progress toward the synthesis of the tetracyclic core of the
TRANSCRIPT
Kalyani J. PatilResearch Topic Seminar
June 3 rd 2006
O
O
O
OHMeO
A B
C D
EO
Progress Toward the Synthesis ofProgress Toward the Synthesis ofthe the Tetracyclic Tetracyclic Core of the Core of the ViridinViridin
FamilyFamily
Kalyani Patil @ Wipf Group
OutlineOutline
• Isolation and Structure
• Biological Activity
• Synthetic Approaches Toward Furanosteroids
• Tetracyclic Core of Viridin - Wipf Group
• Future Work
Kalyani Patil @ Wipf Group
• Isolated from fungi• Possess antifungal, antibiotic, and anti-inflammatory activity• Potent inhibitors of phosphatidylinositol 3-kinase (PI3-K)
Structure of Structure of FuranosteroidsFuranosteroids
O
O
O
OHMeO
HO
ViridiolO
O
O
OHMeO
Viridin (2 nM)
A B
C D
EO
O
O
O
OH
Demethoxyviridin (0.1 nM)
OO
O
O
OH
HO
Demethoxyviridiol
O
O
O
O
Wortmannin (4.2 nM)
OAc
O
MeO
O
H
HH
12
3
20
4 510
19
67
8911
12
13
18
1415
16
17
Kalyani Patil @ Wipf Group
Isolation of Isolation of FuranosteroidsFuranosteroids
O
O
O
OHMeO
HO
ViridiolO
O
O
OHMeO
Viridin
O
O
O
O
O
Wortmannin
OAc
O
MeO
Isolated in 1945 from Gliocladium virens
Structure Determined in 1966 by X-Ray Crystallography
Originally Isolated as Antifungal Agent
Isolated from Gliocladium deliquescens and G. virens
Antifungal and Phytotoxic Metabolite
Isolated in 1957 from Penicillium wortmannii and in 1972 from Myrothecium roridium
Structure Determined in 1972 Kalyani Patil @ Wipf Group
Planar Planar Polycyclics Polycyclics from Marine Spongefrom Marine SpongeXestospongiaXestospongia
O
O
O O
(+)-Halenaquinone
O
OH
OH O
O
O
O
O O
O
(+)-Halenaquinol(+)-XestoquinoneIsolated from Xestospongia Sapre in 1960
Isolated from Xestospongia Exigue in 1983
• Antibacterial Activity• Cardiotonic Properties• Inhibition of pp60 Kinase• Inhibition of EGF Kinase• Inhibition of the Dual Specificity Phosphatase Cdc25
Kalyani Patil @ Wipf Group
Phosphatidylinositol-3-Kinase (PI-3-Kinase)Phosphatidylinositol-3-Kinase (PI-3-Kinase)
• Important Enzyme for Intracellular Signaling
• Phosphorylation of Inositol Lipids at the 3-Position: Primary Enzymatic Activity of the PI-3-Kinases
• Different Members of the PI-3-Kinase Family Generate Different Lipid Products
Kalyani Patil @ Wipf Group
Signaling Through PI-3K Lipid ProductsSignaling Through PI-3K Lipid Productsandand their Targetstheir Targets
Rameh, L. E.; Cantley, L. C. J. Biol. Chem. 1999, 274, 8347.Kalyani Patil @ Wipf Group
Phosphatidylinositol-3-Kinase (PI-3-Kinase)Phosphatidylinositol-3-Kinase (PI-3-Kinase)
• PI-3-Kinase was initially purified and cloned as a heterodimeric complex consisting of
110 kDa catalytic subunit p110 α85 kDa regulatory/adaptor subunit p85 α
• 9 mammalian PI-3-Kinases have been identified
• Divided into 3 classes based on sequence homology and substrate preference in vitro
Kalyani Patil @ Wipf Group
FuranosteroidsFuranosteroids: Proposed Biosynthesis: Proposed Biosynthesis
Hanson, J. R. Nat. Prod. Rep. 1995, 12, 381.
