Synthetic approaches towards the novel 1,3-dioxo-1,2-dithiolane moiety in the antitumour antibiotic substance leinamycin

Abstract

A number of complementary synthetic approaches to the β-thiolactone intermediate 9 for elaboration to the novel 1,3-dioxo-1,2-dithiolane moiety 6 found in the antitumour antibiotic substance leinamycin 1 are described.

Thus, deprotection of the benzylthio ether produced from 3-methylbut-2-enoic acid and toluene-α-thiol, leads to the mercapto acid 12 which on cyclisation produces the thiolactone 13. α-Methylation of the thiolactone 13, followed by α-oxygenation then gives rise to the substituted β-thiolactone 9. The β-thiolactone 9 is also produced when: (i) the sodium glycidate 17 is stirred with sodium sulfide leading to 18, followed by thiolactonisation; (ii) thioacetone is treated with the ketene derived from 2-acetoxypropanoyl chloride; and (iii) by irradiation of 3-methyl-2-trimethylsilyloxybut-2-ene 22 with thiophosgene leading to 23, followed by hydrolysis.

The β-thiolactone 9 is then converted in three steps into the 1,3-dioxo-1,2-dithiolane 6 by: (i) ring opening to the thioic acid 15, using hydrogen sulfide–triethylamine; (ii) ring closure of 15 to 8 in the presence of aqueous ferric chloride; and finally (iii) oxidation using dimethyldioxirane.

Treatment of the ethyl glycidate 19 with disodium disulfide in hot ethanol for 3 days provides the 1,2-dithiolane 8 directly, but in low yields (11–15%).

When the aforementioned reaction sequences are translated to the glycidate 24, derived from 4-methylcyclohex-3-enone and α-chloropropanoic acid, the syntheses of the key intermediates 25, 27 and 26en route to the spiro-fused 1,3-dioxo-1,2-dithiolane 7 and leinamycin 1(see Scheme 1) were secured.