The convergent total synthesis of Sch725674 has been accomplished by starting from (R)‐1,2‐epoxyheptane and assembling five modules in a highly stereoselective manner to give the final product in 6.6 % overall yield. The same strategy was extended to the synthesis of its C‐4 epimer. Key reactions of the synthetic pathway include a Jacobsen hydrolytic kinetic resolution of an epoxide followed by its regioselective opening through a Yamaguchi–Hirao alkynylation, and ring‐closing metathesis reaction to furnish the unique 14‐membered ring macrolactone. In addition, the influence of protecting groups on the efficiency of the ring‐closing metathesis (RCM) macrocyclization has been studied to maximize its yields.