Organocatalytic enantioselective conjugate addition of aldehydes to maleimides

Abstract

The highly enantioselective direct organocatalytic conjugate addition of aldehydes to maleimides is presented.

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.…”

Efficient Synthesis of γ-Lactams by a Tandem Reductive Amination/Lactamization Sequence

“…16 To a stirred solution of the maleimide (1 g, 1 equiv) in CHCl 3 (25 mL) was added pyrrolidine (30 mol%) and the aldehyde (2 equiv). The reaction mixture was heated at 65 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted with EtOAc (2 × 20 mL).…”

Organocatalytic Highly Enantioselective Conjugate Addition of Aldehydes to Alkylidine Malonates

“…[1] In the research field of organocatalysis, [2,3] there are several elegant reports on the amine-catalyzed asymmetric addition of ketones and aldehydes to nitrostyrenes. [4][5][6] Moreover, well-designed catalytic enantioselective conjugate additions of aldehydes to vinyl sulfones, [7] maleimides, [8] benzoquinones, [9] enones [10] and vinyl phosphonates [11] have recently been reported. However, only the amine-catalyzed conjugate addition of ketones to alkylidinemalonates is known.…”

“…solute and relative configuration of acid 9, generated from the mild oxidation of 3h and recrystallization, was assigned by X-ray crystallographic analysis and comparison to the literature [8,11] {[Eq. (3)], Figure 1}.…”