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Homochirale 2,4‐disubstituierte 1,3‐Dioxane aus ( S )‐(−)‐Äpfelsäure: Stereoselektive Synthese und Untersuchung der NMDA‐Rezeptoraffinität aller vier Stereoisomerer
Author(s) -
Wünsch Bernhard,
Diekmann Heike,
Höfner Georg
Publication year - 1993
Publication title -
liebigs annalen der chemie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 0170-2041
DOI - 10.1002/jlac.1993199301208
Subject(s) - chemistry , stereoselectivity , diastereomer , stereochemistry , protonation , dimethylamine , deprotonation , acetal , medicinal chemistry , organic chemistry , catalysis , ion
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 BH 3 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 LiAlH 4 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 3 H‐(+)‐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.