An enantioselective synthetic route to (+)-dynemicin A (1) is described that involves as the key and final step the Diels-Alder cycloaddition of the quinone imine 6 with the isobenzofuran 107 followed by an oxidative workup to provide (+)-1 in 40% yield. The synthetic route begins with the condensation of (-)-menthyl acetoacetate and trans-ethyl crotonate to form the crystalline cyclohexanedione 14, which is then transformed to the enantiomerically pure quinone imine 6 in 23 steps with an average yield of 85% and an overall yield of 2-3%. Key features of this sequence include the coupling of the enol triflate 11 and the arylboronic acid 10 (90%), the thermal deprotection/internal amidation of the coupling product 18 (84%), the use of 2-chloropyridine as an economical alternative to 2,6-di-tert-butylpyridine to promote the reaction of the quinolone 9 and triflic anhydride (85%), the highly stereoselective addition of the (Z)-enediyne 31 to the quinoline 61 (89%), intramolecular acetylide addition within the acetylenic ketone 66 (94%), and oxidation of the phenol 76 with iodosobenzene to afford the quinone imine precursor 77 in 89% yield. Both the quinone imine and isobenzofuran components of the final coupling reaction can be varied, thus providing an ideal route for the preparation of a wide variety of dynemicin analogs.