, 7983.Uemura, D., et al. Heterocycl. Commun. 1995, 1, 207
Norte, M., et al. Tetrahedron, 1999, 55, 5539.
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Synthetic Efforts Towards Norzoanthamine
Total synthesis:• Miyashita, Norzoanthamine-2004
Partial synthesis:• Tanner• Williams • Uemura • Stoltz• Theodorakis• Kobayashi
Miyashita, M., et al. Science, 2004, 305, 495.
H
HMe
O
O
N
O
Me
H
O O
A B
CD
EF
G
N
H
OO
H
Me
MeMe
O
O
O
Me
H
H
Me
A
B C
D
E
F
G
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H
HMe
O
Me
O
N
O
Me
H
O O
bis-amino-acetallization
H
HMe
O
MeO
OH
Me
H
CO2H
O
ONH2
1) methylation at C9(quaternary caobon atom)
2) coupling
H
ONBoc
MeO
OTBS
H
HMe
OAc
MeCO2Me
H
Me
OTBSintramolecularDiels-Alder reaction
OTBS
H
HMe
OAc
CO2Me
Ophotosensitizedoxidation
OAc
MeMe
OTBS
Me
O
adol reaction
O TBS
Me
OHC
OTMS
MeMe
OTIPS
conjugateaddition
CuLi Me
OTIPS2 Me
O
Retrosynthetic Analysis of Norzoanthamine
41 steps, 3.5% overall yield (average of 92% yield per step)• Key steps: • IMDA to set stereochemistry of the BC rings• Use of kinetic isotope effect for installation of alkyne• Bis-aminoacetalization for the construction of the DEFG rings
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Synthesis of the ABC Ring SystemO
Me
CuLi Me
OTIPS2
TMSCl
OTMS
MeMe
OTIPS
BuLi, -30 oC;ZnBr2, -78 oC;
OOHC
Me
TBS
1) Im2C=S2) Et3SiH(Ph3P)3RhCl
3) K2CO3, MeOH4) LiBEt3H
84% two steps
78%
OH
MeMe
OTIPS
OTBS
Me 1) Ac2O2) TBAF3) MnO2
4) MeLi5) TPAP NMO
91%
OAc
MeMe
OTBS
Me
O
hv, O2 rose bengal
TBAF MeI
OAc
Me
O
O
Me
Me
COOMeTBSOTfMe2NEt
100%
OAc
Me
OTBS
O
Me
Me
COOMe
97%
OAc
MeMe
O
O
Me
OTBS
O
Me
O
MeMe
OTIPS
O
OH
TBS
Me
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O
MeMe
OTIPS
OTBS
MeEt3SiH
(Ph3P)3RhCl
OTES
MeMe
OTIPS
OTBS
Me
K2CO3,MeOH
O
MeMe
OTIPS
OTBS
Me
O
OH
MeMe
OTIPS
OTBS
Me
LiBEt3H
O
MeMe
OTIPS
O
OH
TBS
Me
Im2C=S
RO
S
NN NNHO
S
N
R H N
HNN-
HNN-
O C S- R
(Im2C=S)
Chugaev Elimination
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Katsumura protocol
Hydrosilylation reaction in the presence of Wilkinson’s catalyst
(Ph3P)3RhCl + Et3SiH Et3SiRh(PPh3)2Cl
H-PPh3
Et3SiRh(PPh3)2Cl
H
R4O
R3R1
R2
R4O
R3R1
R2
R4Et3SiO
R3R1
R2
Rh(PPh3)2Cl
H
OSiEt3
R4
Cl(Ph3P)2Rh
R2
R1
R3
H
-Rh(PPh3)2Cl
1,2-adduct 1,4-adduct Ojima I., et al. Organometallics, 1982, 1, 1390
O TMS
hv, O2
O TMS
R
O OOHO O
O TMS
hv, O2
O TMS
R
O OOHO O
R R
R R
Katsumura K., et al. Tetrahedron Lett. 1985, 38, 4625
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OAc
Me
OTBS
O
Me
Me
COOMe
CO2MeMeTBSO
OMe
Me OAc
CO2Me
O
Me OAc
A
BMe
Me
OTBS
O
OTBS
H
HMe
OAc
HMe
CO2Me
O
OTBS
H
HMe
OAc
HMe
CO2Me
Me Me+
72:28
HF· pyridineO
O
H
HMe
OAc
HMe
CO2Me
Me
51% two steps
1,2,4-trichlorobenzene
240 oC
Key Intramolecular Diels-Alder Reaction
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O
O
H
HMe
OAc
HMe
CO2Me
Me
1) K-Selectride -78 oC to 0 oC
2) TBSOTf
86%
H
HMe
OAc
HMe
Me
O
O
1) Ti(OEt)42) TESOTf
3) DIBAL
80%
OTBS H
HMe
OTES
HMe
Me
O
OTBS
OH
Ph3PCH3Brt-BuOK
99%
H
HMe
OTES
HMe
Me
OTBS
OH
1) 9-BBN H2O2, NaOH
2) ( NH4)6Mo7O24 Bu4NCl, K2CO3 H2O2
H
HMe
OTES
HMe
Me
OTBS
OH
O
THF-HMPA
