CREST—A program for the exploration of low-energy molecular chemical space

The Journal of Chemical Physics, Год журнала: 2024, Номер 160(11)

Опубликована: Март 21, 2024

Conformer–rotamer sampling tool (CREST) is an open-source program for the efficient and automated exploration of molecular chemical space. Originally developed in Pracht et al. [Phys. Chem. Phys. 22, 7169 (2020)] as driver calculations at extended tight-binding level (xTB), it offers a variety molecular- metadynamics simulations, geometry optimization, structure analysis capabilities. Implemented algorithms include procedures conformational sampling, explicit solvation studies, calculation absolute entropy, identification protonation deprotonation sites. Calculations are set up to run concurrently, providing single-node parallelization. CREST designed require minimal user input comes with implementation GFNn-xTB Hamiltonians GFN-FF force-field. Furthermore, interfaces any quantum chemistry force-field software can easily be created. In this article, we present recent developments code show selection applications most important features program. An novelty refactored backend, which provides significant speed-up small or medium-sized drug molecules allows more sophisticated setups, example, mechanics/molecular mechanics minimum energy crossing point calculations.

Язык: Английский

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Multiplicative enhancement of stereoenrichment by a single catalyst for deracemization of alcohols

Science, Год журнала: 2023, Номер 382(6669), С. 458 - 464

Опубликована: Окт. 26, 2023

Stereochemical enrichment of a racemic mixture by deracemization must overcome unfavorable entropic effects as well the principle microscopic reversibility; recently, photochemical reaction pathways unveiled energetic input light have led to innovations toward this end, most often ablation stereogenic C(sp3)-H bond. We report photochemically driven protocol in which single chiral catalyst two mechanistically different steps, C-C bond cleavage and formation, achieve multiplicative enhancement stereoinduction, leads high levels stereoselectivity. Ligand-to-metal charge transfer excitation titanium coordinated phosphoric acid or bisoxazoline efficiently enriches alcohols that feature adjacent fully substituted centers enantiomeric ratios up 99:1. Mechanistic investigations support pathway sequential radical-mediated scission formation through common prochiral intermediate reveal that, although overall stereoenrichment is high, selectivity each individual step moderate.

Язык: Английский

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Catalytic Deracemization Reactions

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(20), С. 10917 - 10929

Опубликована: Май 13, 2023

Deracemization, which converts a racemate into its single enantiomer without separation of the intermediate, has gained renewed interest in asymmetric synthesis with inherent atomic economy and high efficiency. However, this ideal process requires selective energy input delicate reaction design to surmount thermodynamical kinetical constraints. With rapid development catalysis, many catalytic strategies concert exogenous have been exploited facilitate nonspontaneous enantioenrichment. In perspective, we will discuss basic ideas accomplish deracemization, categorized by three major sources including chemical (redox)-, photo- mechanical from attrition. Emphasis be given features underlying deracemization mechanism together perspectives on future development.

Язык: Английский

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Catalytic Photochemical Deracemization via Short‐Lived Intermediates

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(50)

Опубликована: Июль 10, 2023

Upon irradiation in the presence of a suitable chiral catalyst, racemic compound mixtures can be converted into enantiomerically pure compounds with same constitution. The process is called photochemical deracemization and involves formation short-lived intermediates. By opening different reaction channels for forward to intermediate re-constitution molecule, entropically disfavored becomes feasible. Since discovery first 2018, field has been growing rapidly. This review comprehensively covers research performed area discusses current developments. It subdivided according mode action respective substrate classes. focus this on scope individual reactions discussion mechanistic details underlying presented reaction.

Язык: Английский

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Deracemization of Atropisomeric Biaryls Enabled by Copper Catalysis

JACS Au, Год журнала: 2024, Номер 4(2), С. 502 - 511

Опубликована: Янв. 17, 2024

Atropisomeric biaryls have found crucial applications in versatile chiral catalysts as well ligands for transition metals. Herein, we developed an efficient crystallization-induced deracemization (CID) method to access from their racemates with a ammonium salt under copper catalysis including BINOL, NOBIN, and BINAM derivatives. After being significantly accelerated by its bidentate diamine ligand, the catalyst exhibits high efficiency selectivity racemizing biaryl skeletons, cocrystal complex would be enantioselectively formed together salt, which on acid-quenching directly deliver without further chromatographic purification. This CID process is easily scalable, was nicely recoverable. Ligand effect studies showed that bulky alkyl substitution indispensable element ensure racemization, probably proceeds via radical-cation intermediate allows axial rotation forming delocalized radical.

