First synthesis of enantiomerically pure (1S,2S)- and (1R,2R)-1,2-diaminocyclobutanecarboxylic acid–ornithine derivative–, from racemic 2-aminocyclobutanone

An easy and efficient one-pot reaction from readily available 2-(N-Cbz) aminocyclobutanone selectively gave, by means of an asymmetric Strecker synthesis in the presence of a chiral benzylic amine, the thermodynamic 1,2-diamino nitriles. Basic hydrolysis, cleavage of the benzylic group and acidic hydrolysis of the resulting trans-1,2-diaminocyclobutanecarbonitrile gave, in a four-step sequence from the ketone, (1S,2S)- or (1R,2R)-1,2-diaminocyclobutanecarboxylic acid, ornithine derivatives. The absolute configuration has been established by X-ray analysis of the corresponding trans-diamino amide.

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2-(N-Benzyloxycarbonyl)amino-1-(1′-phenylethyl)aminocyclobutanecarbonitrileC21H23N3O2Ee >99%[α]D20=-181 (c 1.00, CHCl3)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (1S,2S,1′S)

2-(N-Benzyloxycarbonyl)amino-1-(1′-phenylethyl)aminocyclobutanecarbonitrileC21H23N3O2Ee >99%[α]36520=-23.6 (c 1.00, CHCl3)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (1R,2R,1′S)

2-(N-Benzyloxycarbonyl)amino-1-(1′-phenylethyl)aminocyclobutanecarboxamideC21H25N3O3Ee >99%[α]D20=-53 (c 1.00, CHCl3)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (1S,2S,1′S)

2-(N-Benzyloxycarbonyl)amino-1-(1′-phenylethyl)aminocyclobutanecarboxamideC21H25N3O3Ee >99%[α]D20=-15.4 (c 1.00, CHCl3)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (1R,2R,1′S) assigned by X-ray analysis

1,2-Di-[(N-tert-butyloxycarbonyl)amino]cyclobutanecarboxamideC15H21N3O5Ee >99%[α]D20=-15 (c 0.25, CHCl3)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (1S,2S)

1,2-Diaminocyclobutanecarboxylic acid·hydrochlorideC5H12N2O2Cl2Ee >99%[α]D20=-4 (c 0.60, H2O)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (1S,2S)