stachybotrys metabolites: a history of mis-identificationccc.chem.pitt.edu/wipf/current...
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Stachybotrys Metabolites: A History of Mis-Identification
Rob HalterSeptember 27th, 2003
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A. S., J. Org. Chem.,2003, 7422.
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Stachybotrys Molecules
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A. S., J. Org. Chem., 2003, 7422.
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Biological Activity
• Variety of biological activity• Antagonists of endothelin (cardiovascular)• Inhibititors of HIV-1 protease• Potent anti-influenza A activity• Selective inhibitor of myo-inositol monophosphatase (manic/depressive
disorders)• Anti-inflammatory
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Reason for Total Synthesis
IC50 = 1.3 mM for HumanETA
IC50 = 1.5 mM for HumanETA
J. Antibiot. 1996, 13 and J. Antibiot. 1995, 1389.
Almost identical biological structure raised flagAlmost identical structure also raised flagTotal synthesis was done to prove structure
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Synthesis of K-76
McMurry, J. E.; Erion, M. D. J. Am. Chem. Soc., 1985, 107, 2712.
OAcO
1. cyclopropytriphenylphosphorane
2. K2CO33. PBr3
Br
CH3COCH2COOMe, BuLi, NaH
O
O
O TBSCl
O
OTBSO
23 25
26 27
Hg(OTFA)2
ClHg
O
O O
57 %
OB
OPh
HO
1. Amberlyst-15
2. NaOH3. t-BuSLi
O
H
O
H
MeO
HO
HO
O
H
O
H
HO
O
41 K-76
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Total Synthesis of Stachyflin
Taishi, T.; Takechi, S.; Mori, S. Tetrahedron Lett., 1998, 39, 4347.
O OMe
OMeBnO
O H
12
1. (MeO3)CH, TsOH
2. 13, TMSOTf
O OMe
OMeBnOOMeO
1. H2, Pd/C then 1N HCl, acetone
2. H2, Pd/C, AcOH
O OMe
OMeOHO
1. TBDPSCl, tBuOK
2. [TfO], KHMDS
17
O OMe
OMeTBDPSOTfO
18
19
1. 15, Pd(PPh3)4, HMPA, THF
2. TBAF3. I2, propylene oxide
I
O
OMe
O
MeO
21
1. DBU, DMSO
2. BH33. H2O2, NaOH4. PCC5. 0.5 N HCl, Acetone O
O O
OMe
O
MeO
OO
22
TMSO
13
OOZnI
15
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Total Synthesis of Stachyflin
Taishi, T.; Takechi, S.; Mori, S. Tetrahedron Lett., 1998, 39, 4347.
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Synthesis of L-671,776
Falck, J. R.; Reddy, K. K.; Chandrasekhar, S. Tetrahedron Lett., 1997, 38, 5245.
OH
TBDPSO
1. Swern
2. Wittig66 %
TBDPSO
OMe
1. TMSCl. NaI, MeOH
2. NaBH4, MeOH3. MsCl, NEt3, then LiBr
TBDPSO
Br
1. n-BuLi, 16, then CuCN, then 4
2. 1 N HCl3. NaBH4, MeOH4. TBDPSCl, DMAP TBDPSO
OMOM
MOMO OTBDPS
(EtO)3SiCl/NaI
TBDPSO
HO OTBDPS
O
1. Bu4NBr3
2. n-Bu3Sn(CH=CH)2 Pd(PPh3)43. OsO4, NaIO44. TBAF
64 %
70 %
74 %
40 %HO
HO OH
O
HO
10
HO
HO OH
O O
H
13
2 3 4
6 7
+
OMOM
MOMOOMe
OMe
16
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Kende’s Retrosynthesis
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Failed Coupling Attempts
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A. S., J. Org. Chem., 2003, 7422.
No aldehyde addition, possiblybecause of steric repulsion betweenmethyl and benzyl group.
No reason given for lack orreactivity, presumably the sameas above.
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Kende’s Synthesis
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A. S., J. Org. Chem., 2003, 7422.
Almost identical coupling works,why??
Benzyl ether interferes with ring formation,stronger conditions also tried.
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Kende’s Synthesis
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A.S., J. Org. Chem., 2003, 7422.
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Wrong Regioisomer
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A. S., J. Org. Chem., 2003, 7422.
X-ray of 22 and 1
1H NMR and 13C NMR spectra of 1do not match authentic sample ofSpirobenzofuranlactam, their target.
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Correct Regio-isomer
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A. S., J. Org. Chem., 2003, 7422.
Spectra of 27 does match thenatural product
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Structure Revision
Structure proposed by Roggo et al. Hasthe wrong regiochemistry around thephenyl ring.
The new structure is consistent withother structures proposed for moleculesisolated from Stachybotrys species.
Correct Structure
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Dimer Formation
Since structure of “monomer” waswrong, it was very possible that thestructure of the “dimer” was alsowrong.The correct structure should beidentical to a molecule alreadyisolated, Stachybocin A.
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NMR Comparision
The NMR spectra confirm that Roggoalso mis-assigned the structure of the“pseudo-dimer”.
The NMR spectra of synthetic “pseudo-dimer” do not match that of previouslyisolated Stachybocin A.