Synthesis of Zaragozic Acid A/Squalestatin S1

Abstract

Abstract A novel synthetic approach to the construction of the zaragozic acids, which was used for the asymmetric synthesis of zaragozic acid A/squalestatin S1 ( 1 ), is described. Fragment 5 , representing the tricarboxylic acid core portion, is assembled in three key steps: 1) Stille coupling to establish the carbon framework; 2) enantioselective dihydroxylation to introduce the absolute stereochemistry; and 3) diastereoselective dihydroxylation to complete the required carbon‐oxygen connectivity. The convergency of this synthesis is demonstrated by the dithiane addition of a variety of C 1 side chains (e.g., 78 ) to advanced intermediate 5 . A multi‐event acid‐catalyzed rearrangement yielded the zaragozic acid core 86 , which was converted to an intermediate obtained from degradation of zaragozic acid A. A second‐generation synthesis of the core of the zaragozic acids is also described. When aldehyde 90 was used instead of 5 , both the yield and diastereoselectivity of the dithiane addition reaction were improved, although the degree of convergency was slightly lower.