Burkholderia cepacia lipase and activated β-lactams in β-dipeptide and β-amino amide synthesis

The work describes fluorine-activated and N-Boc-activated β-lactams as acyl donors to N-nucleophiles in the presence of Burkholderia cepacia lipase (lipase PS-D). Fluorine activation at the β-lactam ring causes the ring to open in high enantioselectivity and allows the preparation of β-dipeptides and β-amino amides. In the case of N-Boc-activation, the chemical ring opening is significant. β-Dipeptide formation can then be considerably enhanced by the presence of lipase PS-D and/or by temperature.

Graphical abstractLipase from Burkholderia cepacia was used for the preparation of enantiopure β-amino amides and β-dipeptides in dry organic solvent.Figure optionsDownload full-size imageDownload as PowerPoint slide

(R)-3,3-Difluoro-4-phenylazetidin-2-oneC9H7F2NOEe = 99%[α]D22=-76.6 (c 1.00, CHCl3)Source of chirality: from enzymatic resolutionAbsolute configuration: (R)

(S)-3-Amino-2,2-difluoro-3-phenyl-N-isopropylpropanamideC12H16F2N2OEe = 99%[α]D22=+4.2 (c 1.00, CHCl3)Source of chirality: from enzymatic resolutionAbsolute configuration: (S)

(3R,4R)-3-Fluoro-4-phenylazetidin-2-oneC9H8FNOEe = 99%[α]D22=-19.1 (c 1.00, CHCl3)Source of chirality: from enzymatic resolutionAbsolute configuration: (3R,4R)

(3R,4R)-1-(tert-Butoxycarbonyl)-3-fluoro-4-phenylazetidin-2-oneC14H16FNO3Ee = 99%[α]D22=-76.0 (c 0.50, CHCl3)Source of chirality: derivatized from the chiral precursorAbsolute configuration: (3R,4R)

(R)-1-(tert-Butoxycarbonyl)-4-phenylazetidin-2-oneC14H17NO3Ee = 99%[α]D22=+114.0 (c 0.48, CHCl3)Source of chirality: derivatized from the chiral precursorAbsolute configuration: (R)

(R)-3-[(S)-3-Amino-2,2-difluoro-3-phenylpropanoyl]aminobutanoic acid tert-butyl esterC17H24F2N2O3Ee = 99%[α]D22=+28.8(c 1.00, CHCl3)Source of chirality: from the chiral precursorsAbsolute configuration: (S,R)

(R)-3-[(2S,3S)-3-tert-Butoxycarbonylamino-2-fluoro-3-phenylpropanoyl]aminobutanoic acid tert-butyl esterC22H33FN2O5Ee = 99%[α]D22=+4.2 (c 0.75, CHCl3)Source of chirality: from the chiral precursorsAbsolute configuration: (S,S,R)

(S)-3-[(2R,3R)-3-tert-Butoxycarbonylamino-2-fluoro-3-phenylpropanoyl]amino-4-phenylbutanoic acid tert-butyl esterC28H37FN2O5Ee = 99%[α]D22=+8.7 (c 1.00, CHCl3)Source of chirality: from the chiral precursorsAbsolute configuration: (R,R,S)

(R)-3-[(R)-3-tert-Butoxycarbonylamino-3-phenylpropanoyl]aminobutanoic acid tert-butyl esterC22H34N2O5Ee = 99%[α]D22=+32.4 (c 1.05, CHCl3)Source of chirality: from the chiral precursorsAbsolute configuration: (R,R)

(S)-3-[(S)-3-tert-Butoxycarbonylamino-3-phenylpropanoyl]amino-4-phenylbutanoic acid tert-butyl esterC28H38N2O5Ee = 99%[α]D22=-15.0 (c 1.00, CHCl3)Source of chirality: from the chiral precursorsAbsolute configuration: (S,S)