Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 1 12Ketoconazole 4a is that it was the first orally active antifungal agent of theimidazole class after clotrimazole.Ketonazole 4a, as compared with amphotericin B and miconazole, iswell tolerated although certain problems in its use in therapy are reported inthe literature (nausea, vomiting or anorexia, abdominal complaints) 30 .Gynecomastia has been reported to occur in 3-8% of patients receivingketoconazole and this may result in a direct effect of the drug on the breasttissue 31. Another adverse reaction associated with ketoconazole is hepatictoxicity. 4a has also been shown to have a similar inhibitory effect on theenzyme responsible for the conversion of lanosterol to cholesterol inmammals and has been demonstrated to lower cholesterol levels inhumans 32,33 . In addition, it inhibits a number of other cytochrome P450enzymes involved in steroidal biosynthesis and drug metabolism. It has alsobeen shown to block adrenal steroidogenesis by inhibition of the corticoid11-β−hydroxylase 34 . For these properties it has been utilized to treatprostate cancer and Cushing's syndrome 35 .Ketoconazole 4a is marketed as racemic mixture of the cis-(2S,4R)and (2R,4S) enantiomers as illustrated in figure 1.9.It is one of the few antifungal agents which has also been synthesizedin enantiopure form. Starting from optically pure (R)- and (S)-solketaltosylate 4e (figure 1.10), by transketalization with apropiate ketones, bothenantiomers of 4a and also the corresponding trans derivatives wereprepared 36 .The same chiral building block has been used to synthesize selectiveinhibitors of the mammalian 14-α-demethylase in order to reduce thecholesterol levels in the humans 37 .The latest stereoselective synthesis of both enantiomers ofKetoconazole 4a has been reported in 1995. Starting from commerciallyavailable (R)- or (S)-epichlorohydrine 38 4f (Fig. 1.10), (+)-or (-)-4aKetoconazole was obtained in nine steps 38 .OOOTsOCl(S)-4e(S)-4fFigure 1.10: (S)-solketal tosylate 4e and (S)-epichlorohydrine 4f.