The first synthesis of a 12-membered macrolide natural product via a RCM protocol: determination of absolute stereochemistry

The first synthesis of (10S,12R)-10-hydroxy-12-methyl-1-oxacyclododecane-2,5-dione and its C12 epimer is reported, thereby assigning the absolute stereochemistry of the natural product. The strategy utilizes a syn selective reduction, Yamaguchi esterification, and ring-closing metathesis as the key steps.

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(2S,4S)-4-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-6-hepten-2-olC23H32O2Si[α]D = +41.3 (c 0.9, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,4S)

(2R,4S)-4-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-6-hepten-2-olC23H32O2Si[α]D = −3.3 (c 2.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,4S)

(1S,3S)-3-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-1-methyl-5-hexenyl-4-(benzyloxy)-6-heptenoateC37H48O4Si[α]D = +25.3 (c 0.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,3S)

(1R,3S)-3-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-1-methyl-5-hexenyl-4-(benzyloxy)-6-heptenoateC37H48O4Si[α]D = +36.5 (c 0.35, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,3S)

(10S,12S)-5-[1-(Benzyloxy)]-10-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-12-methyl-1-oxa-7-cyclododecen-2-oneC35H44O4Si[α]D = +9.5 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (10S,12S)

(10S,12R)-5-[1-(Benzyloxy)]-10-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-12-methyl-1-oxa-7-cyclododecen-2-oneC35H44O4Si[α]D = +45.9 (c 0.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (10S,12R)

(10S,12S)-10-Hydroxy-12-methyl-1-oxacyclododecane-2,5-dioneC12H20O4[α]D = +68.1 (c 0.46, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (10S,12S)

(10S,12R)-10-Hydroxy-12-methyl-1-oxacyclododecane-2,5-dioneC12H20O4[α]D = −52.2 (c 0.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (10S,12R)