(MeO)2C=O LiOt-Bu
89%
H
AcOO
H
Me
MeH
MeOOC O
Me
Methylation
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Trost protocol
O
MoO
HO
H BaseMo
OOH2O2
HOH
OHOH OH
O
88%
OH
OHOH
O
78%
( NH4)6Mo7O24 Bu4NCl, K2CO3
H2O2
( NH4)6Mo7O24 Bu4NCl, K2CO3
H2O2
Trost B. M., et al. Tetrahedron Lett. 1984, 25, 173
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O
OLi
H
MeMe
OOMe
O
OLi
H
MeMe
O
MeI
90%O-methylation
O
OMe
H
MeMe
O
LHMDS
THF-DMPU
-15 oC
Me
MeOLi
O
H
O
H
H
TESO
MeH
TBS
CH3-I
MeI
71%
C-methylation
O
H
HMe
OTES
Me
OH
Me
MeO
OTBS
Me
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O
H
HMe
OTES
Me
OH
Me
MeO
OTBS
Me
1) MeLi
2) TBSCl
84% O
H
HMe
OTES
Me
H
Me
MeO
OTBS
Me
Me
OTBS Tf2ODBU
O
H
HMe
OTES
Me Me
Me
OTBS
OTBS
+
O
H
HMe
OTES
Me
O
Me
Me
OTBS
Me
65%
24%
Tf2O
OTBS
O
Me
H
H
Tf2O
H- shiftH
OTf
MeO
H
Me
The Kinetic Isotope Effect
H
HMe
OTES
HMe
Me
O
OTBS
OH
Ph3PCD3BrKHMDS
H
HMe
OTES
HMe
Me
OTBS
D
D
OH
6 steps
59% 7 steps
H
HMe
OTES
Me
OTBS
H
O
OTBS
D D
OMe
O
H
HMe
OTES
Me Me
Me
OTBS
OTBS +
O
H
HMe
OTES
Me
O
Me
Me
OTBS
Me81% 9%
D D
D
D
Tf2ODBU
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Construction of the DEFG Rings
O
H
HMe
OTES
Me
H
Me
Me
OTBS
OTBS
D D+
H
ONBoc
MeO
1) n-BuLi
2) Dess-Martin periodinane
82%O
H
HMe
OTES
Me
H
Me
Me
OTBS
OTBS
D D
O ONBoc
Me
1) H2, PtO2
2) AcOH (aq.)
O
H
HMe
O
Me
H
Me
Me
OH
D
BocN
DMe
O
TBAF, 70 oC
then (NH4)6Mo7O24K2CO3, H2O2
O
H
HMe
OH
Me
H
Me
Me
OTBS
D
BocN
DMe
O
O
H
HMe
O
MeCO2Me
H
Me
MeBocN
Me
O
O
1) TPAP2) NaClO2
3) TMSCHN2
1) TMSCl
LHMDS
-65 oC
2) Pd(OAc)2
56% 4 steps O
H
HMe
O
MeCO2Me
H
Me
MeBocN
Me
O
O
O
H
HMe
OTES
Me
H
Me
Me
OTBS
OTBS
D D
BocHN
Me
HO
O
OTBS
O
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R OTMS
Pd(OAc)2
-TMSOAc OPd
R
OAc
2
H
R
R'
R'
O
-HPdOAc
Oxidant or Base
Ito-Saegusa method
Ito Y., Hirao T., Saegusa T., J. Org. Chem. 1978, 43, 1011
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O
H
HMe
O
MeCO2Me
H
Me
MeBocN
Me
O
O
AcOHH2O
100 oC
H
HMe
O
MeCO2Me
H
MeO
N
O
Me
AcO-
TFAH2O
110 oC
H
HMe
O
MeO
N
O
Me
H
O OHCF3CO2
-
basic-Al2O3
MeOH
81% 3 steps
H
HMe
O
MeO
N
O
Me
H
O O
N
H
OO
H
Me
MeMe
O
O
O
Me
H
H
Me
A
B C
D
E
F
G
Completion of Norzoanthamine
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O
H
HMe
O
Me
CO2MeH
Me
MeBocN
Me
O
O
TBSOTfEt3N
-78 oC98% O
H
H
OTBS
Me
CO2MeH
Me
MeBocN
Me
O
O
O
H
H
TBSO
Me
CO2MeH
Me
MeBocN
Me
O
O
LDA, -55 oC
MeI
83%
Me
1) AcOH, H2O rt to 105 oC
2) TFA, H2O
110 oC
3) Et3N, MeOH
63%
H
HMe
O
MeO
N
O
Me
H
O O
N
H
OO
H
Me
MeMe
O
O
O
Me
H
H
Me
A
B C
D
E
F
G
Me
Me
Zoanthamine
Total Synthesis of Zoanthamine
Miyashita, M., et al. Chem.Eur. J. 2009, 15, 6626
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O
H
HMe
O
MeCO2H
H
Me
MeBocN
Me
O
O
AcOHH2O
100 oC
78%
H
HMe
O
MeO
N
O
Me
H
O O
1) TMSCl
LDA
-50 oC
2) Pd(OAc)2 CaCO3
H
HMe
O
MeO
N
O
Me
H
O O
TFA
50 oC
Me
OH
MeO
N
O
Me
H
O O
1) TBSNO3 57%(4 steps)
2) LDA, -78 oC
MeI
Me
TBSO
MeO
N
O
Me
H
O O
Me
Total Synthesis of Zoanthenol
TASF
53% (2 steps)
MeMe
O
N
O
Me
H
O O
Me
Zoanthenol
OH
Miyashita, M., et al. Chem. Asian J. 2011, 6, 922Miyashita, M., et al. Angew. Chem., Int. Ed. 2009, 48, 8905