17
Stachybotrys Metabolites: A History of Mis-Identification Rob Halter September 27th, 2003 Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A. S., J. Org. Chem., 2003, 7422.
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.
Stachybotrys Molecules
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A. S., J. Org. Chem., 2003, 7422.
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
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
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
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
Total Synthesis of Stachyflin
Taishi, T.; Takechi, S.; Mori, S. Tetrahedron Lett., 1998, 39, 4347.
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
Kende’s Retrosynthesis
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.
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.
Kende’s Synthesis
Dong, W.-P.; Zhong, M.; Guo, X.-C.; Kende, A.S., J. Org. Chem., 2003, 7422.
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.
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
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
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.
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.
