English

Numerous drugs are chiral, generally only one enantiomer is therapeutically active while the other antipode is completely inactive or shows often undesired and/or toxic side effects. For this reason, all new chiral drugs are now formulated in enantiopure form. Non-steroidal anticancer and antifungal drugs contain the same chemical structure e.g. Bifonazole 6a and non-steroidal aromatase inhibitors such as the Menarini anticancer drug 18. They are characterized by the presence of single chiral centre in benzhydrilic position. The present work was aimed at new procedures for the synthesis of both Bifonazole 6a and the Menarini aromatase inhibitors 18 in enantiomeric pure form. In order to prepare enantiopure synthons and final products several synthetic methods were developed. A chiral lithium aluminiumhydride complex with (R)-(-)-2-isoindolinyl-butan-1-ol (R)-(-)-24 as auxiliary was used for the asymmetric reduction of ketones 25a-d and 26a,c in order to obtain the corresponding enantiopure alcohols. Racemic and enantiopure alcohols 27a-c,g,m and 31a-1 were used as starting materials in multi-step syntheses for the corresponding N-imidazole derivatives in racemic and enantiopure forms. Involved are three reaction steps: (a) Mitsunobu reaction with 4,5-dicyano imidazole to obtain the N-4,5-dicyanoimidazole derivatives 33a-m; (b) hydrolyses of the N-imidazole-4,5-dicarbonitrile derivatives 33a-m to the corresponding diacids 34a-m, (c) thermic decarboxylation of the diacids 34a-m to the final N-imidazole derivatives 35a-d. This synthetic procedure was exceptionally well suited for the production of enantiopure N-alkyl imidazole derivatives 34a,b, instead gave high chemical yield but complete racemic products with benzylic alcohols 31d and benzhydroles 27a-c. Using a modified Marckwald procedure starting from chiral amines (S)-(+)-44 and (S)-(+)-51 it was possible to synthesize the imidazole ring and to obtain the corresponding enantiopure (S)-(+)-1-(2-octyl) imidazole (S)-(+)-35a and (S)-(+)-1-phenyl-1-ethyl imidazole (S)-(+)-54. (S)-(+)-35a presented an identical specific rotation as the corresponding compound obtained from the three step synthesis discussed above and proved the inversion of the configuration during the Mitsunobu reaction. In order to obtain the enantiopure aryl-2-benzo[b]furan methanols 27 a new synthetic method was considered instead of the asymmetric reduction of the corresponding ketones that lead to poor results. The use of the lipase SAMII allowed the synthesis of enantiopure 1-aryl-2-propyn-1-ols (R)-(-)-58a-c,e,h-l in high enantiomeric excesses and good chemical yields via hydrolysis of corresponding racemic acetates 60a-c and chloroacetates 61a-l (Scheme 7.4). The racemic and enantiopure 1-aryl-2-propyn-1-ols 58 a-l were cyclized with 2-iodophenol to the corresponding aryl-2-benzo[b]furan carbinols 27g-h and 63a-d and with 2-N-Mesyl iodoaniline to aryl-2-(N-mesyl)indol carbinols 64a-g using Pd(0) as catalyst. Both products were obtained in high e.e. and chemical yield. These constitute the first applications of Pd catalyses with enantiopure arylpropynols. The reaction conditions were optimized in order to maximize chemical yields and enantiomeric excesses. Finally an hypothesis for the mechanism of cyclization was formulated. The first step is the Pd ⁰ catalyzed addition of the acetylenic compound to the 2-iodophenol leading to 62; the second step is the CuI catalyzed cyclization to benzo[b]furane derivatives 27 or to N-Ms-indol derivatives 64. In conclusion the present work led to advances in the stereoselective synthesis of antifungal agents such as bifonazole 6a and the aromatase inhibitors 18; in fact the application of the described methodology to an enantiopure amine may probably lead to the target molecule in enantiopure form.