Synthesis of (2S,2′S)-bimorpholine N,N′-quaternary salts as chiral phase transfer catalysts

(2S,2′S)-Bimorpholine was synthesized starting from (R,R)-tartaric acid ester acetal in six steps in 50% of the total yield. Key steps include: cyanide catalyzed amidation and one-step cyclization with p-toluenesulfonyl imidazole. Derivatization of N,N′-dibenzyl bimorpholine afforded quaternary bimorpholinium salts, which were used as chiral phase transfer alkylation catalysts.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(4R,5R)-N,N′-Bis(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxamideC11H20N2O6[α]D22=-20.9 (c 2.40, MeOH)Source of chirality: (R,R)-dimethyl tartrateAbsolute configuration: (4R,5R)

2,2′-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]bis(methyleneimino)}diethanolC11H24N2O4[α]D23=-28.0 (c 2.63, MeOH)Source of chirality: (R,R)-dimethyl tartrateAbsolute configuration: (4S,5S)

2,2′-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]bis[methylene(benzylimino)]}diethanolC25H36N2O4[α]D23=-8.4 (c 2.37, MeOH)Source of chirality: (R,R)-dimethyl tartrateAbsolute configuration: (4S,5S)

(2S,3S)-1,4-Bis[(2-hydroxyethyl)(benzyl)amino]butane-2,3-diolC22H32N2O4[α]D22=-25.2 (c 4.87, MeOH)Source of chirality: (R,R)-dimethyl tartrateAbsolute configuration: (2S,3S)

(2S,2′S)-4,4′-Dibenzyl-2,2′-bimorpholineC22H28N2O2[α]D23=+49.4 (c 6.36, MeOH)Ee 99% (chiral HPLC analysis)Source of chirality: (R,R)-dimethyl tartrateAbsolute configuration: (2S,2′S)

(2S,2′S)-4,4′-Dibenzyl-4,4′-dimethyl-2,2′-bimorpholinium diiodideC24H34N2O2I2[α]D22=+41.2 (c 4.74, MeOH)Source of chirality: (R,R)-dimethyl tartrateAbsolute configuration: (2S,2′S, N and N′ unknown)

(2S,2′S)-4,4,4′,4′-Tetrabenzyl-2,2′-bimorpholinium dibromideC36H42N2O2Br2[α]D22=-53.7 (c 2.5, MeOH)Source of chirality: (R,R)-dimethyl tartrateAbsolute configuration: (2S,2′S)