Approaches to the Core of Cortistatin A: A Hypervalent Iodine-Induced Double Annulation Enables a Concise Synthesis of the Pentacyclic Core Structure of the Cortistatins John Maciejewski Wipf Group - Current Literature 14 November 2009 Frie, J. L.; Jeffery, C. S.; Sorensen, E. J. Org. Lett. 2009, ASAP Me OTBS O O H N O O HO Me OH N H N cortistatin A steps John Maciejewski @ Wipf Group Page 1 of 12 12/28/2009
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Approaches to the Core of Cortistatin A:A Hypervalent Iodine-Induced Double Annulation Enables a Concise Synthesis
of the Pentacyclic Core Structure of the Cortistatins
John MaciejewskiWipf Group - Current Literature
14 November 2009
Frie, J. L.; Jeffery, C. S.; Sorensen, E. J. Org. Lett. 2009, ASAP
MeOTBS
O
OH
N
O
O
HO
MeOH
N H
N
cortistatin A
steps
John Maciejewski @ Wipf Group Page 1 of 12 12/28/2009
Isolation and Biological Activity
O
HO
CH3OH
N H
N
cortistatin A : R = H
cortistatin B : R = OH
R
O
HO
CH3OH
N H
N
O
R
cortistatin C : R = H
cortistatin D : R = OH
Cortistatin A1 of 11 rearranged steroidal alkaloids isolated from marine sponge Corticium simplexInhibitor of angiogenesis - potential antitumor agentPotent - IC50 of 1.8 nM for human umbilical vein endothelial (HUVEC) cellsSuppresses HUVEC cell growth - cytostatic; mechanism is unknownStructure determined by MS, 2D NMR (COSY, HMQC, HMBC) analysis, and X-ray
Three total syntheses of cortistatin A completedOthers focus on methodologies to prepare core of molecule
J. Am. Chem. Soc. 2006, 128, 3148
John Maciejewski @ Wipf Group Page 2 of 12 12/28/2009
Sarpong Group - Core Approach
Key steps:PtCl2 catalyzed enyne cycloisomerizationoxidative dearomatization/ether formation
O
H
Me OTBS
O
OMe
PMBO
H
Me
TBSO
O
OMe
PMBO
H
Me
TBSOOMe
PMBO
OMe
PMBO
H
MeOTBS
OMe
TESO
H
MeOTBS
O
OMe
HO
H
MeOTBS
HO
OMe
O
H
CH3OTBS
O
KOH, EtOH/DCM
51%
1) K-selectride, THF2) NaBH4, MeOH/DCM
3) KHSO4, toluene65% (3 steps)
PtCl2 (cat.)
benzene, -40 oC
61%
TsNHNH2, NEt3
95%
OMe
PMBO
H
MeOTBS
1) MgBr2-OEt2, Me2S2) TESCl, imid.
3) m-CPBA, DCM46% (3 steps)
n-BuLi, THF
PIDA
60% (2 steps)
Angew. Chem. Int. Ed. 2008, 47, 6650
John Maciejewski @ Wipf Group Page 3 of 12 12/28/2009
Danishefsky Group - Core Approach
OTBS
Br
OO
NEt2
Me
O
O
OHC
OTBS
O
Me
O
O
OTBS
TBSO
O
Me
O
O
OTBS
TBSO
O
O O
OMe
t-BuLi, Et2O
-78 oC to 80 oC
44%
OTBS
O
O
Et2N
Me OO
OTBS
O
OTBS
O
O
Et2N
Me OO
OTBS
O
O
Me
O
O
OTBS
TBSO
THF, 130 oC
100%
1) I2, MeOH
2) MsCl, py, DCM 78% (2 steps)
O
Me
O
O
OMs
TBSO
TBAF, THF
88%
advanced intermediates
electrocyclization
Snieckus reaction
Key steps:retro-6π-electrocyclization/epimerization
alkylative de-aromatizationTetrahedron Lett. 2008, 49, 6610
John Maciejewski @ Wipf Group Page 4 of 12 12/28/2009
Magnus Group - Core approach
Org. Lett. 2009, 11, 3938
Key steps:[4+2] cycloaddition
ionization/ring expansion
OO
O
O
HO
O
H
Me
MeO2C
O
OTBS
H
Me
MeO2C
O
OTBS
H
MeO
O
OTBS
H
Me
OLi
Li
O
HOMe OTBS
O
HOMe OTBS
HH
OH
Me OTBS
EtOH/MeNO2
BF3-OEt282%
LiNH2/THF
BrCH2CO2Me75%
1) LiAl(t-BuO)3H
2) TBSCl/imid. DMF 92% (2 steps)
1) LiAlH4
2) DMP THF
43% 43%
Tf2O, DTBMP
70%
[4+2] cycloaddition
O
OTBS
H
Me
O
Li
O
HOMe OTBS
HR
R
?
