Formal Total Syntheses of the (−)-Salicylihalamides A and B From d-Glucose and l-Rhamnose

Two formal total syntheses of the (−)-salicylihalamides, based on chiral pool approaches, are reported. d-Glucose and l-rhamnose were used to prepare advanced intermediates 23 and 54, which can be converted in three or four steps, respectively, to the target compounds. The synthesis of 23 from a known d-glucose-derivative was accomplished in 12 steps and 17% overall yield, and the synthesis of 54 from a known l-rhamnose-derivative was done in nine steps and 6% overall yield. A key step in the synthesis was a ring-closing metathesis reaction to prepare the macrocyclic ring system. It was demonstrated that the phenolic protecting group was critical for inducing the preferential formation of the desired E isomer. It was further shown that the protecting group at the C13 hydroxyl group had no significant influence on the E:Z ratio during the ring-closing metathesis reaction.