Pyranone natural products as inspirations for catalytic reaction discovery and development

Benjamin R. McDonald, Karl A. Scheidt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Conspectus Natural products continue to provide a ealth of opportunities in the areas of chemical and therapeutic development. These structures are effective measuring sticks for the current state of chemical synthesis as a field and constantly inspire ne approaches and strategies. Tetrahydropryans and tetrahydropyran-4-ones are found in numerous bioactive marine natural products and medicinal compounds. Our interest in exploring the therapeutic potential of natural products containing these motifs provided the impetus to explore ne methods to access highly functionalized, chiral pyran molecules in the most direct and rapid fashion possible. This goal led to exploration and development of a Leis acid-mediated Prins reaction beteen a chiral β-hydroxy-dioxinone and aldehyde to produce a pyran-dioxinone fused product that can be processed in a single pot operation to the desired tetrahydropyran-4-ones in excellent yield and stereoselectivity. Although the Prins reaction is a commonly employed approach toard pyrans, this method uniquely provides a 3-carboxy-trisubstituted pyran and utilizes dioxinones in a manner that as underexplored at the time. The 3-carboxy substituent served as a key synthetic handhold hen this method as applied to the synthesis of highly functionalized pyrans ithin the macrocyclic natural products neopeltolide, okilactiomycin, and exiguolide. hen employed in challenging macrocyclizations, this tetrahydropyranone forming reaction proved highly stereoselective and robust.Another major thrust in our lab has been the synthesis of benzopyranone natural products, specifically flavonoids, because this broad and diverse family of compounds possesses an equally broad range of biological and medicinal applications. ith the goal of developing a broad platform toard the synthesis of enantioenriched flavonoid analogs and natural products, a biomimetic, asymmetric catalytic approach toard the synthesis of 2-aryl benzopyranones as developed. A bifunctional hydrogen bonding/Brønstead base catalyst as ultimately found to enable this transformation in analogous manner to the biosynthesis via the enzyme chalcone isomerase. Employing thiourea catalysts derived from the pseudoenantiomeric quinine and quinidine, alkylidene β-ketoesters can be isomerized to 3-carboxy flavanones and decarboxylated in a single pot operation to stereodivergently provide highly enantioenriched flavanones in excellent yield. This method as applied to the synthesis of the abyssinone family of natural products, as ell as the rotenoid, deguelin. An analogous method to isomerize chalcones as developed and applied to the synthesis of isosilybin A. In both of these related endeavors, the need for novel enabling methodologies toard the efficient creation of targeted molecular complexity drove the discovery, development and deployment of these stereoselective catalytic transformations.

Original languageEnglish (US)
Pages (from-to)1172-1183
Number of pages12
JournalAccounts of chemical research
Volume48
Issue number4
DOIs
StatePublished - Apr 21 2015

ASJC Scopus subject areas

  • Chemistry(all)

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