A Dötz benzannulation route to the enantioselective synthesis of (−)- and (+)-juglomycin A

Two synthetic routes based on a Dötz benzannulation toward the enantioselective synthesis of naphthoquinone antibiotics (−)- and (+)-juglomycin A are described. The stereoinducing step is based on asymmetric dihydroxylation. The syntheses are completed in seven to eight steps from Fischer carbene 12.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(4R,5R)-4-Hydroxy-5-(1′,4′,5′-trimethoxynaphthalen-2′-yl)dihydrofuran-2(3H)-oneC17H18O6Ee = 99.5[α]D25=-11.2 (c 0.6, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (4R,5R)

(2S,3R)-Ethyl 5-(tert-butyldimethylsilyloxy)-2,3-dihydroxypentanoateC13H28O5SiEe = 92[α]D25=-3.6 (c 0.9, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (2S,3R)

(2S,3R)-Ethyl 2,3-isopropylidenedioxy-5-(tert-butyldimethylsilyloxy)pentanoateC16H32O5Si[α]D25=+11.6 (c 1.16, CHCl3)Initial source of chirality: asymmetric dihydroxylationAbsolute configuration: (2S,3R)

(3R,4R)-3,4-Isopropylidenedioxy-6-(tert-butyldimethylsilyloxy)hex-1-yneC15H28O3Si[α]D25=+7.7 (c 0.86, CHCl3)Initial source of chirality: asymmetric dihydroxylationAbsolute configuration: (3R,4R)

(1′R,2′R)-2-(1′,2′-Isopropylidenedioxy)-4′-(tert-butyldimethylsilyloxy)butyl-4,5-dimethoxynaphthalen-1-olC25H38O6Si[α]D25=+3.7 (c 0.48, CHCl3)Initial source of chirality: asymmetric dihydroxylationAbsolute configuration: (1′R,2′R)

(1R,2R)-tert-Butyldimethyl-[1-(1′,4′,5′-trimethoxynaphthalen-2′-yl)-1,2-isopropylidenedioxy-4-butoxy]silaneC26H40O6Si[α]D25=+22.4 (c 0.86, CHCl3)Initial source of chirality: asymmetric dihydroxylationAbsolute configuration: (1R,2R)

(1R,2R)-1-(1′,4′,5′-Trimethoxynaphthalen-2′-yl)-1,2-isopropylidenedioxybutan-4-olC20H26O6[α]D25=+30.5 (c 0.24, CHCl3)Initial source of chirality: asymmetric dihydroxylationAbsolute configuration: (1R,2R)

(3R,4R)-4-(1′,4′,5′-Trimethoxynaphthalen-2′-yl)-3,4-isopropylidenedioxybutanoic acidC20H24O7[α]D25=+19.4 (c 0.20, CHCl3)Initial source of chirality: asymmetric dihydroxylationAbsolute configuration: (3R,4R)

(2′R,3′R)-2-(3′-Hydroxy-5′-oxotetrahydrofuran-2′–yl)-5-methoxynaphthalene-1,4-dioneC15H12O6[α]D25=-57.8 (c 0.20, MeOH)Initial source of chirality: asymmetric dihydroxylationAbsolute configuration: (2′R,3′R)

(−)-Juglomycin AC14H10O6[α]D25=-51.6 (c 0.25, CDCl3)Initial source of chirality: asymmetric dihydroxylationAbsolute configuration: (2R,3R)