Kinetic Resolution of Racemic α-Arylalkanoic Acids with Achiral Alcohols via the Asymmetric Esterification Using Carboxylic Anhydrides and Acyl-Transfer Catalysts

Shiina, Isamu; Nakata, Kenya; Ono, Katsushige; Onda, Yu Suke; Itagaki, Makoto

doi:10.1021/ja103490h

Cited by 116 publications

(67 citation statements)

References 38 publications

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“…Optimization studies: We were reluctant to use the rather expensive p-methoxybenzoic anhydride (PMBA) [19] preferred by Shiina [20] as a stoichiometric condensing agent and opted instead for benzoic anhydride. Although the first results in HBTM-catalyzed KR of ( AE )-a-phenylpropionic acid 6 were encouraging (Scheme 4), we found it difficult to separate benzoic acid from the unreacted a-phenylpropionic acid, which complicated our experimental protocol.…”

Section: Resultsmentioning

confidence: 99%

“…Cleaner reaction was observed with pivalic anhydride, [20] but the reaction rate was similarly slow (Table 7, entry 4). Fortunately, benzoic anhydride employed in Shiinas original protocol [17] proved to be more successful, giving the desired ester in 90 % yield with 91 % ee after 24 h (Table 7, entry 5).…”

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confidence: 91%

“…Finally, addition of DHPB 37 (10 mol %), [34] the achiral analogue of HBTM 4, resulted in complete racemization within the same reaction time, suggesting that the N-acylated intermediate loses its stereochemical integrity faster than the anhydride. [20,29] Furthermore, the rate of substrate racemization is faster than that of the alcoholysis step, as is evidenced by the fact that a-(phenylthio)propionic acid enriched in the slow-reacting (R)-enantiomer produced the ester in almost the same ee value under the standard DKR conditions as did the racemate (Table 7, entry 8).…”

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confidence: 96%

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Kinetic Resolution of α‐Substituted Alkanoic Acids Promoted by Homobenzotetramisole

Yang

Birman

2011

Chemistry A European J

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A new method for catalytic nonenzymatic kinetic resolution of α-substituted alkanoic acids has been developed, which relies on their activation with DCC followed by enantioselective alcoholysis of the intermediate symm-anhydrides in the presence of the amidine-based catalyst homobenzotetramisole (HBTM). Moderate to excellent selectivity factors (s=5-96) have been obtained in the case of several classes of substrates, namely, α-aryl-, α-aryloxy/alkoxy-, α-halo-, α-azido-, and α-phthalimido-alkanoic acids. Under similar conditions, α-(arylthio/alkylthio)-alkanoic acids undergo dynamic kinetic resolution providing corresponding esters in up to 92% ee and up to 93% yield.

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Section: Resultsmentioning

confidence: 99%

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confidence: 91%

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confidence: 96%

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Kinetic Resolution of α‐Substituted Alkanoic Acids Promoted by Homobenzotetramisole

Yang

Birman

2011

Chemistry A European J

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“…In this procedure, a racemic mixture of α-arylpropanoic acids was separated into the corresponding chiral carboxylates and the recovered chiral carboxylic acids with high selectivity. A mechanistic study 24 revealed that this enantioselective esterification proceeds through a mixed anhydride (MA), a reactive intermediate formed from the substrate and the coupling reagent, followed by formation of a transition state (TS) with the achiral alcohol and chiral BTM. Furthermore, acceleration of the racemization process in a polar reaction media such as DMF led to the development of the corresponding DKR system for α-arylpropanoic acids.…”

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confidence: 99%

Nonenzymatic, Enantioconvergent Dynamic Kinetic Resolution (DKR) of Racemic 2-(1H-Pyrrol-1-yl)alkanoic Acids as α-Amino Acid Equivalents

et al. 2015

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We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-discriminating step via catalytic esterification. The combination of pivalic anhydride as an activating agent, bis(α-naphthyl)methanol as an achiral alcohol, (R)-BTM as a chiral acyl-transfer catalyst, and Hünig's base converted racemic 2-(1H-pyrrol-1-yl)alkanoic acids to the corresponding chiral carboxylates, which can be transformed into chiral α-amino acid derivatives with maintained high enantiopurity.α-Amino acids have long been considered fundamental moieties in organic chemistry, and the enantio-controlled and catalytic construction of the chiral α-position of α-amino acids has been targeted as an attractive synthetic goal. 16In order to provide large amounts of chiral α-amino acids from racemic α-amino acids, dynamic kinetic resolution (DKR) 7,8 has been anticipated to be an ideal method. While a wide range of enzymatic DKRs 911 for α-amino acid derivatives has been disclosed as reliable methodologies, non-enzymatic DKRs have also emerged as promising approaches during the last decade. However, major examples of the successful nonenzymatic DKR of chiral α-amino acids have involved the catalytic ring-opening alcoholysis of cyclic precursors, such as racemic urethane-protected α-amino acid N-carboxyanhydrides (Deng 12 ) and racemic 2-phenylazlactones (Seebach, 13 Fu,14 Berkessel, 1517 Connon,18,19 Birman,20,21 etc.). Note that the DKR systems for racemic 2-phenylazlactones principally allowed production of N-benzoyl amino acids with high enantiopurities.As illustrated in Figure 1, we have reported the effective kinetic resolution (KR) of racemic α-arylpropanoic acids 22 using carboxylic anhydride as the coupling agent, bis(α-naphthyl)-methanol as the achiral alcohol, and benzotetramisole (BTM) 23 as the chiral acyl-transfer catalyst. In this procedure, a racemic mixture of α-arylpropanoic acids was separated into the corresponding chiral carboxylates and the recovered chiral carboxylic acids with high selectivity. A mechanistic study 24 revealed that this enantioselective esterification proceeds through a mixed anhydride (MA), a reactive intermediate formed from the substrate and the coupling reagent, followed by formation of a transition state (TS) with the achiral alcohol and chiral BTM. Furthermore, acceleration of the racemization process in a polar reaction media such as DMF led to the development of the corresponding DKR system for α-arylpropanoic acids. 25Despite the growing number of DKR systems reported to date, there has yet been no example of a catalytic DKR system for protected α-amino acids via direct esterification using acyclic precursors. Moreover, to the best of our knowledge, there are no examples of catalytic DKR systems for any racemic α-nitrogencontaining carboxylic acids. In the present study, we report the first DKR of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which can then be converted to α...

