Synthetic Studies of an 18-Membered Antitumor Macrolide, Tedanolide. 5. Stereoselective Synthesis of the C13-C23 Part via Condensation of Two Fragments, C13-C17 and C18-C21, by Taking Advantage of the 3,4-Dimethoxybenzyl Protecting Group
Chemical and pharmaceutical bulletin
Tedanolide (1), a highly cytotoxic 18-membered macrolide, was isolated from a Caribbean sponge, Tedania ignis, and its structure determined by Schmitz et al. in 1984. 2,3) In contrast to many typical macrolides, 4) the structure of 1 is unusual; having four labile aldol units, an a-epoxy alcohol and an 18-membered lactone formed between C16-primary alcohol and C1-carboxyl group, the synthesis of 1 seemed to be difficult. As part of our synthetic studies of 1 we reported in 1996 the synthesis of
... 96 the synthesis of the 18-membered lactone (2), 5) a key intermediate to 1, via highly efficient macrolactonization 6) of the corresponding seco-acid (3), which was designed with the aid of molecular mechanics (MM2-CONFLEX3) 7) calculations and synthesized by condensation of four fragments, the C1-C7 (4), C8-C11 (5a), C13-C17 (6) and C18-C21 (5b), 8) although the procedure required many improvements. In previous papers 9) we reported improved syntheses of 4 and 5a, and their coupling to the C1-C12 part (7) , half the molecule 3. Recently Masamune 10) and Taylor 11) reported syntheses of C3-C12 and C15-C19 portions, respectively. In this full paper we describe a synthesis of the C13-C23 part (8), another half of the molecule 3, via coupling between 6 and 5b. The former 6 was synthesized starting from methyl An efficient and stereoselective synthesis of the C13-C23 part (8) was achieved starting from methyl (R)and (S)-3-hydroxy-2-methylpropionates (9) via coupling of the C13-C17 aldehyde (6), prepared by Evans asymmetric aldol reaction, with the C18-C21 iodoalkene (5b) by taking advantage of the 3,4-dimethoxybenzyl protecting group.