Dual Catalyst Control in the Chiral Diamine-Dipeptide-Catalyzed Asymmetric Michael Addition

Abstract

By example of conjugate addition of 2-nitropropane to 2-cyclohexen-1-one, it is shown that the combination of H-Leu-His-OH and (1R,2R)-(+)-1,2-diphenylethylenediamine as co-catalysts in a suitable ratio can lead to a new catalytic system for the C-C bond formation reactions. Although neither co-catalyst is sufficiently effective independently in terms of yield or enantioselectivity, their combination results in a drastic increase in yields (up to 86%) and absolute selectivities (up to 91% ee).The recent contributions by several groups in the field of asymmetric synthesis with amino acids 1 and short-chain peptides 2 as efficient chiral catalysts appear to be very interesting for chemists from academia as well as from industry. 3 Although amino acids such as proline and phenylalanine and derivatives have been used for a long time in enantioselective catalytic reactions, 4,5 the use of peptide-like enzyme mimics is a recent development and continues to receive growing interest for the C-C bond forming reactions.The Michael addition is one of the most frequently used C-C bond formation reactions in organic synthesis. 6 The development of asymmetric methodologies for this type of reaction has not only broadened its scope and applicability but has also provided insight into fundamental stereochemical aspects important to other carbon-carbon bond forming reactions such as Strecker synthesis, aldol and Diels-Alder reactions.Proline 1c,e and N-terminal prolyl di-and tripeptides 2e,g have been reported recently as organic catalysts for asymmetric Michael additions.To the best of our knowledge, no report is known of proline-free dipeptides catalyzing such reactions.Herein we report a new catalytic system, based on dipeptides, for C-C bond formation reactions by example of asymmetric Michael additions.The formation of C-C bonds by conjugate addition of appropriate carbanionic reagents to a,b-unsaturated carbonyl compounds is one of the most useful methods of remote functionalization in organic synthesis. 1c,6 Initially, we evaluated various dipeptides (H-Phe-His-OH, H-His-Phe-OH, H-Lys-Phe-OH, H-Leu-Arg-OH, H-Val-Arg-OH, HLys-Arg-OH, H-Lys-Tyr-OH, H-Lys-His-OH, H-HisLeu-OH, H-Leu-His-OH) as catalysts for the known asymmetric conjugate addition of 2-nitropropane to 2-cyclohexen-1-one (Scheme 1). Scheme 1Reactions were run at room temperature in DMSO or DMF under conditions employing 15 mol% of dipeptide and trans-2,5-dimethylpiperazine (3) as additive (Figure 1). 7 The peptides H-Leu-His-OH (1) and H-HisLeu-OH (2) were found to be the most promising dipeptide catalysts regarding enantioselectivities and yields. In DMSO much better yields (53%, 95%; entries 1 and 3, respectively), but overall lower enantioselectivities (29%, 26% ee, respectively) were observed in the presence of peptides 1 and 2, relative to the results in less polar DMF (24%, 29% yields and 31%, 41% ee, entries 2 and 4 of Table 1, respectively). Peptide 1 in the absence of additives gave the R-product in DMSO with 13% yield and 42% ee (entry 5) and in DMF w...

Modularly Designed Organocatalytic Assemblies for Direct Nitro‐Michael Addition Reactions

“…[13] These results clearly evince that catalytic activity and directing effects are, in this case, the result of the self-assembled catalysts instead of synergistic effects. [14] Moreover, this conclusion is also supported by NMR spectroscopy [13] of the l-proline and QD-1 mixture. The scope of this approach was then evaluated, under the optimized conditions, with various ketone, aldehyde, and nitroalkene substrates.…”

Use of (R)-Mandelic Acid as Chiral Co-Catalyst in the Michael Addition Reaction Organocatalyzed by (1S,4S)-2-Tosyl-2,5-diazabicyclo[2.2.1]heptane under Solvent-Free Conditions

“…In order to further improve the stereoselectivity of the reaction catalyzed by bicyclic amine 2, it was decided to explore a multiple catalysis strategy, [26][27][28][29][30][31][32][33][34][35] by combining catalytic agents, rather than designing new catalysts. Three chiral acids (mandelic, tartaric and camphor sulfonic acid) available in both enantiomeric forms were selected as chiral additives in the Michael addition reaction with (1S,4S)-2-tosyl-2,5-diazabicyclo[2.2.1]heptane as the main catalyst.…”

“…[32] The same reaction was also studied by Tsogoeva´s group using the dipeptide H-Leu-His-OH in conjunction with a chiral diamine. [33] In all cases, the authors reported a synergic effect between the two units with respect to the individual chiral catalysts.…”

Recent Advances in Asymmetric Organocatalytic 1,4‐Conjugate Additions

“…Using the conjugate addition of 2-nitropropane to cyclohex-2-en-1-one as an example, we further showed, [10] for the first time, that the combination of the dipeptide H-LeuHis-OH and (1R,2R)-(+)-1,2-diphenylethylenediamine as co-catalysts produced a new catalytic system for C-C bondformation reactions (Scheme 1). Although neither co-catalyst was sufficiently effective independently in terms of yield or enantioselectivity, their combination resulted in a drastic increase in yields (up to 86 %) and selectivities (up to 91 % ee), indicating the possibility of synergistic effects.…”