Organocatalytic Kinetic Resolution Research Articles

Asymmetric Organocatalytic Reactions of Activated Racemic Allenes

AbstractAsymmetric organocatalytic reactions of various electron‐deficient racemic allenes with a wide variety of nucleophiles and electrophiles were reviewed. The literature on enantioselective functionalization of allenes that employs chiral phosphine, amine, phase transfer, bifunctional, and Brønsted acid catalysis is presented along with the mechanisms. In addition, the review emphasizes methods of obtaining enantioenriched allenes from racemic allenes via organocatalytic (dynamic) kinetic resolution techniques. The synthetic utility of the developed methodologies toward the target‐orientated biologically active molecules is narrated along with the examples.

Asymmetric synthesis of binaphthyls through photocatalytic cross-coupling and organocatalytic kinetic resolution

Asymmetric synthesis of binaphthyls through photocatalytic cross-coupling and organocatalytic kinetic resolution

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 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.

Front Cover: Mechanistic Insights into the Organocatalytic Kinetic Resolution of Oxazinones through Alcoholysis (Eur. J. Org. Chem. 3/2022)

The Front Cover represents a metaphor for the enantioselectivity produced by the organocatalyst in the studied reaction. Just like a traveler would never choose the dark and unsafe pathway and would always go through the light and easy road, the catalyst leads the reactants through the lowest energy transition state, producing the R enantiomer of the product over the S. Cover design by Inigo Iribarren. More information can be found in the Full Paper by C. Trujillo et al.

Mechanistic Insights into the Organocatalytic Kinetic Resolution of Oxazinones through Alcoholysis

AbstractA complete computational study has been performed in order to rationalise the results of a new organocatalytic approach to the kinetic resolution of 4‐substituted oxazinones which results in highly enantioenriched and orthogonally‐protected β‐amino acids. DFT‐analysis elucidated the preferable binding orientation of the 4‐oxazinone under study, predicted the formation of the observed major R product with a calculated ee in good agreement with the experimental data and allowed a complete mechanistic and stereochemical understanding of the catalysis. The alcoholytic kinetic resolution of a 7‐memebered ring analogue to generate enantioenriched γ‐amino acids was experimentally and computationally investigated for the first time.

Indirect Tertiary Alcohol Enantiocontrol by Acylative Organocatalytic Kinetic Resolution.

The stereocontrol of tertiary alcohols represents a recurrent challenge in organic synthesis. In the present paper, we describe a simple, efficient, and indirect method to enantioselectively prepare tertiary alcohols through a chiral isothiourea catalyzed selective acylation of adjacent secondary alcohols. This transformation enables the kinetic resolution (KR) of easily prepared racemic diastereoenriched secondary/tertiary diols providing both monoesters and starting diols in highly enantioenriched forms (s-value >200).

An Organocatalytic Kinetic Resolution of Aziridines by Thiol Nucleophiles.

We report the first organocatalytic kinetic resolution of unactivated aziridines by sulfur nucleophiles with excellent enantioselectivity. A suitable chiral phosphoric acid was found to catalyze the intermolecular ring opening under mild conditions, furnishing a range of highly enantioenriched β-amino thioethers and aziridines, both of which are useful synthetic building blocks.

Kinetic resolution of 2,2-disubstituted-1,3-diketones via carbene catalysis

Organocatalytic kinetic resolution of 1,3-diketones with central quaternary stereocenters was achieved for the first time. The resolution proceeds via two basic modes, and the inherent principles between the different combinations of ketone groups and the resolution patterns were also disclosed.

Kinetic resolution of sterically hindered secondary alcohols catalyzed by aminophosphinite organocatalyst

Kinetic resolution of secondary alcohols by benzoylation using a phosphinite derivative of (1S,2R)-1-amino-2-indanol as the catalyst was investigated. The aminophosphinite catalyst is effective for the kinetic resolution of aryl cycloalkyl carbinols with a small number of examples for organocatalytic kinetic resolution to achieve resolution with s = up to 44. Although the benzoylation of phenylalkanols proceeded with a low selectivity, 1-arylalkanols bearing at least one substituent at the ortho position on the benzene ring or a branched alkyl group on the carbinol carbon were resolved with acceptable selectivity.

