Highly Enantioselective Catalytic Kinetic Resolution of α‐Branched Aldehydes through Formal Cycloaddition with Homophthalic Anhydrides

Farid, Umar; Aiello, Maria Luisa; Connon, Stephen J.

doi:10.1002/chem.201902422

Cited by 11 publications

(7 citation statements)

References 61 publications

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“…Racemic primary alcohols [2-(naphthalen-1-yl)propan-1-ol, 2-(naphthalen-2-yl)propan-1-ol, 2-(4-isobutylphenyl)propan-1-ol, and 2-(6-methoxynaphthalen-2-yl)propan-1-ol], 2-(4-methoxyphenyl)-3-methylbutan-1-ol, and 2-methyl-4-phenylbutan-1-ol were prepared from the corresponding ketone by a known literature procedure via Wittig reaction followed by hydrolysis with an acid and reduction using NaBH 4 . The NMR data were found to be in accordance with the literature. , …”

Section: Methodsmentioning

confidence: 99%

“…Its derivatives are also used as precursors for the total synthesis of natural products . Chiral 2-phenyl-1-propanol can be obtained by various methods − (Scheme ). In 2017, Rychnovsky et al reported the kinetic resolution of 2-phenyl-1-propanol using homobenzotetramisole (HBTM) and resolution proceeded with a selectivity ( s ) of ≤6.2 (Scheme e) …”

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confidence: 99%

“… a (a) Kinetic resolution of racemic alcohols using lipase, (b) hydroboration and oxidative hydrolysis, (c) asymmetric hydrogenation, (d) kinetic resolution of racemic aldehydes, and (e) organocatalytic kinetic resolution …”

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confidence: 99%

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Integrated Experimental and Computational Studies on the Organocatalytic Kinetic Resolution of β-Unfunctionalized Primary Alcohols Using a Chiral 1,2-Diamine: The Importance of Noncovalent Interactions

et al. 2022

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The enantioselective kinetic resolution of β-unfunctionalized primary alcohols with benzoyl chloride was carried out in the presence of a catalytic amount of a novel chiral 1,2-diamine derived from (S)-proline. Several valuable chiral 2-substituted propan-1-ols were obtained with good enantioselectivities. Density functional theory calculations revealed that the noncovalent interaction, such as CH−π interaction, is crucial for the enantioselectivity of the resolution. This study was conducted through an interplay between experiment and computation.C hiral 2-phenyl-1-propanol is a promising synthon because this skeleton has applications in anti-inflammatory drugs such as naproxol, ibuprofen, and others. Its derivatives are also used as precursors for the total synthesis of natural products. 1 Chiral 2-phenyl-1-propanol can be obtained by various methods 2−6 (Scheme 1). In 2017, Rychnovsky et al. reported the kinetic resolution of 2-phenyl-1-propanol using homobenzotetramisole (HBTM) and resolution proceeded with a selectivity (s) of ≤6.2 (Scheme 1e). 6 The kinetic resolution of racemic alcohols has been widely utilized to construct valuable chiral building blocks for the synthesis of pharmaceuticals and natural compounds. 7 In particular, the enzymatic kinetic resolution of racemic alcohols has been used as one of the most effective methods 8 for the synthesis of optically active alcohols. In recent decades, the asymmetric acylation of alcohols using organocatalysts has emerged as a powerful approach, and the kinetic resolution of racemic secondary alcohols has been reported many times. 9 However, the kinetic resolution of racemic primary alcohols is limited to a few examples. 10 In 2005, our group reported the first non-enzymatic kinetic resolution of primary alcohols using chiral 1,2-diamine organocatalysts. 11 Chiral 1,2-diamines derived from (S)-proline are excellent organocatalysts for the catalytic asymmetric synthesis of many valuable organic compounds. Pioneering studies by T. Mukaiyama established various asymmetric syntheses using chiral 1,2-diamines readily derived from (S)-proline, including reduction of acetophenone, 12 Grignard reaction to alde-

