The nonenolide hypocreolide A was isolated from culture filtrates of the ascomycete Hypocrea lactea. It exhibits moderate antimicrobial activity against various tested fungi and bacteria. Since neither the relative nor the absolute stereochemistry of the compound could be initially assigned, a stereochemically flexible total synthesis was developed. The two stereogenic centers were formed in high enantioselectivity and yield using transition metal catalyzed asymmetric reactions. While attempts to construct the ten-membered lactone in a ring-closing olefin metathesis gave disappointing results, a combination of cross metathesis and macrolactonization provided the title compound in nine steps and 12% overall yield.