Pyridine-containing chiral macrocycles for the enantioselective recognition of amino acid derivatives and their molecular dynamics simulations

Two novel C2-symmetric optically active pyridine-15-crown-5 type ligands containing lipophilic chains at the stereogenic centres, macrocycles 5 and 6, were prepared from (S)-1,2-propanediol and (S)-3-aryloxy-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These novel macrocycles have been shown to be strong complexing agents for primary organic ammonium salts (with K values of up to 1363.5 M−1, ΔGo of up to 17.86 kJ mol−1 and a selectivity ratio of 80:20) by 1H NMR titration method. These macrocyclic host exhibited enantioselective binding towards the l-enantiomer of phenylalanine methyl ester hydrochloride with KL/KD up to 8.57 in CDCl3 containing 0.25% CD3OD. Experimental results have been detailed with molecular dynamic calculations at atomic level concerning the molecular recognition and discrimination properties of a chiral pyridino-15-crown-5. The binding free energies were calculated as ∼−25 kJ mol−1. The results indicated that the host binds and discriminates valine salts better than phenylalanine salts. The molecular dynamics, MM/PBSA calculations are consistent with the 1H NMR results.

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(2S,9S)-4,7-[N-(S)-α-Phenyl ethyl]diaza-2,9-decanediolC24H36O2N2[α]D25=-72.9 (c 3.4, CHCl3)Source of chirality: (S)-2-propanediolAbsolute configuration: (2S,9S)

(1S,8S)-3,6-[N-(S)-α-Phenyl ethyl]diaza-1,8-diphenoxymethyl-1,8-decanediolC36H44O4N2[α]D34=-40.5 (c 0.74, CHCl3)Source of chirality: (S)-3-phenoxypropane-1,2-diolAbsolute configuration: (1S,8S)

(4S,11S)-4,11-Dimethyl-6,9-bis(1-phenylethyl)-3,12-dioxa-6,9,18-triaza bicyclo[12.3.1]octadeca-1(18),14,16-trieneC31H41N3O2[α]D30=-241 (c 0.067, CHCl3)Source of chirality: (S)-2-propanediolAbsolute configuration: (4S,11S)

(4S,11S)-4,11-Benzyloxy-6,9-bis(1-phenylethyl)-3,12-dioxa-6,9,18-triaza bicyclo[12.3.1]octadeca-1(18),14,16-trieneC43H49N3O4[α]D30=-47 (c 1.00, CHCl3)Source of chirality: (S)-3-phenoxypropane-1,2-diolAbsolute configuration: (4S,11S)