Stereoselective synthesis of cyclobutyl γ-amino acids leading to branched peptides with a cyclobutane core

Alternative synthetic routes are provided to synthesize γ-amino acids in their free form or conveniently protected for their selective incorporation into ramified γ-peptides with a cyclobutane core. The key synthetic-step involves the stereoselective conjugate addition of nitromethane to chiral cyclobutyl alkenoates prepared from (−)-verbenone.

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(S)-tert-Butyl 3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]-4-nitrobutanoateC18H31NO6[α]D = −22.0 (c 1.00, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (3S,1′R,3′R)

(S)-tert-Butyl 4-amino-3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]butanoateC18H33NO4[α]D = −8.3 (c 0.48, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (3S,1′R,3′R)

(S)-tert-Butyl 4-(4-(tert-butoxycarbonylamino)butanamido)-3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]butanoateC27H485N2O7[α]D = +7.3 (c 2.5, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (3S,1′R,3′R)

(S)-tert-Butyl 4-benzyloxycarbonylamino-3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]butanoateC26H39NO6[α]D = +14.6 (c 0.55, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (3S,1′R,3′R)

(S)-tert-Butyl 3-[(1R,3R)-3-acetyl-2,2-dimethylcyclobutyl-4-benzyloxycarbonylamino]butanoateC24H35NO5[α]D = +37.4 (c 2.12, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (3S,1′R,3′R)

(1R,3R)-3-[(S)-1-Benzyloxycarbonylamino-4-tert-butoxy-4-oxobutan-2-yl]-2,2-dimethylcyclobutanecarboxylic acidC23H33NO6[α]D = +93.3 (c 0.15, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (1R,3R,3′S)

(1R,3R)-Methyl 3-[(S)-1-benzyloxycarbonylamino-4-tert-butoxy-4-oxobutan-2-yl]-2,2-dimethylcyclobutanecarboxylateC24H35NO6[α]D = +64.4 (c 0.29, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (1R,3R,3′S)

(S)-4-[(1R,3R)-2,2-Dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]pyrrolidin-2-oneC14H23NO3[α]D = −15.4 (c 0.65, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (4S,1′R,3′R)

(S)-tert-Butyl-4-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]-2-oxopyrrolidine-1-carboxylateC19H15NO5[α]D = −23.7 (c 2.5, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (4S,1′R,3′R)

(S)-Methyl-4-tert-butoxycarbonylamino-3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]butanoateC20H35NO6[α]D = −34.2 (c 1.2, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (3S,1′R,3′R)

(1R,3R)-Methyl-3-[(S)-1-tert-butoxycarbonylamino-4-methoxy-4-oxobutan-2-yl]-2,2-dimethylcyclobutanecarboxylateC18H35NO6[α]D = −13.3 (c 2.5, CH2Cl2)Source of chirality: (−)-verbenone and stereoselective synthesisAbsolute configuration: (1S,1′R,3′R)