SYNTHESIS OF ZARAGOZIC ACID A SQUALESTATIN S1

A novel synthetic approach to the construction of the zaragozic acids, which was used for the asymmetric synthesis of zaragozic acid A/squal estatin S1 (1),is described. Fragment 5, representing the tricarboxyli c acid core portion, is assembled in three key steps: 1) Stille coupli ng to establish the carbon framework; 2) enantioselective dihydroxylat ion to introduce the absolute stereochemistry; and 3) diastereoselecti ve dihydroxylation to complete the required carbon-oxygen connectivity . The convergency of this synthesis is demonstrated by the dithiane ad dition of a variety of C1 side chains (e.g., 78) to advanced intermedi ate 5, A multi-event acid-catalyzed rearrangement yielded the zaragozi c acid core 86, which was converted to an intermediate obtained from d egradation of zaragozic acid A. A second-generation synthesis of the c ore of the zaragozic acids is also described. When aldehyde 90 was use d instead of 5, both the yield and diastereoselectivity of the dithian e addition reaction were improved, although the degree of convergency was slightly lower.