Regio- and stereoselective synthesis of the enantiomers of monoterpene-based β-amino acid derivatives

The regio- and stereospecific addition of chlorosulfonyl isocyanate to cis-δ-pinene enantiomers has furnished monoterpene-fused β-lactams. The observed regioselectivity can be explained by ab initio DFT modeling of transition state structures. In contrast with the less reactive α-pinane-fused β-lactam 4, the resulting β-lactams 5 and 13 containing an amino group connected to a secondary carbon possess similar reactivity to the cycloalkane-fused analogues and can be easily converted to the β-amino acid and its protected derivatives. The base-catalyzed isomerization of the cis-amino ester afforded the corresponding trans-amino ester in moderate yield.

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(1R,2R,5S,6R,7R)-6,8,8-Trimethyl-3-azatricyclo[5.1.1.02,5]nonan-4-oneC11H17NO[α]D20=-85.0 (c 0.25, EtOH)Source of chirality: (1R,2R,3R,5S)-(−)-isopinocampheolAbsolute configuration: 1R,2R,5S,6R,7R

(1R,2R,3S,4R,5R)-2-Amino-4,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxylic acid hydrochlorideC11H20ClNO2[α]D20=-23.0 (c 0.25, EtOH)Source of chirality: (1R,2R,3R,5S)-(−)-isopinocampheolAbsolute configuration: 1R,2R,3S,4R,5R

Ethyl (1R,2R,3S,4R,5R)-2-amino-4,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxylateC13H23NO2[α]D20=-30 (c 0.25, EtOH)Source of chirality: (1R,2R,3R,5S)-(−)-isopinocampheolAbsolute configuration: 1R,2R,3S,4R,5R

(1R,2R,5S,6R,7R)-N-tert-Butoxycarbonyl-6,8,8-trimethyl-3-azatricyclo [5.1.1.02,5]nonan-4-oneC13H23NO2[α]D20=-83 (c 0.25, EtOH)Source of chirality: (1R,2R,3R,5S)-(−)-isopinocampheolAbsolute configuration: 1R,2R,5S,6R,7R

(1R,2R,3S,4R,5R)-2-tert-Butoxycarbonylamino-4,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxylic acidC16H27NO4[α]D20=-7 (c 0.25, EtOH)Source of chirality: (1R,2R,3R,5S)-(−)-isopinocampheolAbsolute configuration: 1R,2R,3S,4R,5R

Ethyl (1R,2R,3R,4R,5R)-2-amino-4,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxylateC13H23NO2[α]D20=-17 (c 0.25, EtOH)Source of chirality:(1R,2R,3R,5S)-(−)-isopinocampheolAbsolute configuration: 1R,2R,3R,4R,5R