John Maciejewski @ Wipf Group Page 5 of 12 12/28/2009
Shair Lab - Enantioselective Total Synthesis
Key step:aza-Prins cyclization to form ether bridge
J. Am. Chem. Soc. 2008, 130, 16864
SiR3
Me OTBS
H
OR
Me OTBS
H
OR
Br
MeOTBS
H
OR
OTES
MeOTBS
H
OR
OAcAcO
TESO
MeOTBS
H
O
OAcAcO
Me2N
Me
H
O
OHHO
Me2NN
Me
H
O
OHHO
Me2NN
1) HCBr3, KOtBu
2) TASF, DMF 66% (2 steps)
OTES
B(pin)
Pd(PPh3)4, THF84%
1) SAD
2) Ac2O, NEt3 51% (2 steps)
1) HF/py2) DMP
3) Me2NH, ZnBr2 65% (3 steps)
MeOO = R
1) TBAF
2) TPAP, NMO 70% (2 steps)
MeO
H
O
OAcAcO
Me2N
1) K2CO3, MeOH2) N2H4-H2O, I2
3) Pd(PPh3)4, CuCl 7-isoquinolinestannane 61% (3 steps)
Ar-SO2NHNH2
NEt3, THF20%
advanced intermediate
aza-Prins cyclization
cortistatin A
John Maciejewski @ Wipf Group Page 6 of 12 12/28/2009
Nicolaou Lab- Enantioselective Total Synthesis
Angew. Chem. Int. Ed. 2008, 47, 7310Key step:
1,4-addition / aldol / dehydration cascade
S
S MeOTBS
HO
HO
OTf
S
S MeOTBS
HO
O
MeOTBS
HO
O
O
MeOTBS
O
OMe
O
OOO
H
Me
O
OO
H
N
Me
O
H
N
O
Me
O
H
NOH
O
Me
O
H
NOHHO
Me2N
Pd(PPh3)4, CuI
85%
1) IBX
2) H2, Pd/BaSO4 52% (2 steps)
K2CO3, dioxane
52%
1) TMSOTF TMSO(CH2)2OTMS
2) TBAF3) SO3-py 45% (3 steps)
1) KHMDS, PhNTf2
2) Pd(PPh3)4 50% (2 steps)
NBpin
1) p-TsOH
2) H2, Pd/C 44% (2 steps)
Me
O
H
N1) TMSOTf, NEt3
2) IBX-MPO 46% (2 steps)
O
1) TBHP
2) CeCl3, NaBH4 56% (2 steps)
Me2NH, Ti(i-PrO)4
45%
advanced intermediate
cortistatin A
John Maciejewski @ Wipf Group Page 7 of 12 12/28/2009
Baran Lab - Enantioselective Total Synthesis
J. Am. Chem. Soc. 2008, 130, 7241
Key steps:Steroid ($1.20/g) as starting material, contains 70% of carbon atoms
Geminal dihalogenation of unactivated hydrocarbon
O
OMe
HMe
O
O
H H
O
OMe
HMe
O
NH
H H
O
OHC
O
OMe
HMe
O
NH
H H
HO
OHC
AcO
OO
OH
MeH
H
MeOH
N OO
OHC
O O
OH
MeHTMSO
N OO
OHC
Br
O
O
OH
MeHTMSO
N OO
OHC
Br
O
OMeAcO
NH
OAc
AcO
OH
Me
NH
OH
HO
O
1) TBHP, DBU
2) NH4OAc Na(BH3)CN HCO2Et 60% (2 steps)
TBAACo(acac)2
48%(76% brsm)
Co(acac)2, O2PhSiH3, HC(OEt)3
TsOH, K2CO365%
1) PIDA, Br2 TMSCl, imid. 57%
