Enantioselective total synthesis of aigialomycin D

An efficient, convergent approach for the total synthesis of aigialomycin D 1 is described. Key features of the synthetic strategy include (a) a Sharpless asymmetric epoxidation reaction and selective opening of a 2,3-epoxy alcohol to elaborate the two hydroxy-bearing stereogenic centers at the C5′ and C6′ positions; (b) a Kocienski modified Julia protocol to construct the two E-configured double bonds; and (c) Yamaguchi macrolactonization to acccess the 14-membered macrocyclic ring.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

((2R,3R)-3-(3-(Benzyloxy)propyl)oxrian-2-yl)methanolC13H18O3Ee = 91%[α]D20=+28 (c 1.50, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 2R,3R

(2R,3S)-6-(Benzyloxy)-1,2-dihydroxyhexan-3-yl benzoateC20H24O5Ee = 91%[α]D20=-19 (c 1.45, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 2R,3S

(2R,3S)-6-(Benzyloxy)hexane-1,2,3-triolC13H20O4Ee = 91%[α]D20=-8 (c 1.50, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 2R,3S

(2R,3S)-6-(Benzyloxy)-2,3-dihydroxyhexyl pivalateC18H28O5Ee = 91%[α]D20=-20 (c 1.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 2R,3S

((4R,5S)-5-(3-(Benzyloxy)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl pivalateC21H32O5Ee = 91%[α]D20=+13 (c 1.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 4R,5S

((4R,5S)-5-(3-Hydroxypropyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl pivalateC14H26O5Ee = 91%[α]D15=+77 (c 0.9, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 4R,5S

((4R,5S)-5-(3-(1-Phenyl-1H-tetrazol-5-ylsulfonyl)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl pivalateC21H30O6N4SEe = 91%[α]D15=-8 (c 1.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 4R,5S

(S)-3-Hydroxybutyl benzoateC11H14O3Ee = 96%[α]D14=+25 (c 2.00, CHCl3)Source of chirality: enantiopure starting materialAbsolute configuration: S

(S)-3-(tert-Butyldimethyl silyl ether)butyl benzoateC17H28O3SiEe = 96%[α]D14=+33 (c 2.05, CHCl3)Source of chirality: enantiopure starting materialAbsolute configuration: S

((S)-4-Hydroxybutan-2-yloxy)(tert-butyl)dimethylsilaneC10H24O2SiEe = 96%[α]D14=+25 (c 2.00, CHCl3)Source of chirality: enantiopure starting materialAbsolute configuration: S

((S)-4-(1-phenyl-1H-tetrazol-5-ylsulfonyl)butan-2-yloxy)(tert-butyl)dimethylsilaneC17H28N4O3SSiEe = 96%[α]D15=+12 (c 1.50, CHCl3)Source of chirality: enantiopure starting materialAbsolute configuration: S

((4R,5S)-5-((E)-4-(2-Bromo-3,5-bis(methoxymethoxy)phenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl pivalateC25H37BrO8Ee = 91%[α]D14=+11 (c 1.20, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 4R,5S

((4R,5S)-5-((E)-4-(2-Bromo-3,5-bis(methoxymethoxy)phenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanolC20H29BrO7Ee = 91%[α]D14=+13 (c 2.00, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 4R,5S

(4S,5S)-5-((E)-4-(2-Bromo-3,5-bis(methoxymethoxy)phenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolane-4-carbaldehydeC20H27BrO7Ee = 91%[α]D14=+3 (c 2.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 4R,5S

((S,4E)-5-((4R,5S)-5-((E)-4-(2-Bromo-3,5-bis(methoxymethoxy)phenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-en-2-yloxy)(tert-butyl)dimethylsilaneC30H49BrO7SiDr = 99%[α]D14=-17 (c 1.00, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: R,S,S

(S,4E)-5-((4R,5S)-5-((E)-4-(2-Bromo-3,5-bis(methoxymethoxy)phenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-en-2-olC24H35BrO7Dr = 99%[α]D15=-3 (c 0.85, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: R,S,S

2-((1E)-4-((4S,5R)-5-((S,E)-4-Hydroxypent-1-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-1-enyl)-4,6-bis(methoxymethoxy)benzoic acidC25H36O9Dr = 99%[α]D15=-20 (c 1.00, CH3COCH3)Source of chirality: asymmetric synthesisAbsolute configuration: R,S,S

(1′E,5′S,6′R,7′E,10′S)-1′,7′-diene-5′,6′-ketal-2,4-bis(methoxymethoxy)resorcyclic macrolideC25H34O8Dr = 99%[α]D15=-120 (c 1.00, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: R,S,S

Aigialomycin DC18H22O6Dr = 99%[α]D15=-21 (c 0.43, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: R,S,S