Total Synthesis of Polycavernoside A, A Lethal Toxin of the Red Alga Polycavernosa tsudai

• Published in: Journal of organic chemistry 2005-07, Vol.70 (14), p.5449-5460
• Main Authors: BLAKEMORE, Paul R., BROWDER, Cindy C., HONG, Jian, LINCOLN, Christopher M., NAGORNYY, Pavel A., ROBARGE, Lonnie A., WARDROP, Duncan J., WHITE, James D.
• Format: Article
• Language: English
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemistry; Antibiotics, Antineoplastic - chemical synthesis; Biological and medical sciences; Carboxylic Acids - chemistry; Cyclization; Disaccharides - chemical synthesis; Glycosylation; Macrolides - chemical synthesis; Marine Toxins - chemical synthesis; Medical sciences; Molecular Structure; Oxidation-Reduction; Plant poisons toxicology; Propionates - chemistry; Rhodophyta - chemistry; Stereoisomerism; Toxicology; Vinyl Compounds - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0503862

[structure: see text] Two approaches to the synthesis of the aglycon 120 of polycavernoside A (1) were developed, only one of which was completed. The successful "second-generation" route assembled the aglycon seco acids 102 and 106 via Nozaki-Hiyama-Kishi coupling of aldehyde 70, prepared from methyl (S)-3-hydroxy-2-methylpropionate (72) and (S)-pantolactone (73), with vinyl bromide 71. The latter was obtained from a sequence which commenced from the silyl ether 24 of 3-hydroxypropionaldehyde and entailed cyclization of (Z)-zeta-hydroxy-alpha,beta-unsaturated ester 82. Regioselective Yamaguchi lactonization of trihydroxycarboxylic acids 102 and 106 and subsequent functional-group adjustments led to macrolactone 120, to which the fucopyranosylxylopyranoside moiety was attached. Stille coupling of the glycosidated aglycon 128 with dienylstannane 129 furnished polycavernoside A in a synthesis for which the longest linear sequence was 25 steps. The overall yield to lactone 120 was 4.7%.