Total synthesis of panaxydol and its stereoisomers as potential anticancer agents

An efficient total synthesis of natural panaxydol 1a and its seven stereoisomers 1b–h was accomplished; four diastereomers of the natural form were prepared for the first time. Our strategy involves the Cadiot-Chodkiewicz cross-coupling reaction of chiral terminal alkynes with bromoalkynes, the asymmetric alkynylation of aldehydes, and the enantioselective Sharpless epoxidation of allylic alcohols. Preliminary in vitro cytotoxicity evaluation indicated that some synthetic panaxydols possess anticancer activities, and (3S,9R,10S)-panaxydol 1e showed a particularly promising cytotoxic effect.

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(3R,9R,10S)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3R,9R,10S)-panaxydol]C17H24O2[α]D20 = −94.8 (c 1.1, CHCl3)Source of chirality: (S)-BINOL, (−)-DIPTAbsolute configuration: (3R,9R,10S)

(3R,9S,10R)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3R,9S,10R)-panaxydol]C17H24O2[α]D20 = +41.2 (c 1.2, CHCl3)Source of chirality: (S)-BINOL, (+)-DETAbsolute configuration: (3R,9S,10R)

(3R,9R,10R)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3R,9R,10R)-panaxydol]C17H24O2[α]D20 = −35.6 (c 0.7, CHCl3)Source of chirality: (S)-BINOL, (−)-DIPTAbsolute configuration: (3R,9R,10R)

(3R,9S,10S)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3R,9S,10S)-panaxydol]C17H24O2[α]D20 = −43.0 (c 1.4, CHCl3)Source of chirality: (S)-BINOL, (+)-DETAbsolute configuration: (3R,9S,10S)

(3S,9R,10S)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3S,9R,10S)-panaxydol]C17H24O2[α]D20 = −43.4 (c 0.6, CHCl3)Source of chirality: (R)-BINOL, (−)-DIPTAbsolute configuration: (3S,9R,10S)

(3S,9S,10R)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3S,9S,10R)-panaxydol]C17H24O2[α]D20 = +90.0 (c 0.5, CHCl3)Source of chirality: (R)-BINOL, (+)-DETAbsolute configuration: (3S,9S,10R)

(3S,9R,10R)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3S,9R,10R)-panaxydol]C17H24O2[α]D20 = +45.6 (c 1.2, CHCl3)Source of chirality: (R)-BINOL, (−)-DIPTAbsolute configuration: (3S,9R,10R)

(3S,9S,10S)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3S,9S,10S)-panaxydol]C17H24O2[α]D20 = +37.0 (c 1.2, CHCl3)Source of chirality: (R)-BINOL, (+)-DETAbsolute configuration: (3S,9S,10S)