Stereoselective synthesis of 2,4-methanoproline homologues

The stereoselective synthesis of 2-azabicyclo[2.2.1]heptane-1-carboxylic acid and 6-azabicyclo[3.2.1]octane-5-carboxylic acid, novel rigid bicyclic proline analogues, is reported. The synthesis was performed in five steps from the corresponding 2-cycloalken-1-ones. A known approach to 2,4-methanoproline is improved. The three amino acids constitute a library of conformationally constrained proline analogues, which can be used for the design of peptidomimetics and peptide models.

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(1R,4S)-2-((1′S)-1-Phenylethyl)-2-azabicyclo[2.2.1]heptane-1-carbonitrileEe = 100%[α]D = −5.1 (c 0.66, MeOH)Source of chirality: separation of diastereomersAbsolute configuration: (1R,4S,1′S)

(1S,4R)-2-((1′S)-1-Phenylethyl)-2-azabicyclo[2.2.1]heptane-1-carbonitrileEe = 100%[α]D = −43.3 (c 0.60, MeOH)Source of chirality: separation of diastereomersAbsolute configuration: (1S,4R,1′S)

7-((1′S)-1-Phenylethyl)-7-azabicyclo[2.2.1]heptane-1-carbonitrileEe = 100%[α]D = −37.6 (c 0.84, MeOH)Source of chirality: S-(−)-α-phenylethylamineAbsolute configuration: (1′S)

(1S,5R)-6-((1′S)-1-Phenylethyl)-6-azabicyclo[3.2.1]octane-5-carbonitrileEe = 100%[α]D = −18.6 (c 0.16, MeOH)Source of chirality: separation of diastereomersAbsolute configuration: (1S,5R,1′S)

(1R,5S)-6-((1′S)-1-Phenylethyl)-6-azabicyclo[3.2.1]octane-5-carbonitrileEe = 100%[α]D = −26.2 (c 0.54, MeOH)Source of chirality: separation of diastereomersAbsolute configuration: (1R,5S,1′S)

(1S,4R)-2-Azabicyclo[2.2.1]heptane-1-carboxylic acidEe = 100%[α]D = −13.7 (c 0.26, MeOH)Source of chirality: separation of diastereomersAbsolute configuration: (1S,4R)

(1R,5S)-6-Azabicyclo[3.2.1]octane-5-carboxylic acid hydrochlorideEe = 100%[α]D = −19.9(c 1.30, MeOH)Source of chirality: separation of diastereomersAbsolute configuration: (1R,5S)

2-Methyl-2-(((1′S)-1-phenylethyl)amino)propanenitrileEe = 100%[α]D = −146.3 (c 0.64, MeOH)Source of chirality: (S)-(−)-α-phenylethylamineAbsolute configuration: (1′S)