An efficient synthesis of the C27–C45 fragment of lagunamide A, a cyclodepsipeptide with potent cytotoxic and antimalarial properties

An efficient and stereoselective synthesis of the entire C27–C45 moiety of lagunamide A has been achieved from 1-[(4S)-4-benzyl-2-thioxothiazolidin-3-yl]propan-1-one in six steps with 22% overall yield. The key step in the synthesis is an asymmetric acetal aldol reaction featuring the enantioselective addition of a chiral thiazolidinethione-derived titanium enolate to an acetal to establish the stereochemistry at C39.

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(5R,6R,7S)-6-Methoxy-5,7-dimethylnon-1-en-4-oneC12H22O2Ee >99%[α]D25=-68.65 (c 0.96, CHCl3)Source of chirality: (S)-2-methylbutanol and asymmetric additionAbsolute configuration: (5R,6R,7S)

(4S,5S,6R)-4-Allyl-2,2,5-trimethyl-6-[(1′S)-1-methylpropyl]-1,3-dioxaneC14H26O2Ee >99%[α]D25=+8.0 (c 0.81, CHCl3)Source of chirality: (S)-2-methylbutanol and asymmetric additionAbsolute configuration: (4S,5S,6R,1′S)

(1S,2R,3R,4S)-1-Allyl-3-methoxy-2,4-dimethylhexoxy]-tert-butyldimethylsilaneC18H38O2SiEe >99%[α]D25=-28.9 (c 1.11, CHCl3)Source of chirality: (S)-2-methylbutanol and asymmetric additionAbsolute configuration: (1S,2R,3R,4S)

Methyl (E)-(5S,6R,7R,8S)-5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2,6,8-trimethyldec-2-enoateC21H42O4SiEe >99%[α]D25=-30.2 (c 0.95, CHCl3)Source of chirality: (S)-2-methylbutanol and asymmetric additionAbsolute configuration: (E,5S,6R,7R,8S)

(E)-(5S,6R,7R,8S)-tert-Butyl(dimethyl)silyl]oxy-7-methoxy-2,6,8-trimethyl-dec-2-enoic acidC20H40O4SiEe >99%[α]D25=-26.7 (c 1.24, CHCl3)Source of chirality: (S)-2-methylbutanol and asymmetric additionAbsolute configuration: (E,5S,6R,7R,8S)

Methyl (2R,3S)-2-hydroxy-3-methylpentanoateC7H14O3Ee >99%[α]D25=-16.2 (c 1.18, CHCl3)Source of chirality: d-allo-isoleucineAbsolute configuration: (2R,3S)

[(1′R,2′S)-1-Methoxycarbonyl-2-methyl-butyl](E)-(5S,6R,7R,8S)-5-[tert-butyl(dimethyl)silyl]-oxy-7-methoxy-2,6,8-trimethyldec-2-enoateC27H56O6SiEe >99%[α]D25=-19.1 (c 0.69, CHCl3)Source of chirality: (S)-2-methylbutanol and d-allo-isoleucineAbsolute configuration: (E,5S,6R,7R,8S,1′R,2′S)

(S)-1,1-Dimethoxy-2-methylbutaneC7H16O2Ee >99%[α]D25=-0.55 (c 1.28, CHCl3)Source of chirality: (S)-2-methylbutanolAbsolute configuration: (S)

(2R,3R,4S)-1-[(4′S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-methoxy-2,4-dimethyl-hexan-1-oneC19H27NO2S2Ee >99%[α]D25=-27.8 (c 1.22, CHCl3)Source of chirality: l-phenylalanine and (S)-2-methylbutanolAbsolute configuration: (2R,3R,4S,4′S)

(4S,5S,6R,7S)-6-Methoxy-5,7-dimethylnon-1-en-4-olC12H24O2Ee >99%[α]D25=-16.0 (c 1.09, CHCl3)Source of chirality: (S)-2-methylbutanol and asymmetric additionAbsolute configuration: (4S,5S,6R,7S)

(4S,5S,6R,7S)-6-Methoxy-5,7-dimethylnon-1-en-4-olC12H24O2Ee >99%[α]D25=+0.4 (c 1.02, CHCl3)Source of chirality: (S)-2-methylbutanol and asymmetric additionAbsolute configuration: (4R,5S,6R,7S)