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Integrated Experimental and Computational Studies on the Organocatalytic Kinetic Resolution of β-Unfunctionalized Primary Alcohols Using a Chiral 1,2-Diamine: The Importance of Noncovalent Interactions

et al. 2022

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“…Later, Müller discovered that the homophthalic anhydride (HPA, 9 ) reacts smoothly with benzaldehyde in a basic medium at room temperature to form dihydroisocoumarin ( 10 ; Scheme 3 ) [ 14 , 15 , 16 ]. This strategy has been recently implemented for the kinetic resolution of racemic α-aryl-substituted branched aldehydes in the presence of a chiral squaramide-based bifunctional catalyst [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

The Castagnoli–Cushman Reaction

et al. 2023

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Since the first reports of the reaction of imines and cyclic anhydrides by Castagnoli and Cushman, this procedure has been applied to the synthesis of a variety of lactams, some of them with important synthetic or biological interest. The scope of the reaction has been extended to the use of various Schiff bases and anhydrides as well as to different types of precursors for these reagents. In recent years, important advances have been made in understanding the mechanism of the reaction, which has historically been quite controversial. This has helped to develop reaction conditions that lead to pure diastereomers and even homochiral products. In addition, these mechanistic studies have also led to the development of new multicomponent versions of the Castagnoli–Cushman reaction that allow products with more diverse and complex molecular structures to be easily obtained.

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“…The diastereocontrol was equally high with aromatic aldehydes (80-94 ee%), albeit lower with aliphatic substrates, favoring the trans isomer in all cases. By developing related organocatalysts 2b, 3a and 3b, the Connon group expanded the scope of the Pinder reaction to encompass the kinetic resolution of chiral aldehydes, the selective formation of cis adducts with aldehydes, and the use of ketones as substrates, respectively [22][23][24][25]. These catalysts are suggested to operate initially by deprotonation of homophthalic anhydride by the basic nitrogen with the resulting ammonium species and the anhydride enolate being in turn held though hydrogen bonds by the Lewis acidic squaramide or urea module of the organocatalyst.…”

Section: Introductionmentioning

confidence: 99%

A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof

et al. 2021

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In general, the Pinder reaction concerns the reaction between an enolisable anhydride and an aldehyde proceeding initially through a Knoevenagel reaction followed by the ring closing process generating lactones with at least two chiral centers. These scaffolds are frequently present in natural products and synthetic bioactive molecules, hence it has attracted intense interest in organic synthesis and medicinal chemistry, particularly with respect to controlling the diastereo- and enantioselectivity. To the best of our knowledge, there has been only one attempt prior to this work towards the development of a catalytic enantioselective Pinder reaction. In our approach, we designed, synthesized, and tested dual chiral organocatalysts by combining BIMAH amines, (2-(α-(alkyl)methanamine)-1H-benzimidazoles, and a Lewis acid motif, such as squaramides, ureas and thioureas. The optimum catalyst was the derivative of isopropyl BIMAH bearing a bis(3,5-trifluoromethyl) thiourea, which afforded the Pinder products from various aromatic aldehydes with diastereomeric ratio >98:2 and enatioselectivity up to 92 ee%. Interestingly, the enantioselectivity of this catalyzed process is increased at higher concentrations and exhibits an isoinversion effect, namely an inverted "U" shaped dependency with respect to the temperature. Mechanistically, these features, point to a transition state involving an entropy-favored heterodimer interaction between a catalyst/anhydride and a catalyst/aldehyde complex when all other processes leading to this are much faster in comparison above the isoinversion temperature.

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Highly Enantioselective Catalytic Kinetic Resolution of α‐Branched Aldehydes through Formal Cycloaddition with Homophthalic Anhydrides

Cited by 11 publications

References 61 publications

Integrated Experimental and Computational Studies on the Organocatalytic Kinetic Resolution of β-Unfunctionalized Primary Alcohols Using a Chiral 1,2-Diamine: The Importance of Noncovalent Interactions

Integrated Experimental and Computational Studies on the Organocatalytic Kinetic Resolution of β-Unfunctionalized Primary Alcohols Using a Chiral 1,2-Diamine: The Importance of Noncovalent Interactions

The Castagnoli–Cushman Reaction

A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof

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