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 degrees C. The transannular Diels-Alder reaction of 22 at 80 degrees 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 accessible to the dienophile in transition state 14 and allylic strain considerations involving the C(16)-Me substituent which enable only one face of the dienophile to be accessible to the diene in transition state 14. The latter effect is operational only in the transannular cycloaddition mode as indicated by the results with 43. An added benefit of this strategy is that the 10-membered lactone is established by a formal ring contraction of the more easily synthesized 18-membered lactone. Attempts to extend this strategy to the transannular Diels-Alder reaction of the C(13)-hydroxyl substituted macrolide 13 have not been successful.