Circular dichroism studies on absolute configuration assignment of peptidomimetics with a terminal chiral 3-arylpropionic acid unit

The relationship between the molecular structure of peptidomimetics 1 and their chiroptical properties has been studied using circular dichroism spectroscopy. It was demonstrated that the sign of the Cotton effects occurring around 230 and 270 nm enables the direct assignment of stereochemistry at C-1 and C-3 carbon atoms. The TD-DFT calculations of the circular dichroism (CD) spectrum of one of the model compounds confirm the absolute stereochemistry assignment made experimentally. Thus, CD spectroscopy proved to be a simple, reliable and general tool for the determination of the absolute configuration of the stereogenic centers of peptidomimetics with a terminal 3-arylpropionic group.

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(3S)-4-{Butyl-[(1R)-1-(ethoxycarbonylmethyl-carbamoyl)-3-methyl-butyl]-carbamoyl}-3-phenyl-butyric acid ethyl esterC27H42N2O6Δε (λ, MeCN) = +2.79 (191.0); +1.29 (206.0); +7.71 (230.0); −0.03 (269.0)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (1R,3S)

(3S)-4-{Butyl-[(1S)-1-(ethoxycarbonylmethyl-carbamoyl)-3-methyl-butyl]-carbamoyl}-3-phenyl-butyric acid ethyl esterC27H42N2O6Δε (λ, MeCN) = +7.83 (190.5); −1.28 (208.5sh); −9.13 (229.0); −0.09 (269.0)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (1S,3S)

(3S)-4-[((1R)-1-Benzylcarbamoyl-3-methyl-butyl)-butyl-carbamoyl]-3-phenyl-butyric acid ethyl esterC30H42N2O4Δε (λ, MeCN) = −3.16 (197.5); +2.18 (208.5); +10.83 (230.0); −0.03 (269.5)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (1R,3S)

(3S)-4-[((1S)-1-Benzylcarbamoyl-3-methyl-butyl)-butyl-carbamoyl]-3-phenyl-butyric acid ethyl esterC30H42N2O4Δε (λ, MeCN) = −13.21 (194.0); +2.55 (210.0); +12.73 (230.0); +0.08 (267.5)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (1S,3S)

(2R)-2-Benzyloxycarbonylamino-4-methyl-pentanoic acidC14H19NO4[α]D22=+16.9 (c 2.00, EtOH)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (2S)

((2R)-2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-acetic acid ethyl esterC18H26N2O5[α]D25=+27.6 (c 1.00, MeOH)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (2R)

(2R)-2-Benzyloxycarbonylamino-4-methyl-pentanoic acid benzylamideC21H26N2O3[α]D26=+18.5 (c 1.26, EtOH)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (2R)

(2S)-2-(Butylamino)-4-methyl-pentanoic acid benzylamideC17H28N2O[α]D23=-7.3 (c 1.01, MeOH)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (2S)

((2R)-2-Butylamino-4-methyl-pentanoylamino)-acetic acid ethyl esterC14H28N2O3[α]D23=+16.8 (c 0.72, MeOH)Chirality source: stereocontrolled synthesis from amino acidAbsolute configuration: (2R)