Enantiodivergent Reactions: Divergent Reactions on a Racemic Mixture and Parallel Kinetic Resolution

Russell, Trisha A.; Vedejs, E.

doi:10.1002/9783527650880.ch6

Cited by 8 publications

(5 citation statements)

References 141 publications

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“…So far this strategy has been difficult to implement in a practical fashion due to challenge of physically separating the reagents and readily isolating the pseudoenantiomeric products. 4 In this report, we describe the combination of flow chemistry, solid supported resolving agents, and readily cleavable tertiary amides for the successful parallel kinetic resolution of chiral, saturated N-heterocycles including piperazines, morpholines, piperdines, tetrahydroisoquinolines, and others. Despite an intrinsic selectivity of only s = 10 -20 in most cases, flow-based parallel kinetic resolution allows the two enantiomers to be isolated in good yield and outstanding enantiomeric excesses, an outcome that would normally require reagents with selectivities in the range of s = 50 -…”

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confidence: 99%

“…Such processes are referred to as regiodivergent or stereodivergent reactions of racemic mixtures and they are more common in organic synthesis. 4 These are attractive processes when they can be implemented, however they do not fully benefit from the inherent advantages of a true parallel kinetic resolution. 19 We have recently reported immobilized chiral acyl hydroxamic acid (PEARL -polymeric reagents for kinetic resolution) for the kinetic resolution of saturated N-heterocycles on both small (100 mg) and preparative (> 20 g) scale (Fig.…”

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confidence: 99%

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Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Kreituss

Bode

2016

Nature Chem

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Kinetic resolution is a common method to obtain enantioenriched material from a racemic mixture. This process will always deliver enantiopure unreacted material if the reactions are allowed to proceed to sufficient conversion and the selectivity is not unity (s > 1). However, the scalemic reaction product often is discarded, meaning, that the yield of this process seldom exceeds 40-45%. Parallel kinetic resolution can grant access to two distinct, highly enantioenriched products from a single racemic starting material. Here we describe the development of a flow-based system that enables practical parallel kinetic resolution (PKR) of a broad range of racemic saturated N-heterocycles. This process provides access to both enantiomers of the racemic starting material in good yield and high enantiopurity; similar results with classical kinetic resolution would require selectivities in the range of s = 100. To achieve this, two immobilized quasienantiomeric acylating agents were designed for the asymmetric acylation of racemic saturated N-heterocycles. Using the flow-based system we could efficiently separate, recover and reuse the polymer-supported reagents. The amide products were obtained in good yields and high enantiopurities and could be readily separated and hydrolyzed to the corresponding amines without detectable epimerization.

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confidence: 99%

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Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Kreituss

Bode

2016

Nature Chem

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“…We envisioned that, instead of an enantioconvergent process involving one racemic electrophile to produce one chiral product (one-to-one), an enantiodivergent process involving one racemic alkylmetallic reagent to produce two chiral products (one-to-two) would be a new strategy for asymmetric coupling chemistry (Figure b). In contrast to the traditional parallel kinetic resolution process, this process relies on a one-pot, two-step enantiodivergent relay coupling via nickel catalysis, which has not been reported so far. In this process, the chiral nickel catalyst enables enantioselective coupling of one enantiomer from the racemic alkylmetallic nucleophiles with an electrophile via kinetic resolution to produce one chiral product.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Functionalization of Racemic Cyclopropylzinc Reagents via Enantiodivergent Relay Coupling

