Synthesis of four enantiomers of 2,3-di(N-Boc-amino)-1-hydroxypropylphosphonates

Enantiomerically pure diethyl (1S,2R)-, (1S,2S)-, (1R,2R)- and (1R,2S)-2,3-di(tert-butoxycarbonyl)amino-1-hydroxypropylphosphonates were synthesised from diethyl (1S,2R,1′S)-, (1S,2S,1′R)-, (1R,2R,1′S)- and (1R,2S,1′R)-[N-(1-phenylethyl)]-2,3-epimino-1-hydroxypropylphosphonates, respectively, via aziridine ring opening with neat TMSN3 followed by hydrogenolysis in the presence of Boc2O. A plausible mechanism for the aziridine ring opening in 2,3-epimino-1-hydroxypropylphosphonates involving the intermediate aziridinium ions was proposed. Significant differences in the rates of the aziridine ring opening between diastereoisomeric phosphonates (1S,2R,1′S) and (1S,2S,1′R) were rationalised taking into account different conformations of the 1-phenylethyl group in both diastereoisomers.

Figure optionsDownload as PowerPoint slide

Diethyl (1S,2R)-2-[(S)-1-phenylethyl]amino-3-azido-1-hydroxypropylphosphonateC15H25N4O4PEe = 100%[α]D20=-65.1 (c 3.07, CHCl3)Source of chirality: (S)-1-phenylethylamineAbsolute configuration (1S,2R,1′S)

Diethyl (1S,2S)-2-[(R)-1-phenylethyl]amino-3-azido-1-hydroxypropylphosphonateC15H25N4O4PEe = 100%[α]D20=+92.8 (c 0.75, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration (1S,2S,1′R)

Diethyl (1S,2S)-2,3-di(N-tert-butoxycarbonylamino)-1-hydroxypropylphosphonateC17H35N2O8PEe = 100%[α]D20=-13.9 (c 2.25, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration (1S,2S)

Diethyl (1S,2R)-2,3-di(N-tert-butoxycarbonylamino)-1-hydroxypropylphosphonateC17H35N2O8PEe = 100%[α]D20=-33.7 (c 1.07, CHCl3)Source of chirality: (S)-1-phenylethylamineAbsolute configuration (1S,2R)