Studies on the Synthesis of Nargenicin A1: Highly Stereoselective Synthesis of the Complete Carbon Framework via the Transannular Diels−Alder Reaction of an 18-Membered Macrolide

A synthesis of the complete carbon skeleton of the nargenicins, represented by tricyclic lactone 45, is described. The key step of the synthesis of 45 is the Yamaguchi macrolactonization of hydroxy acid 44 which is followed by the facile transannular Diels−Alder reaction of the 18-membered macrolide 22. This sequence provides tricycle 45 in 66% yield, along with a 14% yield of tricycle 46 which is epimeric at C(10). Macrolide 22 was obtained in 38% yield when the macrolactonization was performed at 80 °C. The transannular Diels−Alder reaction of 22 at 80 °C provided tricycle 45 as the exclusive product (85% yield). In contrast, the intramolecular Diels−Alder reaction of seco ester 43 provided a mixture of trans-fused 47 in 56% yield and the desired cis-fused cycloadduct 48 in only 27% yield. Two independent stereochemical control features determine the success of the transannular Diels−Alder reaction of 22:  the C(6)−Br steric directing group that dictates that only one of the two faces of the diene is ac...