RESUMEN
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.
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Productos Biológicos , Técnicas de Química Sintética , Preparaciones Farmacéuticas , Productos Biológicos/síntesis química , Productos Biológicos/química , Catálisis , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Estereoisomerismo , Especificidad por Sustrato , Cromatografía con Fluido Supercrítico , Espectrometría de Masas , Técnicas de Química Sintética/métodosRESUMEN
The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon-nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)-discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N-alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon-nitrogen bridge, and a reductive N,O-acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)-discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen-bridged discorhabdin and paves the way for future biological evaluation of such compounds.
RESUMEN
Understanding the mechanism of small molecules is a critical challenge in chemical biology and drug discovery. Medicinal chemistry is essential for elucidating drug mechanism, enabling variation of small molecule structure to gain structure-activity relationships (SARs). However, the development of complementary approaches that systematically vary target protein structure could provide equally informative SARs for investigating drug mechanism and protein function. Here we explore the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML). Through this approach, termed CRISPR-suppressor scanning, we elucidate drug mechanism of action by showing that LSD1 enzyme activity is not required for AML survival and that LSD1 inhibitors instead function by disrupting interactions between LSD1 and the transcription factor GFI1B on chromatin. Our studies clarify how LSD1 inhibitors mechanistically operate in AML and demonstrate how CRISPR-suppressor scanning can uncover novel aspects of target biology.
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Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Modelos Moleculares , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
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.
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Hidrocarburos Yodados/química , Estirenos/síntesis química , Catálisis , Estructura Molecular , Estereoisomerismo , Estirenos/químicaRESUMEN
Here we demonstrate that highly ß-selective glycosylation reactions can be achieved when the electronics of a sulfonyl chloride activator and the reactivity of a glycosyl donor hemiacetal are matched. While these reactions are compatible with the acid- and base-sensitive protecting groups that are commonly used in oligosaccharide synthesis, these protecting groups are not relied upon to control selectivity. Instead, ß-selectivity arises from the stereoinversion of an α-glycosyl arylsulfonate in an SN2-like mechanism. Our mechanistic proposal is supported by NMR studies, kinetic isotope effect (KIE) measurements, and DFT calculations.
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Ácidos Sulfónicos/química , Teoría Funcional de la Densidad , Glicosilación , Cinética , Modelos Moleculares , Conformación MolecularRESUMEN
Redox flow batteries based on quinone-bearing aqueous electrolytes have emerged as promising systems for energy storage from intermittent renewable sources. The lifetime of these batteries is limited by quinone stability. Here, we confirm that 2,6-dihydroxyanthrahydroquinone tends to form an anthrone intermediate that is vulnerable to subsequent irreversible dimerization. We demonstrate quantitatively that this decomposition pathway is responsible for the loss of battery capacity. Computational studies indicate that the driving force for anthrone formation is greater for anthraquinones with lower reduction potentials. We show that the decomposition can be substantially mitigated. We demonstrate that conditions minimizing anthrone formation and avoiding anthrone dimerization slow the capacity loss rate by over an order of magnitude. We anticipate that this mitigation strategy readily extends to other anthraquinone-based flow batteries and is thus an important step toward realizing renewable electricity storage through long-lived organic flow batteries.
RESUMEN
Polarization transfer is demonstrated as a sensitive technique for the measurement of isotopic fractionation of protonated carbons at natural abundance. This method allows kinetic isotope effects (KIEs) to be determined with substantially less material or shorter acquisition time compared with traditional experiments. Computations quantitatively reproduce the KIEs in a Diels-Alder reaction and a catalytic glycosylation. The glycosylation is shown to occur by an effectively concerted mechanism.
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Isótopos de Carbono , Reacción de Cicloadición , Glicosilación , Cinética , Teoría CuánticaRESUMEN
Stereochemical editing strategies have recently enabled the transformation of readily accessible substrates into rare and valuable products. Typically, site selectivity is achieved by minimizing kinetic complexity by using protecting groups to suppress reactivity at undesired sites (substrate control) or by using catalysts with tailored shapes to drive reactivity at the desired site (catalyst control). We propose "network control," a contrasting paradigm that exploits hidden interactions between rate constants to greatly amplify modest intrinsic biases and enable precise multisite editing. When network control is applied to the photochemical isomerization of hexoses, six of the eight possible diastereomers can be selectively obtained. The amplification effect can be viewed as a mesoscale phenomenon between the limiting regimes of kinetic control in simple chemical systems and metabolic regulation in complex biological systems.
