Asymmetric synthesis of febrifugine and isofebrifugine using yeast reduction

Abstract

The antimalarial agents febrifugine ((+)-1) and isofebrifugine ((+)-2) were asymmetrically synthesized from chiral piperidin-3-ol ((+)-4), which was prepared by the reductive dynamic optical resolution of the 3-piperidone derivatives ((±)-3) using baker's yeast.Febrifugine ((+)-1) is an antimalarial agent that was isolated from Dichroa febrifuga and Hydrangea umbellata along with isofebrifugine ((+)-2). 1a-c The plane structure 2a of (+)-1 and (+)-2 was first proposed in 1950. Subsequently, the relative 2b and absolute 2c structures were proposed on the basis of Baker's synthetic work. 3a-c The relative configuration 2d of (+)-1 was corrected in 1973 and then the absolute structures 2e,f of (+)-1 and (+)-2 were corrected in 1999 (Fig. 1). We previously synthesized the racemates of (+)-1 and (+)-2 via the unusual Claisen rearrangement and highly diastereoselective reduction. 4a,b In this paper, we describe the asymmetric synthesis of (+)-1 and (+)-2 based on our synthetic method.

Synthesis, Stereochemistry, and Antimicrobial Activity of 2,6-Diaryl-3-(arylthio)piperidin-4-ones

“…17,18) Piperidin-3-one derivatives are used as precursors for the synthesis of antimalarial agents febrifugine and isofebrifugine. 19) Earlier reports have indicated that biological activity is significant in piperidone systems possessing aromatic substitutions in the 2-and/or 6-positions.…”

Detailed studies on the enantioselective synthesis and HPLC enantioseparation of N‐protected 3‐hydroxyglutarimides

“…1 Recently, we have demonstrated that (S)-3-hydroxyglutarimide could serve as a useful building block for the asymmetric synthesis of bioactive piperidines such as (+)-febrifugine, (+)-isofebrifugine, 2 (+)-L-733,060, and (+)-CP-99,994. 3,4 In the early phase of these studies, it was observed that the optical rotation of benzyl [ 5 and +78.5 (c = 1.0, EtOH) 6 }. This implied that racemization took place in the synthetic route, probably during the base-promoted ring-expansion reaction leading to 3-hydroxyglutarimide.…”

Biological Potential and Chemical Properties of Pyridine and Piperidine Fused Pyridazine Compounds: Pyridopyridazine a Versatile Nucleus

“…Among the nitrogen containing six-member heterocylic compounds, the pyridine or piperidine structural is often found in naturally occurring bioactive compounds such as alkaloids 2 . Piperidinone derivatives are used as precursors for the synthesis of anti-malarial, febrifugine, and isofebrifugine 3 . Piperidinones display varied and potent biological properties like antiviral, antitumour, analgesic, local anaesthetic, antimicrobial, fungicidal, herbicidal, insecticidal, antihistaminic, antiinflammatory, anticancer, CNS stimulant, and depressant properties [4][5][6] .…”