O PMe
Me
OOO
PO
O O
O
MeP OO
OP O
O
O+
Me
Me Me Me
Me
Me
MeMe
Squalane
Me
Me Me
Me
Me
MeMe
Me O
Squalane 2,3-Epoxide
MeMeMe
Me
Me
MeH
Me
Me
Lanosterol
O
O
OO
MeOHMeO
Viridin O
O
O
OO
Me
Wortmannin
Me
H
AcOMeO
Kalyani Patil @ Wipf Group
WortmanninWortmannin: Mechanism-Based Inhibitor: Mechanism-Based Inhibitorof PI-3-Kinaseof PI-3-Kinase
O
O
O
OO
AcO
H
MeO
A B
C D
K802(p110 PI-3 kinase)
NH2
Wortmannin
O
O
OO
AcO
H
MeO
OHHN
K802(p110 PI-3 kinase)
• An Irreversible Inhibitor of PI-3-Kinase
• Nucleophilic Attack at the Electrophilic C-20 Position of the Furan Ring by Lys802 of p110 PI-3-Kinase
Kalyani Patil @ Wipf Group
PKB Regulation Through Inhibition of thePKB Regulation Through Inhibition of thePhophorylation Phophorylation at the 3-Position of at the 3-Position of Inositol Inositol LipidsLipids
Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053.
Structural Analogs and ICStructural Analogs and IC5050 Values for inValues for invitro PI-3 vitro PI-3 Kinase Kinase InhibitionInhibition
O
O
O
OO
AcO
H
MeO
WortmanninIC50 = 4.2 nM
O
O
OHOH
IC50 = 4600 nM
MeO
O
O
OHOHHO
IC50 = > 32,000 nM
O
O
OH
OO
AcO
H
MeO
IC50 = 0.4 nM
O
O
O
OO
AcO
H
MeO
IC50 = >500 nM
O
O
O
OOH
MeO
IC50 = 6 nM
O
O
O
OOH
MeO
IC50 = 16.7 nM
O
O
OOH
MeO
IC50 = 271 nM
AcO
OKalyani Patil @ Wipf Group
Synthesis of Synthesis of FuranosteroidsFuranosteroids
O
O
O
OHMeO
O
O
O
O
OO
Me
Me
H
AcOMeO
O
O
O O
O
Viridin
Halenaquinone
Wortmannin
RODRIGO - o-Benzoquinone Monoketals Cascade Reactions
SORENSEN - Alkyne Trimerization and Electrocyclic Rearrangement
HARADA - Chiral Building Block
RODRIGO - o-Benzoquinone Monoketals Cascade Reactions
SHIBASAKI - Asymmetric Intramolecular Cascade Heck-Suzuki Couplings
SHIBASAKI - Chiral Building Block
SHIBASAKI - Diastereoselective Intramolecular Heck Coupling and Diosphenol ClaisenKalyani Patil @ Wipf Group
Synthesis of Synthesis of Pentacyclic Pentacyclic Core of Core of Viridin Viridin --RodrigoRodrigo
Souza, F. E. S.; Rodrigo, R. Chem. Commun. 1999, 1947.
OMeOH
1) K2CO3, CO2 (800 psi), 200 °C2) BBr3, CH2Cl2, -78 °C to rt
72%OH
OH
CO2HPhI(O2CCF3)2, THF
O2N86% OH
OH
NO2
1) K2CO3, Me3OBF4, CH2Cl22) Ac2O, pyridine
3) p-ClC6H4NCO, NEt3, C6H6, rt, 36h4) NaOH, H2O, THF
OHOAc
NOH2, Pd/C, H3BO3,MeOH/THF/H2Oquant.
