SYNTHESIS OF ENANTIOMERICALLY PURE BIS(HYDROXYMETHYL)-BRANCHED CYCLOHEXENYL AND CYCLOHEXYL PURINES AS POTENTIAL INHIBITORS OF HIV

The synthesis of the enantiomerically pure bis(hydroxymethyl)-branched cyclohexenyl and cyclohexyl purines is described. Racemic trans-4,5-b is(methoxycarbonyl)cyclohexene [(+/-)-6] was reduced with lithium alum inum hydride to give the racemic diol (+/-)-7. Resolution of(+/-)-7 vi a a transesterification process using lipase from Pseudomonas sp. (SAM -II) gave both diols in enantiomerically pure form. The enantiomerical ly pure diol (S,S)-7 was benzoylated and epoxidized to give the epoxid e 9. Treatment of the epoxide 9 with trimethylsilyl trifluoromethanesu lfonate and 1,5-diazabicyclo-[5.4.0]undec-5-ene followed by dilute hyd rochloric acid gave ,5-bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10). Acetylation of 10 gave acetoxy-4,5-bis[(benzoyloxy)-methyl]cycl ohex-2-ene (11). -Acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (1 1) was converted to the adenine derivative 12 and guanine derivative 1 3 via palladium(0)-catalyzed coupling with adenine and 2-amino-6-chlor opurine, respectively. Hydrogenation of 12 and 13 gave the correspondn ing saturated adenine derivative 14 and guanine derivative 15. ,5-Bis[ (benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10) was converted to the adenine derivative 16 and guanine derivative 1? via coupling with 6-ch loropurine and 2-amino-6-chloropurine, respectively, using a modified Mitsunobu procedure. Hydrogenation of 16 and 17 gave the corresponding saturated adenine derivative 18 and guanine derivative 19. Compounds 12-19 were evaluated for activity against human immunodeficiency virus (HIV), but mere found to be inactive. Further biological testings are underway.