Synthesis of New Didemnin B Analogs for Investigations of Structure/Biological Activity Relationships
1994
Modifications were introduced in the side chain of didedemnin B to af- ford several analogs (1f-1j) for biological testing in order to identi- fy the features responsible for the bioactivity of the natural products (1a-1c). To achieve our goal, two changes were made in the proline ring of the β-turn side chain. Initially, a hydroxyl group was incorporated at the C-4 position of the ring to increase the polar nature of the mo- lecule. Secondly, unsaturation was introduced at C-3 and C-4 to increa- se the rigidity of the ring and to provide a site for tritiation to fol- low the drug pathway in biological systems. Improvements were also in- troduced in the macrocycle construction to produce gram quantities of this unit (1d) for the preparation of the planned analogs. The linear precursor to the macrocycle was oxidized more effectively with 1,1,1- triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1H)-one (Dess-Martin perio- dinane reagent), and cyclization yields were increased substantially by using a new coupling reagent, pentafluorophenyl diphenylphosphinate (FDPP)
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