Enantiomerically pure phosphonate analogues of cis- and trans-4-hydroxyprolines

All the enantiomers of O,O-diethyl 4-hydroxypyrrolidinyl-2-phosphonates, phosphonate analogues of cis- and trans-4-hydroxyprolines, have been obtained for the first time. The synthetic strategy involved 1,3-dipolar cycloaddition of (R)- and (S)-N-(1-phenylethyl)-C-(diethoxyphosphoryl)nitrones to allyl alcohol and separation of the corresponding O,O-diethyl 5-(hydroxymethyl)-2-(1-phenylethyl)isoxazolidinyl-3-phosphonates, which were subsequently mesylated and hydrogenated to undergo intramolecular cyclisation. Absolute configurations of the enantiomeric proline phosphonates were established after N- and O-derivatization with (S)-O-methylmandelic acid employing the Trost model.

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N-[(S)-1-Phenylethyl]-C-(diethoxyphosphoryl)nitroneC13H20NO4PEe = 100%[α]D20=+7.5 (c 1.9, CHCl3)Source of chirality: (S)-1-phenylethylamineAbsolute configuration: (S)

Diethyl (2S,4S)-4-hydroxypyrrolidinyl-2-phosphonateC8H18NO4PEe = 100%[α]D20=-4.6 (c 1.0, CH3OH)Source of chirality: (S)-1-phenylethylamineAbsolute configuration: (2S,4S)

Diethyl (2S,4R)-4-hydroxypyrrolidinyl-2-phosphonateC8H18NO4PEe = 100%[α]D20=+10.7 (c 1.1, CH3OH)Source of chirality: (S)-1-phenylethylamineAbsolute configuration: (2S,4R)

Diethyl (3S,5R)-5-(hydroxymethyl)-2-[(S)-1-phenylethyl]isoxazolidinyl-3-phosphonateC16H26NO5PEe = 100%[α]D20=-3.8 (c 1.1, CHCl3)Source of chirality: (S)-1-phenylethylamineAbsolute configuration: (3S,5R,1′S)

Diethyl (3R,5R)-5-(hydroxymethyl)-2-[(S)-1-phenylethyl]isoxazolidinyl-3-phosphonateC16H26NO5PEe = 100%[α]D20=-63.6 (c 1.5, CHCl3)Source of chirality: (S)-1-phenylethylamineAbsolute configuration: (3R,5R,1′S)

Diethyl (3R,5R)-5-(hydroxymethyl)-2-[(R)-1-phenylethyl]isoxazolidinyl-3-phosphonateC16H26NO5PEe = 100%[α]D20=+1.6 (c 1.3, CHCl3)Source of chirality: (R)-1-phenylethylamineAbsolute configuration: (3R,5R,1′R)