STUDIES ON THE SYNTHESIS OF NARGENICIN A(1) - 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, repres ented by tricyclic lactone 45, is described. The key step of the synth esis of 45 is the Yamaguchi macrolactonization of hydroxy acid 44 whic h is followed by the facile transannular Diels-Alder reaction of the 1 8-membered macrolide 22, This sequence provides tricycle 45 in 66% yie ld, 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 2 2 at 80 degrees C provided tricycle 45 as the exclusive product (85% y ield). In contrast, the intramolecular Diels-Alder reaction of seco es ter 43 provided a mixture of trans-fused 47 in 56% yield and the desir ed cis-fused cycloadduct 48 in only 27% yield. Two independent stereoc hemical control features determine the success of the transannular Die ls-Alder reaction of 22: the C(6)-Br steric directing group that dicta tes that only one of the two faces of the diene is accessible to the d ienophile in transition state 14 and allylic strain considerations inv olving the C(16)-Me substituent which enable only one face of the dien ophile to be accessible to the diene in transition state 14. The latte r effect is operational only in the transannular cycloaddition mode as indicated by the results with 43. An added benefit of this strategy i s that the 10-membered lactone is established by a formal ring contrac tion of the more easily synthesized 18-membered lactone. Attempts to e xtend this strategy to the transannular Diels-Alder reaction of the C( 13)-hydroxyl substituted macrolide 13 have not been successful.