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

Chapter 4 105CNNH N2 NCN nC 6 H 13NH 2nC 6 H 13H 2 N(±)-44CH(OEt) 3(±)-46CNIsopentyl nitriteNNNaOH EtOHNNnC 6 H 13(±)-50CO 2 HnC 6 H 13(±)-49ONH 2Scheme 4.9: Second attempt to assign the stereochemistry of the Mitsunobu-hydrolysisdecarboxylationreaction. This was done only with the racemic compounds.Unfortunately all attempts to hydrolize the amide (±)-49 to thecorresponding acid (±)-50 failed and it was thus impossible to obtain thefinal target compound using this synthetic pathway.Next, the strategy was changed in favour of a Markwald procedure 3 .For this, the racemic and enantiopure 2-octyl amines (±)-44 and (+)-(S)-44,1-phenyl-1-ethylamine (±)-51 and (+)-(S)-51 (commercially available) werealkylated with bromoacetaldehyde dimethylacetal in order to provide themonoalkylated products 52a (62% yield) and 52b (70 % yield) in racemicand enantiopure form. These compounds were cyclized to racemic andenantiopure N-1-alkyl-5-mercapto imidazoles 53a and 53b respectivelyusing KCNS in a aqueous HCl/THF solution. In both cases the yield was84%. The final desulfuration was performed with Raney-Ni and affordedcompounds 2-octylimidazole 35a and 1-phenylethyl-1-imidazole 54 inracemic and enantiopure form with an enantiomeric excess of higher than98% e.e. In scheme 4.8 all reaction sequences are shown.(+)-(S)-35a thus obtained proved to be identical in all respects,including specific rotation with (+)-(S)-35c derived from (-)-(R)-2-octanol(-)-(R)-31c via the Mitsunobu-hydrolysis-decarboxylation sequence.