title: Diastereoseletive Transannular Oxa-Conjugate Addition Generates the 2,6-cis-Disubstituted Tetrahydropyran of Neopeltolide.
abstract: Transannular 2,6-disubstituted pyrans, like the one found in the cytotoxic marine natural product neopeltolide, are a key functional group in many polyketides. While oxa-conjugate additions have been shown to provide direct and rapid access to tetrahydropyrans in acyclic neopeltolide intermediates, a transannular strategy for construction of this ring system in a macrocyclic core has not been investigated. In this study, we demonstrate that a transannular oxa-conjugate addition strategy is a viable approach to the construction of the bicyclic core of neopeltolide. We show that transannular addition occurs readily with an α,β-unsaturated ketone as the Michael acceptor and does not occur when an α,β-unsaturated ester is the Michael acceptor. Our data indicates that oxa-conjugate addition is reversible and that the stereochemical outcome can be under thermodynamic control. Using computational chemistry, we show that the lowest energy diastereomer is the desired cis-pyran found in neopeltolide, and we experimentally demonstrate that the trans and cis diastereomers are interconvertible under reaction conditions with the cis-pyran product predominating. This oxa-conjugate addition strategy should provide a viable route to accessing the fully elaborated macrocyclic core of neopeltolide.
authors.affiliation: Department of Chemistry & Biomolecular Sciences, University of Ottawa , Ottawa, Ontario, Canada K1N 6N5.
authors.forename: Taylor P A
authors.initials: TP
authors.lastname: Hari
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: Burkardt I
authors.initials: BI
authors.lastname: Wilke
authors.affiliation: Department of Chemistry & Biomolecular Sciences, University of Ottawa , Ottawa, Ontario, Canada K1N 6N5.
authors.forename: James A
authors.initials: JA
authors.lastname: Davey
authors.affiliation: Department of Chemistry & Biomolecular Sciences, University of Ottawa , Ottawa, Ontario, Canada K1N 6N5.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Boddy