New Auxiliaries for Copper-Catalyzed Asymmetric Michael Reactions: Generation of Quaternary Stereocenters at Room Temperature

Abstract

Dialkyl amides of L-valine, L-isoleucine, and L-tert-leucine (2) are excellent chiral auxiliaries for the construction of quaternary stereocenters at ambient temperature. Enaminoesters 3, prepared from these auxiliaries 2 and Michael donors 1, undergo a copper-catalyzed asymmetric Michael reaction with methyl vinyl ketone (MVK, 4) to afford products 5 in 70-90% yield and 90-99% ee (enantiomeric excess). The exclusion of moisture or oxygen is not necessary. The auxiliaries 2 are readily available by standard procedures. After workup they can be recovered almost quantitatively.

Copper-Catalyzed Asymmetric Michael Reactions with α-Amino Acid Amides: Synthesis of an Optically Active Piperidine Derivative

“…Column chromatography was accomplished on Merck silica gel (Type 60, 0.063Ϫ0.200 mm) or ICN alumina (Al 2 O 3 90, basic, activity stage I) using ethyl acetate (EA) and hexanes (PE) as solvents. (S)-(ϩ)-O-Acetylmandelic acid [16] and the auxiliary 2 [13] were synthesized according to literature procedures.…”

“…Recently, we reported the application of α-amino acid dialkyl amides as chiral auxiliaries for copper-catalyzed asymmetric Michael reactions. [12,13] Herein we wish to prove the compatibility of our method with substrates with carbamate functions. Therefore, we have prepared an optically active piperidine derivative bearing a quaternary stereocenter with 97% ee at room temperature applying the method recently developed in our laboratory.…”

Enantioselective Construction of Quaternary Stereocenters

“…Similar enantioselectivities were achieved with open-chain 1,3-dicarbonyl compounds as donors. [31] The auxiliaries, such as 37, are readily prepared from natural a-amino acids and can be recovered almost quantitatively after workup. In contrast to other transition metal catalyzed reactions, quaternary stereocenters are generated at ambient temperature in excellent selectivities and high yields under very mild reaction conditions by applying this procedure.…”

Coordination Compounds Based on 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic Acid

“…The ability of the prepared coordination compounds to catalyze enantioselective reactions was tested on the Henry nitroaldol addition of nitromethane with 2-nitro-or 4-nitrobenzaldehyde (Scheme 5), under the conditions described in [19], and on the Michael addition reaction of ethyl 2-oxocyclohexanecarboxylate with but-3-en-2-one (Scheme 6), under the condition described in [20][21][22][23]. In the nitroaldol addition of nitromethane with 4-nitrobenzaldehyde the highest enantioselective efficiency was observed with the coordination compound 5a containing Cu…”

“…+31.4 (c = 1, CH 2 Cl 2 ). -1-(3-oxobutyl)cyclohexanecarboxylate (8) The reaction of ethyl 2-oxocyclohexanecarboxylate with but-3-en-2-one catalyzed with the coordination compounds (Scheme 6) was carried out by known procedures [20][21][22][23]. A solution (or suspension) of ethyl 2-oxocyclohexanecarboxylate (0.16 mL, 1 mmol) and coordination compound (5 mol %, 0.05 mmol) in CH 2 Cl 2 (1 mL) was vigorously stirred and treated with but-3-en-2-one (0.20 mL, 2 mmol).…”