RESUMEN
Autonomous process optimization (APO) is a technology that has recently found utility in a multitude of process optimization challenges. In contrast to most APO examples in microflow reactor systems, we recently presented a system capable of optimization in high-throughput batch reactor systems. The drawback of APO in a high-throughput batch reactor system is the reliance on reaction sampling at a predetermined static timepoint rather than a dynamic endpoint. Static timepoint sampling can lead to the inconsistent capture of the process performance under each process parameter permutation. This is important because critical process behaviors such as rate acceleration accompanied by decomposition could be missed entirely. To address this drawback, we implemented a dynamic reaction endpoint determination strategy to capture the product purity once the process stream stabilized. We accomplished this through the incorporation of a real-time plateau detection algorithm into the APO workflow to measure and report the product purity at the dynamically determined reaction endpoint. We then applied this strategy to the autonomous optimization of a photobromination reaction towards the synthesis of a pharmaceutically relevant intermediate. In doing so, we not only uncovered process conditions to access the desired monohalogenation product in 85 UPLC area % purity with minimal decomposition risk, but also measured the effect of each parameter on the process performance. Our results highlight the advantage of incorporating dynamic sampling in APO workflows to drive optimization toward a stable and high-performing process.
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We present a general model for understanding the stereochemical course of intramolecular Michael reactions. We show that the addition of ß-ketoester enolates to α,ß-unsaturated esters and imides bearing adjacent stereocenters (X, Y = H, Me, OR) leads to high levels of asymmetric induction. Reinforcing and nonreinforcing stereochemical relationships are evaluated from the syn and anti reactant diastereomers. On the basis of synthetic, spectroscopic, and computational studies, we propose that the outcomes of these reactions can be rationalized by a dipole-minimized chair transition-state model.
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Ácidos Carboxílicos/química , Imidas/química , Ésteres , Estructura Molecular , EstereoisomerismoRESUMEN
A full account of our total synthesis of the galbulimima alkaloids GB 13 and himgaline is provided. Using a strategy adapted from the proposed biosynthesis of the GB alkaloid family, a linear precursor underwent successive intramolecular Diels-Alder, Michael, and imine aldol cyclizations to form the polycyclic alkaloid core. We now show that modification of this strategy can also deliver an advanced intermediate en route to the related alkaloid himandridine. The success of the key imine aldol cyclization is acutely sensitive to substrate structure and solvent, including a case in which cyclization was spontaneous in protic solvents. A detailed computational investigation of the course of the reaction closely correlates with, and suggests a rationale for, the observed patterns of imine aldol reactivity.
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Alcaloides/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos/síntesis química , Iminas/química , Alcaloides/química , Técnicas de Química Sintética , Ciclización , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Modelos Moleculares , Conformación Molecular , Especificidad por Sustrato , TemperaturaRESUMEN
An unusual intramolecular kinetic isotope effect (KIE) in the reaction of dichloroketene with cis-2-butene does not fit with a simple asynchronous cycloaddition transition state, but it can be predicted from trajectory studies on a bifurcating energy surface. The origin of the KIE is related to a high propensity for transition state recrossing in this system, with heavier masses recrossing less. The KIE can also be predicted by a statistical model that treats the cycloaddition as a stepwise mechanism, the rate-limiting second step being associated with an entropic barrier for formation of the second carbon-carbon bond. The relevance of this stepwise mechanism to other asynchronous but seemingly concerted cycloadditions is suggested by examination of organocatalytic Diels-Alder reactions.
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Alquenos/química , Dicloroetilenos/química , Entropía , Cetonas/síntesis química , Isótopos de Carbono/química , Ciclización , Cetonas/química , Cinética , Estructura Molecular , Teoría CuánticaRESUMEN
Cancer drivers require statistical modeling to distinguish them from passenger events, which accumulate during tumorigenesis but provide no fitness advantage to cancer cells. The discovery of driver genes and mutations relies on the assumption that exact positional recurrence is unlikely by chance; thus, the precise sharing of mutations across patients identifies drivers. Examining the mutation landscape in cancer genomes, we found that many recurrent cancer mutations previously designated as drivers are likely passengers. Our integrated bioinformatic and biochemical analyses revealed that these passenger hotspot mutations arise from the preference of APOBEC3A, a cytidine deaminase, for DNA stem-loops. Conversely, recurrent APOBEC-signature mutations not in stem-loops are enriched in well-characterized driver genes and may predict new drivers. This demonstrates that mesoscale genomic features need to be integrated into computational models aimed at identifying mutations linked to diseases.
