Macrocycle formation by ring-closing metathesis. Application to the syntheses of novel macrocyclic taxoids

A series of novel macrocyclic taxoids 6 and 6' bearing 16-, 17-, and 18-mem bered rings connecting the substituents at the C-2 and C-3' positions were designed and synthesized. The syntheses of these macrocycles 6 and 6' were accomplished using the highly efficient ruthenium-catalyzed ring-closing me tathesis (RCM) of taxoid-omega,omega'-dienes 7 in the key step. Taxoid-omeg a,omega'-dienes 7 were obtained through the ring-opening coupling of 4-alke nyl-beta-lactams 9 with 2-alkenoylbaccatins 8 in good to high yields. Altho ugh various novel pentacyclic macrocycles 6 and 6' were successfully synthe sized, there were cases in which the desired RCM did not proceed. The scope and limitation of RCM in its application to highly functionalized complex substrates are discussed. All macrocyclic taxoids 6 and 6' were found to be cytotoxic, with some of them exhibiting submicromolar IC50 values against a human breast cancer cell line.