Enantioselective Synthesis of Succinimides by Michael Addition of Aldehydes to Maleimides Organocatalyzed by Chiral Primary Amine‐Guanidines

Abstract

The monoguanylation of (1S,2S)‐ and (1R,2R)‐cyclohexane‐1,2‐diamine affords chiral primary amine‐guanidines that are used as chiral organocatalysts in the enantioselective Michael addition of aldehydes, particularly α,α‐disubstituted aldehydes, to maleimides. The reaction is carried out in the presence of imidazole, as an additive, in aqueous N,N‐dimethylformamide, as the solvent, and affords the corresponding enantioenriched succinimides in high or quantitative yields with enantioselectivities up to 96 % ee. Theoretical calculations (DFT and M06–2X) suggest a different hydrogen‐bonding coordination pattern between the maleimide (C=O) and the catalyst (NH groups) is responsible for the enantioinduction switch that is observed when the reaction is carried out using primary amine‐guanidines versus primary amine‐thioureas as the organocatalysts.

Solvent‐Induced Reversal of Enantioselectivity in the Synthesis of Succinimides by the Addition of Aldehydes to Maleimides Catalysed by Carbamate‐Monoprotected 1,2‐Diamines

“…Thus, 2-ethylbutanal (7b) afforded succinimides (S)-9ba (55% ee) and (R)-9ba (68% ee) using CHCl 3 and DMF/H 2 O 2/1 v/v as solvents, respectively ( Table 2, entries 19 and 20). In addition, cyclopentane-(7c) and cyclohexanecarbaldehyde (7d) gave almost quantitative amounts of succinimides (S)-9ca and (S)-9da in 49 and 14% ee, respectively, when CHCl 3 was the reaction solvent, whereas (R)-9ca and (R)-9da in 61 and 35% ee, respectively, were isolated using DMF/H 2 O 2/1 v/v as solvent ( Table 2, entries [21][22][23][24]. Moreover, the use of a α-monosubstituted aldehyde such as propanal (7e) in the two solvents, allowed obtaining the Michael adducts (R,S)/(S,S)-9ea and (S,R)/(R,R)-9ea, respectively, as mixtures of diastereomers, with enantioselections up to 36 and 76%, respectively, for the major isomer [ Table 2, entries 25 and 26, see footnotes d) and e)].…”

“…[21] The first organocatalytic Michael addition of aliphatic aldehydes to N-aryl-maleimides used α,α-phenylprolinol silyl ether as organocatalyst, although the "difficult" α,α-disubstituted aldehydes resulted in much lower enantioselectivities. [22] Since then, different chiral bifunctional primary amine-bearing organocatalysts have been applied to the enantioselective Michael addition of these α,α-disubstituted aldehydes to maleimides leading to enantioenriched succinimides, most of them being primary amine-thioureas, [23] although primary amine-guanidines, [24] amino acids, [25] amino acids combined to amine-thioureas, [26] amines, [27] or 1,2-diamines [28] have also being used.…”

Peptide‐Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes to Maleimide

“…[1] Effective methods for the stereoselective synthesis of succinimides are therefore valuable. [1,[3][4][5] Ty pically, N-protected maleimides are employed, presumably to circumvent potential side reactions arising from the nucleophilicity of unprotected maleimides. [1,[3][4][5] Ty pically, N-protected maleimides are employed, presumably to circumvent potential side reactions arising from the nucleophilicity of unprotected maleimides.…”

Enantioselective addition of aryl ketones and acetone to nitroalkenes organocatalyzed by carbamate-monoprotected cyclohexa-1,2-diamines

“…Thus, the addition of the basic imidazole (20 mol%), something that proved beneficial in some conjugate addition reactions, 18 was detrimental for the enantioselectivity in this case, compared to when no additive was used (Table 1, compare entries 5 and 11). Therefore, we switched to the use of carboxylic acids as additives (20 mol%), as it is known that they can facilitate the interconversion of the different intermediates of the catalytic enamine cycle.…”