A practical synthesis of the lipophilic side chain of the polyoxypeptins

The lipophilic side chain of the cyclic depsipeptide polyoxypeptin A (1) and B (2), strong apoptosis inducers, has been synthesised as an ester of mixed methyl ketal 18. The key step is an asymmetric anti-aldol reaction of the designed 2-(N-2-methylbenzyl-N-2,4,6-trimethylbenzyl) amino-1-phenylpropyl ester 8 by means of a combination of LDA–Cp2ZrCl2 (0.3 equiv.) for enolation and transmetallation into the zirconium enolate for aldolization. By using a non-boron associated anti-aldol reaction, 10 g of the key lactone 6 were synthesised in six steps from 8 and in 48% overall yield.