Synthesis and NMDA receptor affinity of fluorinated dioxadrol analogues

Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists

“…17,18 Whereas, the piperidine ring of derivatives with a proton (e.g., 3-7) or a PMB-group (e.g., 22) attached to the N-atom adopts the 1 C 4 -conformation the corresponding Cbz-derivatives (e.g., 23-27) exist in the 1 C 4 -conformation (compare Schemes 5 and 6). Due to allylic strain 26,27 the N-acyl-residue of 23-27 forces the substituent in 2-position to adopt an axial orientation, which is only possible after changing the piperidine ring conformation.…”

“…Whereas, the reaction of (R,S)-17 in the presence of the chiral Lewis acid (S)-21 led to 23% yield of the cycloaddition products with poor diastereoselectivity, the other possible combinations of chiral Lewis acid and imine did not yield any products. (Table 1, entries [16][17][18][19] Obviously most combinations of chiral Lewis acid (21) and chiral auxiliary (phenylethylamine) are mismatched pairs.…”

“…17,18 Since the absolute (S)-configuration of C-4 of the dioxolane ring is known from the synthesis starting with enantiomerically pure D-mannitol, the absolute configuration at 2-and 4-position of the piperidine ring is also (S).…”

“…[12][13][14][15] Recently we have reported on the synthesis of racemic dioxadrol derivatives bearing various substituents (NR 2 , OR, @O, F) in position 4 of the piperidine ring. [16][17][18] It was shown that like-configuration (RS/RS) of the ring junction, that is, the same configuration of the 2-position of the piperidine ring and 4-position of the dioxolane ring, and axial orientation of the C-4-substituent (also RS-configuration) are crucial for high NMDA receptor affinity. In particular, 4-oxo [(±)-4], 4-hydroxy [(±)-5], 4-fluoro [(±)-6], and 4,4-difluoro [(±)-7] derivatives of dioxadrol [(±)-3] with the same configuration at all centers of chirality reveal promising NMDA receptor affinity of 470, 44, 27, and 81 nM, respectively.…”

“…In particular, 4-oxo [(±)-4], 4-hydroxy [(±)-5], 4-fluoro [(±)-6], and 4,4-difluoro [(±)-7] derivatives of dioxadrol [(±)-3] with the same configuration at all centers of chirality reveal promising NMDA receptor affinity of 470, 44, 27, and 81 nM, respectively. [16][17][18] The affinities of these compounds (±)-4-(±)-7 are in an interesting range between the affinities of enantiomerically pure dexoxadrol [(S,S)-3] and memantine (2b).…”