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1.
J Am Chem Soc ; 146(11): 7165-7172, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38451542

RESUMO

We report asymmetric potassium-isothiourea-boronate-catalyzed Wittig olefinations of 4-substituted cyclohexanones with non-stabilized phosphorus ylides to afford highly enantioenriched axially chiral alkenes. The optimal catalyst features an unusual macrocyclic amide-potassium-boronate chelate. Kinetic and spectroscopic analyses are consistent with a Lewis acid mechanism for the catalytic olefination that results in the formation of the oxaphosphetane adduct under cryogenic conditions. Thermal fragmentation of the oxaphosphetane to the alkene product occurs after the reaction is complete. Computational studies indicate that cycloaddition proceeds via a stepwise mechanism involving enantiodetermining polar 1,2-addition to afford an intermediate potassium betaine complex.

2.
J Am Chem Soc ; 145(28): 15036-15042, 2023 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-37428959

RESUMO

A catalytic protio-semipinacol ring-expansion reaction has been developed for the highly enantioselective conversion of tertiary vinylic cyclopropyl alcohols into cyclobutanone products bearing α-quaternary stereogenic centers. The method relies on the cocatalytic effect of a chiral dual-hydrogen-bond donor (HBD) with hydrogen chloride. Experimental evidence is provided for a stepwise mechanism where protonation of the alkene generates a short-lived, high-energy carbocation, which is followed by C-C bond migration to deliver the enantioenriched product. This research applies strong acid/chiral HBD cocatalysis to weakly basic olefinic substrates and lays the foundation for further investigations of enantioselective reactions involving high-energy cationic intermediates.

3.
Nature ; 616(7955): 84-89, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36787801

RESUMO

Asymmetric transition-metal catalysis represents a powerful strategy for accessing enantiomerically enriched molecules1-3. The classical strategy for inducing enantioselectivity with transition-metal catalysts relies on direct complexation of chiral ligands to produce a sterically constrained reactive metal site that allows formation of the major product enantiomer while effectively inhibiting the pathway to the minor enantiomer through steric repulsion4. The chiral-ligand strategy has proven applicable to a wide variety of highly enantioselective transition-metal-catalysed reactions, but important scenarios exist that impose limits to its successful adaptation. Here, we report a new approach for inducing enantioselectivity in transition-metal-catalysed reactions that relies on neutral hydrogen-bond donors (HBDs)5,6 that bind anions of cationic transition-metal complexes to achieve enantiocontrol and rate enhancement through ion pairing together with other non-covalent interactions7-9. A cooperative anion-binding effect of a chiral bis-thiourea HBD is demonstrated to lead to high enantioselectivity (up to 99% enantiomeric excess) in intramolecular ruthenium-catalysed propargylic substitution reactions10. Experimental and computational mechanistic studies show the attractive interactions between electron-deficient arene components of the HBD and the metal complex that underlie enantioinduction and the acceleration effect.

4.
Org Lett ; 24(48): 8826-8831, 2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36450043

RESUMO

Although solutions of hydrogen chloride in ethereal solvents like diethyl ether or dioxane are commonly employed in the laboratory, the solution structure of these reagents has yet to be firmly established. Here, we analyze solutions of ethereal hydrogen chloride or deuterium chloride in toluene, in dichloromethane, or in the absence of a co-solvent by in situ infrared spectroscopy. The resulting spectra are inconsistent with free HCl or often-proposed 1:1 HCl-ether complexes but closely match the predicted spectra of oxonium ions generated via protonation of diethyl ether. Molecular dynamics simulation of the oxonium chloride complexes provides evidence for an outer-sphere contact ion pair. These results suggest new approaches for tuning the acidity of strong Brønsted acids in organic solvents and demonstrate the importance of conducting spectroscopic measurements under reaction-relevant conditions.

5.
Nature ; 610(7933): 680-686, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36049504

RESUMO

Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals and natural products1-3. A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized4-8. We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized9. Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalytic reactions from the outset10,11. Multisubstrate screening is achieved by conducting high-throughput chiral analyses by supercritical fluid chromatography-mass spectrometry with pooled samples. When applied to Pictet-Spengler reactions, the multisubstrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation, which even displayed high enantioselectivity for substrate combinations outside of the screening set.


