DES-N-TETRAMETHYLTRIOSTIN-A AND BIS-L-SERYLDES-N-TETRAMETHYLTRIOSTIN-A, SYNTHETIC ANALOGS OF QUINOXALINE ANTIBIOTICS

The synthesis of the des-N-tetramethyl analogue of the quinoxaline depsipeptide antibiotic triostin A has been accomplished, as also has the synthesis of the corresponding bis-L-serine analogue. The synthesis of des-N-tetramethyltriostin A (2) proceeded by coupling L-alanine β,β,β-trichloroethyl ester with N-benzyloxycarbonyl-D-serine to give dipeptide Z-D-Ser-Ala-OTce. Depsipeptide bond formation was effected using N,N-dicyclohexylcarbodiimide in pyridine to provide tri-depsipeptide 3. Coupling of 3 with Boc-Cys(Acm)-OH gave tetradepsipeptide 4, which, by removal of appropriate protective groups, was converted to tetradepsipeptides 5 and 6. Fragment coupling of 5 and 6 furnished the octadepsipeptide 7 containing the amino acid sequence of the antibiotic. A sequence of deprotection and cyclization converted 7 to the cyclic octadepsipeptide 8. Treatment of 8 with iodine in methanol effected formation of disulfide 9. Removal of the N-benzyloxycarbonyl groups in 9 followed by N-acylation with 2-quinoxalinecarbonyl chloride gave des-N-tetramethyltriostin A (2). Analogue 2 was found to bind to DNA and, in common with the natural quinoxaline antibiotics, to do so as a bifunctional intercalating agent. The bis-L-serine analogue of 2 was prepared following the above procedure to furnish a quinoxaline antibiotic that showed no appreciable binding to DNA. © 1978, American Chemical Society. All rights reserved.