synthesis of the steroidal natural product ouabain ... · synthesis of the steroidal natural...
TRANSCRIPT
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Synthesis of the Steroidal Natural Product Ouabainand Aglycone Ouabagenin
OHHO
O OO O
and Aglycone Ouabagenin
HOOH
HO
HO
H
OH
OH
HOOH
HO
HO
H
OHOH
OHOHO
OH
OOH
Ouabain Ouabagenin
Matt HaleyFebruary 20 2008February 20, 2008
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Background
HOOHHO
H
O O
HOOHHO
O O
HO
OH
OHOHO
HO
HO
HO
H
OH
OH
‐isolated from the African ouabio tree
OH
Ouabain Ouabagenin
isolated from the African ouabio tree (Acokanthera ouabio) in 1888 by Arnaud‐cardiac glycoside elicits effect by binding to myocardial Na+, K+‐ATPase (responsible for regulating intracellularNa , K ATPase (responsible for regulating intracellularNa+ transport‐used in Africa to make poison arrows‐unique steroid structure:q
‐sugar at the 3β position‐β butenolide ring at C17Acokanthera oblongifolia
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Synthetic Efforts to Date
‐completed total synthesis of ouabain and ouabagenin reported by Deslongchamps in 2008
‐completed tetracyclic core reported by Overman in 1998
t di t d AB bi li f t t d b J i 2003‐studies towards AB bicyclic fragment reported by Jung in 2003
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Deslongchamps’ Retrosynthetic AnalysisO
OR''
PGO
R''
OOPG
E
OPG
OOPGPGO
Haldol
Michael addition
R3Si
E
OO
O
OO
HR3Si
H
E
CO2R'O
HR3Si
H
OH
H
+
Wittig
ROMichael addition
R''PGOPGO
OOR'''
O
O
Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272
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Synthesis of Cyclic Enone
O
( S )
O
LiAl(t B O) H
OH
(Me2PhSi)Et2ZnLi
96%PhMe2Si
(±)
LiAl(t-BuO)3H
THF, -60 °C, 16h99% >14:1
PhMe2Si(±)
Amino Lipase PS powder
i-Pr2O, 60 °C, 23 h
OH
PhMe2Si
O 1) i. KHii. HCO2Et
2) PhSeCl, pyr
O O
2 , , PhMe2Si
OR
48% PDC
93%
PhMe2Si
O
3) H2O2, CH2Cl274% 3 steps
PhMe2Si
PhMe2Si
50%
R = AcMeO-
PhMe2Si
R = HMeO99%
Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 811Trudeau, S.; Deslongshamps, P. J. Org. Chem. 2004, 69, 832
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Synthesis of Cyclic Enone
O 1. NaBH4, 94% CN O 1. NaBH4, 96%
O
O2. TsCl, pyr, 93%3. NaCN, DMSO, 85%
O
CN 1. (CH2OH)2, pTSA, 95%2. DIBAL-H, 91%
O
O
O 2. 1 M HCl, acetone, 95%3. TBDPSCl, imid, DMF, 99%
AcOAcOOTBDPS Pb(OAc)4
88%+
OTBDPSOTBDPS 1. NaIO4, RuCl3, 80%2. EtSH, DCC, DMAP, 81%
O OO
88%1 : 8.3
OTBDPS 1 Et3SiH Pd(OAc)2AcO
OTBDPS
AcO
OOEtS
1. Et3SiH, Pd(OAc)2,acetone, sieves
2. HPh3P
EtO
OO
OO
O O3. 80% AcOH (aq)
68% 3 steps
O
Yang, Z.; Shannon, D.; Truong, V‐L.; Deslongshamps, P. Org. Lett. 2002, 4, 4693
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Synthesis of Ouabagenin
AcOOTBDPS
O
O O1. Cs2CO3, 85%
OTBDPS
+
O
O OAc1. Li(Et3CO)3AlH, 89%2. PMBOC(NH)CCl3, La(OTf)3, 83%
OH
OO
PhMe2Si2. [Pd(PPh3)4],morpholine, 92%
+OO
HPhMe2Si
H
OTBDPS
OOAcPMBO
KHMDS, 83%
OTBDPS
OOAcPMBO
H1. K2CO3, THF, MeOH, 98%2. NaBH4, 97%
OO
HPhMe2Si O
HPhMe2Si
OH
H H
OTBDPSOHPMBO OTBDPS
OO
PMP
O
HO
HPhMe2Si
H
OH
H
DDQ, 84%
O
O
HPhMe2Si
H
