Antineoplastic Agents. 599. Total Synthesis of Dolastatin 16

The first 23-step total synthesis
of the cyclodepsipeptide dolastatin
16 (1) has been achieved. Synthesis of the dolaphenvaline
and dolamethylleuine amino acid units using simplified methods improved
the overall efficiency. The formation of the 25-membered macrocycle
employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed
a key step in the synthesis. Regrettably, the synthetic dolastatin
16 (1), while otherwise identical (by X-ray crystal structure
and spectral analyses) with the natural product, did not reproduce
the powerful (nanomolar) cancer cell growth inhibition displayed by
the natural isolate. Presumably this result can be attributed to conformation(s)
of the synthetic dolastatin 16 (1) or to a chemically
undetected component isolated with the natural product.