A New Approach to Models of the 4,5-Dihydroxycyclopentenone Core of the Kodaistatins A–D: Elucidation of the Diol Configuration in Kodaistatin A

5 years ago

A New Approach to Models of the 4,5-Dihydroxycyclopentenone Core of the Kodaistatins A–D: Elucidation of the Diol Configuration in Kodaistatin A

Reinhard Brückner, David Peter

The kodaistatins A–D are strongly anti-diabetic natural products from Aspergillus terreus that hold some promise of a novel diabetes cure. However, considerations of that kind face two drawbacks: 1) The kodaistatins A–D contain a heavily substituted pulvinone/cyclopentenone combination; 2) they are 1,2-diols, the 3D structures of which have not been assigned yet. However, we can exclude two of the four possible stereostructures. We conclude that kodaistatin A is a trans-, not a cis-diol from NMR comparisons with a pair of cis, trans-isomeric kodaistatin models, which we synthesized in 11 and 12 steps, respectively. The stereocenters of the diol moiety arose from stereocomplementary, highly diastereoselective aldol additions of a lithium enolate or the corresponding silyl ketene acetal. The cyclopentenone moieties stemmed from intramolecular aldol additions and ensuing dehydrations. The requisite enolates were obtained by the reduction of α-bromoketones with samarium diiodide. Aldols are the key: We determined the relative configuration in the diol moiety of the natural product kodaistatin A, an anti-diabetic lead, being trans. This follows from NMR comparisons with cis, trans-isomeric models, which we synthesized in 11–12 steps. Early-stage aldolizations ensured stereocomplementarity by using either a lithium enolate or an enol silane. Cyclopentanone formations by intramolecular aldol additions of samarium enolates ensued.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701185