Formal total synthesis of aspergillides A and B

The formal total synthesis of the cytotoxic 14-membered macrolides, aspergillides A and B is described. A combination of a chiron approach and an asymmetric synthesis is adopted for the synthesis of the target macrolides. The required 2,6-syn and 2,6-anti tetrahydropyrans were constructed via a tandem Sharpless asymmetric epoxidation and 6-exo cyclization on δ-hydroxy allylic alcohols, as the key steps. The requisite chiral synthon was prepared from l-ascorbic acid.

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(S)-4-((S)-1-(4-Methoxybenzyloxy)but-3-enyl)-2,2-dimethyl-1,3-dioxolaneC17H24O4[α]D25=-26.9 (c 3.75, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (1S,1′S)

tert-Butyl ((S)-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(4-methoxybenzyloxy)propoxy)diphenylsilaneC32H42O5Si[α]D25=-33.3 (c 0.64, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (3S,1′S)

(2S,3S)-5- (tert-Butyldiphenylsilyloxy)-3-(4-methoxybenzyloxy)pentane-1,2-diolC29H38O5Si[α]D25=+31.3 (c 4.4, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (2S,3S)

tert-Butyl ((S)-3-(4-methoxybenzyloxy)-3-((S)-oxiran-2-yl)propoxy)diphenylsilaneC29H36O4Si[α]D25=-23.2 (c 3.1, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (S,S)

(3S,4S)-1-(tert-Butyldiphenylsilyloxy)-3-(4-methoxybenzyloxy)oct-7-en-4-olC32H42O4Si[α]D25=+8.4 (c 3.6, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (3S,4S)

(3S,4S)-4-(benzyloxy)-3-(4-methoxybenzyloxy)oct-7-enyloxy(tert-butyl)diphenylsilaneC39H48O4Si[α]D25=-39.9 (c 1.65, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (3S,4S)

(6S,7S,E)-Methyl 6-(benzyloxy)-9-(tert-butyldiphenylsilyloxy)-7-(4-methoxybenzyloxy)non-2-enoateC41H50O6Si[α]D25=-55.1 (c 3.75, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (6S,7S,2E) (Assigned by chemical transformation and NMR spectroscopy)

(6S,7S,E)-6-(Benzyloxy)-9-(tert-butyldiphenylsilyloxy)-7-(4-methoxybenzyloxy)non-2-en-1-olC40H50O5Si[α]D25=-41.3 (c 3.1, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (6S,7S,2E) (Assigned by chemical transformation and NMR spectroscopy)

(R)-1-((2R,5R)-5-((S)-3-(tert-Butyldiphenylsilyloxy)-1-(4-methoxybenzyloxy)propyl)tetrahydrofuran-2-yl)ethane-1,2-diolC33H44O6Si[α]D25=-3.8 (c 1.2, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (1R,2R,5R,5′S) (Assigned by chemical transformation and NMR spectroscopy)

(6S,7S,E)-6-(Benzyloxy)-9-(tert-butyldiphenylsilyloxy)non-2-ene-1,7-diolC32H42O4Si[α]D25=-11.3 (c 1.35, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (6S,7S,2E) (Assigned by chemical transformation and NMR spectroscopy)

(R)-1-((2R,5S,6S)-5-(Benzyloxy)-6-(2-(tert-butyldiphenylsilyloxy)ethyl)-tetrahydro-2H-pyran-2-yl)ethane-1,2-diolC32H42O5Si[α]D25=-63.7 (c 2.0, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (1R,2R,5S,6S) (Assigned by chemical transformation and NMR spectroscopy)

(2-((2S,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-pyran-2-yl)ethoxy)(tert-butyl)diphenylsilaneC32H40O3Si[α]D25=-45.75 (c 1.1, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (2S,3S,6R) (Assigned by chemical transformation and NMR spectroscopy)

2-((2S,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-pyran-2-yl)ethanolC16H22O3[α]D25=-39.8 (c 0.55, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (2S,3S,6R) (Assigned by chemical transformation and NMR spectroscopy)

2-((2S,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-pyran-2-yl)acetic acidC16H20O4[α]D25=-31.0 (c 0.25, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (2S,3S,6R) (Assigned by chemical transformation and NMR spectroscopy)

