The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via a coupling procedure of three segments A, B, and C. The unsaturated lactone moiety of fostriecin, corresponding to segment A, was constructed from a known Horner-Emmons reagent, and the stereochemistry of the C-5 position was introduced by asymmetric reduction with (R)-BINAl-H. Segment B having a series of stereogenic centers was synthesized from (R)-malic acid and the stereogenic centers at the C-8 and C-9 positions were prepared by a combination of Wittig reaction and Sharpless asymmetric dihydroxylation reaction. The conjugated Z,Z,E-triene moiety of fostriecin, corresponding to segment C, was eventually constructed by Wittig reaction and Stille coupling reaction. The phosphate moiety, which is known to be essentially important for the antitumor activity, was introduced via two routes: (i) direct phosphorylation of the monohydroxyl derivative in which other hydroxyl groups are protected with silyl groups; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative. Although the former route is basically the same as those reported by other groups, the latter route is novel and more effective than the former one. The present total synthesis would serve as a versatile synthetic route to not only fostriecin, but also its various analogues including stereoisomers.

Fostriecin, a potent and promising antitumor antibiotic, was stereoselectively synthesized via a convergent route involving a three-segement coupling procedure.

Stereoselective Reactions. Part 23. Design, Synthesis, and Structure-Cytotoxicity Relationships of Aza-Steganes. -With a view to obtaining new antitumor agents the title compounds (V)-( VIII) are prepared. The debromobenzylation of compound (IVb) proceeds analogously to that of (IVa). The azaisopicrostegane (VIII) is prepared in the same way as (IV). Compounds (V) and (VIII) show higher cytotoxicities than (VI) and (VII). The X-ray analysis of (VIII) shows that the dibenzocyclooctadiene skeleton adopts a boat-chair conformation which is necessary for the observed biological activity. -(KUB-OTA, Y.; KAWASAKI, H.; TOMIOKA, K.; KOGA, K.; Tetrahedron 49 (1993) 15, 3081-3090; Inst. Sci. Ind. Res.,

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