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Herein, we report a nine-step synthesis of belzutifan enabled by a novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, the final ketone reduction in the synthesis proceeds with high diastereoselectivity, leading to the expedient assembly of the stereotriad. In contrast to the original 16-step synthesis, this route avoids a lengthy bromination-oxidation sequence and introduces the sulfone functionality via nucleophilic aromatic substitution, obviating the need for transition metal catalysis.
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P(v) iminophosphorane compounds are accessed via electrochemical oxidation of commercially available P(iii) phosphines, including mono-, di- and tri-dentate phosphines, as well as chiral phosphines. The reaction uses inexpensive bis(trimethylsilyl)carbodiimide as an efficient and safe aminating reagent. DFT calculations, cyclic voltammetry, and NMR studies provide insight into the reaction mechanism. The proposed mechanism reveals a special case of sequential paired electrolysis. DFT calculations of the frontier orbitals of an iminophosphorane are compared with those of the analogous phosphines and phosphine oxides. X-ray crystallographic studies of the ligands as well as a Ni-coordination complex provide structural insight for these ligands. The utility of these iminophosphoranes as ligands is demonstrated in nickel-catalyzed cross-electrophile couplings including C(sp2)-C(sp3) and C(sp2)-C(sp2) couplings, an electrochemically driven C-N cross-coupling, and a photochemical arylative C(sp3)-H functionalization. In some cases, these new ligands provide improved performance over commonly used sp2-N-based ligands (e.g. 4,4'-di-tert-butyl-2,2'-bipyridine).
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Memory formation and forgetting unnecessary memory must be balanced for adaptive animal behavior. While cyclic AMP (cAMP) signaling via dopamine neurons induces memory formation, here we report that cyclic guanine monophosphate (cGMP) signaling via dopamine neurons launches forgetting of unconsolidated memory in Drosophila. Genetic screening and proteomic analyses showed that neural activation induces the complex formation of a histone H3K9 demethylase, Kdm4B, and a GMP synthetase, Bur, which is necessary and sufficient for forgetting unconsolidated memory. Kdm4B/Bur is activated by phosphorylation through NO-dependent cGMP signaling via dopamine neurons, inducing gene expression, including kek2 encoding a presynaptic protein. Accordingly, Kdm4B/Bur activation induced presynaptic changes. Our data demonstrate a link between cGMP signaling and synapses via gene expression in forgetting, suggesting that the opposing functions of memory are orchestrated by distinct signaling via dopamine neurons, which affects synaptic integrity and thus balances animal behavior.
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Neuronas Dopaminérgicas , Proteómica , Animales , Sistemas de Mensajero Secundario , Transducción de Señal , Memoria , Drosophila , Guanina , Histona DemetilasasRESUMEN
Density functional theory (DFT) benchmark studies of 1H and 13C NMR chemical shifts often yield differing conclusions, likely due to non-optimal test molecules and non-standardized data acquisition. To address this issue, we carefully selected and measured 1H and 13C NMR chemical shifts for 50 structurally diverse small organic molecules containing atoms from only the first two rows of the periodic table. Our NMR dataset, DELTA50, was used to calculate linear scaling factors and to evaluate the accuracy of 73 density functionals, 40 basis sets, 3 solvent models, and 3 gauge-referencing schemes. The best performing DFT methodologies for 1H and 13C NMR chemical shift predictions were WP04/6-311++G(2d,p) and ωB97X-D/def2-SVP, respectively, when combined with the polarizable continuum solvent model (PCM) and gauge-independent atomic orbital (GIAO) method. Geometries should be optimized at the B3LYP-D3/6-311G(d,p) level including the PCM solvent model for the best accuracy. Predictions of 20 organic compounds and natural products from a separate probe set had root-mean-square deviations (RMSD) of 0.07 to 0.19 for 1H and 0.5 to 2.9 for 13C. Maximum deviations were less than 0.5 and 6.5 ppm for 1H and 13C, respectively.
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An electrochemical, nickel-catalyzed reductive coupling of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization and evaluation of a broad scope of pharmaceutically relevant structurally diverse aryl halides, including complex drug-like substrates. In addition, the transformation is compatible with both primary and secondary alkylpyridinium salts with distinct conditions. Mechanistic insights were critical to enhance the efficiency of coupling using secondary alkylpyridinium salts. Systematic comparisons of the electrochemical and non-electrochemical methods revealed the complementary scope and efficiency of the two approaches.
