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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. Natural Products Isolated from the Zoanthids. PGA2. Zoanthoxanthin. Zoanthoxanthin. - PowerPoint PPT Presentation
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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
Natural Products Isolated from the Zoanthids
Zoanthoxanthin
PGA2
Zoanthoxanthin
H
HMe
O
MeO
N
O
Me
H
O O
Me
Zoanthamine
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
