Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines

Abstract

A procedure for the enantioselective synthesis of α-substituted glutamates and pyroglutamates via a cyclopropenimine-catalyzed Michael addition of amino ester imines is described. Enantioselectivities of up to 94% have been achieved, and a variety of functional groups were found to be compatible. The impact of the catalyst structure and imine substitution is discussed. Compared to other methods, this protocol allows for a broader and more enantioselective access to pyroglutamate derivatives.

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.…”

“…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.…”

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

“…[27] In fact, triethylamine (Et 3 N), 1,4-Diazabicyclo[2.2.2]octane (DABOC), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) were used as achiral organosuperbases in many reactions. In recent decade, several types of chiral organosuperbases [28,29] including amidine, [30][31][32] guanidine, [33][34][35][36][37][38][39][40][41] cyclopropenimine, [42][43][44][45][46][47] iminophosphorane, [48][49][50][51][52][53][54][55][56] and azaphosphatrane [57][58][59][60] have been developed and used as catalysts for direct deprotonation of substrates with high pK a values in asymmetric Michael reaction, Mannich reaction, amination, oxidation, aldol reaction and [3 + 2] cycloaddition. Benzophenone-protected glycine t-butyl ester 1 a bearing not only high pK a but also bulky group was regarded as a challenging substrate for asymmetric Michael addition.…”