Ring-expanded chiral rhombamine macrocycles for efficient NMR enantiodiscrimination of carboxylic acid derivatives

Novel 46-membered chiral rhombamine macrocycles (R,R,R,R)-8a and 8b were synthesized by [2+2] cyclocondensation reactions of (R,R)-1,2-diaminocyclohexane with the corresponding dialdehydes and subsequent reduction with NaBH4. The X-ray crystal structure of 1:4 dioxane complex with (R,R,R,R)-8a indicated a rhombus conformation of the chiral macrocycle. Compounds (R,R,R,R)-8a and 8b were tested as chiral shift reagents for a wide range of α-substituted carboxylic acids and amino acid derivatives. Enantiodiscrimination of 1H NMR signals was observed with ΔΔδ values of up to 0.214 ppm.

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C66H68N4[α]D25 = −18 (c 0.1, CHCl3)Source of chirality: (1R,2R)-diaminocyclohexaneAbsolute configuration: (R,R,R,R)

C64H64N4O2[α]D25 = −40 (c 0.1, CHCl3)Source of chirality: (1R,2R)-diaminocyclohexaneAbsolute configuration: (R,R,R,R)