First total synthesis of the E- and Z-isomers of cytospolide-D

A simple, convergent, and efficient approach for the total synthesis of the bioactive E- and Z-isomers of cytospolide-D is described. The key features of the synthetic strategy include stereoselective methylation, regioselective epoxide opening, olefin cross-metathesis, and a Yamaguchi protocol reaction for the formation of the E-olefinic geometry of the 10 membered ring; Steglich esterification and ring-closing metathesis reaction for the formation of the 10 membered ring with a Z-olefinic geometry in the skeleton. l-Malic acid was used as a chiral pool starting material for the construction of the olefinic acid fragment while d-mannitol was used as a chiral pool starting material for the building of the olefinic alcohol fragment.

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(2S,3R)-Dimethyl 2-hydroxy-3-methylsuccinateC7H12O5[α]D27=+18.7 (c 0.233, CHCl3)Source of chirality: (L)-malic acid and stereoselective synthesisAbsolute configuration: (2S,3R)

(2S,3S)-3-Methylbutane-1,2,4-triolC5H12O3[α]D27=+53.55 (c 0.33, CHCl3)Source of chirality: (L)-malic acid and stereoselective synthesisAbsolute configuration: (2S,3S)

((2S,4S,5S)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)methanolC13H18O4[α]D26.9=+31.5 (c 0.366, CHCl3)Source of chirality: (L)-malic acid and stereoselective synthesisAbsolute configuration: (2S,4S,5S)

(2S,4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4-vinyl-1,3-dioxaneC14H18O3[α]D26.9=+76.0 (c 0.097, CHCl3)Source of chirality: (L)-malic acid and stereoselective synthesisAbsolute configuration: (2S,4R,5S)

(2S,3R)-3-(4-Methoxybenzyloxy)-2-methylpent-4-en-1-olC14H20O3[α]D26.9=-51.4 (c 0.13, CHCl3)Source of chirality: (L)-malic acid and stereoselective synthesisAbsolute configuration: (2S,3R)

(2R,3R)-3-(4-Methoxybenzyloxy)-2-methylpent-4-enoic acidC14H18O4[α]D26.9=-69.3 (c 0.066, CHCl3)Source of chirality: (L)-malic acid and stereoselective synthesisAbsolute configuration: (2R,3R)

(S)-1-((R)-1,4-Dioxaspiro[4.5]decan-2-yl)pent-4-en-1-olC13H22O3[α]D27.2=+7.5 (c 0.106, CHCl3)Source of chirality: (D)-mannitol and stereoselective synthesisAbsolute configuration: (S,R)

(R)-2-((S)-1-(Benzyloxy)pent-4-enyl)-1,4-dioxaspiro[4.5]decaneC20H28O3[α]D26.8=+0.02 (c 0.109, CHCl3)Source of chirality: (D)-mannitol acid and stereoselective synthesisAbsolute configuration: (R,S)

(2R,3S)-3-(Benzyloxy)hept-6-ene-1,2-diolC14H20O3[α]D26.9=-66.3 (c 0.149, CHCl3)Source of chirality: (D)-mannitol and stereoselective synthesisAbsolute configuration: (2R,3S)

(R)-2-((S)-1-(Benzyloxy)pent-4-enyl)oxiraneC14H18O2[α]D27.2=-16.7 (c 0.108, CHCl3)Source of chirality: (D)-mannitol and stereoselective synthesisAbsolute configuration: (R,S)

(5S,6R)-5-(Benzyloxy)undec-1-en-6-olC18H28O2[α]D27.2=-0.4 (c 0.102, CHCl3)Source of chirality: (D)-mannitol and stereoselective synthesisAbsolute configuration: (5S,6R)

(2R,3R)-((5S,6R)-5-(Benzyloxy)undec-1-en-6-yl) 3-(4-methoxybenzyloxy)-2-methylpent-4-enoateC32H44O5[α]D27.2=-11.7 (c 0.066, CHCl3)Source of chirality: (L)-malic acid,(D)-mannitol and stereoselective synthesisAbsolute configuration: (2R,3R,5S,6R)

(3R,4R,9S,10R,Z)-9-(Benzyloxy)-4-(4-methoxybenzyloxy)-3-methyl-10-pentyl-3,4,7,8,9,10-hexahydro-2H-oxecin-2-oneC30H40O5[α]D27.2=+101.1 (c 0.043, CHCl3)Source of chirality: (L)-malic acid, (D)-mannitol and stereoselective synthesisAbsolute configuration: (3R,4R,9S,10R,Z)

(3R,4R,9S,10R,Z)-4,9-Dihydroxy-3-methyl-10-pentyl-3,4,7,8,9,10-hexahydro-2H-oxecin-2-oneC15H26O4[α]D27.2=+9.5 (c 0.88, CHCl3)Source of chirality: (L)-malic acid, (D)-mannitol and stereoselective synthesisAbsolute configuration: (3R,4R,9S,10R,Z)

(2R,3R,8S,9R,E)-8-(Benzyloxy)-9-hydroxy-3-(4-methoxybenzyloxy)-2-methyltetradec-4-enoic acidC30H42O6[α]D27.2=-95.7 (c 0.076 CHCl3)Source of chirality: (L)-malic acid, (D)-mannitol and stereoselective synthesisAbsolute configuration: (2R,3R,8S,9R,E)

(3R,4R,9S,10R,E)-9-(Benzyloxy)-4-(4-methoxybenzyloxy)-3-methyl-10-pentyl-3,4,7,8,9,10-hexahydro-2H-oxecin-2-oneC30H40O5[α]D24=-76.5 (c 0.33 CHCl3)Source of chirality: (L)-malic acid, (D)-mannitol and stereoselective synthesisAbsolute configuration: (3R,4R,9S,10R,E)

(3R,4R,9S,10R,E)-4,9-Dihydroxy-3-methyl-10-pentyl-3,4,7,8,9,10-hexahydro-2H-oxecin-2-oneC15H26O4[α]D26.7=-83.3 (c 0.238 CHCl3)Source of chirality: (L)-malic acid, (D)-mannitol and stereoselective synthesisAbsolute configuration: (3R,4R,9S,10R,E)