Total Synthesis of Spiculoic Acid A

1
Oxetane vs. Dihydropyran Formation via a
Transannular Oxa-conjugate Addition
Stephen Houghton and Christopher N.
Boddy Department of Chemistry, Syracuse
University Syracuse, NY 13244
Laulimalide
Synthesis of macrocycle
Anti diastereomer
Oxa-conjugate additions

• Cytotoxic marine polyketide
• Potential anticancer agent
• Isolated from sponge in trace amounts
• Likely from symbiotic bacteria on sponge
• Epoxide is essential

Transannular oxa-conjugate additions can be
highly stereoselective
Anti diastereomer produces trans oxetane
Biosynthetic origin of Dihydropyran is unclear
E1cB-like mechanism
J. Org. Chem., 1988, 53, 3644-3646
Pyran and cis olefin may form via a non-enzymatic
method
Pacific marine sponge Cacospongia mycofijiensis
Biological activity

• IC50 10-50 ng/mL
• Stabilizes microtubules
• Similar quantitatively to taxol
• Binds to different site on tubulin polymer
• Active on Taxol epothilones A and B resistant
  cell lines

• Elimination is likely rate determining
• Not reversible
• Intermediate is not observed

Stereochemical assignment
Cis triene from cyclic carbonate

desoxylaulimalide
Microtubules shown in green
Test hypothesis with a model system
How are most cycloethers formed?
Acc. Chem. Res. 1998 31, 9-17. Used Rychnovsky
13C NMR method to determine stereochemistry.
Diols produce oxetanes
1,2-diol type structure implicates epoxide
opening mechanism
Triene may access dihydropyran
Computational studies

• Predict a stereoselective elimination
• E isomers cannot undergo oxa-conjugate addition

monensin
Epoxide opening does not explain all cycloethers

• Highly strained trans oxetane formed
• Basic conditions are unreactive

Two possible mechanisms
trans oxetane
Cis triene under Amberlyst conditions yields a
new compound as shown by LC-MS which could be the
dihydropyran
4 possible diastereomers
scytophycin C
laulimalide
Michael addition may generate cycloethers
cis triene

• SN2 displacement
• Elimination/Addition
• If SN2, anti diastereomer will produce cis oxetane

uncharacterized new compound
Acknowledgements The Boddy Research Group,
Deborah Kerwood, Syracuse University Dept. of
Chemistry