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

Chapter 4 112enantiopure azides. It was possible to determinate the enantiomeric excessof the amines by chiral HPLC. As expected, all amines were racemicexcept for (+)-56d which showed an e.e. of 20%. Thus, more than 50% ofenantiomeric excess was lost during the conversion of the alcohol (+)-27mto the amine (+)-56d. Again it was clear that these methods are notsuitable to obtain the target molecule in enantiopure form.4.6 Synthesis of separable pairs of diastereoisomers from (±)-34e and(±)-43a.4,5-imidazoledicarboxylate derivative (±)-34e and 5-imidazolecarboxylatederivative (±)-43a were obtained as intermediates in the"Mitsunobu-hydrolysis-decarboxylation" procedure. They were consideredas an exceptional opportunity to generate pairs of separablediastereoisomers. The first attempt involved the synthesis of chiral amides.For this (+)-(R)-1 Naphtyl-1-ethyl amine and (+)-(R)-1-Phenyl-1-ethylamine were used , carbonyldiimidazole (CDI) was the coupling reagentand dry dioxane was the solvent (Scheme 4.16).H 2 N-CH-MeRNRCDI,dry dioxaneNRNR 1(±)-43a R=CO 2 H R 1 =H(±)-34e R=R 1 =CO 2 HNR 1(±)-57a R=CONH(C*H Me)1Naphtyl R 1 =H(±)-57b R=R 1 =CONH(C*HMe) 1Naphtyl(±)-57c R=CONH(C*HMe)Ph R 1 =H(±)-57d R=R 1 =CONH(C*HMe)PhScheme 4.16: Synthesis of separable diasteroisomeric amides.Chemical yields were very high (>95%), and no racemizationoccurred during the reactions. More than one hundred TLC eluationsystems were tried to separate the diastereoisomers. Finally withCH 2 Cl 2: MeOH:AcOH 98:1:1 it was possible to separate thediastereoisomers (±)-57b and (±)-57d while it proved impossible to