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Total Synthesis of the Potent cAMP Signaling AgonistTotal …lac.dicp.ac.cn/wxbg/FC-3.pdf ·...
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Total Synthesis of the Potent cAMP Signaling Agonist Total Synthesis of the Potent cAMP Signaling Agonist (−)-Alotaketal A Reporter: Xian Feng Cai Reporter: Xian-Feng Cai Checker : Mu-Wang Chen Date: 2012/5/29 1 Yang, J. et al J. Am. Chem. Soc. 2012, DOI: 10.1021/ja303529z
Transcript of Total Synthesis of the Potent cAMP Signaling AgonistTotal …lac.dicp.ac.cn/wxbg/FC-3.pdf ·...
Total Synthesis of the Potent cAMP Signaling AgonistTotal Synthesis of the Potent cAMP Signaling Agonist (−)-Alotaketal A
Reporter: Xian Feng CaiReporter: Xian-Feng Cai
Checker : Mu-Wang Chen
Date: 2012/5/29
1
Yang, J. et al J. Am. Chem. Soc. 2012, DOI: 10.1021/ja303529z
目录
1. 简介
2. 反合成分析
3. Alotaketal A (1)的合成
4. 总结与讨论
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1. 简介
H
OH
O
O
OH
H
H
alotaketal A (1)
O
O
OH
OH
H1. Isolation from the marine sponge Hamigera sp.
OH
OO
collected in Papua New Guinea in 2009.2. Their chemical structures were elucidated by
analysis of spectroscopic data and they activate the cAMP cell signaling pathway with EC ’s of 18
alotaketal B (2)the cAMP cell signaling pathway with EC50 s of 18 and 240 nM, respectively.
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Andersen, R. J. et al Org. Lett. 2009, 11, 5166
2. 反合成分析
OH
OH
H5 7
2224
15 1719 25
TBSOH
OPMB
O
O
H
H13
21
913
11
17
20
O
OH
H
1 6
10
23 OTBS
SOH
OPMB
OTBS
O
TBSO
H 7O
I
OTBS
8
O OO
OHO
9 10
4
3. Alotaketal A (1)的合成
OFeCl3, MeMgBr;
TMSCl TMSOPhNO, HOAc
DCM
-78 oC to rt60%
O
OH
HClO, DCM64%
60% OH11 S1 9
O Cl O Cl TBSO IHCO2H, DEAD
PPh3, THF70%
1) NaBH4, CeCl3 7H2OMeOH, 92%;
2) TBSCl, imidazole
OH OCHO OCHO
70% 2) TBSCl, imidazoleDMF, 96%;
3) NaI, acetone, quant.12 13 14
5
Yang, J. et al Org. Lett. 2010, 12, 5072
6
7
Yamamoto, H. et al Tetrahedron 1990, 46, 4595
8
O O O OTfaq. LiOH, Tf2O, hexane MeMgBr, CuCN, ether
EtO EtO98% 95%
20 S2
EtO
O
H
O1) DIBAL-H, THF-hexane, 97%
2) DMP, DCM, 96%
OHS O
21 22
OH
NS
S O
Sn(OTf)2, N-ethylpiperidineDCM, 80%
S O
23I(OAc)
O
O
NS23 (OAc)3
DMP
9
H
Sn(OTf)2, N-ethylpiperidineDCM
S O
S N
SSn
O
H
TfO
RH
OS N
OOH
RO
H
22 NS Sn
R =
S22
23
Nagao, Y. et al J. Org. Chem. 1986, 51, 2391
10
11
Bunnelle, W. H. et al Tetrahedron Lett. 1987, 28, 6261
12
TBSOH
X
TBSO
O OH
18 X = H
OTBS
I
8
SmI2, THF
87 X = OPMB
X X
TBSO
O
H
H
OH
HO
O
H
H
OHTBAF, THF
H
OTBS
H
OH
26 X = H6 X = OPMB
27 X = H28 X = OPMB
13
14
HO
O
H
OH
OH R
OH27
+ H+, - H2O
R =NH OTs
PPTS
HOH
O R
HOH
HO R
HOH
HO R+ H+
OH
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OH
OH
A D
- H+
HOH
HOH
HOH
+ H+- H+ + H+ - H+
HO
OHH
O R
HO
OHH
O R
HO
OH
O R
+ H+
- H+
15
30B C
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4. 总结与讨论
1. Two stages of SmI2-mediated reductive allylation reaction for assembling the polycycle and fragment coupling;
2. Hg(OAc)2-mediated selective alkene oxidation;
3 The subtlety of the spiroketalization/isomerization of the3. The subtlety of the spiroketalization/isomerization of the unprecedented spiroketal ring system.
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Signaling through cyclic adenosine monophosphate (cAMP)[环腺苷Signaling through cyclic adenosine monophosphate (cAMP)[环腺苷酸], the paradigm for the second messenger concept, is fundamentalto a diverse range of cellular processes. Such signaling is typicallyinitiated by the binding of hormones to cell-surface G protein-y g pcoupled receptors (GPCRs)[G蛋白耦联受体 ], which leads to therecruitment of cellular guanine-nucleotide[鸟嘌呤核苷酸 ] bindingproteins (G proteins) and activation of adenylyl cyclases (ACs)[腺苷酰 环 化 酶 ], the enzymes responsible for converting adenosinetriphosphate (ATP)[腺苷三磷酸] to cAMP. The elevated level of cAMPin turn regulates downstream cellular functions through effectors
蛋白激酶such as cAMP-dependent protein kinase (PKA)[蛋白激酶] and thecAMP−GTP [鸟苷三磷酸] exchange factor Epac[Epac蛋白是鸟嘌呤核苷酸关键转换因子]. Formation of cAMP by ACs and degradation by
AMP ifi h h di t (PDE )[磷酸二酯酶类] ll ti lcAMP-specific phosphodiesterases (PDEs)[磷酸二酯酶类] collectivelydetermine cellular cAMP levels.
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In summary, we have completed the first total synthesis of (−)-alotaketal A and confirmed its assigned absolute configuration. Thesynthesis features two Barbier-type intra-and intermolecular SmI2-
di t d d ti ll l ti f th ffi i t f ti f t kmediated reductive allylations for the efficient formation of two keyC−C bonds. These reactions will likely find further applications incomplex natural product synthesis. Also notable are the Hg(OAc)2-mediated selective functionalization of the ∆7 22 alkene and themediated selective functionalization of the ∆7,22 alkene and thesubtlety of the spiroketalization/isomerization of the unprecedentedspiroketal ring system. We have also examined the cAMP agonisticactivity of alotaketal A using the FRET-based[福斯特共振能量转移]activity of alotaketal A using the FRET-based[福斯特共振能量转移]AKAR4[致活酶活性指示器] and ICUE3 reporters and revealed thestructure−activity relationships of these cAMP signaling pathwaymodulators These studies set the stage for further investigationsmodulators. These studies set the stage for further investigationsof the mode of action of alotaketal A, which will be reported in duecourse.
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