| The total synthesis of (---)-exiguolide was completed in 26 steps (longest linear) by employing an iterative Prins cyclization strategy to form both tetrahydropyrans of the natural product, with concurrent closure of the 16-membered macrolide and the second pyran ring. The importance of the powerful bond-forming ability of this strategy was highlighted by the resurgence of Prins macrocyclizations in natural product synthesis in recent years. Furthermore, the convergency of this approach allowed important preliminary biological studies on this polyketide natural product and analogs to be completed. The inherent synthetic versatility of the bicyclic pyran dioxinone intermediate from this methodology was also translated into a diversity-oriented synthesis of small molecule libraries for the Chicago Tri-institutional Center for Chemical Methods and Development. In addition, the scope of this method has been expanded to access related heterocyclic motifs and other reactivities, resulting in the development of a novel catalytic, asymmetric oxidative Prins cyclization. |
