Highly Stereoselective Total Synthesis of Fully Hydroxy-Protected Mycolactones A and B and Their Stereoisomerization upon Deprotection

摘要

Unprecedentedly efficient and highly (≥98%) stereoselective syntheses of mycolactones A and B sidechains relied heavily on Pd-catalyzed alkenylation (Negishi version) and were completed in 11 longest linear steps from ethyl (S)-3-hydroxybutyrate in 12% and 11% overall yields, respectively, roughly corresponding to an average of 82% yield per step. The synthesis of mycolactone core was realized by using Pd-catalyzed alkenyl–allyl coupling and an epoxide-opening reaction with a trialkylalkenylaluminate as key steps. Fully hydroxy-protected mycolactones A and B of ≥98% isomerical purity were synthesized successfully for the first time. However, unexpected 4/3-5/4 inseparable mixtures of mycolactones A and B were obtained upon deprotection.