Enzymatic Desymmetrization of Prochiral 2-Substituted-1,3-propanediols:  A Practical Chemoenzymatic Synthesis of a Key Precursor of SCH51048, a Broad-Spectrum Orally Active Antifungal Agent

Two examples of a practical enzymatic desymmetrization of a 2-substituted-1,3-propanediol and their application to the synthesis of SCH51048, a broad-spectrum orally active antifungal, are described. In each case, enzymatic catalysis under both hydrolytic and transesterification conditions is described. In the first example the key intermediate, the R,S-monoester of triol 6, was obtained via Amano Lipase AK catalyzed hydrolysis of the dibutyrate 11b, or Novo SP435 catalyzed acetylation of triol 6. In the second example, desymmetrization of diol 13a using Novo SP435 or of dibutyrate 13c using Amano Lipase CE furnished the S-monoester (S)-14b,c, a key intermediate in a new efficient synthesis of SCH51048. Optimization of the Novo SP435 acetylation of diol 13a and the scaleup of the reaction is also described.