OH
H
Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272
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Synthesis of Ouabagenin
O S
PMPPMP
OTBDPS
O
OO
HPhMe Si
O
H
OH
1. TBSOTf, NEt3, 90%2. DDQ, 2,6-di-tert -butyl-4-methylpyridine, 100%
OTBDPS
OO
H
O
H
OHOPhMe2SiOPhMe2SiH
1. NaBH4, 96%2 mCPBA NaHCO3 85%
OTBDPS
OOO
PMP
1. MsCl, pyr, 98%OTBDPS
OOHHO
PMP
O
2. mCPBA, NaHCO3, 85% O
HPhMe2Si
H
OHOH
O
2. i. LiBH4, DME, rt, 24 hii. reflux 8 hiii. silica
58%
O
HPhMe2Si
H
OH
OH
PMP
Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272
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Synthesis of Ouabagenin
OTBDPS
OOHHO
HPMP
O
1. Ac2O, pyr, DMAP, 90%2 TBAF 88%
OH
OOHAcO
HPMP
O
Hg(OAc)2, AcOH:AcOOH (1:1), 93%
HPhMe2Si
OH
OH
2. TBAF, 88%
HPhMe2Si
OH
OH
g( )2, ( ),
OH
OOH
H
AcO
H
OH
PMP
O
HHO
OH
OH
dTamao oxidation:
Hg(OAc)2
R RM
R RRhydrolysis
Si
PhHgOAc
R 1
Me
MeSi R 1
Me
O MeO
Si R 1
Me
Me OO O
R 1OSi
O
O
Me
MeR 1
R
HO
hydrolysis
O OH
O
Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272Jones, G. R. Tetrahedron, 1996, 52, 7599
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Synthesis of Ouabagenin
OH
OOHAcO
HPMP
O1. TBDPSCl, imid, 75%2. Ac2O, pyr, DMAP, 65%
OTBDPS
OOAcAcO
HPMP
O
HHO
OH
OH
HAcO
OH
OH
OTBDPS
OOAcAcO
HPMP
O
1. TBAF, 90%2 DMP 75%
O
OOAcAcO
HPMP
O[(PPh3)3RhCl], PPh3,iPrOH, TMSCHN2, 67% O
OAcAcO
HPMP
O
HAcO
H
OH
OH
2. DMP, 75%
HAcO
H
OH
OH
iPrOH, TMSCHN2, 67%
HAcO
H
OH
OH
Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272
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Rhodium Catalyzed Methylenation
NN
Rh(I)TMS H
NN
i-PrOH
TMS H
ClRh(PPh3)3
PPh
N2
TMS H
NN
Rh(I)
H
i-PrO-
PPh
TMS H
PPh3
H
i-PrO-
PPh3
PPh3i PrOTMS+
HHi-PrOTMS+
Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126, 320
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B
Synthesis of Ouabagenin
OOAcAcO
HPMP
O
1. OsO4, NMO, 95:5, 82%2 nBu SnO benzene reflux
OOAcAcO
HPMP
OOSn
O
nBunBu
NBS CHClH
AcOOH
OH
2. nBu2SnO, benzene, reflux
HHO
H
OH
OH
NBS, CHCl3
73% 2 steps
OOAcAcO
HPMP
OOH
O
Ph3PCCO, TEA, 68%O
OAcAcOPMP
O
O O
0.5 N Na2CO3, MeOH, 85%H
HOOH
OH
O
HHO
H
OH
OH
PMP 2 3, ,
HOOHHO
O O
HO
HHO
H
OH
OHouabageninouabagenin
Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 127241 steps
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Synthesis of Ouabain
OHOHO
OH
OHBzCl, pyr, DMAP, 82%
OBzOBzO
OBz
OBz1. AcBr, MeOH2. Ag2CO3, acetone, 58% 2 steps OBzO
BzOOBz
OHK2CO3, Cl3CCN
68%
OBzO
O Cl3
NH
O OO O
BzOOBz
O O
+
TMSOTf, 4 Å M.S.
90% OOAc
H
O
H
OH
O
1. 2 N HCl, MeOH, 92%2. 0.5 N Na2CO3, MeOH 88% HO
OH
HO
HO
H
OH
OOAc
H
O
H
OH
O O HO
OH
OHOBzO
BzOOBz
OOH
OHOHO
OHouabain47 steps
OHHO
O OO O
HHO
OH
OH
HOOH
HHO
HO
H
OH
OH
conc. HCl, acetone, 80%O
OH
H
O
H
OH
1. Ac2O, pyr, DMF, DMAP, 78%2. 0.5 N Na2CO3, MeOH, 70%
OHHOOH
Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272
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C13 of Synthetic Sample of Ouabain
Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272
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Overman Synthetic Efforts
Intramolecular Heck Approach:
