Total syntheses of conformationally constrained didemnin B analogues. Replacements of N,O-dimethyltyrosine with L-1,2,3,4-tetrahydroisoquinoline and L-1,2,3,4-tetrahydro-7-methoxyisoquinoline

The design and synthesis of two conformationally constrained analogues of d idemnin B are described. The [N,O-Me(2)Tyr(5)] residue of didemnin B was re placed with L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) and L- 1,2,3,4-tetrahydro-7-methoxyisoquinoline-3-carboxylic acid (MeO-Tic), which mimic the N,O-dimethylated tyrosine while constraining the conformation of the molecule. Preliminary results indicate that the conformation of the [N ,O-Me(2)Tyr(5)] residue closely matches the conformation imposed by the Tic replacement.