84%
OHOAc
OH O
PhI(O2CCF3)2, THF
HO
OOMe
Me
OO O
OH O
OH
H
OMe
+
31% 33%
Cl2CHCHCl2reflux, 48 h65%
p-TsOH50%
O
O
OH
p-Chloranil,xylenes, reflux60%O
O
O
Kalyani Patil @ Wipf Group
Retrosynthetic Retrosynthetic Analysis of (Analysis of (±±)-)-Viridin Viridin --SorensenSorensen
O
O
OO
MeOOH
Viridin
O
OP
OOP'
OP
O
OP
OOP'
OP
O
OP
OH
Electrocyclic Rearrangement
Rh CatalyzedCyclotrimerization
Kalyani Patil @ Wipf Group
Synthesis of (Synthesis of (±±)-)-Viridin Viridin - Sorensen- Sorensen
Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem. Int. Ed. 2004, 43, 1947.
O
OTBS
O
OTES
OTBS
O
OTBS
OOTES
OTBS
OH
OTBS
OH
[RhCl(PPh3)3,EtOH, 80 °C
88%
i) (COCl)2, DMSO, Et3N; 85%ii) 2-TMS-3-vinylfuran, n-BuLi, THF; 94%iii) TES-Cl, imidazole, DMAP, DMF; 88%
TMS
Hunig' base, 140 °C,Xylenes; then DDQ, rt
83%
TMS
i) Allyl bromide, CsF, DMF; 67%ii) Mesitylene, 165 °C, 40 min; 91% O
OTBS
O
i) RCM; 95%ii) SeO2, dioxane, 100 °Ciii) DMP, CH2Cl2, rt; 58%
O i) NaBH4, EtOH; 98%ii) OsO4, TMEDA; 76%iii) Triphosgene, THF/H2O; 95%iv) Ethyl vinyl ether, PPTS, rt; 91% O
OTBS
O
OEE
O
OO
Kalyani Patil @ Wipf Group
Synthesis of (Synthesis of (±±)-)-Viridin Viridin - Sorensen- Sorensen
Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem. Int. Ed. 2004, 43, 1947.
O
O
OO
MeOOH (±) - Viridin
23 steps 5%
O
OTBS
O
OEE
O
OO
i) LiOH, THF/H2O; 97%ii) TBS-OTf, 2,6-lutidine; 95%iii) NaHMDS; then MeOTf; 75%
O
OTBS
O
OEE
MeO
TBSO
i) TBAF, THF; 97%ii) DMP, CH2Cl2, rt; 98%iii) PPTS, MeOH, rt; 84%
Kalyani Patil @ Wipf Group
Retrosynthetic Retrosynthetic Analysis of Analysis of Wortmannin Wortmannin --ShibasakiShibasaki
O
O
O
OOH
AcOMeO
Wortmannin
AcO H
TBSOMeO OO
H
OOSEMO
BnO
TfO H
OOSEMO
BnO O
O
CO2MeH
IntramolecularHeck
OO
Diosphenol-ClaisenRearrangement
Kalyani Patil @ Wipf Group
Synthesis of (Synthesis of (±±)-)-Wortmannin Wortmannin - - ShibasakiShibasaki
O
OMe
CO2MeH
(Racemic)
27% H
HO OOMe
TfOi) SEMCl, 2,6-lutidine
ii) 9-BBN
I OBn
Me
[PdCl2(dppf)]56%
H
SEMO OOMe
TfOBnO
Pd(OAc)2
65% H
SEMO OOMe
BnO Me
dr = 18:1
i) CsF, DMFii) PDC, NaOAciii) DIBAL-Hiv) TBSCl, imid.
