The Use of <i>N</i>‐Alkyl‐2,2′‐bipyrrolidine Derivatives as Organocatalysts for the Asymmetric Michael Addition of Ketones and Aldehydes to Nitroolefins

The legacy of Gilbert Newton Lewis (1875-1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor-acceptor bonding is evident in the eponymous foundations of electron-pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Brønsted acids), and helped overthrow the "modern cult of the proton". His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.

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“…(1) in Scheme 42]. [186] Aldol reactions between two aldehydes, a challenging process in the context of Lewis acid catalysis, has been performed …”

Section: "Organocatalysis": N-p* Lewis Base Catalysis With Aminesmentioning

confidence: 99%

Lewis Base Catalysis in Organic Synthesis

2008

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“…7 Alexakis found that chiral bipyrrolidines catalyze the addition of both aldehyde and ketone to nitroolefins efficiently with high enantioselectivities and diastereoselectivities. [8][9][10][11] Kotsuki has shown that chiral pyrrolidine-pyridine conjugate bases catalyze the Michael addition of cyclohexanone with nitroolefins, giving the adducts in almost quantitative yields with excellent diastereoselectivity (up to 99:1) and high enantioselectivity (up to 99% ee). However, when isovaleraldehyde was used as the substrate, poor enatioselectivity (22% ee) was observed.…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2007

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“…The (2S, 3S) configuration determined for product 3 is consistent with this mechanism. The inactivation of catalyst 10 is possible through the direct reaction with nitroolefin to provide E, [20] and the reverse reaction would release 10 back into the catalytic cycle. The low reactivity of aliphatic nitroolefins might be caused by low availability of free catalyst 10 through catalyst sequestration in E. In summary, we have developed the first antiselective Michael reaction of aldehydes and nitroolefins with simple primary amine/thiourea catalyst 10.…”

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confidence: 99%

anti‐Selective Asymmetric Michael Reactions of Aldehydes and Nitroolefins Catalyzed by a Primary Amine/Thiourea

2009

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In the last decade, remarkable progress has been made toward direct catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products under operationally simple and environmentally friendly conditions. [1] In enamine catalysis, significant effort has focused on understanding the origin of diastereo-and enantioselectivity in organocatalysis. These studies have facilitated the design of syn-selective aldol and anti-selective Mannich reactions not originally addressed by organocatalytic methods. [2][3][4][5] The organocatalytic Michael reaction is often regarded as one of the most efficient and broadly applicable carbon-carbon bond-forming reactions known because a wide variety of acceptors can be employed and high stereoselectivity has been realized. [6] Although a large number of reports on the organocatalytic Michael reaction of aldehydes have been published, to the best of our knowledge, all of these reactions are syn selective.[7] Several studies, however, have reported success in the anti-selective organocatalytic Michael reaction of ketones.[8] Herein, we report the first highly anti-selective asymmetric Michael reactions of aldehydes and nitroolefins using a strategy designed to control the configuration of the reacting enamine.The predominant stereochemical outcome of the enamine-based Michael reaction was first explained in the classic studies of Seebach and co-workers.[9] Seebach deduced that high syn selectivity can be explained by an acyclic synclinal transition-state model (Scheme 1 a).[9a] In this transition state, the thermodynamically stable E enamine reacts with E nitroolefins in a synclinal arrangement, in which the actual donor and acceptor atoms are situated close to each other (see NO 2 and NR'R'' in Scheme 1 a).We have explored two routes for control of the overall diastereoselectivity of organocatalytic enamine reactions: 1) controlling the face selectivity of the reactive enamine to affect anti-Mannich reactions [2] and 2) controlling the E/Z configuration of the reactive enamine to affect anti-Mannich and syn-aldol reactions (Scheme 1 b). [3] For the anti-Michael reactions described herein, we have taken the latter approach.The classic organocatalytic Michael reaction of aldehydes and ketones utilizes pyrrolidine-based catalysts which react via E-enamine intermediates with nitroolefins and other Michael acceptors in synclinal transition states to provide predominately syn-configured Michael products. The Z-enamine intermediate formed using secondary amine catalysts are significantly less favored. Movement from a secondary amine catalyst to a primary amine catalyst provides steric latitude which enables Z-enamine formation with ketones. A caveat, however, is that Z-enamine formation from aldehydes is likely to be more difficult than that from ketones since the E-configured enamine derived from an aldehyde minimizes steric conflicts between the catalyst and Scheme 1. a) Synclinal transition-state model, b) anti-Mannich and synaldol...

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The Use of N‐Alkyl‐2,2′‐bipyrrolidine Derivatives as Organocatalysts for the Asymmetric Michael Addition of Ketones and Aldehydes to Nitroolefins

Cited by 256 publications

References 120 publications

Lewis Base Catalysis in Organic Synthesis

Lewis Base Catalysis in Organic Synthesis

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

anti‐Selective Asymmetric Michael Reactions of Aldehydes and Nitroolefins Catalyzed by a Primary Amine/Thiourea

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