Synthesis of Zaragozic Acid A/Squalestatin S1

Abstract

AbstractA 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.