title: Enantioselective, Convergent Synthesis of the Ineleganolide Core by a Tandem Annulation Cascade.
abstract: An enantioselective and diastereoselective approach toward the synthesis of the polycyclic norditerpenoid ineleganolide is disclosed. A palladium-catalyzed enantioselective allylic alkylation is employed to stereoselectively construct the requisite chiral tertiary ether and facilitate the synthesis of a 1,3-cis-cyclopentenediol building block. Careful substrate design enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold by a diastereoselective cyclopropanation-Cope rearrangement cascade under unusually mild conditions. Computational evaluation of ground state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures. This work represents the first successful synthesis of the core structure of any member of the polycyclic norcembranoid diterpene family of natural products. Advanced synthetic manipulations generated a series of natural product-like compounds that were shown to possess selective secretory antagonism of either interleukin-5 or interleukin-17. This bioactivity stands in contrast to the known antileukemic activity of ineleganolide and suggests the norcembranoid natural product core may serve as a useful scaffold for the development of diverse therapeutics.
authors.affiliation: Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Craig
authors.affiliation: Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Roizen
authors.affiliation: Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Russell C
authors.initials: RC
authors.lastname: Smith
authors.affiliation: Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Jones
authors.affiliation: Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Virgil
authors.affiliation: Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Stoltz