Assuntos
Produtos Biológicos , Técnicas de Química Sintética , Preparações Farmacêuticas , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Estereoisomerismo , Especificidade por Substrato , Cromatografia com Fluido Supercrítico , Espectrometria de Massas , Técnicas de Química Sintética/métodos
6.
J Am Chem Soc ; 144(34): 15812-15824, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-35994741

RESUMO

The mechanism of chiral hydrogen-bond donor (HBD) and hydrogen chloride (HCl) co-catalyzed Prins cyclizations was analyzed through a combination of experimental and computational methods and revealed to involve an unexpected and previously unrecognized mode of alkene activation. Kinetic and spectroscopic studies support the participation of a catalytically active HCl·HBD complex that displays reduced Brønsted acidity relative to HCl alone. Nevertheless, rate acceleration relative to the HCl-catalyzed background reaction as well as high levels of enantioselectivity are achieved. This inverse Brønsted correlation is ascribed to chloride-mediated substrate activation in the rate-limiting and enantiodetermining cyclization transition state. Density functional theory (DFT) calculations, distortion-interaction analysis, and quasiclassical dynamics simulations support a stepwise mechanism in which rate acceleration and enantioselectivity are achieved through the precise positioning of the chloride anion within the active site of the chiral thiourea to enhance the nucleophilicity of the alkene and provide transition-state stabilization through local electric field effects. This mode of selective catalysis through anion positioning likely has general implications for the design of enantioselective Brønsted acid-catalyzed reactions involving π-nucleophiles.


Assuntos
Alcenos , Tioureia , Alcenos/química , Ânions , Catálise , Cloretos , Ciclização , Halogênios , Ácido Clorídrico , Estereoisomerismo , Tioureia/química
7.
Science ; 376(6598): 1230-1236, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35679409

RESUMO

The stereoselective synthesis of molecules bearing stereogenic phosphorus(V) centers represents an enduring challenge in organic chemistry. Although stereospecific nucleophilic substitution at P(V) provides a general strategy for elaborating optically active P(V) compounds, existing methods for accessing the requisite chiral building blocks rely almost entirely on diastereocontrol using chiral auxiliaries. Catalytic, enantioselective methods for the synthesis of synthetically versatile stereogenic P(V) building blocks offer an alternative approach to stereogenic-at-P(V) targets without requiring stoichiometric quantities of chiral control elements. Here, we report an enantioselective hydrogen-bond-donor-catalyzed synthesis of aryl chlorophosphonamidates and the development of these products as versatile chiral P(V) building blocks. We demonstrate that the two leaving groups on these chlorophosphonamidates can be displaced sequentially and stereospecifically to access a wide variety of stereogenic-at-P(V) compounds featuring diverse substitution patterns.

8.
Nature ; 608(7921): 74-79, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35709829

RESUMO

The identification of general and efficient methods for the construction of oligosaccharides stands as one of the great challenges for the field of synthetic chemistry1,2. Selective glycosylation of unprotected sugars and other polyhydroxylated nucleophiles is a particularly significant goal, requiring not only control over the stereochemistry of the forming bond but also differentiation between similarly reactive nucleophilic sites in stereochemically complex contexts3,4. Chemists have generally relied on multi-step protecting-group strategies to achieve site control in glycosylations, but practical inefficiencies arise directly from the application of such approaches5-7. Here we describe a strategy for small-molecule-catalyst-controlled, highly stereo- and site-selective glycosylations of unprotected or minimally protected mono- and disaccharides using precisely designed bis-thiourea small-molecule catalysts. Stereo- and site-selective galactosylations and mannosylations of a wide assortment of polyfunctional nucleophiles is thereby achieved. Kinetic and computational studies provide evidence that site-selectivity arises from stabilizing C-H/π interactions between the catalyst and the nucleophile, analogous to those documented in sugar-binding proteins. This work demonstrates that highly selective glycosylation reactions can be achieved through control of stabilizing non-covalent interactions, a potentially general strategy for selective functionalization of carbohydrates.