Kinetic Resolution of 5-Substituted Oxazinones with Bifunctional Chiral Base/Squaramide Organocatalysts

5-Substituted oxazinones provide N-protected β2-amino acid esters upon alcoholytic ring opening. Thus far, this access to enantiopure β2-amino acids has been restricted to the use of enzymes (hydrolases) as catalysts for the kinetic resolution of racemic 5-substituted oxazinones, and branched alkyl or ortho-substituted aryl groups on the substrate oxazinone’s 5-position were typically not tolerated. We herein report that certain bifunctional chiral base/squaramide organocatalysts, in particular those derived from cis-1,2-diaminocyclohexane or 9-amino-9-epi-quinine, allow the first organocatalytic kinetic resolution of this ‘difficult’ class of oxazinone substrates, affording N-protected β2-amino acid esters with selectivity factors up to 43.

Synthesis of chiral (tetrazolyl)methyl-containing acrylates via silicon-induced organocatalytic kinetic resolution of Morita-Baylis-Hillman fluorides.

Reported herein is a new approach for the asymmetric installation of a (tetrazolyl)methyl group via Si/F activation using organocatalytic kinetic resolution of racemic MBH-fluorides.

ChemInform Abstract: Dihydrooxazine N‐Oxide Intermediates as Resting States in Organocatalytic Kinetic Resolution of Functionalized Nitroallylic Amines with Aldehydes.

AbstractFurther hydrolysis of the title intermediates provides tetrahydropyridines in high yields and with high diastereo‐ and enantioselectivities.

Dihydrooxazine N-Oxide Intermediates as Resting States in Organocatalytic Kinetic Resolution of Functionalized Nitroallylic Amines with Aldehydes.

Kinetic resolution of nitroallylic amines was established using chiral α,α-l-diphenylprolinol silyl ether auxiliary through isolation of the dihydrooxazine N-oxide intermediates. Further hydrolyzing the resting states provided tetrahydropyridines in high chemical yields and high to excellent stereoselectivities (up to >20:1 dr and 98% ee). A detailed mechanistic explanation for stereoselective protonation in the dihydrooxazine was probed computationally. In addition, the probable intermediates in α-halogenation of aldehydes (masked with enamines) were isolated to provide crystallographic evidence.

Organocatalytic Kinetic Resolution of Sulfoximines with Enals

Organocatalytic Kinetic Resolution of Sulfoximines with Enals

Organocatalytic Kinetic Resolution of Sulfoximines.

An efficient kinetic resolution of sulfoximines with enals was realized using chiral N-heterocyclic carbene (NHC) catalysts. The stereoselective amidation proceeds without additional acyl transfer agent. Both enantiomers of the sulfoximines can be obtained with excellent ee values (up to 99% ee and -97% ee, respectively). Performing the catalysis on a gram scale allowed using the recovered sulfoximine (+)-1j in an asymmetric synthesis of FXa inhibitor F.

ChemInform Abstract: Recent Advances in Organocatalytic Kinetic Resolution for the Synthesis of Functionalized Products

AbstractReview: [46 refs.

Organocatalyzed nucleophilic addition of pyrazoles to 2H-azirines: asymmetric synthesis of 3,3-disubstituted aziridines and kinetic resolution of racemic 2H-azirines.

The first organocatalytic asymmetric nucleophilic addition of arylpyrazoles to 2H-azirines and kinetic resolution of racemic 2H-azirines have been realized. Chiral aziridines were obtained with up to 98% yields and up to 99.9% ee. Meanwhile, simply changing the ratio of reactants, optically active 2H-azirines were recovered in good yields with excellent enantioselectivities.

Recent Advances in Organocatalytic Kinetic Resolution for the Synthesis of Functionalized Products

AbstractThis Minireview describes organocatalytic kinetic resolution (OCKR) that has evolved on the basis of using small organic catalysts through enamine/iminium ion, N‐heterocyclic carbene, and hydrogen‐bonding catalysis. The review includes the use of recent methodologies for which the evolution of OCKR mainly involves creating new stereogenic center(s) in functionalized products through the formation of a C−C, C−N, C−O, C−X, or C−S bond. The combination of OCKR with sequential reactions and its association with desymmetrization and dynamic kinetic resolution are also described.

ChemInform Abstract: Control of Five Contiguous Stereogenic Centers in an Organocatalytic Kinetic Resolution via Michael/Acetalization Sequence: Synthesis of Fully Substituted Tetrahydropyranols.

AbstractThe conversion of aldehydes with a range of aryl substituted secondary nitroallylic alcohols in the presence of a chiral prolinol derivative furnishes the title products with excellent stereoselectivities.

ChemInform Abstract: Organocatalytic Kinetic Resolution of Racemic Secondary Nitroallylic Alcohols Combined with Simultaneous Desymmetrization of Prochiral Cyclic Anhydrides.

AbstractIn the presence of chiral catalyst CTC, the reaction affords hemiesters of type (III) and (VI) with good to excellent enantioselectivity.