Diastereoselective Synthesis of 2,3,6-Trisubstituted Tetrahydropyran-4-ones via Prins Cyclizations of Enecarbamates: A Formal Synthesis of (+)-Ratjadone A

Abstract

Enecarbamates are shown to be excellent terminating groups for Prins cyclizations. A noteworthy feature of this methodology is the easy, stereoselective construction of the cyclization precursors by alkylation of metalated (E)-enecarbamates with epoxides. The stereochemistry of the resultant trisubstituted (E)-enecarbamates is then transferred with high fidelity to afford the frequently observed and biologically significant all-cis-2,3,6-trisubstituted tetrahydropyran substructures of naturally occurring compounds. Other substituted tetrahydropyrans, including 2,3,5,6-tetrasubstituted, cis-2,3-disubstituted, and cis-2,6-disubstituted, are also accessible. This methodology facilitated an exceptionally concise formal total synthesis of the nuclear export inhibitor (+)-ratjadone A.

(+)-Sorangicin A: evolution of a viable synthetic strategy

“…Equally daunting, Mitsunobu inversion of the undesired diastereomer led only to elimination. At the time that these results were recorded, a nearly identical observation, including Mitsunobu elimination, was reported by Funk and Cossey 65 for an analogous 2,3,6- cis - cis -trisubstituted tetrahydropyranone. More recently, Yadav and co-workers 10a corroborated both observations in their synthesis of an advanced THP fragment for (+)-sorangicin A.…”

(+)-Sorangicin A: evolution of a viable synthetic strategy

“…Equally daunting, Mitsunobu inversion of the undesired diastereomer led only to elimination. At the time that these results were recorded, a nearly identical observation, including Mitsunobu elimination, was reported by Funk and Cossey 65 for an analogous 2,3,6- cis - cis -trisubstituted tetrahydropyranone. More recently, Yadav and co-workers 10a corroborated both observations in their synthesis of an advanced THP fragment for (+)-sorangicin A.…”

(+)-Sorangicin A Synthetic Studies. Construction of the C(1−15) and C(16−29) Subtargets

“…Equally daunting, Mitsunobu inversion of the undesired diastereomer resulted only in elimination. A nearly identical observation, including Mitsunobu elimination, was recently reported by Funk and Cossey for an analogous 2,3,6- cis - cis -trisubstituted tetrahydropyranone ), calling upon 1,4-stereoinduction to install the C(25) hydroxyl prior to pyran ring formation.…”

Evolution of a Total Synthesis of (−)-Kendomycin Exploiting a Petasis−Ferrier Rearrangement/Ring-Closing Olefin Metathesis Strategy

“…Continuing with this analysis, recognition of the cis -5,9-disubstituted tetrahydropyran in (−)-kendomycin ( 1 ) suggested the Petasis−Ferrier union/rearrangement tactic recently developed in our laboratory to construct similarly substituted cis -2,6-disubstituted tetrahydropyrans. , Required here would be the sterically congested aromatic aldehyde 6 and β -hydroxy acid 7 .…”

(+)-Sorangicin A: evolution of a viable synthetic strategy

“…Equally daunting, Mitsunobu inversion of the undesired diastereomer led only to elimination. At the time that these results were recorded, a nearly identical observation, including Mitsunobu elimination, was reported by Funk and Cossey 65 for an analogous 2,3,6- cis - cis -trisubstituted tetrahydropyranone. More recently, Yadav and co-workers 10a corroborated both observations in their synthesis of an advanced THP fragment for (+)-sorangicin A.…”

(+)-Sorangicin A Synthetic Studies. Construction of the C(1−15) and C(16−29) Subtargets

“…Equally daunting, Mitsunobu inversion of the undesired diastereomer resulted only in elimination. A nearly identical observation, including Mitsunobu elimination, was recently reported by Funk and Cossey for an analogous 2,3,6- cis - cis -trisubstituted tetrahydropyranone ), calling upon 1,4-stereoinduction to install the C(25) hydroxyl prior to pyran ring formation.…”

Evolution of a Total Synthesis of (−)-Kendomycin Exploiting a Petasis−Ferrier Rearrangement/Ring-Closing Olefin Metathesis Strategy

“…Continuing with this analysis, recognition of the cis -5,9-disubstituted tetrahydropyran in (−)-kendomycin ( 1 ) suggested the Petasis−Ferrier union/rearrangement tactic recently developed in our laboratory to construct similarly substituted cis -2,6-disubstituted tetrahydropyrans. , Required here would be the sterically congested aromatic aldehyde 6 and β -hydroxy acid 7 .…”

(+)-Sorangicin A: evolution of a viable synthetic strategy

“…Equally daunting, Mitsunobu inversion of the undesired diastereomer led only to elimination. At the time that these results were recorded, a nearly identical observation, including Mitsunobu elimination, was reported by Funk and Cossey 65 for an analogous 2,3,6- cis - cis -trisubstituted tetrahydropyranone. More recently, Yadav and co-workers 10a corroborated both observations in their synthesis of an advanced THP fragment for (+)-sorangicin A.…”

(+)-Sorangicin A Synthetic Studies. Construction of the C(1−15) and C(16−29) Subtargets

“…Equally daunting, Mitsunobu inversion of the undesired diastereomer resulted only in elimination. A nearly identical observation, including Mitsunobu elimination, was recently reported by Funk and Cossey for an analogous 2,3,6- cis - cis -trisubstituted tetrahydropyranone ), calling upon 1,4-stereoinduction to install the C(25) hydroxyl prior to pyran ring formation.…”

Evolution of a Total Synthesis of (−)-Kendomycin Exploiting a Petasis−Ferrier Rearrangement/Ring-Closing Olefin Metathesis Strategy

“…Continuing with this analysis, recognition of the cis -5,9-disubstituted tetrahydropyran in (−)-kendomycin ( 1 ) suggested the Petasis−Ferrier union/rearrangement tactic recently developed in our laboratory to construct similarly substituted cis -2,6-disubstituted tetrahydropyrans. , Required here would be the sterically congested aromatic aldehyde 6 and β -hydroxy acid 7 .…”