RCM mediated synthesis of macrosphelides I and G

The total synthesis of 16-membered macrolides, macraosphelides I and G, has been achieved starting from ethyl-(S)-lactate and (S)-malic acid. A combination of Jacobsen’s hydrolytic kinetic resolution and Sharpless epoxidation is used for the creation of two stereogenic centres, while Yamaguchi esterification and ring-closing metathesis strategies were used for the construction of the lactone ring.

Graphical abstractRCM mediated synthesis of macrosphelides I and G from (S)-lactic acid, (S)-malic acid and propylene oxide is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide

(4R,5S)-5-(Benzyloxy)-4-[1-(tert-butyl)-1,1-dimethylsilyl]oxyhexanoic acidC19H32O4Si[α]D = +22.0 (c 0.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4R,5S)

(2S,3R)-3-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4-penten-2-olC11H24O2Si[α]D = +51.7 (c 0.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)

(3R)-3-Acryloyloxybutanoic acidC7H10O4[α]D = +10.3 (c 0.2, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (3R)

(E,5S)-5-[(4-Methoxybenzyl)oxy]-2-hexenoic acidC14H18O4[α]D = +58.1 (c 0.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5S)

(1R)-3-[((1S,2R)-2-Hydroxy-5-[(1S,2R)-2-hydroxy-1-methyl-3-butenyl]oxy-1-methyl-5-oxopentyl)oxy]-1-methyl-3-oxopropyl acrylateC18H28O8[α]D = +1.3 (c 0.5, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,1aS,2aR,1bS,2bR)

(1S,2R)-2-Hydroxy-1-methyl-3-butenyl (E,5S)-5-[(3R)-3-(acryloyloxy)butanoyl]oxy-2-hexenoateC18H26O7[α]D = −23.7 (c 0.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,5aS,3bR)

Macrosphelide I (1)C16H24O8[α]D = +9.6(c 0.15, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,8R,9S,14R,15S)

Macrosphelide G (2)C16H22O7[α]D = +54.3 (c 0.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,8R,9S,15S)