39%
H
OOMe
BnO MeTBSO i) OsO4, NMO
ii) LAHiii) MeI, Ag2Oiv) Ac2O, DMAP, py
38%H
OOMe
MeTBSO
AcOMeO
i) CrO3, 3,5-diMe-pyrazoleii) TMSOTf, Hunig's baseiii) DMDO, PPTS, MeOHiv) (COCl)2, DMSOv) Allyl bromide, K2CO3
44%
H
OOMe
MeTBSO
AcOMeO
OO
i) Xylene, 200 °Cii) NaBH4, CeCl3iii) HC(OMe)3, PPTS
67%H
OOMe
MeTBSO
AcOMeO
OO
OMe
Mizutani, T.; Honzawa, S.; Tosaki, S-y.; Shibasaki, M. Angew. Chem. Int. Ed. 2002, 41, 4680.Kalyani Patil @ Wipf Group
Mizutani, T.; Honzawa, S.; Tosaki, S-y.; Shibasaki, M. Angew. Chem. Int. Ed. 2002, 41, 4680.
Synthesis of (Synthesis of (±±)-)-Wortmannin Wortmannin - - ShibasakiShibasaki
H
OOMe
MeTBSO
AcOMeO
OO
OMe
i) OsO4, NMOii) (n-Bu)4NIO4iii) K2CO3, MeOHiv) TPAP, NMO
44%
H
OOMe
MeTBSO
OO
OMe
O
H
MeO
O
i) HC(NMe2)3, DMFii) Phosphate buffer pH 4-5
72%H
OOMe
MeTBSO
OO
OMe
O
H
MeO
O
HO
i) Me2SO4, K2CO3ii) 1N NaOHiii) PDC, NaOAc
55% H
OOMe
MeTBSO
OH
O
H
MeO
O
MeO
(COCl)2, DMSO75% H
OOMe
MeTBSO
OH
O
MeO
O
MeO
Et2NH, DCM H
OOMe
Me
TBSO
OH
O
MeO
O
Et2N
1N HCl60% H
OOMe
MeTBSO
O
MeO
OO
O
O O O
i) HF-TEAii) Ac2O, py
31%H
Me
MeAcO
O
MeO
OO
O
O
(±) - Wortmannin 41 steps 0.04%
Kalyani Patil @ Wipf Group
Synthesis of (Synthesis of (±±)-)-Halenaquinol Halenaquinol - Rodrigo- Rodrigo
(±) - Halenaquinol 10 steps 4%
PhS
OH
+
Me
OHOMe
PhI(O2CCF3)2, NaHCO3
O
O
SPhMe H H
OMe
+ Me
O
O
OMe
SPhTrimethylbenzene, 168 °C
36% O
SPh
O
Me H H
OMe
O
OMe
OMeToluene, 120 °C
94%O
SPh
O
Me H H
OMe
OMe
OMe
Oi) NaOMe, MeOHii) TFA, DCM
97%O
SPh
O
Me HOMe
OMe
i) p-Chloranilii) TiCl4, AcOH-H2O
29%O
O
MeOMe
OMe
O
i) CAN, MeOH-H2Oii) Na2S2O4, acetone-H2O
45%O
O
MeOH
OH
O
Sutherland, H. S.; Souza, F. E. S.; Rodrigo, R. G. A. J. Org. Chem. 2001, 66, 3639.Kalyani Patil @ Wipf Group
Yamaguchi, Y.; Hayakawa, K.; Kanematsu, K. Chem. Commun. 1987, 515.
Furan Ring Transfer ReactionFuran Ring Transfer Reaction
OO
OO
heatO
HB
O
O
HO
O
O
O
O
OHMeO
Viridin
O
t-BuOK, t-BuOH, 83 °C
Claisen Rearrangement
Kalyani Patil @ Wipf Group
O
O
O
OHMeO
Viridin
O O
O
X
O
O X
O
OO IMDAF O
OO
O
X
OH
O
Me
O
OH
Bn N C
CH2Cl2O
OO
O
HN
Me
Bn
Me2AlCl-78 °C to rt O
HN
O
OO
Bn
Me
77%
Sequential Sequential PasseriniPasserini//DielsDiels-Alder Reaction-Alder Reaction
Wright, D. L.; Robotham, C. V.; Aboud, K. Tetrahedron Lett. 2002, 43, 943.Kalyani Patil @ Wipf Group