Small Peptide‐Catalyzed Enantioselective Addition of Ketones to Nitroolefins

Abstract

Abstract:The direct small peptide-catalyzed enantioselective Michael addition of ketones to nitroolefins is presented. Simple di-and tripeptides derived from alanine catalyze the asymmetric Michael additions with high stereoselectivity and furnish the corresponding Michael products in high yield with up to 68 : 1 dr and 98% ee. The study demonstrates that small, readily prepared peptides with increased structural complexity as compared to the parent amino acid mediate the asymmetric Michael reaction with superior reactivity and enantioselectivity.Keywords: asymmetric catalysis; ketones; Michael reaction; nitroolefins; peptides The Michael addition is a fundamental carbon-carbon bond-forming reaction in organic synthesis.[1] Therefore, chemists have developed several catalytic asymmetric protocols for this important reaction.[2] In recent years, an intense research effort has been made to find nontoxic chiral organic molecules as catalysts for enantioselective reactions.[3] For example, Miller [4] and Jacobsen [5] have employed catalytic peptides and peptide-like molecules as catalysts for asymmetric additions. Their structural diversity, availability and modularity could make them ideal asymmetric organocatalysts for a variety of transformations.[6] Proline [7] and N-terminal prolylpeptides [8] have been described as catalysts for the asymmetric Michael reaction. However, only moderate enantioselectivity is typically obtained. For example, proline and N-terminal prolyldipeptides catalyze the asymmetric formation of g-nitroketones with 5 -76% ee and 0 -31% ee, respectively. Proline-derived derivatives have been proven to be more succesful for the asymmetric Michael reaction. [9 -12] Recently, Alexakis, [13] Kotsuki, [14] Wang [15] and Hayashi [16] reported excellent highly enantioselective Michael conjugate additions that were catalyzed by chiral pyrrolidine-based catalysts. However, they are generally more complex and prepared in more steps than a simple amino acid or peptide catalysts. Herein, we present that simple dipeptides with a catalytic primary amine residue catalyze the direct asymmetric Michael addition of ketones to nitroolefins with high stereoselectivity and furnish the corresponding g-nitro ketones with up to 68 : 1 dr and 98% ee.Based on our research interest in asymmetric catalysis, [17] we recently found that acyclic aliphatic amino acids catalyze asymmetric intermolecular aldol reactions and Mannich reactions with high stereoselectivities.[18] The lessons from these studies made us interested in whether acyclic amino acids as well as small peptides derived from them could react with a ketone and form a catalytic chiral enamine, which could serve as a nucleophile in Michael additions to nitroolefins [Eq. (1)]. We expected that addition of a small excess of water would increase the efficiency and circumvent the need of adding an acidic additive. In addition, water would facilitate hydrogen bonding and proton transfer, which could plausibly improve the enantioselectivity of the Michael reaction. ð...

Enantioselective and diastereoselective Michael addition of ketone/aldehyde to trans‐nitroolefins catalyzed by a novel chiral pyrrolidine‐thiourea

“…12 Wang et al described a chiral pyrrolidine sulfonamide catalyst, with which, they realized the Michael conjugate additions of aldehydes to nitrostyrenes with high levels of enantioselectivity (89-99% ee) and diastereoselectivity (20:1 dr). 13 Very recently, some simple diamines and triamines, 14 functionalized chiral ionic liquids, 15 and small peptids 16 were reported as efficient catalysts for the addition of cyclic ketones and some aldehydes to nitroolefins.…”

Asymmetric Conjugate Addition of Ketones to β‐Nitrostyrenes by Means of 1,2‐Amino‐Alcohol‐Derived Prolinamides as Bifunctional Catalysts

“…A related study by Enders showed a strong solvent effect in the reaction since in MeOH the enantioselectivity could be increased to 76% for the major syn diastereomer in the reaction between 3-pentanone and trans-β-nitrostyrene employing a 20 mol% of Lproline as catalyst. [7] Since these preliminary studies, very effective catalytic systems (2-20) [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] have been developed for the asymmetric Michael reaction of ketones with nitroalkenes being the process generally syn-selective (Scheme 1). Best improvements to this reaction have been mostly achieved using pyrrolidine-based catalytic derivatives.…”

“…Furthermore, catalyst 15 and the fluorous sulfonamide 19 can be easily recycled by precipitation and fluorous solid-phase extraction, respectively, and reused without significant loss of activity and stereoselectivity. [7] up to 76% ee 2 [8] up to 81% ee 3 [9] up to 99% ee [18] up to 86% ee 13 [19] up to 91% ee up to 91% ee 5 [11] up to 68% ee 6 [12] up to 92% ee 7 [13] up to 94% ee 8 [14] up to 87% ee 9 [15] up to 98% ee 10 [16] up to 98% ee 11 [17] up to 91% ee 14 [20] up to 98% ee 15 [21] up to 99% ee 16 [22] up to 90% ee 17 [23] up to 99% ee 18 [24] up to 99% ee 20 [26] up to 97% ee 19 [25] up to 95% ee …”

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.…”