Evidence of the Electronic Factor for the Highly Enantioselective Catalytic Efficiency of <i>Cinchona</i>-Derived Phase-Transfer Catalysts

Yoo, Mi‐Sook; Jeong, Byeong‐Seon; Lee, Jeong-Hee; Park, Hyeung‐geun; Jew, Sang‐sup

doi:10.1021/ol050123u

Cited by 74 publications

(26 citation statements)

References 26 publications

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“…Mechanistically, the present intramolecular aza-Michael addition seems to work quite differently from most of the described phase-transfer-catalyzed alkylation reactions, in which a templating effect of molecules of water or cations is used to rationalize high levels of stereoinduction. [14] In fact, in our system, comparable enantiomeric excesses were recorded with several inorganic bases (LiOH, NaOH, and CsOH; solid and in aqueous solution), and the presence of coordinating groups at the ortho position of the phenyl ring (in 4 e; known to favor rigid catalyst conformations) led to a marked drop in induction (Table 1, entry 5). Remarkably, lowering of the reaction temperature to À20 and À45 8C caused an increase of stereoinduction to 72 and 91 %, respectively (Table 1, entries 16 and 17), with no significant variation in the chemical yield (91-93 %).…”

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confidence: 61%

Enantioselective Phase‐Transfer‐Catalyzed Intramolecular Aza‐Michael Reaction: Effective Route to Pyrazino‐Indole Compounds

et al. 2008

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The preparation of enantiomerically pure compounds has become a stringent requirement for pharmaceutical synthesis. [1] In this context, asymmetric catalysis is probably the most attractive procedure for the synthesis of active pharmaceutical ingredients (APIs) due to environmental, operational, and economic benefits.3,4-Dihydropyrazino[1,2-a]indol-1(2H)-ones 1 (see Scheme 1) have attracted much attention due to the broad scope of their biological activities (that is, their antifungal properties, noncompetitive antihistamine activity, and specific inhibition of serotonergic receptors).[2] Moreover, recent patents reported the effectiveness of the corresponding 1,2,3,4-tetrahydropyrazino[1,2-a]indoles 2 (Scheme 1) as antiobesity agents and in the treatment and prevention of noninsulin-dependent diabetes. [3] From these studies, the importance of the absolute configuration of the stereocenters on the pharmacological activity emerged clearly. Moreover, since the piperazine compounds 2 are readily obtainable from 1,[3] the development of an effective stereoselective synthetic route to pyrazino-indol-1-ones 1 would be extremely valuable. The use of chiral pools and the resolution of racemates are the only synthetic routes to 1 and 2 to date. [3][4][5] During our ongoing research addressing the functionalization of polycyclic indoles, [6] we recently communicated an efficient Pd-catalyzed approach to tetrahydro-b-carbolines through regio-and enantioselective C3-allylic nucleophilic alkylation (up to 97 % ee).[7] Unfortunately, all our attempts to exploit such an approach to perform enantioselective indolyl-N1 ring-closing reactions were unsuccessful. Herein, we describe the first highly enantioselective synthesis of molecular motifs of type 1 through a phase-transfer-catalyzed [8] aza-Michael addition.[9]The employment of a metal-free approach [10] stems from our recent findings on the intramolecular base-catalyzed synthesis of 1, from readily available precursors 3 (Scheme 2).[11] However, the use of Lewis acid catalysis in the present ring-closing reaction failed, probably due to the poor electrophilic character of the a,b-unsaturated ester and to low catalyst turnover as a result of starting material/ product inhibition (that is, a metallo-poisoning effect exerted by the strongly coordinating amide group). Searching for an enantioselective variant, we firstly turned our attention to chiral organic bases such as the Cinchona alkaloids and sparteine, which gave disappointing results in the cyclizations of 3 a (X = H; toluene, reflux, 48 h, 0 % ee). We reasoned that the unsatisfactory stereoinduction could be ascribable to the formation of flexible and not sufficiently tight ion pairs between the ammonium salt of the quinuclidine ring and the nucleophilic indolate intermediate (Figure 1 a).

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confidence: 61%

Enantioselective Phase‐Transfer‐Catalyzed Intramolecular Aza‐Michael Reaction: Effective Route to Pyrazino‐Indole Compounds

et al. 2008

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“…In fact, the use of the C9-O-allyl catalyst 4 c gave 1 a in nearly racemic form (Table 1, entry 3). [14] In fact, in our system, comparable enantiomeric excesses were recorded with several inorganic bases (LiOH, NaOH, and CsOH; solid and in aqueous solution), and the presence of coordinating groups at the ortho position of the phenyl ring (in 4 e; known to favor rigid catalyst conformations) led to a marked drop in induction (Table 1, entry 5). [12] A steady improvement in enantiocontrol was obtained by introducing electron-withdrawing substituents on the benzyl group; these are known to favor tighter contact ion pairing with consequent strengthening of the substrate-catalyst interaction.…”

