Synthetic studies of an 18-membered antitumor macrolide, tedanolide. 6. Synthesis of a key intermediate via a highly efficient macrolactonization of computer-aid designed seco-acid.

from the Caribbean “fire sponge” Tedania ignis in 1984; its relative and absolute structure was determined by X-ray analysis and revealed an unusual structural feature: four labile aldol units, an 18-membered lactone formed at a primary hydroxyl instead of the usual secondary hydroxyl, and an a-epoxy alcohol. Because of its novel and complex structure as well as strong biological activity, 1 has recently attracted considerable synthetic attention. In 1996, as part of our synthetic studies of 1 we reported in a preliminary communication on the synthesis of the 18membered lactone (2), a key intermediate to 1, via modified Yamaguchi macrolactonization of the corresponding secoacid (3). Quite recently, the synthesis of two fragments, C1— C12 (4) and C13—C23 (5) f ) as precursors to 3 starting from methyl (R)and (S)-3-hydroxy-2-methylpropionates was reported in detail. In this full paper we describe the synthesis of 2 via the quite efficient cyclization of 3, which was carried out by coupling between 4 and 5. In macrolide synthesis the most crucial step to success is usually macrocyclization of a seco-acid to the corresponding lactone, and hence it is extremely important to design a secoacid derivative suitable for macrolactonization, that is, on the basis of conformational analyses the seco-acid should be designed so that its global conformation is as close as possible to that of the corresponding lactone. Only recent computational chemistry can predict the significantly populated conformers of such complex molecules with considerable accuracy within a reasonable computation time. After careful calculations by virtue of a molecular mechanics (MM) method (CONFLEX-MM2), we chose 3 and 2 as the most promising seco-acid and its cyclized lactone, respectively. The most dominant conformations of 3a and 2a as calculation models for 3 and 2, respectively, are shown in Fig. 2. Synthesis of the Seco-Acid (3) The kinetic enolate of the C1—C12 ketone (4) was first prepared with a slight excess of lithium hexamethyldisilazide (LHMDS) at 278 °C, and then allowed to react with ca. one-third equivalent of the June 2000 Chem. Pharm. Bull. 48(6) 855—860 (2000) 855