N-Substituent effects on the diethylzinc addition to benzaldehyde catalysed by bicyclic 1,4-amino alcohols

Chiral enantiopure bicyclic 1,4-amino alcohols were synthesised by a new methodology that provided a common precursor, which was easily N-functionalised with a wide variety of substituents. The final compounds were used as chiral ligands in a model study of the enantioselective addition of diethyl zinc to benzaldehyde, aimed at understanding the influence of the N-substituent on both the rate and stereoselectivity of the reaction. This set of experiments also provided interesting insight into the non-catalysed addition that occurred by employing commercially available Et2Zn solutions.

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(1S,5R,7R)-(3-Phenyl-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-yl)methanolC12H15NO3Ee > 97%[α]D26=-33.1 (c 0.82, CHCl3)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)

(1S,5S,7R)-(3-(4-Methoxyphenyl)-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-yl)methanolC13H17NO4Ee > 97%[α]D24=-41.8 (c 0.58, CHCl3)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)

(1S,5R,7R)-(3-o-Tolyl-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-yl)methanolC13H17NO3Ee > 97%[α]D26=-90.2 (c 1.2, CHCl3)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)

(1S,5R,7R)-(3-(2-Fluoroethyl)-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-yl)methanolC8H14FNO3Ee > 97%[α]D26=-73.8 (c 0.48, CHCl3)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)

(1S,5R,7R)-(3-(2,2,2-Trifluoroethyl)-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-yl)methanolC8H12F3NO3Ee > 97%[α]D24=-67.8 (c 0.12, CHCl3)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)

(1S,5R,7R)-(3-(Toluene-4-sulfonyl)-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-yl)methanolC13H17NO5SEe > 97%[α]D26=-7.1 (c 1.0, CHCl3)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)

(1S,5R,7R)-(3-Methanesulfonyl-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-yl)methanolC7H13NO5SEe > 97%[α]D26=-40.4 (c 0.70, CH3OH)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)

(1S,5R,7R)-7-Hydroxymethyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-3-carboxylic acid methyl esterC8H13NO5Ee > 97%[α]D26=-44.2 (c 0.51, CHCl3)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)

(1S,5R,7R)-(3-Propyl-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-yl)methanolC9H17NO3Ee > 97%[α]D24=-68.5 (c 0.20, CHCl3)Source of chirality: (−)-2,3-O-isopropylidene-d-erythronolactoneAbsolute configuration: (1S,5S,7R)