alkaloids of the welwitindolinonefamily for july [email protected]. the welwitindolinone...
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SYNTHESIS OF NATURAL PRODUCTS
Alkaloids of the Welwitindolinone Family
SYNAPS
University of Crete
Tuesday 26th July 2011
Nigel S. Simpkins
School of Chemistry
University of Birmingham, U.K.
THE WELWITINDOLINONE ALKALOIDS - ISOLATION
▪ Isolated by from blue-green algae (cyanobacteria)
Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.
Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994, 116, 9935.
▪ Challenging synthesis
Welwitindolinone A isonitrile syntheses – Barran, Wood
Welwistatin – synthetic progress – see Trost, Org. Lett., 2009, 11, 3782.
(review: C. Avendano and J. C. Menendez, Curr. Org. Synth., 2004, 1, 65).
▪ Interesting biological activities (e.g. reversal of MDR)
THE WELWITINDOLINONE ALKALOIDS - ACTIVITY
MDR reversing activity
Welwistatin (R = NCS, R1 = Me) attenuates
resistance of MCF-7/ADR cells to vinblastine
taxol, actinomycin D, etc. at doses as low as
0.1 mM (non-cytotoxic level).
Also chemosensitization of SK-VLB-1 cells at
levels comparable to verapamil.
Smith and co-workers, Mol. Pharm. 1995, 47, 241.
THE WELWITINDOLINONE ALKALOIDS - BIOSYNTHESIS (I)
NH
NC
Me
H
Me
NH
Cl
NC
MeMe H
NH
CN
H
ClMe
H
Me
Me
NH
Cl
NC
Me
H
H
Me
Me
NH
O
O
Cl
Me
MeCNH
HMe
NH
O
Cl
CN
Me
H HMe
NH
O
CN
Cl
H
Me
Me
Me
NH
O
CN
Cl
H
Me
Me
Me
O
[O]
Cl
ClH
H
H
H [O]
12-epi-hapalindole E isonitrile
12-epi-fischerindole G isonitrile
12-epi-hapalindole G isonitrile
welwitindolinone B isonitrile
welwitindolinone A isonitrile
Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.
Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994, 116, 993.
THE WELWITINDOLINONE ALKALOIDS - BIOSYNTHESIS (II)
NMe
O
O
Cl
Me
MeCNOH
MeH
NMe
O
O
O
Me
MeCN
O
Me
NMe
O
O
Cl
Me
MeSCNH
HMe
NH
O
O
Cl
Me
MeCNH
HMe
NMe
O
O
Cl
Me
MeCNH
HMe
NMe
O
O
Cl
Me
MeCNO
HMe
OH
NMe
O
O
Cl
Me
MeCNOH
HMe
O
NMe
O
O
Cl
Me
MeSCNH
HMe
[H]
3-Hydroxy-N-methyl-welwitindolinone D isonitrile
N-Methylwelwitindolinone B isonitrile
N-MethylwelwitindolinoneB isothiocyanate
N-MethylwelwitindolinoneC isothiocyanate
N-MethylwelwitindolinoneC isonitrile
1O2
Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.
Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994, 116, 993.
THE WELWITINDOLINONE ALKALOIDS - BIOSYNTHESIS (III)
P. S. Baran and co-workers. J. Am. Chem. Soc. 2008, 130, 17938.
THE WELWITINDOLINONE ALKALOIDS - STRUCTURAL ANALYSIS
NMe
O
O
Cl
Me
MeSCNH
HMe
N-MethylwelwitindolinoneC isothiocyanate
NCS
NMe
Cl
OH
O
H
Distinctive overall shape
4 Asymmetric centres
3 Quaternary centres
Unusual vinyl chloride
NCS function
Oxindole
THE WELWITINDOLINONE ALKALOIDS - RETROSYNTHESIS
NMe
O
O
Cl
Me
MeSCNH
HMe
welwistatin
NMe
O
Cl
Me
MeX
HMe
NMe
O
O
Me
MeX
H
NMe
O
Z
Me
MeX
H
NZ
O
Z
X
NZ
O
Z
X
Hal +
E.g. option 1 - Cyclohexanone (enone) arylation, indole Michael, FG interconversions,
enolate substitution, late oxindole installation.
THE WELWITINDOLINONE ALKALOIDS - RETROSYNTHESIS
E.g. option 2- Oxindole Michael, Intramolecular enolate arylation, 6-ring annulation
enolate substitution and FG manipulation...(Steve Martin, Org. Lett, 2010, 12, 2492).