supporting

confidence: 61%

Enantioselective Phase‐Transfer‐Catalyzed Intramolecular Aza‐Michael Reaction: Effective Route to Pyrazino‐Indole Compounds

et al. 2008

View full text Add to dashboard Cite

The preparation of enantiomerically pure compounds has become a stringent requirement for pharmaceutical synthesis. [1] In this context, asymmetric catalysis is probably the most attractive procedure for the synthesis of active pharmaceutical ingredients (APIs) due to environmental, operational, and economic benefits.3,4-Dihydropyrazino[1,2-a]indol-1(2H)-ones 1 (see Scheme 1) have attracted much attention due to the broad scope of their biological activities (that is, their antifungal properties, noncompetitive antihistamine activity, and specific inhibition of serotonergic receptors). [2] Moreover, recent patents reported the effectiveness of the corresponding 1,2,3,4-tetrahydropyrazino[1,2-a]indoles 2 (Scheme 1) as antiobesity agents and in the treatment and prevention of noninsulin-dependent diabetes. [3] From these studies, the importance of the absolute configuration of the stereocenters on the pharmacological activity emerged clearly. Moreover, since the piperazine compounds 2 are readily obtainable from 1, [3] the development of an effective stereoselective synthetic route to pyrazino-indol-1-ones 1 would be extremely valuable. The use of chiral pools and the resolution of racemates are the only synthetic routes to 1 and 2 to date. [3][4][5] During our ongoing research addressing the functionalization of polycyclic indoles, [6] we recently communicated an efficient Pd-catalyzed approach to tetrahydro-b-carbolines through regio-and enantioselective C3-allylic nucleophilic alkylation (up to 97 % ee). [7] Unfortunately, all our attempts to exploit such an approach to perform enantioselective indolyl-N1 ring-closing reactions were unsuccessful. Herein, we describe the first highly enantioselective synthesis of molecular motifs of type 1 through a phase-transfer-catalyzed [8] aza-Michael addition. [9] The employment of a metal-free approach [10] stems from our recent findings on the intramolecular base-catalyzed synthesis of 1, from readily available precursors 3 (Scheme 2). [11] However, the use of Lewis acid catalysis in the present ring-closing reaction failed, probably due to the poor electrophilic character of the a,b-unsaturated ester and to low catalyst turnover as a result of starting material/ product inhibition (that is, a metallo-poisoning effect exerted by the strongly coordinating amide group).Searching for an enantioselective variant, we firstly turned our attention to chiral organic bases such as the Cinchona alkaloids and sparteine, which gave disappointing results in the cyclizations of 3 a (X = H; toluene, reflux, 48 h, 0 % ee). We reasoned that the unsatisfactory stereoinduction could be ascribable to the formation of flexible and not sufficiently tight ion pairs between the ammonium salt of the quinuclidine ring and the nucleophilic indolate intermediate (Figure 1 a). Scheme 2. Base-catalyzed synthesis of 1. Bn: benzyl; DMSO: dimethylsulfoxide.Figure 1. Chiral organic bases versus phase-transfer catalysis in the enantioselective ring closure of 3. Scheme 1. Examples of polycyclic indolyl-...

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“…The authors propose that the 2′-F substituent is involved in internal hydrogen bonding via a water molecule, which results in a more rigid catalyst conformation (Figure 6). This model was corroborated by the success of catalysts containing 2′- N -oxopyridine ( 1g ) or 2′-cyanophenyl ( 1h ) moieties; [22] these groups have previously been established, through a series of X-ray crystal structures, to form internal hydrogen-bonding networks similar to those of fluorophenyl substituents. [23] …”

Section: Chiral Cation-directed Catalysismentioning

confidence: 91%

Asymmetric Ion‐Pairing Catalysis

2012

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Charged intermediates and reagents are ubiquitous in organic transformations. The interaction of these ionic species with chiral neutral, anionic, or cationic small molecules has emerged as a powerful strategy for catalytic, enantioselective synthesis. This review describes developments in the burgeoning field of asymmetric ion-pairing catalysis with an emphasis on the insights that have been gleaned into the structural and mechanistic features that contribute to high asymmetric induction.

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Evidence of the Electronic Factor for the Highly Enantioselective Catalytic Efficiency of Cinchona-Derived Phase-Transfer Catalysts

Cited by 74 publications

References 26 publications

Enantioselective Phase‐Transfer‐Catalyzed Intramolecular Aza‐Michael Reaction: Effective Route to Pyrazino‐Indole Compounds

Enantioselective Phase‐Transfer‐Catalyzed Intramolecular Aza‐Michael Reaction: Effective Route to Pyrazino‐Indole Compounds

Enantioselective Phase‐Transfer‐Catalyzed Intramolecular Aza‐Michael Reaction: Effective Route to Pyrazino‐Indole Compounds

Asymmetric Ion‐Pairing Catalysis

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