A New Approach to Models of the 4, 5‐Dihydroxycyclopentenone Core of the Kodaistatins A–D: Elucidation of the Diol Configuration in Kodaistatin A. Issue 50 (27th June 2017)

• Record Type: Journal Article
• Authors: Peter, David; Brückner, Reinhard
• Is Part Of: Chemistry. Volume 23:Issue 50(2017)
• Page Start: 12104
• Page End: 12109
• Publication Date: 2017-06-27
• Subjects: aldol reaction -- α-bromoketones -- cyclopentenone -- samarium enolate -- structure elucidation; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201701185
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : 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.