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Absolute Configuration and Total Synthesis of (+)-Curacin A, an Antiproliferative Agent from the Cyanobacterium Lyngbya majuscula

1997; American Chemical Society; Volume: 119; Issue: 1 Linguagem: Inglês

10.1021/ja9629874

1943-2984

James D. White, Tae‐Seong Kim, Mitch Nambu,

Alkaloids: synthesis and pharmacology

The absolute configuration of curacin A was determined as (2R,13R,19R,21S)-1 by comparison of degradation products 2 and 3 with the same materials prepared by asymmetric synthesis. The total synthesis of 1 was completed from (1R,2S)-2-methylcyclopropanecarboxylic acid (8) and the amino alcohol derivative 46. The latter was prepared from 4-pentynal (14) and the Garner aldehyde (43). Asymmetric allylation of 14 followed by methylation of the derived alcohol 16 gave 17, which was subjected to zirconation−iodination to yield 18. The latter was coupled to the vinyl boronate 21, prepared from 4-pentynyl acetate (20), in the presence of Pd(0), and the resultant trienol 22 was converted to phosphonium iodide 24. Wittig reaction of the ylide from 24 with 43 afforded tetraene 44 which produced 45 upon methanolysis. The mesylate 46 was advanced to thioester 48 either by direct coupling with potassium thiolate 47 obtained from (−)-8 or indirectly via 49. The amino thioester liberated from 48 underwent thermal cyclization to give (+)-curacin A.