Nature presents us countless numbers of natural products with complex and fascinating structures and useful properties. Macrodiolides belong to one relatively small but interesting class of natural products exhibiting many different bioactivities. In this review, total syntheses of macrodiolides containing oxacyclic rings will be discussed; only those approaches that led to successful total syntheses will be highlighted. Total syntheses of some of the oxacyclic macrodiolides (swinholide A and aplasmomycin) were already discussed in a previous review by Norcross and Patterson; 1 therefore, discussions of the more recent developments will be included here. In discussing total syntheses of these compounds, emphasis is naturally on the methods used for macrocycle formation. The other important facet will be the reactions employed for oxacycle synthesis, particularly for those containing oxolane (tetrahydrofuran) and oxane (tetrahydropyran) moieties.

Pamamycins are the best known macrodiolides containing oxolane moieties. The total synthesis of pamamycin 607 (1), 2 the prototype member of the pamamycin family, was achieved recently. A number of other macrodiolides containing oxolane systems are also known, for example, feigrisolide C and D, 3 IKD 8344, 4 and pyrrolizidine alkaloids such as nemorensine, 5 mulgediifoline, 6 and retroisosenine, 7 but total syntheses of these compounds are yet to be reported. More recently, the total synthesis of amphidinolide X (2) 8 was reported. Successful synthetic efforts were reported for SCH 351448 (3) 9 and swinholide A (4), 10 which are 28-and 40-membered symmetric macrodiolides containing oxane and oxene (dihydropyran) moieties. Early synthesis of swinholide A (4) was reviewed previously; 1 therefore, this review will deal with the more recent total synthesis. Cycloviracin B1 (5) 11 and glucolipsin A (6) 12 possess unique macrodiolide structures incorporating cyclic acetal units, and the recent success stories on total syntheses will be discussed. Macrodiolides such as boromycin (7), 13 tartrolon B (8), 14 debromoaplysiatoxin (9), 15 and aplysiatoxin (10) 15 exhibit cyclic hemiketal structural units (Figure 1), and total syntheses of these compounds will be summarized in this review. The total synthesis of aplasmomycin16 was already discussed in the previous review article1 and omitted here.