Simple Cyclohexanediamine-Derived Primary Amine Thiourea Catalyzed Highly Enantioselective Conjugate Addition of Nitroalkanes to Enones

Mei, Kui; Jin, Mei; Zhang, Shilei; Li, Ping; Liu, Wenjing; Chen, Xiaobei; Xue, Fei; Duan, Wenhu; Wang, Wei

doi:10.1021/ol9010322

Cited by 108 publications

(34 citation statements)

References 74 publications

(24 reference statements)

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“…Surprisingly, the primary amine/sulfonamide catalyst 9 5e, 14 showed excellent enantioselectivity (97 % ee ), though its reactivity was low. The best result was obtained with the primary amine/thiourea 10 15. With this catalyst, the anti product formed in good yield with excellent diastereo‐ and enantioselectivity within four hours 16.…”

Section: Methodsmentioning

confidence: 97%

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

Uehara¹,

Barbas²

2009

Angewandte Chemie

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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 synaldo...

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Section: Methodsmentioning

confidence: 97%

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

Uehara¹,

Barbas²

2009

Angewandte Chemie

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“…[c] Determined by HPLC or GC analysis. [d] Reaction was finished after 48 h. [e] The absolute configurations were determined by comparison with the literature 4i…”

Section: Asymmetric Michael Addition Of Nitromethane To Chalcone[a]mentioning

confidence: 99%

Early intrauterine transfusion in severe red blood cell alloimmunization

Yinon

Visser

Kelly

et al. 2010

Ultrasound in Obstet & Gyne

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Objective To determine perinatal outcome in pregnancies with early severe red blood cell (RBC) IUT was 20.4 (range,[16][17][18][19][20][21][22] weeks, and between one and nine transfusions were needed during pregnancy. Transfusion was via the intrahepatic vein (IHV) (n = 19), umbilical vein (n = 6) or umbilical artery (n = 2), or was intracardiac (n = 2) or intraperitoneal (n = 1). Overall perinatal survival rate was 80% and did not differ between hydropic and non-hydropic fetuses. Median gestation at delivery, after exclusion of six intrauterine fetal deaths, was 36.7 (range, 27.8-38.4)

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“…The thiourea also plays an essential role in promoting reactivity and enantioinduction (entries 1-5 vs. entries 6-7), suggesting that the dual H-bond donor component may be involved directly in electrophile activation ( vide infra ) 10. It is noteworthy that the relatively simple thiourea 1 11 proved to be optimal, as more elaborate primary aminothiourea catalysts bearing additional stereochemical elements afforded no advantage (e.g. 4 , entry 5) 8…”

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confidence: 99%

Enantioselective Catalytic α-Alkylation of Aldehydes via an S_N1 Pathway

2010

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Primary aminothiourea derivatives are shown to catalyze enantioselective alkylation of α-arylpriopionaldehdyes with diarylbromomethane. Evidence for a stepwise, S N 1 mechanism in the substitution reaction induced by anion binding to the catalyst is provided by catalyst structureactivity studies, kinetic isotope effects, linear free-energy relationship studies, and competition experiments.The anion-binding properties of urea and thiourea derivatives have been exploited recently in enantioselective catalytic reactions involving heteroatom-stabilized carbocations, such as N-acyliminium and oxocarbenium ions. 1,2 Experimental and computational data point to a consistent mechanistic framework wherein the H-bond donor catalysts promote these reactions by anion-abstraction from a neutral organic precursor to generate the more reactive cationic electrophile (Scheme 1). 1b We reasoned that, with the appropriate catalyst and nucleophilic partner, this mode of electrophile activation might also be applicable to catalysis of S N 1 pathways via formation and reactions of carbocations that are not heteroatom-stabilized. 3 Herein we report the successful application of this activation mode to formation of benzhydryl cations in the context of an asymmetric α-alkylation of α-branched aldehydes.The α-alkylation of 2-phenylpropionaldehyde (6a) with bromodiphenylmethane (benzhydryl bromide, 7a) was chosen as a model reaction (Table 1). Classical studies with benzhydryl derivatives have helped to establish much of the conceptual foundations of carbocation reactivity, 4 and these compounds have been especially useful for characterizing the nature and stereochemical properties of ion pairs. 5 The α-alkylation of aldehydes was deemed particularly worthy of investigation because of the high value of chiral aldehydes bearing α-quaternary stereocenters as synthetic intermediates, 6 and the inherent challenges associated with asymmetric catalysis of this type of transformation. 7 A broad screen of potential catalysts in the alkylation of 2-phenylpropionaldehyde with bromodiphenylmethane led to the discovery that primary aminothiourea derivatives were unique in inducing good reactivity and enantioselectivity (Table 1). 8 This class of catalysts has been applied

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Simple Cyclohexanediamine-Derived Primary Amine Thiourea Catalyzed Highly Enantioselective Conjugate Addition of Nitroalkanes to Enones

Abstract: A highly enantioselective conjugate addition of nitroalkanes to enones has been developed. The process is efficiently catalyzed by a simple chiral cyclohexanediamine-derived primary amine thiourea with a broad substrate scope.

Cited by 108 publications

References 74 publications

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

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

Early intrauterine transfusion in severe red blood cell alloimmunization

Enantioselective Catalytic α-Alkylation of Aldehydes via an S_N1 Pathway

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Simple Cyclohexanediamine-Derived Primary Amine Thiourea Catalyzed Highly Enantioselective Conjugate Addition of Nitroalkanes to Enones

Abstract: A highly enantioselective conjugate addition of nitroalkanes to enones has been developed. The process is efficiently catalyzed by a simple chiral cyclohexanediamine-derived primary amine thiourea with a broad substrate scope.

Cited by 108 publications

References 74 publications

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

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

Early intrauterine transfusion in severe red blood cell alloimmunization

Enantioselective Catalytic α-Alkylation of Aldehydes via an SN1 Pathway

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Enantioselective Catalytic α-Alkylation of Aldehydes via an S_N1 Pathway