2) DBU, LiCl, 85%
SmI2, TBCHD
1) LiBr, Li2CO3
2) AlH3, THF, Ac2O 58% (3 steps)
MgBr2-Et2O2,6-(t-Bu)2py
PPTS, H2O, K2CO382%
1) N2H4, I2, NEt3
2) Pd(PPh3)4 53% (2 steps)
NMe3Sn
N Raney Ni
50%(~100% brsm)
Me
NH
OH
HO
O
N
Me
NH
OH
HO
O
O
cortistatin A
John Maciejewski @ Wipf Group Page 8 of 12 12/28/2009
Oxidative Cyclodearomatization/[3+2] CycloadditionTitle Paper
O
OMe
O
OTBSMe
O
OTBSMe
CO2HO
OTBSMe
H
O
OTBSMe
H O
Me OTBS
OTBS
NMe
O
OTBS
N
Me
OH
1) NaBH4, EtOH
2) TBSCl, imid. DMF 87% (2 steps)
MMC, DMF
85%
1) H2, Pd/BaSO4
2) [H2C=N+(CH3)2]I
90% (2 steps)
toluene, 110 oC
54%
regio- and diastereoselective
Org. Lett. 2009, ASAP
John Maciejewski @ Wipf Group Page 9 of 12 12/28/2009
Oxidative Cyclodearomatization/[3+2] CycloadditionTitle Paper
Org. Lett. 2009, ASAP
O
Me OTBS
OTBS
NMe
O H
Me OTBS
OTBS
NMe
O H
MeO2C
Me OTBS
OTBS
HO H
MeO2C
Me OTBS
OH
HO H
HO
1) KHMDS, THF Commins' reagent, 96%
2) CO, PdCl2dppf (10 mol%) 76%
1) CH3I, THF, 100%2) Zn dust, THF/AcOH, 97%
3) m-CPBA, DCM, 73%
1) H2, Pd/C, 100%2) LiAlH4, THF, 68%
3) TBAF, THF, 99%
DMP, DCM
Me OTBS
O
O H
O
NaHCO354%
N OH
H
R
Me OTBS
O
O H
NO
R
Me OTBS
O
O H
O
N
OH
R
other conjugate addition products
various N-alkyl hydroxyl amines failed to be selective
John Maciejewski @ Wipf Group Page 10 of 12 12/28/2009
Oxidative Cyclodearomatization/[3+2] CycloadditionTitle Paper
Me OTBS
OH
HO H
HO
Me OTBS
OH
HO H
NHO
Me OTBS
O
O HNO
SO3-py, DCMNEt3, DMSO, 57%
HONH3Cl, EtOH, 100%
PIDA, CF3CH2OH
rt then 50 oC, 80%
MeOTBS
O
OH
N
O
O
HO
MeOH
N H
N
cortistatin A
steps
Org. Lett. 2009, ASAP
John Maciejewski @ Wipf Group Page 11 of 12 12/28/2009
Summary
Use of an oxidative cyclodearomatization/[3+2] cycloaddition to prepare cortistatin coreBaran, Nicolaou, and Shair have synthesized cortistatin AOther laboratories continue to investigate methodologies to prepare cortistatin core
MeOTBS
O
OH
N
O
O
HO
MeOH
N H
N
cortistatin A
steps
John Maciejewski @ Wipf Group Page 12 of 12 12/28/2009
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