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Synthesis of drug metabolites, which often have complex structures, is an integral step in the evaluation of drug candidate metabolism, pharmacokinetic (PK) properties, and safety profiles. Frequently, such synthetic endeavors entail arduous, multiple-step de novo synthetic routes. Herein, we present the one-step Shono-type electrochemical synthesis of milligrams of chiral α-hydroxyl amide metabolites of two orexin receptor antagonists, MK-8133 and MK-6096, as revealed by a small-scale (pico- to nano-mole level) reaction screening using a lab-built online electrochemistry (EC)/mass spectrometry (MS) (EC/MS) platform. The electrochemical oxidation of MK-8133 and MK-6096 was conducted in aqueous media and found to produce the corresponding α-piperidinols with exclusive regio- and stereoselectivity, as confirmed by high-resolution nuclear magnetic resonance (NMR) characterization of products. Based on density functional theory (DFT) calculations, the exceptional regio- and stereoselectivity for this electrochemical oxidation are governed by more favorable energetics of the transition state, leading to the preferred secondary carbon radical α to the amide group and subsequent steric hindrance associated with the U-shaped conformation of the cation derived from the secondary α-carbon radical, respectively.
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Amidas , Antagonistas de los Receptores de Orexina , Oxidación-Reducción , Carbono , Estrés OxidativoRESUMEN
A general and diastereoselective fluorination/glycosylation strategy for the synthesis of 2'-fluorinated nucleosides has been developed. Electrophilic fluorination of a glycal with NFSI provided the 1',2'-difunctionalized furanoside intermediate with high diastereoselectivity. The TBS-protected 2'-deoxyfluorosulfonimide sugar was prepared on an 80 g scale and isolated as a crystalline, bench-stable single diastereomer. This intermediate was found to undergo a subsequent glycosylation reaction with a variety of heteroaryl nucleophiles with generally good diastereoselectivities.
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Halogenación , Nucleósidos , Glicosilación , EstereoisomerismoRESUMEN
Employment of a combination of an organophotoredox catalyst with Wilkinson's catalyst (Rh(PPh3)3Cl) has given rise to an unprecedented method for hydrogen-isotope exchange (HIE) of aliphatic C(sp3)-H bonds of complex pharmaceuticals using T2 gas directly. Wilkinson's catalyst, commonly used for catalytic hydrogenations, was exploited as a precatalyst for activation of D2 or T2 and hydrogen atom transfer. In this combined methodology and mechanistic study, we demonstrate that by coupling photocatalysis with Rh catalysis, carbon-centered radicals generated via photoredox catalysis can be intercepted by Rh-hydride intermediates to deliver an effective hydrogen atom donor for hydrogen-isotope labeling of complex molecules in one step. By optimizing the ratio of the photocatalyst and Wilkinson's catalyst to balance the rate of the dual catalytic cycles, we can achieve efficient HIE and high recovery yield. This protocol was readily applied to direct HIE of C(sp3)-H bonds in 10 complex drug molecules, showing high isotope incorporation efficiency and exceptionally good functional group tolerance and demonstrating this approach as a practical and attractive labeling method for deuteration and tritiation.
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Carbono , Hidrógeno , Carbono/química , Catálisis , Hidrógeno/química , Hidrogenación , Tritio/químicaRESUMEN
An effective strategy has been developed for the photoredox-catalyzed decarboxylative addition of cyclic amino acids to both vinylogous amides and esters leading to uniquely substituted heterocycles. The additions take place exclusively trans to the substituent present on the dihydropyridone ring affording stereochemical control about the new carbon-carbon bond. These reactions are operationally simplistic and afford the desired products in good to excellent isolated yields.
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Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light-mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars.
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A class of organocatalysts that are highly active for the conversion of 2'-deoxynucleosides to furanoid glycals have been discovered. These phosphorimides, (Ph2PS)2NH and (Ph2PSe)2NH, were shown to effectively mediate persilylation of 2'-deoxynucleosides allowing the elimination of the nucleobase giving the corresponding glycal. These mild conditions were demonstrated in the syntheses of glycals with various substitution patterns while minimizing the formation of undesired byproducts and expanding the scope of this methodology.
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NucleósidosRESUMEN
A facile one-pot strategy for 13CN and 14CN exchange with aryl, heteroaryl, and alkenyl nitriles using a Ni phosphine catalyst and BPh3 is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)2 to facilitate enrichment using the nonlabeled parent compound as the starting material, eliminating de novo synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [14C] belzutifan to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh3 is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of 14C labeled tracers for clinical development.
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In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to access tetrahydrofuro[3,4-b]furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an alkenol derived from d-glucofuranose diacetonide was capable of furnishing the B-ring and installing the desired heteroaryl group in a single step. Using this approach, key intermediate 1.3-A was delivered on a gram scale in a 62% yield and 9.1:1 dr in favor of the desired S-isomer. After deprotection of 1.3-A, a late-stage glycosylation was performed under Mitsunobu conditions to install the pyrrolopyrimidine base. This provided serviceable yields of nucleoside analogues in the range of 31-48% yield. Compound 1.1-C was profiled in biochemical and cellular assays and was demonstrated to be a potent and cellularly active PRMT5 inhibitor, with a PRMT5-MEP50 biochemical IC50 of 0.8 nM, a MCF-7 target engagement EC50 of 3 nM, and a Z138 cell proliferation EC50 of 15 nM. This work sets the stage for the development of new inhibitors of PRMT5 and novel nucleoside chemical matter for alternate drug discovery programs.
