Nonenzymatic Kinetic Resolution Research Articles

Kinetic Resolution of BINOLs and Biphenols by Atroposelective, Cu-H-Catalyzed Si-O Coupling with Hydrosilanes.

A nonenzymatic kinetic resolution of monoprotected BINOL and biphenol derivatives by atroposelective Si-O coupling with hydrosilanes is described. The reaction relies on a previously unprecedented Cu-H-catalyzed silylation of phenols. The catalyst system consisting of CuCl, (R,R)-Ph-BPE, and NaOtBu enables the enantioselective coupling of the phenolic hydroxy group with a hydrosilane with moderate to good selectivity factors.

Kinetic Resolution of Electron-Deficient Bromohydrins via Copper(II)-Catalyzed C-C Bond Cleavage.

Herein, we report a nonenzymatic kinetic resolution (KR) of α,β-unsaturated ketone-derived bromohydrins (up to s = 211) with N-bromosuccinimide (NBS) in the presence of a chiral Cu(II)-Box catalyst via the C-C bond cleavage of the fast reacting enantiomer. A one-pot synthesis-KR approach of the same has also been realized with excellent enantioselectivities (up to 99% ee). Both protocols are found to be effective for a variety of substrates, leading to enantioenriched bromohydrins. The synthetic utility of this process has been demonstrated by exploring a new strategy to convert the resolved enantiomer to an optically active epoxide.

Photoexcited Chiral Copper Complex-Mediated Alkene E → Z Isomerization Enables Kinetic Resolution.

While asymmetric synthesis has been established as a powerful synthetic tool for the construction of versatile enantioenriched molecules in the most efficient and practical manner, the resolution of racemates is still the most universal industrial approach to the synthesis of chiral compounds. However, the direct formation of enantiopure Z-isomers through the catalytic nonenzymatic kinetic resolution of racemic E-alkenes remains challenging. Herein, we disclose an unprecedented enantioselective E → Z isomerization mediated by a photoexcited chiral copper complex. This catalytic system enables kinetic resolution of 2-styrylpyrrolidines. This process is difficult to realize under thermal conditions. Mechanistic experiments and density functional theory (DFT) calculations revealed that different overall sensitization rates of the substrate-catalyst complex of the two enantiomers led to the observed excellent kinetic resolution efficiency. This photochemical transformation expands the potential of kinetic resolution beyond their established ground-state reactivity, furnishing a novel reaction mode for enantioselective catalysis at its excited state.

Kinetic resolution of cyclic benzylic azides enabled by site- and enantioselective C(sp3)\u2013H oxidation

Catalytic nonenzymatic kinetic resolution (KR) of racemates remains one of the most powerful tools to prepare enantiopure compounds, which dominantly relies on the manipulation of reactive functional groups. Moreover, catalytic KR of organic azides represents a formidable challenge due to the small size and instability of the azido group. Here, an effective KR of cyclic benzylic azides through site- and enantioselective C(sp3)–H oxidation is described. The manganese catalyzed oxidative KR reaction exhibits good functional group tolerance, and is applicable to a range of tetrahydroquinoline- and indoline-based organic azides with excellent site- and enantio-discrimination. Computational studies elucidate that the effective chiral recognition is derived from hydrogen bonding interaction between substrate and catalyst.

Recent Advances in Catalytic Nonenzymatic Kinetic Resolution of Tertiary Alcohols

AbstractThe kinetic resolution (KR) of racemates is one of the most widely used approaches to access enantiomerically pure compounds. Over the past two decades, catalytic nonenzymatic KR has gained popularity in the field of asymmetric synthesis due to the rapid development of chiral catalysts and ligands in asymmetric catalysis. Chiral tertiary alcohols are prevalent in a variety of natural products, pharmaceuticals, and biologically active chiral compounds. The catalytic nonenzymatic KR of racemic tertiary alcohols is a straightforward strategy to access enantioenriched tertiary alcohols. This short review describes recent advances in catalytic nonenzymatic KR of tertiary alcohols, including organocatalysis and metal catalysis.1 Introduction2 Organocatalysis2.1 Peptide Catalyst2.2 Chiral Phosphoric Acid Catalyst2.3 Chiral Lewis Base Catalyst2.4 Chiral Quaternary Ammonium Salt Catalyst3 Metal Catalysis3.1 Mixed La-Li Heterobimetallic Catalyst3.2 Rh Catalyst3.3 Hf Catalyst3.4 Pd Catalyst3.5 Cu Catalyst3.6 Ag Catalyst4 Conclusion and Outlook

Non-Enzymatic Kinetic Resolution and Desymmetrization of α-Quaternary Carboxylic Acids via Chiral Bifunctional Sulfide-Catalyzed Bromolactonization

Abstract Kinetic resolution of racemic carboxylic acids is a reliable method to enantioselectively prepare chiral carboxylic acids. Although efficient catalytic kinetic resolutions of chiral α-tertiary carboxylic acids have been reported, the kinetic resolution of α-quaternary carboxylic acids bearing an all-carbon quaternary stereocenter has remained a formidable challenge. Herein, we report a precious example of a kinetic resolution of α-quaternary carboxylic acids via a chiral bifunctional sulfide-catalyzed bromolactonization of alkynes. The ability of chiral sulfides to recognize α-quaternary carboxylic acids was evaluated via the catalytic enantioselective desymmetrizing bromolactonization of achiral α,α-dipropargyl carboxylic acids, which is a reaction that is related to target kinetic resolution. The optimum chiral sulfide was successfully applied to the efficient kinetic resolution of α-propargyl carboxylic acids that bear an all-carbon quaternary stereocenter.

