Chiral Cyclopropenimine‐catalyzed Asymmetric Michael Addition of Bulky Glycine Imine to α,β‐Unsaturated Isoxazoles

Abstract

A highly efficient asymmetric Michael addition of bulky glycine imine to α,β‐unsaturated isoxazoles has been achieved by using 5 mol% of chiral cyclopropenimine as a chiral organo‐superbase catalyst under mild conditions. Michael adducts were obtained in excellent yields (up to 97%) and stereoselectivities (up to >99 : 1 dr and 98% ee). A significant solvent effect was found in these chiral organosuperbase catalyzed asymmetric Michael reactions. Gram‐scale preparation of Michael adducts and their transformations are realized to provide corresponding products without loss of stereoselectivities. The configurations of Michael adduct was determined by single‐crystal X‐ray diffraction analysis.

Phosphine Catalyzed Michael-Type Additions: The Synthesis of Glutamic Acid Derivatives from Arylidene-α-amino Esters

“…This methodology does not employ benzene as a solvent and the crude reaction materials were not impurified with variable amounts (10–25%) of the corresponding pyrrolidines (formed by 1,3-dipolar cycloadditions), such as occurred in a previous communication [ 16 ]. In addition, no sophisticated halogenated compounds were employed as electrophiles [ 15 ] and the presence of strong bases was avoided [ 17 , 18 , 19 , 20 , 21 ]. The access to different synthetic glutamates was ensured and the family of the corresponding pyroglutamate derivatives was successfully obtained by simple organic transformations.…”

“…13 C{1H} NMR spectra were referenced to CDCl 3 at 77.16 ppm. Chemical yields and purities of compounds 2 and 6 were calculated by the integration of 1 H NMR spectra using dimethyl terephthalate as the internal standard [17]. Low-resolution electron impact (EI) mass spectra were obtained at 70 eV using a Shimadzu QP-5000 via injection or DIP; fragment ions in m/z are given with relative intensities (%) in parentheses.…”

“…Considering this last approach, α-substituted glutamates have been mainly obtained via the Michael-type additions of glycine derivatives (glycine templates) onto the corresponding α,β-unsaturated reagents. This reliable strategy employs N -arylidene-α-amino acid esters [ 14 , 15 , 16 ] or tert -butyl N -benzylidieneamino glycinate [ 17 , 18 , 19 , 20 , 21 , 22 ] ( Scheme 1 a) and even activated N -arylideneaminomalonates [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ] ( Scheme 1 b) as starting materials. In all cases, phase transfer catalysis (PTC) conditions or the employment of organic superbases are the most common trends to complete the reaction.…”

Chiral cyclopropenimine-catalyzed enantioselective Michael additions between benzophenone-imine of glycine esters and α,β-unsaturated pyrazolamides

“…Inspired by this point, we conceived that the asymmetric conjugated addition between N -protecting glycinates and α,β-unsaturated carbonyl compounds could be carried out in the presence of chiral organosuperbases 11 (CSB) as catalysts. Recently, we have realized an asymmetric Michael addition of benzophenone-imine of glycine esters to α,β-unsaturated isoxazoles by a chiral cyclopropenimine catalyst 12,13 (Lambert catalyst) to provide the corresponding Michael adducts in high yields and enantioselectivities under mild conditions. Following our continuous efforts on CSB-catalyzed Michael reactions for challenging substrates with high p K a values, herein, we would like to report a highly efficient enantioselective Michael addition of benzophenone-protected glycine derivatives (glycine imines) to β-substituted α,β-unsaturated pyrazolamides by using CSB-1 as a chiral organocatalyst under very mild conditions.…”