Язык: Английский

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Photoexcited Palladium-Catalyzed Deracemization of Allenes

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(30), С. 21137 - 21146

Опубликована: Июль 18, 2024

The different enantiomers of specific chiral molecules frequently exhibit disparate biological, physiological, or pharmacological properties. Therefore, the efficient synthesis single is particular importance not only to pharmaceutical sector but also other industrial sectors, such as agrochemical and fine chemical industries. Deracemization, a process during which racemic mixture converted into nonracemic product with 100% atom economy theoretical yield, most straightforward method access enantioenriched challenging task due decrease in entropy microscopic reversibility. Axially allenes bear distinctive structure two orthogonal cumulative π-systems are acknowledged synthetically versatile synthons organic synthesis. selective creation axially high optical purity under mild reaction conditions has always been very popular hot topic remains challenging. Herein, photoexcited palladium-catalyzed deracemization nonprefunctionalized disubstituted disclosed. This provides an economical strategy accommodate broad scope good enantioselectivities yields (53 examples, up 96% yield 95% ee). use suitable palladium complex visible light irradiation essential factor achieving this transformation. A metal-to-ligand charge transfer mechanism was proposed based on control experiments density functional theory calculations. Quantum mechanical studies implicate dual modes asymmetric induction behind our new protocol: (1) sterically controlled stereoselective binding one allene enantiomer ground-state (2) facile, noncovalent interaction-driven excited-state isomerization toward opposite enantiomer. success newly established photochemical should provide inspiration for expansion multisubstituted will open mode enantioselective catalysis.

Язык: Английский

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Enantioselective organocatalytic strategies to access noncanonical α-amino acids

Chemical Science, Год журнала: 2024, Номер 15(16), С. 5832 - 5868

Опубликована: Янв. 1, 2024

Organocatalytic asymmetric synthesis has evolved over the years and continues to attract interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, chemical biology. They employed elaboration peptides proteins with enhanced activities and/or improved properties compared their natural counterparts, as chiral catalysts, ligand design, for syntheses complex molecules, including products. The linkage ncAA enantioselective organocatalysis, subject this perspective, tries imitate biosynthetic process. Herein, we present contemporary earlier developments field organocatalytic activation simple feedstock materials, providing potential ncAAs diverse side chains, unique three-dimensional structures, a high degree functionality. These strategies, useful forging wide range C-C, C-H, C-N bonds combinations thereof, vary from classical name reactions, such Ugi, Strecker, Mannich most advanced concepts deracemisation, transamination, carbene N-H insertion. Concurrently, some interesting mechanistic studies/models, information on chirality transfer Finally, perspective highlights, through diversity (AAs) not selected by nature protein incorporation, generic modes activation, induction, reactivity commonly used, enamine, hydrogen bonding, Brønsted acids/bases, phase-transfer reflecting increasingly important role applied chemistry.

Язык: Английский

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Creating a Defined Chirality in Amino Acids and Cyclic Dipeptides by Photochemical Deracemization

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(47)

Опубликована: Окт. 4, 2023

Abstract 2,5‐Diketopiperazines are cyclic dipeptides displaying a wide range of applications. Their enantioselective preparation has now been found possible from the respective racemates by photochemical deracemization (53 examples, 74 % to quantitative yield, 71–99 ee ). A chiral benzophenone catalyst in concert with irradiation at λ=366 nm enables establish configuration stereogenic carbon atom C6 will. If other centers present diketopiperazines they remain unaffected and stereochemical editing is single position. Consecutive reactions, including conversion into N ‐aryl or ‐alkyl amino acids reduction piperazines, occur without compromising newly created center. Transient absorption spectroscopy revealed that processes one enantiomer 2,5‐diketopiperazines preferentially reversible hydrogen transfer responsible for process. The remarkably long lifetime protonated ketyl radical implies yet unprecedented mode action.

Язык: Английский

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Photochemical Deracemization of 3‐Substituted Oxindoles

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(30)

Опубликована: Май 22, 2023

Abstract Racemic 3‐substituted oxindoles were successfully converted into enantiomerically pure or enriched material (up to 99 % ee ) upon irradiation at λ =366 nm in the presence of a chiral benzophenone catalyst (10 mol %). The photochemical deracemization process allows predictable editing stereogenic center carbon atom C3. Light energy compensates for associated loss entropy and enables decoupling potentially reversible reactions, i.e. hydrogen transfer (photochemical) from (thermal) carbonyl group catalyst. major enantiomer is continuously several catalytic cycles. obtained shown be valuable intermediates further transformations, which proceeded with complete retention center.

Язык: Английский

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Electrocatalytic cyclic deracemization enabled by a chemically modified electrode

Nature Catalysis, Год журнала: 2024, Номер 7(8), С. 878 - 888

Опубликована: Июль 11, 2024

Язык: Английский

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