Homochirale 2,4‐disubstituierte 1,3‐Dioxane aus (S)‐(−)‐Äpfelsäure: Stereoselektive Synthese und Untersuchung der NMDA‐Rezeptoraffinität aller vier Stereoisomerer

Homochiral 2,4‐Disubstiuted 1,3‐Dioxanes from (S)‐(−)‐Malic Acid: Stereoselective Synthesis and Investigation of the NMDA Receptor Affinity of All Four Stereoisomers Starting from a single enantiomerically pure compound, (S)‐(−)‐malic acid, all four stereoisomeric 4‐dimethylaminomethyl‐2‐phenyl‐1,3‐dioxanes (S,S)‐15 (S,R)‐16, and (R,S)‐16 are prepared: Transacetalisation of benzaldehyde dimethyl acetal (6b) with (S)‐(−)‐methyl 2,4‐dihydroxybutyrate (7a), which is obtained by chemoselective BH3 reduction of (S)‐(−)‐malic acid monoester 8b, yields the diastereomeric 1,3‐dioxane derivatives (S,S)‐10 and (R,S)‐11 in a 85:15 ratio. LDA deprotonation of (S,S)‐10 followed by protonation leads to C‐4 epimerisation [(S,S)‐10:(S,R)‐11 = 30:70]. The thermodynamically controlled 88:12 equilibrium of (R,R)‐10 and (S,R)‐11 is reached by treatment of (S,R)‐11 with acid. Aminolysis with dimethylamine and subsequent LiAlH4 reduction 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 3H‐(+)‐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 with the NMDA receptor.