Evidence for an Enol Mechanism in a Highly Enantioselective Mannich‐Type Reaction Catalyzed by Primary Amine–Thiourea

Yalalov, Denis A.; Tsogoeva, Svetlana B.; Shubina, Tatyana E.; Martynova, I. M.; Clark, Timothy W.I.

doi:10.1002/ange.200800849

Cited by 36 publications

(11 citation statements)

References 92 publications

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“…The connection of the ene unit to the proline residue is proven by through-bond correlations ( 1 H, 13 C HMBC spectrum; Figure 2 c) of H1 to Ca and Cd, thereby ruling out the existence of a potential enol that was recently suggested for a different but related organocatalyst. [41,42] This finding is additionally supported by through-space correlations ( 1 H, 1 H NOESY spectrum; Figure 2 a and d) of H1 and H2 to Ha and Hd.…”

supporting

confidence: 68%

The Elusive Enamine Intermediate in Proline‐Catalyzed Aldol Reactions: NMR Detection, Formation Pathway, and Stabilization Trends

2010

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Dedicated to Professor Horst Kessler on the occasion of his 70th birthdayThe detection and characterization of intermediates in organic reactions is crucial for the understanding of mechanisms and the rational optimization of reaction conditions. However, especially in the rapidly expanding field of asymmetric organocatalysis, [1][2][3][4] mechanistic studies are scarce compared to new synthetic applications. Therefore, organocatalysis was characterized as still being "in its exploratory discovery phase before it can become contemplating".[5] Among the different organocatalytic activation modes and the wide range of identified general concepts, [6,7] Brønsted acid [8,9] and Lewis base catalysis [10] have proven to be broadly applicable. After the proline-catalyzed aldol reactions (both origin [11,12] and prototype [13] for asymmetric aminocatalysis), secondary amines [14][15][16] are preferentially employed to activate substrates via iminium [17] or enamine intermediates.[18] The generally accepted mechanism of enamine catalysis [14,19] is based upon experimental [20] and theoretical studies [21] that suggest a central enamine intermediate in the proline-catalyzed reactions.To the best of our knowledge, such enamine intermediates have never been detected in situ; only product enamines [22,23] or dienamines, [24] and dienamine intermediates [25] have been reported-for different catalysts. In contrast, putative enamine intermediates were synthesized, isolated, and characterized, [5,[26][27][28] and recently an enamine intermediate was observed in the crystal structure of an aldolase antibody. [29] So far, in situ NMR spectroscopic approaches have only resulted in the detection of the isomeric oxazolidinones, [20,[30][31][32][33][34] supposedly resulting from an "unwanted and rate-diminishing parasitic equilibrium", [20,35] which was believed to be responsible for the inability to observe the enamines. In fact, equilibria involving oxazolidinones have been reported [20,[32][33][34] and their energetic preference has been calculated. [36] An alternate mechanistic model of prolinecatalyzed aldol reactions that attributes a pivotal role to the predominant oxazolidinones has been proposed, [33] and indeed such oxazolidinones have successfully been used as "soluble proline catalysts". [31][32][33][34] The detection of enamine intermediates in prolinecatalyzed aldol reactions is the missing piece of evidence for the commonly accepted mechanism of enamine catalysis. Moreover, the structural characterization of key enamine intermediates, the elucidation of their formation, and their stabilization are important for a better understanding of and the control of organocatalytic reactions, which could in turn present new options in accelerating and controlling enaminecatalyzed reactions.Herein we present our real-time NMR studies that detail the first detection and structural characterization of enamine intermediates in proline-catalyzed aldol reactions. In addition, their direct formation from oxazolidinones is evidenced in the...

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confidence: 68%

The Elusive Enamine Intermediate in Proline‐Catalyzed Aldol Reactions: NMR Detection, Formation Pathway, and Stabilization Trends

2010

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“…[31] However, some recently published works such as the one of Tsogoeva and mainly Wong brought some evidence in favour of an enol mechanism. [32] Both of them would lead to the same absolute configuration as proved above.…”

Section: Resultsmentioning

confidence: 58%

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes and Synthetic Applications

et al. 2010

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The purpose of this study is to point out the synthetic utility of a new class of Michael acceptors (nitrodienes and nitroenynes). The highly enantioselective organocatalytic Michael addition of carbonyl compounds to these functionalized nitroolefins has been carried out in the presence of (S)-diphenylprolinol silyl ether to achieve some interesting building blocks in high selectivities. The adducts thus obtained can be easily converted by taking advantage of the corresponding unsaturated carbon-carbon bond. In presence of the double bond, metathesis or electrophilic activation could be carried out whereas in the presence of the triple bond electrophilic activation could be conducted. We thus focused on a gold-catalyzed cyclization of the bis-homopropargylic alcohol to afford the corresponding substituted tetrahydrofuran. Then, we also demonstrated that organic and gold catalysts were compatible in a one-pot process. Indeed, we developed a one-pot enantioselective organocatalytic Michael addition to a nitroenyne followed by a gold-catalyzed acetalization/cyclization to achieve tetrahydrofuranyl ethers in high diastereoand enantioselectivities with excellent yields.

