Total synthesis of aculeatins A and B from d-glucose

A simple and highly efficient total synthesis of cytotoxic dioxa-dispiroketals aculeatins A and B is disclosed. The key steps include alkynylation of a chiral aldehyde and in situ deprotection, spirocyclization of a 3,5-acetonide protected ketone.

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(3aR,5S,6aR)-2,2-Dimethyl-5-[(Z)-1-tridecenyl] perhydrofuro[2,3-d][1,3]dioxoleC20H36O3[α]D = −10.5 (c 0.92, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (3aR,5S,6aR)

(3aR,5R,6aR)-2,2-Dimethyl-5-tridecyl perhydrofuro[2,3-d][1,3]dioxoleC20H38O3[α]D = −12.3 (c 1.7, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (3aR,5R,6aR)

(3R,5R)-5-Tridecyltetrahydro-2,3-furandiolC17H34O3[α]D = +5.1 (c 0.5, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (3R,5R)

(3R,5R)-1-Octadecene-3,5-diolC18H36O2[α]D = +3.2 (c 0.87, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (3R,5R)

(4R,6R)-2,2-Dimethyl-4-tridecyl-6-vinyl-1,3-dioxaneC21H40O3[α]D = +1.25 (c 0.68, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (4R,6R)

2-[(4S,6R)-2,2-Dimethyl-6-tridecyl-1,3-dioxane-4yl]-1-ethanolC21H42O3[α]D = +25 (c 0.68, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (4S,6R)

4-[4-(Benzyloxy)phenyl]-1-[(4S,6R)-2,2-dimethyl-6-tridecyl-1,3-dioxane-4-yl]-3-butyn-2-olC36H52O4[α]D = −28 (c 0.68, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (4S,6R)

4-{(3S)-4-[(4S,6R)-2,2-Dimethyl-6-tridecyl1,3-dioxan-4-yl]-3-hydroxybutyl}phenolC29H50O4[α]D = −25 (c 0.68, CHCl3)Source of chirality: d-glucose, chiral alkynylationAbsolute configuration: (3S,4S,6R)

1-[(4R,6R)-2,2-Dimethyl-6-tridecyl-1,3-dioxane-4-yl]-4-(4-hydroxyphenyl)-2-butanonelC29H48O4[α]D = −3.9 (c 0.55, CHCl3)Source of chirality: d-glucoseAbsolute configuration: (4R,6R)

Aculeatin AC26H42O4[α]D = −5.2 (c 0.73, CHCl3)Source of chirality: d-glucose, spirocyclizationAbsolute configuration: (2R,4R,6R)

Aculeatin BC26H42O4[α]D = +54 (c 0.2, CHCl3)Source of chirality: d-glucose, spirocyclizationAbsolute configuration: (2R,4R,6S)