HOMOCHIRAL 2,4-DISUBSTITUTED 1,3-DIOXANES FROM (S)-(-)-MALIC ACID - STEREOSELECTIVE SYNTHESIS AND INVESTIGATION OF THE NMDA RECEPTOR AFFINITY OF ALL 4 STEREOISOMERS

Starting from a single enantiomerically pure compound, (S)-(-)-malic a cid, all four stereoisomeric 4-dimethylaminome-thyl-2-phenyl-1,3-dioxa nes (S,S)-15, (R,R)-15 (S,R)-16, and (R,S)-16 are prepared: Transaceta lisation of benzaldehyde dimethyl acetal (6b) with (S)-(-)-methyl 2,4- dihydroxybutyrate (7a), which is obtained by chemoselective BH3 reduct ion of (S)-(-)-malic acid monoester Ob, yields the diastereomeric 1,3- dioxane derivatives (S,S)-10 and (R,S)-11 in a 85:15 ratio. LDA deprot onation of (S,S)-10 followed by protonation leads to C-4 epimerisation [(S,S)-10:(S,R)-11 = 30:701. The thermodynamically controlled 88:12 e quilibrium of (R,R)-10 and (S,R)-11 is reached by treatment of (S,R)-1 1 with acid. Aminolysis with dimethylamine and subsequent LiAlH4 reduc tion transform the four stereoisomeric esters (S,S)-10, (R,R)-10, (S,R )-11 and (R,S)-11 to give the amines (S,S)-15, (R,R)-15, (S,R)-16 and (R,S)-16, respectively. In the H-3-(+)-MK 801 displacement experiment (S,S)-15, (R,R)-15, (S,R)-16 and (R,S)-16 show a very little affinity to the phencyclidine binding site in the cation channel associated wit h the NMDA receptor.