Kinetic Resolution of Neopentylic Secondary Alcohols by Cu–H-Catalyzed Enantioselective Silylation with Hydrosilanes

A nonenzymatic kinetic resolution of sterically congested alcohols having a quaternary carbon atom in the β-position is reported. The catalyst system CuCl/NaOtBu/(R,R)-Ph-BPE together with a 3,5-xylyl-substituted tertiary hydrosilane enable enantioselective silylation of the hydroxy group. Several alcohols are obtained with good to excellent selectivity factors, and there are no other known straightforward methods to access these motifs.

Making the Silylation of Alcohols Chiral: Asymmetric Protection of Hydroxy Groups.

The non-enzymatic kinetic resolution of racemic mixtures of alcohols by silylation had been unknown before the turn of the century. This stands in stark contrast to established acylation techniques. The same applies to the related desymmetrization of diols. This might come as a surprise, given the significance of silyl ethers as protecting groups in multistep synthesis of complex molecules. The situation changed after a seminal report by Ishikawa nearly twenty years ago. Since then, enantioselective silylation of alcohols has matured and grown into an independent research field with organocatalytic and transition-metal-catalyzed approaches providing powerful solutions. This Minireview summarizes these recent advances with particular emphasis on the stereoselective dehydrogenative coupling of alcohols and hydrosilanes.

Kinetic Resolution of Tertiary Propargylic Alcohols by Enantioselective Cu-H-Catalyzed Si-O Coupling.

A broad range of tertiary propargylic alcohols were kinetically resolved by catalyst-controlled enantioselective silylation. This non-enzymatic kinetic resolution is catalyzed by a Cu-H species and makes use of the commercially available precatalyst MesCu/(R,R)-Ph-BPE and a simple hydrosilane as the resolving reagent. Both alkyl,aryl- as well as dialkyl-substituted propargylic alcohols participate, and especially high selectivity factors are achieved when the alkyne terminus carries a TIPS group, which also enables facile post-functionalization in this position (s up to 207).

Effective Guest Inclusion by a 6‐O‐Modified β‐Cyclodextrin Dimer in Organic Solvents

A 6-O-tert-butyldimethylsilylated β-cyclodextrin (TBDMS-β-CD) dimer, in which two TBDMS-β-CD rings are connected in a head-to-head fashion by a m-xylylene linker, effectively forms inclusion complexes with pyrene and naphthalene in nonpolar organic solvents such as cyclohexane and benzene. This TBDMS-β-CD dimer shows a higher inclusion ability toward these guests than a TBDMS-β-CD dimer bearing a p-xylylene linker due to the greater cooperation of the two TBDMS-β-CD rings for the guest inclusion. Unlike the corresponding monomer, the TBDMS-β-CD dimer bearing a m-xylylene linker is also a good host even in polar organic solvents such as tetrahydrofuran. High chiral recognition of aromatic amines and alcohol is realized by utilizing inclusion within the cavity of the TBDMS-β-CD dimer in cyclohexane. In particular, an extremely high binding selectivity for (S)-1-(1-naphthyl)ethylamine and (S)-1-(1-naphthyl)ethanol over the corresponding (R)-isomers is achieved. Moreover, by utilizing the high chiral recognition with the TBDMS-β-CD dimer in cyclohexane, a non-enzymatic kinetic resolution of racemic 1-(1-naphthyl)ethylamine via enantioselective N-benzoylation is attained with an enantiomer excess of up to 87 % and an s-factor of 15.

Kinetic Resolution of β-Hydroxy Carbonyl Compounds via Enantioselective Dehydration Using a Cation-Binding Catalyst: Facile Access to Enantiopure Chiral Aldols.

A practical and highly enantioselective nonenzymatic kinetic resolution of racemic β-hydroxy carbonyl (aldol) compounds through enantioselective dehydration process was developed using a cation-binding Song's oligoethylene glycol (oligoEG) catalyst with potassium fluoride (KF) as base. A wide range of racemic aldols was resolved with extremely high selectivity factors ( s = up to 2393) under mild reaction conditions. This protocol is easily scalable. It provides an alternative approach for the syntheses of diverse biologically and pharmaceutically relevant chiral aldols in enantiomerically pure form. For example, racemic gingerols could participate in this kinetic resolution with superb efficiency ( s > 240), affording both enantiomerically pure gingerols and corresponding shogaols simultaneously in a single step. The dramatic effectiveness of such kinetic resolution process can be ascribed to systematic cooperative hydrogen-bonding catalysis in a densely confined supramolecular chiral cage in situ generated from the chiral catalyst, substrate, and KF.