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Transformación Celular Neoplásica/genética , Citidina Desaminasa/genética , Neoplasias/genética , Proteínas/genética , Biología Computacional , Genómica , Células HEK293 , Humanos , MutaciónRESUMEN
Nucleophilic aromatic substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chemical research, providing a broadly useful platform for the modification of aromatic ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addition-elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C-F bonds.
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Derivados del Benceno/química , Carbono/química , Isótopos de Carbono/química , Flúor/química , Marcaje Isotópico , Cinética , Espectroscopía de Resonancia MagnéticaRESUMEN
Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners; thus, carbohydrate synthesis is not easily predictable. Here we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of trans-1,2-, cis-1,2-, and 2-deoxy-ß-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.
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Glicósidos/síntesis química , Tiourea/análogos & derivados , Catálisis , Glicosilación , EstereoisomerismoRESUMEN
Synthesis of non-activated electron-rich and sterically hindered 18F-arenes remains a major challenge due to limitations of existing radiofluorination methodologies. Herein, we report on our mechanistic investigations of spirocyclic iodonium(III) ylide precursors for arene radiofluorination, including their reactivity, selectivity, and stability with no-carrier-added [18F]fluoride. Benchmark calculations at the G2[ECP] level indicate that pseudorotation and reductive elimination at iodine(III) can be modeled well by appropriately selected dispersion-corrected density functional methods. Modeling of the reaction pathways show that fluoride-iodonium(III) adduct intermediates are strongly activated and highly regioselective for reductive elimination of the desired [18F]fluoroarenes (difference in barriers, ΔΔG > 25 kcal·mol-1). The advantage of spirocyclic auxiliaries is further supported by NMR spectroscopy studies, which bolster evidence for underlying decomposition processes which can be overcome for radiofluorination of iodonium(III) precursors. Using a novel adamantyl auxiliary, sterically hindered iodonium ylides have been developed to enable highly efficient radiofluorination of electron-rich arenes, including fragments of pharmaceutically relevant nitrogen-containing heterocycles and tertiary amines. Furthermore, this methodology has been applied for the syntheses of the radiopharmaceuticals 6-[18F]fluoro-meta-tyrosine ([18F]FMT, 11 ± 1% isolated radiochemical yield, non-decay-corrected (RCY, n.d.c.; n = 3), and meta-[18F]fluorobenzylguanidine ([18F]mFBG, 14 ± 1% isolated RCY, n.d.c., n = 3) which cannot be directly radiolabeled using conventional nucleophilic aromatic substitution with [18F]fluoride.
RESUMEN
NMR spectroscopy is a crucial tool in organic chemistry for the routine characterization of small molecules, structural elucidation of natural products, and study of reaction mechanisms. Although there is evidence that thermal motions strongly affect observed resonances, conventional predictions are performed only on stationary structures. Here we show that quasiclassical molecular dynamics provides a highly accurate and broadly applicable method for improving shielding predictions. Gas-phase values of the absolute shieldings of protons and carbons are predicted to nearly within experimental uncertainty, while the chemical shifts of large systems such as natural products are closely reproduced. Importantly, these results are obtained without the use of any empirical corrections. Our analysis suggests that the linear scaling factors currently employed are primarily a correction for vibrational effects. As a result, our method extends the reach of prediction methods to the study of molecules with unusual dynamics such as the iconic and controversial [18]annulene. Our predictions agree closely with experiment at both low and high temperatures and provide strong evidence that the equilibrium structure of [18]annulene is planar and aromatic.
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Computational studies have suggested that η(3)-lithium enolates in which the cation is partially bound to both carbon and oxygen may be important reactive intermediates. DFT calculations are used to demonstrate that explicitly solvated acetone enolates are largely O-bound. With this premise in mind, the stereochemical course of intermolecular Michael additions is examined. The results are generally consistent with what is observed experimentally and the model advanced by Heathcock and co-workers.