Synthesis of chiral C/N-functionalized morpholine alcohols: study of their catalytic ability as ligand in asymmetric diethylzinc addition to aldehyde

A broad variety of chiral C/N-functionalized morpholine alcohols sharing a common structural motif in the 3-(hydroxymethyl)morpholine 6 were prepared from enantiomerically pure serine for the purpose of studying their catalytic ligand properties. The asymmetric addition of diethylzinc to benzaldehyde in the presence of 10 mol % of chiral C/N-functionalized morpholine alcohols gave 1-phenyl-1-propanol in 59–81% yield with 10–30% ee. The addition of 10 mol % of n-butyl lithium to the reaction mixture resulted in a significant enhancement of the stereoselectivity in the case of ligands bearing the two geminal phenyl substituents on the backbone. In the presence of n-butyl lithium and using (S)-3-(hydroxydiphenylmethyl)morpholine (S)-19 as the chiral promoter, (S)-1-phenyl-1-propanol was obtained in 81% yield with 76% ee. The geminal diphenyl-class of morpholine ligands was examined for the diethylzinc addition to four different aldehydes in the presence of n-butyl lithium. (S)-N-Benzyl-3-(hydroxydiphenylmethyl)morpholine (S)-27 was found to be most enantioselective in the case of 4-methoxybenzaldehyde to give (R)-alcohol in 87% yield with 80% ee. Catalysts (S)-19 and its N-methyl derivative (S)-26 gave alcohols with an (S)-absolute configuration while the N-benzylated derivative (S)-27 gave the opposite enantiomeric products. The tentative transition state models to account for the observed product stereoselectivity with morpholine ligands holding the geminal diphenyl group on the β-amino alcohol segment are proposed.

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(S)-3-(Hydroxymethyl)morpholineC5H11NO2[α]D27=-17.2 (c 1.4, 1 M HCl)Source of chirality: l-serineAbsolute configuration: (S)

(3S,5S)-3-(Benzyloxymethyl)-5-(hydroxymethyl)morpholineC13H19NO3[α]D26=+3.7 (c 1.0, MeOH)Source of chirality: d-serine and (S)-2,3-O-isopropylideneglycerolAbsolute configuration: (3S,5S)

(3R,5S)-3-(tert-Butyldiphenylsilyloxymethyl)-5-(hydroxymethyl)morpholineC22H31NO3Si[α]D24=-11.5 (c 1.1, MeOH)Source of chirality: d-serine and (S)-2,3-O-isopropylideneglycerolAbsolute configuration: (3R,5S)

(3S,5S)-3-(Benzyloxymethyl)-5-(tert-butyldiphenylsilyloxymethyl)morpholineC29H37NO3Si[α]D24=+2.2 (c 1.0, CHCl3)Source of chirality: d-serine and (R)-2,3-O-isopropylideneglycerolAbsolute configuration: (3S,5S)

(3S,5S)-3-(tert-Butyldiphenylsilyloxymethyl)-5-(hydroxymethyl)morpholineC22H31NO3[α]D26=-0.6 (c 1.4, MeOH)Source of chirality: d-serine and (R)-2,3-O-isopropylideneglycerolAbsolute configuration: (3S,5S)

(3S,5S)-N-Allyl-3-(benzyloxymethyl)-5-(hydroxymethyl)morpholineC16H23NO3[α]D26=+47 (c 1.3, CHCl3)Source of chirality: d-serine and (S)-2,3-O-isopropylideneglycerolAbsolute configuration: (3S,5S)

(3S,5S)-N-Propionyl-3-(benzyloxymethyl)-5-(hydroxymethyl)morpholineC16H23NO4[α]D24=+22.2 (c 1.6, CHCl3)Source of chirality: d-serine and (S)-2,3-O-isopropylideneglycerolAbsolute configuration: (3S,5S)

(3S,5S)-N-(2,2-Diphenyl-2-hydroxyethyl)-3,5-bis(benzyloxymethyl)morpholineC34H37NO4[α]D23=+35.2 (c 1.0, CHCl3)Source of chirality: d-serine and (R)-2,3-O-isopropylideneglycerolAbsolute configuration: (3S,5S)

(S)-3-(Hydroxydiphenylmethyl)morpholineC17H19NO2[α]D25=-105.5 (c 1.7, CHCl3)Source of chirality: l-serineAbsolute configuration: (S)

(S)-N-Methyl-3-(hydroxydiphenylmethyl)morpholineC18H21NO2[α]D29=-157.2 (c 0.9, CHCl3)Source of chirality: l-serineAbsolute configuration: (S)

(S)-N-Benzyl-3-(hydroxydiphenylmethyl)morpholineC24H25NO2[α]D28=-81.4 (c 1.0, CHCl3)Source of chirality: l-serineAbsolute configuration: (S)