Highly Diastereo‐ and Enantioselective Direct Aldol Reactions of Aldehydes and Ketones Catalyzed by Siloxyproline in the Presence of Water

Abstract

Proline-based organocatalysts have been developed for a highly enantioselective, direct aldol reaction of aldehydes and ketones in the presence of water. While several surfactant-proline combined catalysts have proved effective, proline derivatives with a hydrophobic moiety such as trans-siloxy-L-proline and cis-siloxy-D-proline, both of which are easily prepared from the same commercially available 4-hydroxy-L-proline, have been found to be the most effective organocatalysts examined in this study, affording the aldol product with excellent diastereo- and enantioselectivities, these two catalysts generating opposite enantiomers. Water affects the selectivity, and poor results are obtained under neat reaction conditions or in dry organic solvents. More than three equivalents of water are required for the best diastereo- and enantioselectivities, while three equivalents is the recommended amount from a synthetic point of view. The reaction proceeds in the organic phase, and also proceeds in the presence of a large amount of water. The large-scale preparation of aldols with the minimal use of an organic solvent, including in the purification step, is described.

Chirally Functionalized Hollow Nanospheres Containing L‐Prolinamide: Synthesis and Asymmetric Catalysis

“…For example, Aratake et al reported that trans-siloxy-l-proline and cis-siloxy-d-proline could efficiently catalyze the direct aldol reaction between aldehydes and ketones in the presence of water, which was attributed to the formation of emulsion with the aid of the catalysts. [39] Zhong et al also found the same phenomena. [40] Numerous examples reported the promotion effect of water in direct asymmetric aldol reactions using amino acid derivatives and polymer-supported organocatalysts.…”

Primary Amino Acid Lithium Salt-Catalyzed Asymmetric Michael Addition of Carbon Nucleophiles to Enones

“…Therefore, cyclohexane was chosen as a solvent for further investigations. 100 72 9 2 MeOH 100 62 4 3 MeCN 11 11 59 4 AcOEt 24 24 68 5 THF 27 22 68 6 CH 2 Cl 2 41 28 68 7 Toluene 60 45 65 8 Cyclohexane 94 69 70 a The reaction was carried out with 2a (0.6 mol), 3a (0.5 mmol) and 1a (0.15 mmol) in a solvent (1 mL) at 25 °C for 72 h; We then synthesized various siloxy amino acids and their alkali metal salts from L-serine, L-threonine (Thr) and L-tyrosine (Tyr) to perform a catalyst screen in cyclohexane (Table 2) [33][34][35][36][37][38][39][40]. Since L-serine derived catalyst 1a gave better results in both yield and enantioselectivity of 4a than did Thr(O-TBS)-OLi (1b) and Tyr(O-TBS)-OLi (1c), L-serine was selected as a basic amino acid and used for further modification of the catalyst ( Table 2, entries 1-3).…”

Pursuing Chemical Efficiency by Using Supported Organocatalysts for Asymmetric Reactions under Aqueous Conditions

“…For instance, Hayashi incorporated an hexanoyloxy group at the 4-position of 4-hydroxy-L-proline, allowing its use in a water/oil emulsion [52] This position of the 4-hydroxy-Lproline has been used to support this molecule to several polymers following different synthetic strategies. For instance, this catalyst has been incorporated to a polystyrene Merrifield resin through a 1,3-dipolar cycloaddition reaction with the corresponding O-propargyl hydroxyproline derivative [53,55].…”