R RORLnPd
RO
OR
R
OR
R
RO
OR
OR
RO
OR
X
OR
OR
Overman, L. E.; et al. J. Org. Chem. 1996, 61, 6760
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Overman Synthetic Efforts
O 1. NaBH4 OTMS
1. Et2NLi, HMPA2.
OI
OH
O
2. Me2NNH23. TMS-imidazole
85% NNMe2
3. AcOH, THF, H2O, NaOAc90%
O O
O
OO
1 MsCl pyr O
CN
1. NaBH4, CeCl3•7H2O, MeOH2. VO(acac)2, t-BuO2H
CN
1. MsCl, pyr2. KCN, 18-C-6, DMSO
O
O
O
( )2, 23. TPAP, NMO
68%
O
O
O
O80%
i. SmI2ii. TMS-imidazole; H2O TMSO
CN
OHO
CN
OHTBAF
2
O
O
OH80%
O
O
OH
Rucker, P. V; Overman, L. E. Tetrahedron Let. 1998, 39, 4643
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Overman Synthetic Efforts
CN
O
CNCN
KHMDS, PhN(Tf)2TfO
O
O
OH Pd(dppb), KOAc, DMA
90%80%OH
O
OO
O
O
OH
CN
(CF CO) O AcOH
CN
AcO1. SeO2, 1,4-dioxane, 80 °C2 DMP 72% (2 steps)
CN
AcO
OTMS
O
O
(CF3CO)2O, AcOH
70% OTMS
OH
cO 2. DMP, 72% (2 steps)
OTMS
OHO
OHHO
O O
HOOH
HHO
HO
H
OH
OHOH
OuabageninRucker, P. V; Overman, L. E. Tetrahedron Let. 1998, 39, 4643Rucker, P. V; Overman, L. E. Heterocycles 2000, 52, 1297
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Jung Synthetic Efforts
Robinson Annulation Approach:
+ EtO
O
RORO
Robinson Annulation Approach:
OMe+ EtO
ORO
HO
Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137
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Jung Synthetic EffortsFirst Attempt:
Me2PhSi
O
O
MeO2C
+Na, MeOH
41%, d.r. 6:1O
Co2MePhMe2Si Hg(TFA)2, AcOH,
TFA, AcOOH
79%
Co2MeOH 1. TBSCl, imid. 85%
2. NaBH4, CeCl3,MeOH, 98%
Co2MeTBSO
mCPBACo2Me
TBSOPCC
O
MeOH, 98%
HO HOO
96%
CO2MeTBSO
OO
Al foil, HgCl2, THFH2O, EtOH, NaHCO3
56% (2 steps)
CO2MeTBSO
OOH
(iBu)3AlCO2Me
TBSO
HOOH
95%
OH
Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137
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Jung Synthetic EffortsMore Successful Approach:
EtO
O
KOtBu, EtOHCO2Et 1. TSBOTf
NE
small scale:OH
OMe+
EtO
O
KOtBu, EtOH
refluxO
NEt3
2. DIBAL51% 3 steps
O
(HOCH2)2, TsOH i. LiAlHii. H2SO437% 3 steps
CO2Et
Olarge scale:
O
Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137
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Jung Synthetic Efforts
O
OHH2O2, NaOH, MeOH
O
OH
O
SeO2
O
OH
O
H2O2, NaHCO3
33% 3 steps O
OH
O
O
OH
Al foil, HgCl2
O
OH
OH
OH1. LiEt3BH
2. HC(OEt)3,MeOH;0 5% HCl
OO
O
H
OH
Ac2O, pyr
92% OO
O
H
OAc
0.5% HCl42% 3 steps
Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137
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Jung Synthetic Efforts
2 C l l i
OH
MM2 Calculations:
OO
HO
-79.86 kcal/mol
O
OH
desired
3.77 kcal/mol
OO
O
H
-83.63kcal/molobservedobserved
Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137
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Jung Synthetic Efforts
OH
changing step sequence:
O
OH
O
O1. Al foil, HgCl22. HC(OEt)3, PPTS
OO
OHi. NaBH4ii. Ac2O, pyr
25% 3 stepsO
O
O
H
OAc
O
use of boron chelate:1. Al foil, HgCl2
H
O
OH
O
O2. LiEt3BH3. HC(OEt)3, MeOH;
0.5% HCl
34% 3 stepsO
O
O
H
OH
OO
HO
OH
+ Ac2O, pyr
89%O
O
AcO
OH
O O
1.1 : 1
Al foil, HgCl2 ii. HC(OEt)3, MeOH;0.5% HCl
HOOH
H
HO
H
OHO
O
O
B
OH
O
OH
OH
OHi. LiEt3BH
Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137
HOOH
Ouabagenin
OH