Assuntos
Técnicas de Química Sintética , Glicosilação , Açúcares , Catálise , Dissacarídeos/síntese química , Dissacarídeos/química , Cinética , Monossacarídeos/síntese química , Monossacarídeos/química , Estereoisomerismo , Açúcares/síntese química , Açúcares/química
9.
ACS Catal ; 12(24): 14836-14845, 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36816226

RESUMO

Hydrogen bond-based organocatalysts rely on networks of attractive noncovalent interactions (NCIs) to impart enantioselectivity. As a specific example, aryl pyrrolidine substituted urea, thiourea, and squaramide organocatalysts function cooperatively through hydrogen bonding and difficult-to-predict NCIs as a function of the reaction partners. To uncover the synergistic effect of the structural components of this catalyst class, we applied data science tools to study various model reactions using a derivatized, aryl pyrrolidine-based, hydrogen-bond donor (HBD) catalyst library. Through a combination of experimentally collected data and data mined from previous reports, statistical models were constructed, illuminating the general features necessary for high enantioselectivity. A distinct dependence on the identity of the electrophilic reaction partner and HBD catalyst is observed, suggesting that a general interaction is conserved throughout the reactions analyzed. The resulting models also demonstrate predictive capability by the successful improvement of a previously reported reaction using out-of-sample reaction components. Overall, this study highlights the power of data science in exploring mechanistic hypotheses in asymmetric HBD catalysis and provides a prediction platform applicable in future reaction optimization.

10.
Science ; 374(6568): 752-757, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34735250

RESUMO

A strategy that facilitates the construction of a wide variety of trisubstituted stereocenters through a catalytically accessed common chiral intermediate could prove highly enabling for the field of synthetic chemistry. We report the discovery of enantioselective, catalytic 1,2-boronate rearrangements for the synthesis of α-chloro pinacol boronic esters from readily available boronic esters and dichloromethane. The chiral building blocks produced in these reactions can undergo two sequential stereospecific elaborations to generate a wide assortment of trisubstituted stereocenters. The enantioselective reaction is catalyzed by a lithium-isothiourea-boronate complex, which is proposed to promote rearrangement through a dual­lithium-induced chloride abstraction orchestrated by Lewis basic functionality on the catalyst scaffold.


Assuntos
Ácidos Borônicos/química , Técnicas de Química Sintética , Catálise , Ésteres/química , Lítio/química , Estrutura Molecular , Estereoisomerismo , Tioureia/química
11.
J Am Chem Soc ; 143(48): 20077-20083, 2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34812618

RESUMO

Cooperative asymmetric catalysis with hydrogen chloride (HCl) and chiral dual-hydrogen-bond donors (HBDs) is applied successfully to highly enantioselective Prins cyclization reactions of a wide variety of simple alkenyl aldehydes. The optimal chiral catalysts were designed to withstand the strongly acidic reaction conditions and were found to induce rate accelerations of 2 orders of magnitude over reactions catalyzed by HCl alone. We propose that the combination of strong mineral acids and chiral hydrogen-bond-donor catalysts may represent a general strategy for inducing enantioselectivity in reactions that require highly acidic conditions.


Assuntos
Álcoois/síntese química , Aldeídos/química , Alcenos/química , Ácido Clorídrico/química , Benzopiranos/síntese química , Catálise , Ciclização , Ligação de Hidrogênio , Quinina/análogos & derivados , Quinina/química , Estereoisomerismo , Tioureia/análogos & derivados , Ureia/análogos & derivados
12.
J Am Chem Soc ; 143(25): 9585-9594, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34152759

RESUMO

Generality in asymmetric catalysis can be manifested in dramatic and valuable ways, such as high enantioselectivity across a wide assortment of substrates in a given reaction (broad substrate scope) or as applicability of a given chiral framework across a variety of mechanistically distinct reactions (privileged catalysts). Reactions and catalysts that display such generality hold special utility, because they can be applied broadly and sometimes even predictably in new applications. Despite the great value of such systems, the factors that underlie generality are not well understood. Here, we report a detailed investigation of an asymmetric hydrogen-bond-donor catalyzed oxetane opening with TMSBr that is shown to possess unexpected mechanistic generality. Careful analysis of the role of adventitious protic impurities revealed the participation of competing pathways involving addition of either TMSBr or HBr in the enantiodetermining, ring-opening event. The optimal catalyst induces high enantioselectivity in both pathways, thereby achieving precise stereocontrol in fundamentally different mechanisms under the same conditions and with the same chiral framework. The basis for that generality is analyzed using a combination of experimental and computational methods, which indicate that proximally localized catalyst components cooperatively stabilize and precisely orient dipolar enantiodetermining transition states in both pathways. Generality across different mechanisms is rarely considered in catalyst discovery efforts, but we suggest that it may play a role in the identification of so-called privileged catalysts.