Tong

Zhang

et al. 2020

J. Am. Chem. Soc.

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Efficient construction of optically pure molecules from readily available starting materials in a simple manner is an ongoing goal in asymmetric synthesis. As a straightforward route, transition-metal-catalyzed enantioconvergent coupling between widely available secondary alkyl electrophiles and organometallic nucleophiles has emerged as a powerful strategy to construct chiral center(s). However, the scope of racemic secondary alkylmetallic nucleophiles for this coupling remains limited in specific substrates because of the difficulties in stereoselective formation of the key alkylmetal intermediates. Here, we report an enantiodivergent strategy to efficiently achieve an array of synthetically useful chiral cyclopropanes, including chiral fluoroalkylated cyclopropanes and enantiomerically enriched cyclopropanes with chiral side chains, from racemic cyclopropylzinc reagents. This strategy relies on a one-pot, two-step enantiodivergent relay coupling process of the racemic cis-cyclopropylzinc reagents with two different electrophiles, which involves kinetic resolution of racemic cis-cyclopropylzinc reagents through a nickel-catalyzed enantioselective coupling with alkyl electrophiles, followed by a stereospecific relay coupling of the remaining enantiomeric cyclopropylzinc reagent with various electrophiles, to produce two types of functionalized chiral cyclopropanes with opposite configurations on the cyclopropane ring. These chiral cyclopropanes are versatile synthons for diverse transformations, rendering this strategy effective for obtaining structurally diversified molecules of medicinal interest.

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“…The drive to make catalytic processes more atom-economic and environmentally benign has resulted in increasingly more efficient methods. Among these, various forms of kinetic resolution are widely used in the separation of enantiomerically pure compounds from a racemic mixture. − In parallel kinetic resolution (PKR), both enantiomers react in such a way that two optically pure products can be isolated. − Although the differences between various forms of kinetic resolution methods are often described on the basis of reversibility, racemization, faster/slower reacting partners, and so on, the underlying semiquantitative energetic details are not readily available.…”

Section: Introductionmentioning

confidence: 99%

Insights on the Origin of Regiodivergence in the Parallel Kinetic Resolution of rac-Aziridines Using a Chiral Lanthanum–Yttrium Bimetallic Catalyst

Kisan

Sunoj

2018

ACS Catal.

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Parallel kinetic resolution of racemic mixtures is an important method used in asymmetric synthesis of chiral compounds. In a recent example, a rac-cis-2,3-substituted chiral N-benzoyl aziridine was reacted with dimethyl malonate, in the presence of a La−Y heterobimetallic chiral BINAM Schiff base (L) catalyst, to form enantiomerically pure (ee > 98%) γ-amino acid derivatives through a ring-opening reaction in nearquantitative yields from both the enantiomers (∼48%). High regio-and enantioselectivities even with a rac-aziridine, having C2 and C3 substituents as similar as ethyl and n-propyl. Through a comprehensive computational investigation, we delineate the origin of regio-divergent and enantioselective formation of γamino ester derivatives. The Gibbs free energy of the transition state for the ring-opening at the propyl substituted C2 carbon leading to 3-benzamidoheptan-4-yl malonate is found to be 7.2 kcal/mol lower than that at the ethyl substituted C3 carbon in the case of (2R,3S)-aziridine. A reversal of the regio-chemical preference for its enantiomeric (2S,3R)-aziridine is noted where the ring-opening occurs at the ethyl substituted C3 carbon. The La−Y catalyst is found to initially "recognize" both the enantiomers of the rac-aziridine rather indiscriminately. The activation barriers for the most-preferred ring-opening for each enantiomer are found to be closely similar, suggesting that both enantiomers would react. The high regio-selectivity in the addition of lanthanum-bound malonate to the aziridine anchored onto the yttrium center is due to a unique geometric disposition of the aziridine in the stereocontrolling ring-opening transition state. The lowest-energy ring-opening transition state for each enantiomer of aziridine exhibited very similar geometries, while notable geometric distortions is identified in the malonate addition to less-preferred site of the same enantiomer.

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Enantiodivergent Reactions: Divergent Reactions on a Racemic Mixture and Parallel Kinetic Resolution

Cited by 8 publications

References 141 publications

Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Stereoselective Functionalization of Racemic Cyclopropylzinc Reagents via Enantiodivergent Relay Coupling

Insights on the Origin of Regiodivergence in the Parallel Kinetic Resolution of rac-Aziridines Using a Chiral Lanthanum–Yttrium Bimetallic Catalyst

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