Simple and inexpensive threonine-based organocatalysts as highly active and recoverable catalysts for large-scale asymmetric direct stoichiometric aldol reactions on water

Nine O-acylated threonines were screened as catalysts at loadings of 0.5–5 mol % for the direct asymmetric stoichiometric aldol reaction on water by using variable amounts of water. These threonine-based organocatalyst were simple, inexpensive, highly active and could be synthesized on a large-scale. Among them, the threonine-based organocatalyst 1a is applicable to the stoichiometric reactions of a wide range of aromatic and heteroaromatic aldehydes with ketones, with the aldol products being obtained with up to 99:1 anti/syn ratios and >99% ee. The threonine-based organocatalyst 1a can be easily recovered and reused, and only a slight decrease in the enantioselectivities was observed after six cycles. This novel threonine-based organocatalyst 1a can be efficiently used in large-scale reactions with the enantioselectivities being maintained at the same level, which offers great possibility for application in industry.

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(2S,3R)-O-(Benzoyloxy)-l-threonineC11H13NO4[α]D20=-12.8 (c 1.02, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)

(2S,3R)-O-(2-Phenylacetoxy)-l-threonineC12H15NO4[α]D20=+28.9 (c 1.26, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)

(2S,3R)-O-(3-Phenylpropanoyloxy)-l-threonineC13H17NO4[α]D20=+14.6 (c 1.2, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)

(2S,3R)-O-(4-Phenylbutanoyloxy)-l-threonineC14H19NO4[α]D20=+14.7 (c 1.0, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)

(2S,3R)-O-(2-(Naphthalen-1-yl))-l-threonineC16H17NO4[α]D20=+27.3 (c 1.3, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)

(2S,3R)-O-(Cyclohexylcarbonyl)-l-threonineC11H19NO4[α]D20=+15.7 (c 1.1, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)

(2S,3R)-O-(1-Adamantylcarbonyl)-l-threonineC15H23NO4[α]D20=+5.4 (c 1.2, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)

(2S,3R)-O-(4-tert-Butylphenyl)-l-threonineC15H21NO4[α]D20=-18.0 (c 1.0, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)

(2S,3R)-O-(n-Octanoyl)-l-threonineC12H23NO4[α]D20=+13.2 (c 1.0, MeOH)Source of chirality: (2S,3R)-threonineAbsolute configuration: (2S,3R)