Lipase-catalysed kinetic resolution as the key step in the synthesis of a new class of optically active 5,6-trans-9,10-dihydrophenanthroline derivatives

New atropisomeric 5,6-trans-9,10-dihydrophenanthroline amino- and hydroxy-derivatives 3–7 possessing two additional stereogenic centres were obtained in high enantiomeric purity by lipase-catalysed kinetic resolution of the corresponding easily accessible racemates. Lipase from Pseudomonas fluorescens (Lipase AK) showed good enantioselectivity (E > 200) in the esterification reaction of trans-5-azido-6-hydroxyl derivative (±)-7, giving access to the enantioforms (+)- and (−)-7 isolated with ee = 97% and ee >98%, respectively. The chemical reduction of azide group furnished the homochiral amino derivatives (+)- and (−)-4 without a loss in enantiomeric purity. For all the substrates investigated, lipase AK revealed a stereopreference for the enantiomer with a (P,R,R)-configuration.

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(5S,6S)-Dihydro-5,6-dihydroxy-1,10-phenanthrolineC12H10N2O2Ee = 94%[α]D25=-75.1 (c 0.4, CH3OH)Source of chirality: enzymatic resolutionAbsolute configuration: (5S,6S)

(5S,6S)-Dihydro-5-hydroxy-6-tert-butoxycarbonylamino-1,10-phenanthrolineC17H19N3O4Ee = 96%[α]D25=+51.9 (c 0.2, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (5S,6S)

(5R,6R)-Dihydro-5-hydroxy-6-tert-butoxycarbonylamino-1,10-phenanthrolineC19H21N3O5Ee = 90%[α]D25=-68.9 (c 0.3, CH3OH)Source of chirality: enzymatic resolutionAbsolute configuration: (5R,6R)

(5S,6S)-Dihydro-5-acetoxy-6-hydroxy-1,10-phenanthrolineC14H12N2O3Ee = 90%[α]D25=+75.0 (c 0.6, CH3OH)Source of chirality: enzymatic resolutionAbsolute configuration: (5S,6S)

(5R,6R)-Dihydro-5,6-diacetoxy-1,10-phenanthrolineC16H14N2O4Ee = 94%[α]D25=-211.4 (c 0.3, CH3OH)Source of chirality: enzymatic resolutionAbsolute configuration: (5R,6R)

(5S,6S)-Dihydro-5-azido-6-hydroxy-1,10-phenanthrolineC12H9N5OEe > 98%[α]D25=-67.5 (c 0.6, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (5S,6S)

(5R,6R)-Dihydro-5-acetoxy-6-azido-1,10-phenanthrolineC14H11N5O2Ee = 97%[α]D25=-264.5 (c 0.6, CH3OH)Source of chirality: enzymatic resolutionAbsolute configuration: (5R,6R)

(5S,6S)-Dihydro-5-amino-6-hydroxy-1,10-phenanthrolineC12H11N3OEe > 98%[α]D25=-51.9 (c 0.1, CH3OH)Source of chirality: enzymatic resolutionAbsolute configuration: (5S,6S)