Assuntos
Éteres Cíclicos/química , Hidrocarbonetos Bromados/síntese química , Compostos de Trimetilsilil/síntese química , Catálise , Ligação de Hidrogênio , Ácidos de Lewis/química , Modelos Químicos , Estereoisomerismo , Compostos de Trimetilsilil/química
13.
J Am Chem Soc ; 143(19): 7272-7278, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33949857

RESUMO

We report a one-step catalytic, enantioselective method for the preparation of homoallylic N-Boc amines directly from acetals. Reactive iminium ion intermediates are generated in situ through the combination of an acetal, a chiral thiourea catalyst, trialkylsilyl triflate, and N-Boc carbamate and are subsequently trapped by a variety of allylsilane nucleophiles. No homoallylic ether byproducts are detected, consistent with allylation of the iminium intermediate being highly favored over allylation of the intermediate oxocarbenium ion. Acetals derived from aromatic aldehydes possessing a variety of functional groups and substitution patterns yield homoallylic amines with excellent levels of enantiomeric enrichment. Experimental and computational data are consistent with an anchoring hydrogen-bond interaction between the protioiminium ion and the amide of the catalyst in the enantiodetermining transition state, and with stereodifferentiation achieved through specific noncovalent interactions (NCIs) with the catalyst pyrenyl moiety. Evidence is provided that the key NCI in the major pathway is a π-stacking interaction, contrasting with the cation-π interactions invoked in previously studied reactions promoted by the same family of aryl-pyrrolidino-H-bond-donor catalysts.


Assuntos
Aminas/síntese química , Tioureia/química , Aminas/química , Catálise , Ligação de Hidrogênio , Estrutura Molecular , Estereoisomerismo
14.
Isr J Chem ; 60(3-4): 461-474, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33132416

RESUMO

Charge-accelerated rearrangements present interesting challenges to enantioselective catalysis, due in large part to the competing requirements for maximizing reactivity (ion-pair separation) and stereochemical communication. Herein, we describe application of a synergistic ion-binding strategy to catalyze the anionic oxy-Cope rearrangement of a symmetric bis-styrenyl allyl alcohol in up to 75:25 e.r. Structure-reactivity-selectivity relationship studies, including linear free-energy-relationship analyses, with bifunctional urea catalysts indicate that H-bonding and cation-binding interactions act cooperatively to promote the chemo- and enantioselective [3,3]-rearrangement. Implications for catalyst designs applicable to other transformations involving oxyanionic intermediates are discussed.

15.
Adv Synth Catal ; 362(19): 4092-4097, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33162875

RESUMO

We report an enantioselective Nazarov cyclization catalyzed by chiral hydrogen-bond-donors in concert with silyl Lewis acids. The developed transformation provides access to tri-substituted cyclopentenones in high levels of enantioselectivity (up to 95% e.e.) from a variety of simple unactivated dienones. Kinetic and mechanistic studies are consistent with a reversible 4π-electrocyclization C-C bond-forming step followed by rate- and enantio-determining proton-transfer as the mode of catalysis.

16.
J Am Chem Soc ; 142(37): 16090-16096, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32845619

RESUMO

We report a strategy for effecting catalytic, enantioselective carbocationic rearrangements through the intermediacy of alkyl iodanes as stereodefined carbocation equivalents. Asymmetric Wagner-Meerwein rearrangements of ß-substituted styrenes are catalyzed by the C2-symmetric aryl iodide 1 to provide access to enantioenriched 1,3-difluorinated molecules possessing interesting and well-defined conformational properties. Hammett and kinetic isotope effect studies, in combination with computational investigations, reveal that two different mechanisms are operative in these rearrangement reactions, with the pathway depending on the identity of the migrating group. In reactions involving alkyl-group migration, intermolecular fluoride attack is product- and enantio-determining. In contrast, reactions in which aryl rearrangement occurs proceed through an enantiodetermining intramolecular 1,2-migration prior to fluorination. The fact that both pathways are promoted by the same chiral aryl iodide catalyst with high enantioselectivity provides a compelling illustration of generality across reaction mechanisms in asymmetric catalysis.


