Total synthesis of 2′-deoxy-2′-arafluoro-tubercidin, -toyocamycin, -sangivamycin and certain related nucleosides

Abstract

A total synthesis of novel nucleosides 2′-deoxy-2′-arafluoro-tubercidin 12, -toyocamycin 23, -sangivamycin 24 and -thiosangivamycin 25 has been accomplished for the first time starting from 4-chloropyrrolo[2,3-d]pyrimidine 4, and 2-bromo-5-(ethoxymethyleneamino)pyrrole-3,4-dicarbonitrile 16. The sodium-salt glycosylation of secondary amines 4 and 16 with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide 5 gave the major β-nucleosides 6 and 17 along with minor amounts of α-anomers 7 and 18. Ammonolysis of compound 6 gave the tubercidin analogue 12. The annulation of epimers 17 and 18 furnished the bromotoyocamycin 21 and its α-anomer 22, respectively. Compound 21 was converted into analogues of toyocamycin 23, sangivamycin 24 and thiosangivamycin 25. Similar functional-group manipulation of substrates 7 and 22 provided the α-anomers of compounds 12, 23, 24 and 25. Among the nucleosides tested, the sangivamycin 24 and thiosangivamycin 25 analogues have shown some interesting anti-(human cytomegalovirus) activity and it was observed that compound 25 is more active than compound 24, but less potent than 9-(1,3-dihydroxypropan-2-yloxymethyl)guanine in vitro.