Stereoselective total synthesis of the cytotoxic lactone (−)-spicigerolide

A highly stereoselective synthesis of the naturally occurring lactone (−)-spicigerolide has been achieved utilizing OsO4-catalyzed dihydroxylation, CBS, Lindlar’s reductions, Still–Gennari, and Grignard reactions as the key reaction steps.

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(4S,5S)-4-[(Benzyloxy)methyl]-2,2-dimethyl-5-vinyl-1,3-dioxolaneC15H20O3[α]D25=+42.0 (c 1.0, CHCl3)Absolute configuration: (4S,5S)Source of chirality: l-(+)-DET

(1S)-1-{(4S,5S)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}ethane-1,2-diolC15H22O5[α]D25=+31.0 (c 1.0, CHCl3)Absolute configuration: (1S,4S,5S)Source of chirality: OsO4-catalyzed asymmetric dihydroxylation

(1S)-1-{(4S,5S)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}ethan-1-olC15H22O4[α]D25=+11.8 (c 1.0, CHCl3)Absolute configuration: (1S,4S,5S)Source of chirality: l-(+)-DET

(4S,5S)-4-[(Benzyloxy)methyl]-5-[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolaneC17H26O5[α]D25=+21.5 (c 1.0, CHCl3)Absolute configuration: (4S,5S,1S)Source of chirality: l-(+)-DET

({(4S,5S)-5-[(1S)-1-(Methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanolC10H20O5[α]D25=+3.6 (c 1.0, CHCl3)Absolute configuration: (4S,5S,1S)Source of chirality: l-(+)-DET

(4R)-6-[(4-Methoxybenzyl)oxy]-4-(methoxymethoxy)-1-{(4R,5S)-5-[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-2-hexyn-1-oneC25H36O9[α]D25=+44.0 (c 1.0, CHCl3)Absolute configuration: (4R,4R,5S,1S)Source of chirality: asymmetric synthesis

(1S,4R)-6-[(4-Methoxybenzyl)oxy]-4-(methoxymethoxy)-1-{(4S,5S)-5-[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-2-hexyn-1-olC25H38O9[α]D25=+18.1 (c 1.0, CHCl3)Absolute configuration: (1S,4S,4S,5S,1S)Source of chirality: CBS reduction

(4S,5S)-4-[(1S,4R)-6-[(4-Methoxybenzyl)oxy]-1,4-di(methoxymethoxy)-2-hexynyl]-5-[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolaneC27H42O10[α]D25=+51.0 (c 1.0, CHCl3)Absolute configuration: (4S,5S,1S,4S,1S)Source of chirality: asymmetric synthesis

(3R,6S)-3,6-Di(methoxymethoxy)-6-{(4S,5S)-5-[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-4-hexyn-1-olC19H34O9[α]D25=-60.8 (c 1.0, CHCl3)Absolute configuration: (3R,6S,4S,5S,1S)Source of chirality: asymmetric synthesis

Methyl(Z,5R,8S)-5,8-di(methoxymethoxy)-8-{(4S,5S)-5-[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-2-octen-6-ynoateC22H36O10[α]D25=-1.0 (c 1.0, CHCl3)Absolute configuration: (Z,5R,8S,4S,5S,1S)Source of chirality: asymmetric synthesis

(1S,2S)-2-(Acetyloxy)-1-[(1S,2S)-1,2-di(acetyloxy)propyl]-4-[(2R)-6-oxo-3,6-dihydro-2H-2-pyranyl]-3-butynyl acetateC20H24O10[α]D25=-41.3 (c 1.0, CHCl3)Absolute configuration: (1S,2S,1S,2S,2R)Source of chirality: asymmetric synthesis

((1S,2S,3Z)-2-(Acetyloxy)-1-[(1S,2S)-1,2-di(acetyloxy)propyl]-4-[(2R)-6-oxo-3,6-dihydro-2H-2-pyranyl]-3-butenyl acetateC20H26O10[α]D25=-23.4 (c 1.0, CHCl3)Absolute configuration: (1S,2S,3Z,1S,2S,2R)Source of chirality: asymmetric synthesis