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“…To the best of our knowledge, only one example was shown in which chiral primary amine-thioureas were developed as the catalysts in direct anti-selective asymmetric Mannich reactions. [8] No report has been found on the reaction catalyzed by chiral secondary amine-thiourea for either anti-or syn-Mannich products.Interested in developing new and broadly useful chiral organocatalysts for asymmetric synthesis, we have previously designed and synthesized a series of …”

mentioning

confidence: 97%

“…Great success has been achieved in the development of syn-selective direct organocatalytic asymmetric Mannich-type reactions [3,4] wile anti-selective Mannich reactions are considerably more challenging and only a limited number of reports were documented. [5][6][7][8] In this context, pyrrolidine-based derivatives were found to be generally more effective catalysts, as demonstrated by the work of the Barbas group: pyrrolidine derivatives (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and 3-pyrrolidinecarboxylic acid as effective catalysts for anti-selective Mannich-type reactions with unmodified aldehydes and ketones as nucleophiles; [5b-d] Blanchets group has developed 3-trifluoromethanesulfonamidopyrrolidine [5g] and Maruokas group has discovered that chiral cyclic amines were effective catalysts with high diastereoselectivity and enantioselectivity; [5h-l] Good results were also achieved by using other organocatalysts, including acyclic primary amino acids, [6] chiral Brønsted acids [7] and primary amine-thioureas [8] in direct anti-selective Mannich reactions. In these catalytic systems, solvents such as DMSO and DMF were often chosen as the reaction media, because most of the catalysts, especially chiral amino acids and some chiral amino sulfonamides were hardly soluble in less polar solvents.…”

mentioning

confidence: 99%

“…Due to the wide utility of these synthons, especially in pure syn-or anti-form, it is highly desirable to develop stereoselective methods. In this respect, the catalytic asymmetric Mannich-type reaction has recently been the subject of intense research, [2][3][4][5][6][7][8] and tremendous efforts have been focused on the development of an organocatalytic asymmetric version of the reaction. Great success has been achieved in the development of syn-selective direct organocatalytic asymmetric Mannich-type reactions [3,4] wile anti-selective Mannich reactions are considerably more challenging and only a limited number of reports were documented.…”

mentioning

confidence: 99%

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4‐Aminothiourea Prolinol tert‐Butyldiphenylsilyl Ether: A Chiral Secondary Amine‐Thiourea as Organocatalyst for Enantioselective anti‐Mannich Reactions

Zhang

Chuan

et al. 2009

Adv Synth Catal

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anti-Selective Mannich reactions of N-pmethoxyphenyl (PMP)-protected a-iminoglyoxylate with unmodified aldehydes or ketones were effectively catalyzed by 4-aminothiourea prolinol tert-butyldiphenylsilyl ether. The reactions led to chiral bamino carbonyl compounds in high yields (up to 94%), excellent diastereo-and enantioselectivities (up to 98% de and > 99% ee). The study demonstrated for the first time that direct Mannich-type reactions of unmodified aldehydes or ketones to aiminoglyoxylate can be promoted by secondary amine-thiourea chiral organocatalyst.Keywords: b-amino carbonyl compounds; 4-aminothiourea prolinol tert-butyldiphenylsilyl ether; asymmetric anti-Mannich reactions; secondary amine-thiourea organocatalyst Direct catalytic asymmetric Mannich reactions are highly effective carbon-carbon bond forming reactions, [1] to build b-amino acids, amino alcohols, amino carbonyls, and their derivatives that contain two adjacent stereocenters. Due to the wide utility of these synthons, especially in pure syn-or anti-form, it is highly desirable to develop stereoselective methods. In this respect, the catalytic asymmetric Mannich-type reaction has recently been the subject of intense research, [2][3][4][5][6][7][8] and tremendous efforts have been focused on the development of an organocatalytic asymmetric version of the reaction. Great success has been achieved in the development of syn-selective direct organocatalytic asymmetric Mannich-type reactions [3,4] wile anti-selective Mannich reactions are considerably more challenging and only a limited number of reports were documented. [5][6][7][8] In this context, pyrrolidine-based derivatives were found to be generally more effective catalysts, as demonstrated by the work of the Barbas group: pyrrolidine derivatives (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and 3-pyrrolidinecarboxylic acid as effective catalysts for anti-selective Mannich-type reactions with unmodified aldehydes and ketones as nucleophiles; [5b-d] Blanchets group has developed 3-trifluoromethanesulfonamidopyrrolidine [5g] and Maruokas group has discovered that chiral cyclic amines were effective catalysts with high diastereoselectivity and enantioselectivity; [5h-l] Good results were also achieved by using other organocatalysts, including acyclic primary amino acids, [6] chiral Brønsted acids [7] and primary amine-thioureas [8] in direct anti-selective Mannich reactions. In these catalytic systems, solvents such as DMSO and DMF were often chosen as the reaction media, because most of the catalysts, especially chiral amino acids and some chiral amino sulfonamides were hardly soluble in less polar solvents. Although these reactions are highly enantioselective, removal of such high boiling-point solvents has engendered inconveniency, especially in practical synthesis. Thiourea-based organocatalysts have been widely used in asymmetric catalysis due to their strong activation efficiency through double hydrogen-bonding. [9] Among them, Chens group has successfully used chiral secon...

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Evidence for an Enol Mechanism in a Highly Enantioselective Mannich‐Type Reaction Catalyzed by Primary Amine–Thiourea

Cited by 36 publications

References 92 publications

The Elusive Enamine Intermediate in Proline‐Catalyzed Aldol Reactions: NMR Detection, Formation Pathway, and Stabilization Trends

The Elusive Enamine Intermediate in Proline‐Catalyzed Aldol Reactions: NMR Detection, Formation Pathway, and Stabilization Trends

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes and Synthetic Applications

4‐Aminothiourea Prolinol tert‐Butyldiphenylsilyl Ether: A Chiral Secondary Amine‐Thiourea as Organocatalyst for Enantioselective anti‐Mannich Reactions

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