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

Summary:Numerous drugs are chiral, generally only one enantiomer is therapeutically activewhile the other antipode is completely inactive or shows often undesired and/or toxicside effects. For this reason, all new chiral drugs are now formulated in enantiopureform. Non-steroidal anticancer and antifungal drugs contain the same chemical structuree.g. Bifonazole 6a and non-steroidal aromatase inhibitors such as the Menarinianticancer drug 18. They are characterized by the presence of single chiral centre inbenzhydrilic position. The present work was aimed at new procedures for the synthesisof both Bifonazole 6a and the Menarini aromatase inhibitors 18 in enantiomeric pureform.In order to prepare enantiopure synthons and final products several syntheticmethods 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 and26a,c in order to obtain the corresponding enantiopure alcohols.Racemic and enantiopure alcohols 27a-c,g,m and 31a-1 were used as startingmaterials in multi-step syntheses for the corresponding N-imidazole derivatives inracemic and enantiopure forms. Involved are three reaction steps: (a) Mitsunobureaction with 4,5-dicyano imidazole to obtain the N-4,5-dicyanoimidazole derivatives33a-m; (b) hydrolyses of the N-imidazole-4,5-dicarbonitrile derivatives 33a-m to thecorresponding diacids 34a-m, (c) thermic decarboxylation of the diacids 34a-m tothe final N-imidazole derivatives 35a-d.This synthetic procedure was exceptionally well suited for the production ofenantiopure N-alkyl imidazole derivatives 34a,b, instead gave high chemical yield butcomplete racemic products with benzylic alcohols 31d and benzhydroles 27a-c.Using a modified Marckwald procedure starting from chiral amines (S)-(+)-44and (S)-(+)-51 it was possible to synthesize the imidazole ring and to obtain thecorresponding enantiopure (S)-(+)-1-(2-octyl) imidazole (S)-(+)-35a and (S)-(+)-1-phenyl-1-ethyl imidazole (S)-(+)-54. (S)-(+)-35a presented an identical specific rotationas the corresponding compound obtained from the three step synthesis discussedabove 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 newsynthetic method was considered instead of the asymmetric reduction of thecorresponding ketones that lead to poor results. The use of the lipase SAMII allowedthe synthesis of enantiopure 1-aryl-2-propyn-1-ols (R)-(-)-58a-c,e,h-l in highenantiomeric excesses and good chemical yields via hydrolysis of correspondingracemic 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 andwith 2-N-Mesyl iodoaniline to aryl-2-(N-mesyl)indol carbinols 64a-g using Pd(0) ascatalyst. Both products were obtained in high e.e. and chemical yield. These constitutethe first applications of Pd catalyses with enantiopure arylpropynols.The reaction conditions were optimized in order to maximize chemical yields andenantiomeric excesses. Finally an hypothesis for the mechanism of cyclization wasformulated. The first step is the Pd 0 catalyzed addition of the acetylenic compound tothe 2-iodophenol leading to 62; the second step is the CuI catalyzed cyclization tobenzo[b]furane derivatives 27 or to N-Ms-indol derivatives 64.In conclusion the present work led to advances in the stereoselective synthesis ofantifungal agents such as bifonazole 6a and the aromatase inhibitors 18; in fact theapplication of the described methodology to an enantiopure amine may probably leadto the target molecule in enantiopure form.