A Formal Total Synthesis of (+)-Tetronolide, the Aglycon of the Tetrocarcins: Enantio- and Diastereoselective Syntheses of the Octahydronaphthalene (Bottom-Half) and Spirotetronate (Top-Half) Fragments

Abstract

A formal total synthesis of (+)-tetronolide, the aglycon of the tetrocarcins, has been achieved by virtue of the development of highly diastereo- and enantioselective syntheses of the bottom- and top-half fragments 4 and 5 reported herein. These fragments previously served as key intermediates in Yoshii's pioneering total synthesis of (+)-tetronolide. The synthesis of the bottom-half octahydronaphthalene unit 4 features the intramolecular Diels−Alder reaction of tetraenal 20 and proceeds in 17 steps and 5−6% yield from d-glyceraldehyde pentylidene acetal 8. The synthesis of the spirotetronate fragment 5 features the highly enantioselective exo selective Diels−Alder reaction of triene 37 and chiral dienophile 25b and proceeds in 14 steps and 10% overall yield from cis-2-butene-1,4-diol (38). An enantioselective synthesis of Boeckman's top-half cyclohexene fragment 6 via the exo selective Diels−Alder reaction of diene 24 and dienophile 25a was also developed, but this route was deemed too inefficient for use in a projected total synthesis of the natural product. The syntheses of 5 and 6 provide important information on the utility of chiral dienophiles 25a and 25b in organic synthesis.