Organocatalytic asymmetric cross-aldol reaction of 2-chloroethoxy acetaldehyde: diversity-oriented synthesis of chiral substituted 1,4-dioxanes and morpholines

Herein we report a facile organocatalytic asymmetric direct cross-aldol reaction of 2-chloroethoxy acetaldehyde with aromatic aldehydes using (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol as an organocatalyst to afford anti-2-(2-chloroethoxy)-1-arylpropane-1,3-diols with excellent enantioselectivities (95–98%) and moderate diastereoselectivities (3.5–7:1). The 1,3-diols, obtained after the aldehyde reduction, represent highly functional intermediates that allow for further diversification into both chiral 1,4-dioxanes and morpholines, compounds that frequently display interesting biological activities.

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anti-(1,4-Dioxan-2-yl)(4-nitrophenyl)methanolC11H13NO5ee = 95%[α]D25=+2.5 (c 0.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S,R)

anti-(4-Benzylmorpholin-2-yl)(4-nitrophenyl)methanolC18H20N2O4ee = 91%[α]D25=+6.0 (c 0.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S,R)

anti-(4-Butylmorpholin-2-yl)(4-nitrophenyl)methanolC15H22N2O4ee = 97%[α]D25=+17.5 (c 0.2, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (S,R)

syn-4-Benzyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4-nitrophenyl)morpholineC24H34N2O4Siee = 94%[α]D25=+10 (c 0.5, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R,S)