A concise enantioselective synthesis of (+)-febrifugine

A short enantioselective synthesis of (+)-febrifugine, a potent antimalarial alkaloid, has been described based on the regioselective asymmetric dihydroxylation of a 1,4-dienic ester as the key step. The strategy also involves chemoselective [3,3]-sigmatropic rearrangement of 1,5-hexadiene-3-ol and intramolecular lactamization of azidolactone for the construction of piperidine core.

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(S)-Dihydro-5-((S)-1-hydroxybut-3-enyl)furan-2(3H)-oneC8H12O3[α]D25=+42 (c 0.6, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (4S,5S)

(S)-1-((S)-Tetrahydro-5-oxofuran-2-yl)but-3-enyl methanesulfonateC9H14O5S[α]D25=+28 (c 1.4, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (4S,5S)

(S)-5-((R)-1-Azidobut-3-enyl)-dihydrofuran-2(3H)-oneC8H11N3O2[α]D25=-21 (c 0.5, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (4R,5R)

(5S,6R)-6-Allyl-5-hydroxypiperidin-2-oneC8H13NO2[α]D25=+10 (c 0.8, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (5S,6R)

(2R,3S)-2-Allylpiperidin-3-olC8H15NO[α]D25=-46 (c 1, MeOH)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (2R,3S)

(2R,3S)-Benzyl 2-allyl-3-hydroxypiperidine-1-carboxylateC16H21NO3[α]D25=-37 (c 1, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (2R,3S)

(2R,3S)-Benzyl 2-allyl-3-(benzyloxy)piperidine-1-carboxylateC23H27NO3[α]D25=-37 (c 0.8, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (2R,3S)