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

Chapter 4 103(+)-(S)-2-octylimidazole (+)-(S)-35a was chosen as target compoundfor the alternative synthetic pathway and (+)-(S)-2-octyl amine (+)-(S)-44(not commercially available) as starting material.The synthesis of (+)-(S)-2-octyl amine (+)-(S)-44 is shown in scheme4.7. For this the commercially available (-)-(R)-2-octanol (-)-(R)-11c wasconverted by Mitsunobu reaction into the (-)-(S)-2-octyl phtalimmidederivative (-)-(S)-45 which by treatment with hydrazine was converted intothe desired (+)-(S)-2-octylamine (+)-(S)-44. Using (+)-(S)-44 the firstsynthesis was performed with racemic (±)-31c in order to check thestrategy and also to obtain reference compounds.OOHPhtalamideDEAD, PPH 3dry THFNONH 2 NH 2RefluxNH 2(-)-( R)-31c (-)-( S)-45 (+)-( S)-44Scheme 4.7: Synthesis of (+)-(S)-44.The thus produced (+)-(S)-44 had identical physical constants incomparison with the data reported in the literature 1 .Racemic 2-octylamine (±)-44 treated with aminomalonitrile and triethylorthoformiate in acetonitrile was leading the N-1-(2-octyl)-4-cyano-5-aminoimidazole (±)-46 5 in good yield. Using the same procedure identicalresults were obtained with enantiopure (+)-(S)-2-octyl amine (+)-(S)-44leading to (+)-(S)-N-1-(2-octyl)-4-cyano-5-aminoimidazole (+)-(S)-46 inenantiopure form in 52% yield and 98% e.e (scheme 4.8).The alkaline hydrolysis of the 5-amino-4-cyano-N-1-imidazolederivatives (±)-46 and (+)-(S)-46 led to the amino acids (±)-47 and (-)-(S)-47, respectively. The hydrolysis conditions were identical to those used forthe hydrolysis of the dicyanoimidazole derivative (±)-33a and (-)-(R)-33a,and no racemization did occur during this step. Compounds (±)-47 and (-)-(S)-47 were decarboxylated to the N-1-(2-octyl)-5-amino imidazole (±)-48and (+)-(S)-48. Also in this case thermal decarboxylation was used sinceduring this step on the compounds (±)-34a and (+)-(S)-34a noracemization occurred.