A concise and stereoselective synthesis of a key fragment C3-C22 unit of tartrolons D and E is demonstrated. Three crucial fragments are combined to form the twenty-carbon chain, which contains four stereogenic centers in the monomeric unit of both natural products. These crucial fragments 9, 10, and 11 were synthesized in highly enantioselective routes from commercial starting compounds in two, eight, and two steps, respectively, and coupled using palladium catalyzed Sonogashira coupling and directed 1,5-asymmetric aldol reaction as key steps.