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

Chapter 1 32These apparently similar two classes of compounds showed acompletely different chemical behavior during our investigation as willbecome clear in the following chapters. Structurally quite simple, thesecompounds contain only one chiral centre in form of a tertiary carbonbound to three different aromatic substituents. The system is prone to formvery stable carbocations 143 under acidic conditions, furthermore themolecules do not posses any site of functionalization which would allow theformation of separable diasteroisomers. The following paragraphs will showthe consequences of these features on the employed general strategies.1.6.1. Approaches based on diasteroisomers.This approach consists in the synthesis of molecules having a"removable anchor" group, such as a carboxylic acid, amine or alcohol,that could be bound to another molecule with defined chirality in order toform a pair of diasteroisomers. The different physico-chemical propertiesof the diasteroisomers can be used to separate them by chromatography orby crystallization. After the separation it is necessary to remove the anchorgroup and to generate the molecule with the defined chiral centre under suchmild conditions as to avoid any possible racemization of the single isomerobtained from the separation. The last step is the removal of the anchorfrom the molecule to generate the free enantiomer of the drug. Again it isnecessary to find the mildest conditions in order to avoid racemizations ofthe final compouds (Fig. 1.20 ).Our target molecules are unfunctionalized and we have designed twodifferent functional groups to be introduced as anchors, either on thearomatic moieties or on the imidazole ring (Fig. 1.19).ArArRNNNN RAr= Biphenyl, Benzofurane R = NH 2 ,COOH,OH.Figure 1.19: Possible positions of anchor groups.