| Autor: |
Hari TP; Department of Chemistry & Biomolecular Sciences, University of Ottawa , Ottawa, Ontario, Canada K1N 6N5., Wilke BI; Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States., Davey JA; Department of Chemistry & Biomolecular Sciences, University of Ottawa , Ottawa, Ontario, Canada K1N 6N5., Boddy CN; Department of Chemistry & Biomolecular Sciences, University of Ottawa , Ottawa, Ontario, Canada K1N 6N5. |
| Abstrakt: |
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. |