ChemInform Abstract: Efficient and Scalable Kinetic Resolution of Racemic 4‐Formyl[2.2]paracyclophane via Asymmetric Transfer Hydrogenation.

Herein we wish to report a new non-enzymatic kinetic resolution of racemic 4-formyl[2.2]paracyclophane based on Noyori asymmetric transfer hydrogenations (KR-ATH). Our approach, which provides an efficient access to enantiopure (Rp)- and (Sp)-4-formyl[2.2]paracyclophane (>99% ee, 39% and 41% isolated yields, respectively), is operationally simple and can be run on the gram-scale thus confirming the practical applicability of this method.

Kinetic resolution of α-methylene-β-hydroxy esters catalyzed by acyl transfer catalyst An-PIQ.

A highly efficient nonenzymatic kinetic resolution of a series of structurally diverse racemic α-methylene-β-hydroxy esters utilizing the acyl transfer catalyst An-PIQ and propionic anhydride is reported. This procedure provides recovered alcohols with extremely high ee's (up to >99%) in reasonable conversions and excellent selectivity factors (S up to 108). Several synthetically important substrates were resolved in gram-scale reactions, and highly optically pure α-methylene-β-hydroxy esters were obtained with excellent S values and good yields.

Nonenzymatic kinetic resolution of α-aryl substituted allylic alcohols catalyzed by acyl transfer catalyst Np-PIQ

Chiral α-aryl substituted allylic alcohols are important versatile synthetic intermediates. We report here an effective nonenzymatic kinetic resolution of racemic α-aryl substituted allylic alcohols by introducing different aryl groups with acyl transfer catalyst Np-PIQ and propionic anhydride, providing moderate to good selectivity factors (S=12–37).

Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst.

The development of new approaches to obtain optically pure β-hydroxy esters is an important area in synthetic organic chemistry since they are precursors of other high value compounds. Herein, the kinetic resolution of racemic β-hydroxy esters using a planar-chiral DMAP derivative catalyst is presented. Following this procedure, a range of aromatic β-hydroxy esters was obtained in excellent selectivities (up to s = 107) and high enantiomeric excess (up to 99% ee). Furthermore, the utility of the present method was demonstrated in the synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide, a key intermediate for bioactive molecules such as fluoxetine, tomoxetine or nisoxetine, in its enantiomerically pure form.

ChemInform Abstract: Kinetic Resolution of 2‐Hydroxy‐2‐aryl‐ethylphosphonates by a Non‐enzymatic Acylation Catalyst.

Optically pure hydroxyphosphonates are widely used as derivatizable compounds that can be incorporated into a variety of synthetic strategies for the preparation of other high value organic products. A non-enzymatic kinetic resolution procedure to obtain chiral 2-hydroxy-2-arylethylphosphonates from the easily available racemic counterparts is described. A range of 2-hydroxy-2-arylethylphosphonates was efficiently resolved employing a planar-chiral DMAP derived catalyst with good selectivities (up to S=68). The chiral hydroxyphosphonates were isolated in good yields and high enantiomeric excess (>94% ee).

Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non-enzymatic acylation catalyst

Optically pure hydroxyphosphonates are widely used as derivatizable compounds that can be incorporated into a variety of synthetic strategies for the preparation of other high value organic products. A non-enzymatic kinetic resolution procedure to obtain chiral 2-hydroxy-2-arylethylphosphonates from the easily available racemic counterparts is described. A range of 2-hydroxy-2-arylethylphosphonates was efficiently resolved employing a planar-chiral DMAP derived catalyst with good selectivities (up to S=68). The chiral hydroxyphosphonates were isolated in good yields and high enantiomeric excess (>94% ee).

Kinetic resolution of primary amines via enantioselective N-acylation with acyl chlorides in the presence of supramolecular cyclodextrin nanocapsules

The non-enzymatic kinetic resolution of primary amines via enantioselective N-acylation with acyl chlorides was accomplished for the first time by using the selective sequestration of one enantiomer within a supramolecular cyclodextrin (CD) nanocapsule in nonpolar solvents. In addition, the first example of a crystalline structure for an inclusion complex between an acyl chloride and a CD derivative is reported.

Metal-Free, Mild, Nonepimerizing, Chemo- and Enantio- or Diastereoselective N-Alkylation of Amines by Alcohols via Oxidation/Imine–Iminium Formation/Reductive Amination: A Pragmatic Synthesis of Octahydropyrazinopyridoindoles and Higher Ring Analogues

A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.

A Practical Access to Highly Enantiomerically Pure Flavanones by Catalytic Asymmetric Transfer Hydrogenation

A surprisingly selective, non-enzymatic kinetic resolution of readily available, racemic β-chiral ketones enabled the title process, which was applied to a rapid synthesis of several bioactive flavanones in virtually enantiopure form (see scheme; MOM=methoxymethyl, Ts=p-toluenesulfonyl).