Synthesis and conformational preferences of cyclic unnatural di- and tripeptides containing an l-valine unit: Part 2

Stereoselective syntheses of non-proteinogenic di- 14a,b, 15a,b and 16a,b and tripeptides 14c, 15c and 16c containing an l-valine unit and a cyclic unnatural α-amino acid have been accomplished starting from the l-valine derived chiral synthon 1. The conformational preferences of these unnatural peptides were investigated by 1H NMR and IR spectroscopies and by molecular modelling calculations. X-ray analysis of pseudopeptides 15a and 15b is also reported.

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(2′S,2S)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acid ethyl esterC16H26N2O4[α]D25=-35.5 (c 0.9, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2S

(2′S,2R)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acid ethyl esterC16H26N2O4[α]D25=+2.8 (c 0.5, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2R

(2′S,2R)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acidC14H22N2O4[α]D25=+5.6 (c 0.5, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2R

(2′S,2S)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acidC14H22N2O4[α]D25=-33.7 (c 0.2, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2S

(2S,2′S,2″R)-2-{[1-(2′-Acetylamino-3′-methyl-butyryl)-4″-methylene-pyrrolidine-2″-carbonyl]-amino}3-methyl-butyric acid methyl esterC19H31N3O5[α]D25=+8.7 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,2′S,2″R

(2′S,2R)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acid pentafluorophenyl esterC20H21F5N2O4[α]D25=-6.9 (c 1, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2R

(2′S,2S)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acid pentafluorophenyl esterC20H21F5N2O4[α]D25=-38.7 (c 0.4, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2S

(2′S,2R)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acid cyclohexylamideC20H33N3O3[α]D25=+6.9 (c 1, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2R

(2′S,2R)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acid benzylamideC21H29N3O3[α]D25=+4.9 (c 1, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2R

(2S,2′S,2″R)-2-{[1-(2′-Acetylamino-3′-methyl-butyryl)-2″-methyl-4″-methylene-pyrrolidine-2″-carbonyl]-amino}3-methyl-butyric acid methyl esterC20H33N3O5[α]D25=+3.7 (c 0.9, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,2′S,2″R

(2′S,2S)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acid cyclohexylamideC20H33N3O3[α]D25=-59.7 (c 0.3, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2S

(2′S,2S)-1-(2′-Acetylamino-3′-methyl-butyryl)-2-methyl-4-methylene-pyrrolidine-2-carboxylic acid benzylamideC21H29N3O3[α]D25=-39.6 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2S

(2S,2′S,2″S)-2-{[1-(2′-Acetylamino-3′-methyl-butyryl)-2″-methyl-4″-methylene-pyrrolidine-2″-carbonyl]-amino}3-methyl-butyric acid methyl esterC20H33N3O5[α]D25=-54.4 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: 2S,2′S,2″S

(2′S,2R)-1-(2′-Acetylamino-3′-methyl-butyryl)-4-methylene-pyrrolidine-2-carboxylic acid cyclohexylamideC19H31N3O3[α]D25=+53.2 (c 1, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2R

(2′S,2R)-1-(2′-Acetylamino-3′-methyl-butyryl)-4-methylene-pyrrolidine-2-carboxylic acid benzylamideC20H27N3O3[α]D25=+50.1 (c 1.8, CHCl3)Source of chirality: l-valineAbsolute configuration: 2′S,2R