Assuntos
Hidrocarbonetos Iodados/química , Estirenos/síntese química , Catálise , Estrutura Molecular , Estereoisomerismo , Estirenos/química
17.
J Am Chem Soc ; 142(35): 14831-14837, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32799536

RESUMO

We report an iodoarene-catalyzed enantioselective synthesis of ß,ß-difluoroalkyl bromide building blocks. The transformation involves an oxidative rearrangement of α-bromostyrenes, utilizing HF-pyridine as the fluoride source and m-CPBA as the stoichiometric oxidant. A catalyst decomposition pathway was identified, which, in tandem with catalyst structure-activity relationship studies, facilitated the development of an improved catalyst providing higher enantioselectivity with lower catalyst loadings. The versatility of the difluoroalkyl bromide products was demonstrated via highly enantiospecific substitution reactions with suitably reactive nucleophiles. The origins of enantioselectivity were investigated using computed interaction energies of simplified catalyst and substrate structures, providing evidence for both CH-π and π-π transition state interactions as critical features.


Assuntos
Hidrocarbonetos Bromados/síntese química , Hidrocarbonetos Iodados/química , Catálise , Halogenação , Hidrocarbonetos Bromados/química , Estrutura Molecular , Estereoisomerismo
18.
J Am Chem Soc ; 142(27): 11865-11872, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32527078

RESUMO

We report highly ß-selective bis-thioureas-catalyzed 1,2-cis-O-pyranosylations employing easily accessible acetonide-protected donors. A wide variety of alcohol nucleophiles, including complex natural products, glycosides, and amino acids were ß-mannosylated and ß-rhamnosylated successfully using an operationally simple protocol under mild and neutral conditions. Less nucleophilic acceptors such as phenols were also glycosylated efficiently in excellent yields and with high ß-selectivities.


Assuntos
Aminoácidos/síntese química , Produtos Biológicos/síntese química , Glicosídeos/síntese química , Fenóis/síntese química , Tioureia/química , Aminoácidos/química , Produtos Biológicos/química , Catálise , Teoria da Densidade Funcional , Glicosídeos/química , Conformação Molecular , Fenóis/química
19.
J Am Chem Soc ; 142(20): 9175-9180, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32364378

RESUMO

A precisely designed chiral squaramide derivative is shown to promote the highly enantioselective addition of trimethylsilyl bromide (TMSBr) to a broad variety of 3-substituted and 3,3-disubstituted oxetanes. The reaction provides direct and general access to synthetically valuable 1,3-bromohydrin building blocks from easily accessed achiral precursors. The products are readily elaborated both by nucleophilic substitution and through transition-metal-catalyzed cross-coupling reactions. The enantioselective catalytic oxetane ring opening was employed as part of a three-step, gram-scale synthesis of pretomanid, a recently approved medication for the treatment of multidrug-resistant tuberculosis. Heavy-atom kinetic isotope effect (KIE) studies are consistent with enantiodetermining delivery of bromide from the H-bond-donor (HBD) catalyst to the activated oxetane. While the nucleophilicity of the bromide ion is expected to be attenuated by association to the HBD, overall rate acceleration is achieved by enhancement of Lewis acidity of the TMSBr reagent through anion abstraction.


Assuntos
Éteres Cíclicos/química , Quinina/análogos & derivados , Catálise , Ligação de Hidrogênio , Estrutura Molecular , Quinina/química , Estereoisomerismo
20.
J Am Chem Soc ; 142(15): 6951-6956, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32223127

RESUMO

Chiral urea derivatives are shown to catalyze enantioselective tail-to-head cyclization reactions of neryl chloride analogues. Experimental data are consistent with a mechanism in which π-participation by the nucleophilic olefin facilitates chloride ionization and thereby circumvents simple elimination pathways. Kinetic and computational studies support a cooperative mode of catalysis wherein two molecules of the urea catalyst engage the substrate and induce enantioselectivity through selective transition state stabilization.


Assuntos
Ligação de Hidrogênio , Catálise , Ciclização , Humanos , Estrutura Molecular , Estereoisomerismo
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