Enantioselective Biomimetic Transamination of β-Keto Carboxylic Acid Derivatives. An Efficient Asymmetric Synthesis of β-(Fluoroalkyl) β-Amino Acids

Biomimetic reductive amination under the continuous-flow reaction conditions

“…The structure and purity of the products 15a-n [11,12,14] and 22a-g [16,17] were confirmed by NMR and compared with the literature data. The enantiomeric composition of compounds 22a-g was determined using SUMICHIRAL OA-4500; eluent: n-hexane/ dichloromethane/ethanol = 60/30/10.…”

“…Taking into account that fluorinecontaining compounds have a tendency for high magnitude of the self-disproportionation of enantiomers via ap-chromatography [22] of evaporation/sublimation [23] the enantiomeric composition of products 22a-g was determined directly on the samples collected from the column before even evaporation of the solvent, using SUMICHIRAL OA-4500; eluent: n-hexane/dichloromethane/ ethanol = 60/30/10. As it follows from the data presented in Table 2, the stereochemical outcome of the isomerization reactions conducted under the continuous-flow conditions, was generally higher as compared with that of in-flask reactions [16,17]. For example, in the case of preparation of the most C-H acidic product 22a, the enantioselectivity was improved from 77 (in-flask) to 93% ee.…”

“…Asymmetric version of this methodology was developed using inexpensive enantiomers of a-(phenyl)ethylamine, as transaminating reagent. In most cases, due to the lower C-H acidity of the chiral amine as compared with that of benzylamine, application of DBU was required [16]. It is interesting to mention that this reductive amination represent a quite rare case of highly (>90% ee) stereoselective proton transfer from a more to a less configurationally stable stereogenic center [17].…”

“…As shown in Scheme 4, the conventional procedure [16,17] for asymmetric biomimetic transamination includes condensation of ketones 16 with chiral amine 17 to form imines 18 followed by their DBU-catalyzed isomerization to Schiff bases 19, which can be easily hydrolyzed to the target amines 20 and acetophenone as a byproduct.…”

“…that, for the indicated above amount of DBU and the imines 21a-e concentration, the elution rate about 1 drop per three seconds provided for >95% conversion of starting compounds 21a-e to the imines 22a-e. For isomerization of b-amino acid derivatives 21f,g the same elution rate can be used, however the temperature in the ''heating zone'' should be raised to 70 8C. The structure and purity of the products 22a-g were confirmed by NMR and compared with the literature data [16,17]. Taking into account that fluorinecontaining compounds have a tendency for high magnitude of the self-disproportionation of enantiomers via ap-chromatography [22] of evaporation/sublimation [23] the enantiomeric composition of products 22a-g was determined directly on the samples collected from the column before even evaporation of the solvent, using SUMICHIRAL OA-4500; eluent: n-hexane/dichloromethane/ ethanol = 60/30/10.…”