Pyranonaphthoquinones are a class of naturally occurring antibiotics which have in common a synthetically interesting isochromanquinone skeleton. Members of this family exhibit a variety of biological activities. Examples are frenolicin B, an anticoccidial agent; kalafungin, an antifungal agent; hongconin, having cardioprotective activity against angina pectoris. Efforts toward the direct synthesis of these natural pyranonaphthoquinones forced us to develop new methodologies. During our research, a general methodology was developed to stereoselectively synthesize the common isochromanquinone skeleton. The key step in the syntheses, a regioselective Diels-Alder reaction, proceeds with complete regiocontrol and in excellent yield. This work has led to extremely direct total syntheses of hongconin, kalafungin, frenolicin B, [alpha], [beta]-epoxyfrenolicin B and their analogs.