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Nucleósidos , Proteína-Arginina N-Metiltransferasas , Proliferación Celular , Inhibidores Enzimáticos , FuranosRESUMEN
An efficient synthesis of nucleoside 5'-monothiophosphates under mild reaction conditions using commercially available thiophosphoryl chloride was achieved with a cinchona alkaloid catalyst. A detailed mechanistic study of the reaction was undertaken, employing a combination of reaction kinetics, NMR spectroscopy, and computational modeling, to better understand the observed reactivity. Taken collectively, the results support an unprecedented mechanism for this class of organocatalyst.
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The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism. We applied both light and heat activation in a synergistic fashion, achieving gram-scale bridged aza-cycle synthesis.
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The introduction of a trifluoromethyl (CF3) group can dramatically improve a compound's biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C-H bonds remain elusive. Here we report the development of a dual-catalytic C(sp3)-H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C-H bonds into the corresponding C(sp3)-CF3 products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a 'Cu-CF3' species is formed during this process and the critical C(sp3)-CF3 bond-forming step involves the copper catalyst.
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Complejos de Coordinación/química , Cobre/química , Hidrocarburos Fluorados/química , Aminas/química , Productos Biológicos/química , Catálisis , Hidrógeno/química , Metilación , Estructura Molecular , Oxidación-Reducción , Procesos FotoquímicosRESUMEN
The mechanism of the aza-Diels-Alder reaction catalyzed by tetraalkylammonium or trialkylsulfonium salts is explored with density functional theory. Favorable electrostatic interactions between the dienophile and the charged catalyst stabilize the highly polar transition state, leading to lower free energy barriers and higher dipole moments. Endo selectivity is predicted for both uncatalyzed and catalyzed systems. We also computationally evaluate the effects of oriented external electric fields (EEFs) on the same aza-Diels-Alder reaction, demonstrating that very strong EEFs would be needed to achieve the catalytic strength of these cationic catalysts.
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Primary amines are an important structural motif in active pharmaceutical ingredients (APIs) and intermediates thereof, as well as members of ligand libraries for either biological or catalytic applications. Many chemical methodologies exist for amine synthesis, but the direct synthesis of primary amines with a fully substituted α carbon center is an underdeveloped area. We report a method which utilizes photoredox catalysis to couple readily available O-benzoyl oximes with cyanoarenes to synthesize primary amines with fully substituted α-carbons. We also demonstrate that this method enables the synthesis of amines with α-trifluoromethyl functionality. Based on experimental and computational results, we propose a mechanism where the photocatalyst engages in concurrent tandem catalysis by reacting with the oxime as a triplet sensitizer in the first catalytic cycle and a reductant toward the cyanoarene in the second catalytic cycle to achieve the synthesis of hindered primary amines via heterocoupling of radicals from readily available oximes.
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Selectivities in (4 + 2) and (2 + 2) cycloadditions of keteniminium cations with 1,3-dienes studied experimentally by Ghosez et al. were explored with ωB97X-D density functional theory. Reactions of keteniminium cations with 1,3-dienes are influenced by the s-cis or s-trans nature of the diene. s-Trans dienes react to give an intermediate enamine that leads to favored formation of (2 + 2) cycloadducts across the keteniminium C-C bond. The first step of the cycloaddition is rate-determining, and reaction occurs by attack on the central carbon of the keteniminium cation and subsequent C-C bond formation. In contrast, s-cis constrained dienes lead to preferential formation of (4 + 2) products by both stepwise and concerted mechanisms involving regioselective addition to the keteniminium C-N bond. Diels-Alder reaction occurs via a concerted mechanism if the diene termini are held in close proximity, as in cyclopentadiene.
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Polienos , Cationes , Reacción de Cicloadición , Conformación Molecular , EstereoisomerismoRESUMEN
Structural features of proton-deficient heteroaromatic natural products, such as the breitfussins, can severely complicate their characterization by NMR spectroscopy. For the breitfussins in particular, the constitution of the five-membered oxazole central ring cannot be unequivocally established via conventional NMR methods when the 4'-position is halogenated. The level of difficulty is exacerbated by 4'-iodination, as the accuracy with which theoretical NMR parameters are determined relies extensively on computational treatment of the relativistic effects of the iodine atom. It is demonstrated in the present study, that the structure of a 4'-iodo breitfussin analog can be unequivocally established by anisotropic NMR methods, by adopting a reduced singular value decomposition (SVD) protocol that leverages the planar structures exhibited by its conformers.