Total Synthesis of
Asteltoxin
Robert Moesch
Organic Synthesis: Design
Dr. Totah CHE 686
1
Asteltoxin Back Round
- Secondary metabolite of Aspergillus
stellatus
- Mycotoxin: toxin from fungus
- Shows potent effects against E. coli
Schreiber, S.L.; Satake, K. J.Am. Chem. Soc. 1983, 105, 6723.
2
http://biology.clc.uc.edu/graphics/Aspergilliussp
Biological Back Round
- Isolated by Robert Vleggaar
in the 1970’s
Figure 1: Aspergillus sp.
- Isolated from maize (corn)
cultures
- Inhibitory effect of E. coli
ATP synthase
- ATPase-F1 is binging sight
- Bicyclic moiety responsible
for binding affinity and
inhibitory effects
. Satre, M. Biochem. Bicophys. Res. Commun. 1981, 100, 267
http://www.pnas.org/content/98/9/4966/F1.large.jpg
Figure 2: ATP synthase
3
S. L. Schreiber’s Retrosynthesis
- Highly convergent
- 3 and 4 made in short
reaction sequences
- 2 is difficult synthon
Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis: Targets,
Strategies and Methods. VCH Publishers: New York, 2003; p. 317-332
4
S. L. Shreiber’s Retrosynthesis
Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis: Targets,
Strategies and Methods. VCH Publishers: New York, 2003; p. 317-332
5
S. L. Shreiber’s Retrosynthesis
Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis: Targets, Strategies
and Methods. VCH Publishers: New York, 2003; p. 317-332
6
S. L. Shreiber’s Retrosynthesis
Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis: Targets, Strategies and Methods. VCH Publishers:
New York, 2003; p. 317-332
7
S. L. Shreiber’s Total Synthesis
Harris, T. M.; Harris, C. M. J. Org. Chem. 1966, 31, 1032.
8
S. L. Shreiber’s Total Synthesis
-First use of [2,3] sigmatropic rearrangment
.
Evans, D.A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147
9
S. L. Shreiber’s Total Synthesis
Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis: Targets,
Strategies and Methods. VCH Publishers: New York, 2003; p.
317-332
Kurti, L.; Czako, B. Strategic Applications of Named Reactions in
Organic Synthesis; Elsevier, 2005; p. 332.
10
S. L. Shreiber’s Total Synthesis
Nicolaou, K.C.; Sorensen, E.J. Classics in
Total Synthesis: Targets, Strategies and
Methods. VCH Publishers: New York, 2003;
p. 317-332
11
S. L. Shreiber’s Total Synthesis
Cram, D.J.; Abd Elhafez, F.A. J. Am. Chem. Soc.
1952, 74, 5828.
12
S. L. Shreiber’s Total Synthesis
13
S. L. Shreiber’s Total Synthesis
- Second (and third) use of [2,3] sigmatropic rearrangements
- Stared carbon: 3:1 mix of β/α epimers; β is desired
Corey, E.J.; Hoover, D.J. Tetrahedron Lett. 1982, 23, 3463.
14
S. L. Shreiber’s Total Synthesis
Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier, 2005; p. 368.
15
S. L. Shreiber’s Total Synthesis
16
S. L. Shreiber’s Total Synthesis
Key Points
- [2+2] photocycloaddition then oxidation gives 5
stereocenters
- Sulfinyl used as synthetic equivalent for aldehyde
- Longest linear sequence is only 8 steps; 17 total steps
- 2% overall yield 1
- Elegant synthesis for being so highly functionalized
1
Calculated by R. Moesch
17
References
-Satre, M. Biochem. Biophys. Res. Commun. 1981, 100, 267.
-Schreiber, S.L.; Satake, K. J.Am. Chem. Soc. 1983, 105, 6723.
-Schreiber, S.L.; Satake, K. J.Am. Chem. Soc. 1984, 106, 4186.
-Corey, E.J.; Hoover, D.J. Tetrahedron Lett. 1982, 23, 3463.
-Harris, T. M.; Harris, C. M. J. Org. Chem. 1966, 31, 1032.
-Evans, D.A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147.
-Steyn, P.S.; Vleggaar, R. J. Chem. Soc., Chem. Commun. 1984, 977.
-Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier, 2005; p. 332.
-Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier, 2005; p. 368.
-Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis: Targets, Strategies and Methods. VCH
Publishers: New York, 2003; p. 317-332.
-Cram, D.J.; Abd Elhafez, F.A. J. Am. Chem. Soc. 1952, 74, 5828.
18