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“…Fore xample,w hen chiral catalyst C6 [16] was employed,d ihydropyridazinone 3aa could be obtained in 91% yield with 92% ee (Scheme3).…”

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confidence: 99%

Organocatalyzed Formal [4+2] Cycloaddition of in situ Generated Azoalkenes with Arylacetic Acids: An Efficient Approach to the Synthesis of 4,5‐Dihydropyridazin‐3(2H)‐ones

Gai

Yuan

et al. 2015

Adv Synth Catal

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An unprecedented [4+ +2] cycloaddition of in situ generated azoalkenes with arylacetic acids has been developed under the catalysis of isothiourea. Ther eaction provideda ne fficienta pproacht o the synthesis of 4,5-dihydropyridazin-3(2H)-one derivatives in moderate to good yields(up to 95%).Keywords: 1,2-diaza-1,3-dienes;4 ,5-dihydropyridazin-3(2H)-ones;i sothioureacatalysis Dihydropyridazinones and pyridazinones are important six-membered aza-heterocycles,a nd are present in aw ide range of bioactive compoundsw ith anti-inflammatory, [1] anti-platelet aggregation [2] and anti-congestive heart failurea ctivities (Figure 1). To the best of our knowledge, the reported synthetic strategies for the synthesiso fd ihydropyridazinones are normally limited to the condensation of costly substrate goxo acids andh ydrazine.[3] Therefore,t he development of an ew strategyt hat allowsr apid access to dihydropyridazinones from readily accessible starting materials using ap ractical method is still highly desirable and an enduring goal of organic chemistry.Organocatalysis is now aw elle stablished instrument in the organic chemists tool box due to the generally stability,h igh quality,i nexpensive price, and lower toxicity compared to transitionm etals.I sothioureas, [4] one kind of frequently used organocatalyst, initially introduced by Birman [5] and Okamoto, [6] could promote the in situ generation of ammonium enolates from ac arboxylic acid, introducing functionalization to the carboxylic acid throughaMichaellactonization sequence. [7] 1,2-Diaza-1,3-dienes, generatedf rom the corresponding a-halo hydrazones,h ave recently been identified as ar obust and versatile synthetic building blocks with wide applications in the assembly of various five-, six-,a nd seven-membered heterocyclic ring systems. [8] In 2014, the Glorius group reported the first example of NHC-catalyzedf ormal [4+ +3] and [4+ +1] annulationso f1 ,2-diaza-1,3-dienes with enals, providing ah ighly enantioselective access to the chiral dihydrodiazepinones [9] (Scheme 1a). TheX iao group [10] andt he Luog roup [11] achieved the [4+ +3] and [4+ +2] annulationso ft he in situ generated 1,2-diaza-1,3-dienes with 1,3-dipoles and olefins employinga n inorganic base,l eading to the important building blocks of the tetrazepine and tetrahydropyridazine types (Scheme 1b,c ). Inspired by these works,w ee nvisaged that the possible [4+ +2] cycloadditionb etween a-halo hydrazones and arylacetic acids under the cat- COMMUNICATIONS alysis of isothiourea wouldp rovide an efficienta ccess to dihydropyridazinone derivatives.H erein, we report the first example of isothiourea-catalyzed formal [4+ +2] annulation reactions of in situ generated azoalkenesw ith arylacetic acids,c onstructing 4,5-dihydropyridazin-3(2H)-one derivatives in moderate to excellent yields (Scheme 1d). We started our investigation with the reaction between readilya vailable a-chloro N-Boc-hydrazone 1a and phenylacetic acid 2a.W hen the reactionw as performed in DCE at ambient temperature,c ompound...

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Kinetic Resolution of Racemic α-Arylalkanoic Acids with Achiral Alcohols via the Asymmetric Esterification Using Carboxylic Anhydrides and Acyl-Transfer Catalysts

Cited by 116 publications

References 38 publications

Kinetic Resolution of α‐Substituted Alkanoic Acids Promoted by Homobenzotetramisole

Kinetic Resolution of α‐Substituted Alkanoic Acids Promoted by Homobenzotetramisole

Nonenzymatic, Enantioconvergent Dynamic Kinetic Resolution (DKR) of Racemic 2-(1H-Pyrrol-1-yl)alkanoic Acids as α-Amino Acid Equivalents

Organocatalyzed Formal [4+2] Cycloaddition of in situ Generated Azoalkenes with Arylacetic Acids: An Efficient Approach to the Synthesis of 4,5‐Dihydropyridazin‐3(2H)‐ones

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