Organocatalytic Entry into 2,6-Disubstituted Aza-Achmatowicz Piperidinones: Application to (−)-Sedacryptine and Its Epimer

Abstract

Enantiomerically pure 2,6-disubstituted piperidinones were synthesized from furfural involving an organocatalyzed Mannich reaction, aza-Achmatowicz reaction, and an N-acyliminium ion-mediated coupling step. This approach was also successfully applied to a total synthesis of (-)-sedacryptine and one of its epimers.

Cutting-Edge and Time-Honored Strategies for Stereoselective Construction of C–N Bonds in Total Synthesis

“…Rutjes and co-workers implemented a proline-catalyzed enantioselective Mannich reaction between acetone and N -Boc-2-furanaldimine in the total synthesis of piperidine alkaloid (−)-sedacryptine. The aldimine was generated in situ from the corresponding phenyl sulfite adduct . In three separate recent reports, Kumar and co-workers describe α-amination of aliphatic aldehydes with azodicarboxylates catalyzed by proline in the enantioselective synthesis of several piperidine alkaloids.…”

Recent Developments in the Stereoselective Synthesis of Nitrogen‐Containing Heterocycles using N‐Acylimines as Reactive Substrates

“…Piperidinones are versatile intermediates in various syntheses of functionalized nitrogenated heterocycles . The organocatalyzed addition of alkanals to the N ‐acylimine produced in situ from α‐amido sulfone 133 results in the stereoselective formation of amino aldehydes 134 which are not isolated but immediately reduced to the corresponding alcohol 135 using sodium borohydride (Scheme ) …”

Iridium-Catalyzed Highly Regioselective and Diastereoselective Allylic Etherification To Access cis-2,6-Disubstituted Dihydropyridinones

“…HRMS (ESI-TOF) m / z : [M + Na] + calcd for C 15 H 19 NO 4 SNa 332.0927, found 332.0934. Compound 3n is a known compound, and the proton and carbon spectrum are fully consistent with literature reported . The regio- and diastereoselectivity are absolutely determined in this case.…”

“…Substituted pyridinium ions or cyclic imines are usually employed as the intermediates for the synthesis of piperidine. Padwa, O’Doherty, and other groups have finished the synthesis of related (±)-all- cis -piperidinol alkaloids or iminosugars through the formation of iminium ions under strongly acidic conditions . The Liu group disclosed an enantioselective C–H oxidation process to generate iminium ions .…”