(1S,5S,11R,14S)-14-(Benzyloxy)-5-methyl-4,15 dioxabicyclo[9.3.1] pen- tadec-9E-en-3-oneC21H28O4[α]D25=-54.5 (c 0.6, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (1S,5S,11R,14S,9E) (Assigned by chemical transformation and NMR spectroscopy)

(3S,4S)-4-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)oct-7-en-3-olC31H40O3Si[α]D25=-7.3 (c 1.47, CHCl3)Source of chirality: l-ascorbic acidAbsolute configuration: (3S,4S)

(3R,4S)-4-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)oct-7-en-3-yl-4-nitrobenzoateC31H40O3Si[α]D25=-15.95 (c 1.03, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (3S,4S) (Assigned by chemical transformation and NMR spectroscopy)

(3R,4S)-4-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)oct-7-en-3-olC31H40O3Si[α]D25=-15.2 (c 1.88, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (3R,4S) (Assigned by chemical transformation and NMR spectroscopy)

((3R,4S)-4-(Benzyloxy)-3-(4-methoxybenzyloxy)oct-7-enyloxy)(tert-butyl)diphenylsilaneC39H48O4Si[α]D25=+1.4 (c 2.3, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (3R,4S) (Assigned by chemical transformation and NMR spectroscopy)

(6S,7R,E)-Methyl-6-(benzyloxy)-9-(tert-butyldiphenylsilyloxy)-7-(4-methoxybenzyloxy)non-2-enoateC41H50O6Si[α]D25=-10.95 (c 2.4, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (6S,7R,2E) (Assigned by chemical transformation and NMR spectroscopy)

(6S,7R,E)-6-(Benzyloxy)-9-(tert-butyldiphenylsilyloxy)-7-(4-methoxybenzyloxy)non-2-en-1-olC40H50O5Si[α]D25=-2.8 (c 4.5, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (6S,7R,2E) (Assigned by chemical transformation and NMR spectroscopy)

(6S,7R,E)-6-(Benzyloxy)-9-(tert-butyldiphenylsilyloxy) non-2-ene-1,7-diolC32H42O4Si[α]D25=-22.9 (c 4.5, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (6S,7R,2E) (Assigned by chemical transformation and NMR spectroscopy)

(S)-1-((2R,5S,6R)-5-(Benzyloxy)-6-(2-(tert-butyldiphenylsilyloxy)ethyl)-tetrahydro-2H-pyran-2-yl)ethane-1,2-diolC32H42O5Si[α]D25=+80.6 (c 2.0, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (1S,2R,5S,6R) (Assigned by chemical transformation and NMR spectroscopy)

(2-((2R,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-pyran-2-yl)ethoxy) (tert-butyl) diphenylsilaneC32H40O3Si[α]D25=+96.0 (c 1.75, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (2R,3S,6R) (Assigned by chemical transformation and NMR spectroscopy)

(2-((2R,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-pyran-2-yl)ethoxy) (tert-butyl) diphenylsilaneC16H22O3[α]D25=+152.5 (c 0.81, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (2R,3S,6R) (Assigned by chemical transformation and NMR spectroscopy)

2-((2R,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-pyran-2-yl)acetic acidC16H20O4[α]D25=+153.2 (c 1.8, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (2R,3S,6R) (Assigned by chemical transformation and NMR spectroscopy)

(S)-Hept-6-en-2-yl-2-((2R,3S,6R)-3-(benzyloxy)-6-vinyl-tetrahydro-2H-pyran-2-yl)acetateC23H32O4[α]D25=+100.8 (c 0.49, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (2R,3S,6R ,1′S) (Assigned by chemical transformation and NMR spectroscopy)

(1R,5S,11R,14S,Z)-14-(Benzyloxy)-5-methyl-4,15-dioxa-bicyclo[9.3.1]- pentadec-9-en-3-oneC21H28O4[α]D25=+68.1 (c 0.27, CHCl3)Source of chirality: l-ascorbic acid and stereoselective synthesisAbsolute configuration: (1R,5S,11R ,14S,9Z) (Assigned by chemical transformation and NMR spectroscopy)