Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity.

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1-4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5-7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.

Pharmacological inhibition of PI5P4Kα/ß disrupts cell energy metabolism and selectively kills p53-null tumor cells.

Most human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase α and ß (PI5P4Kα and PI5P4Kß) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4Kα/ß kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4Kαß inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer drugs.

Synthesis of N-Acylsulfenamides from (Hetero)Aryl Iodides and Boronic Acids by One-Pot Sulfur-Arylation and Dealkylation.

A general one-pot approach to diverse N-acylsulfenamides from a common S-phenethylsulfenamide starting material is reported. This approach was demonstrated by C-S bond formation utilizing commercially abundant (hetero)aryl iodides and boronic acids to provide sulfilimine intermediates that undergo thermal elimination of styrene. In contrast, all prior approaches to N-acylsulfenamides rely on thiol inputs to introduce sulfenamide S-substituents. A broad scope of reaction inputs was demonstrated including for approved drugs and drug precursors with dense display of functionality. Several different types of sulfur functionalization were performed on a sulfenamide derived from a complex precursor of the blockbuster anticoagulant drug apixaban, highlighting the utility of this approach for the introduction of high oxidation state sulfur groups in complex bioactive compounds. Mechanistic studies established that the key styrene elimination step proceeds by a concerted elimination that does not require reagents or catalysts, and therefore, this one-pot approach should be applicable to the synthesis of N-acylsulfenamides utilizing diverse electrophiles and reaction conditions for C-S bond formation.

Preparation of Sulfilimines by Sulfur-Alkylation of N-Acyl Sulfenamides with Alkyl Halides.

Sulfur alkylation of N-acyl sulfenamides with alkyl halides provides sulfilimines in 47% to 98% yields. A broad scope was established with a variety of aryl and alkyl sulfenamides, including for different N-acyl groups. Alkyl halides with different steric and electronic properties were effective inputs, including methyl, primary, secondary, benzyl, and propargyl halides. A proof-of-concept asymmetric phase-transfer alkylation was also demonstrated. A sulfilimine product was readily converted to an N-acyl and to a free sulfoximine, which represent important motifs in medicinal chemistry.

C-H bond activation and sequential addition to two different coupling partners: a versatile approach to molecular complexity.

Sequential multicomponent C-H bond addition is a powerful approach for the rapid, modular generation of molecular complexity in a single reaction. In this approach, C-H bonds are typically added across π-bonds or π-bond isosteres, followed by subsequent coupling to another type of functionality, thereby forming two σ-bonds in a single reaction sequence. Many sequential C-H bond addition reactions have been developed to date, including additions across both conjugated and isolated π-systems followed by coupling with reactants such as carbonyl compounds, cyanating reagents, aminating reagents, halogenating reagents, oxygenating reagents, and alkylating reagents. These atom-economical reactions transform ubiquitous C-H bonds under mild conditions to more complex structures with a high level of regiochemical and stereochemical control. Surprising connectivities and diverse mechanisms have been elucidated in the development of these reactions. Given the large number of possible combinations of coupling partners, there are enormous opportunities for the discovery of new sequential C-H bond addition reactions.

Imine Directed Cp*RhIII -Catalyzed N-H Functionalization and Annulation with Amino Amides, Aldehydes, and Diazo Compounds.

A multicomponent annulation that proceeds by imine directed Cp*RhIII -catalyzed N-H functionalization is disclosed. The transformation affords piperazinones displaying a range of functionality and is the first example of transition metal-catalyzed multicomponent N-H functionalization. A broad range of readily available α-amino amides, including those derived from glycine, α-substituted, and α,α-disubstituted amino acids, were effective inputs and enabled the incorporation of a variety of amino acid side chains with minimal racemization. Branched and unbranched alkyl aldehydes and various stabilized diazo compounds were also efficient reactants. The piperazinone products were further modified through efficient transformations. Mechanistic studies, including X-ray crystallographic characterization of a catalytically competent five-membered rhodacycle with imine and amide nitrogen chelation, provide support for the proposed mechanism.

Catalytic Enantioselective Sulfur Alkylation of Sulfenamides for the Asymmetric Synthesis of Sulfoximines.

Sulfoximines are increasingly incorporated in agrochemicals and pharmaceuticals, with the two enantiomers of chiral sulfoximines often having profoundly different binding interactions with biomolecules. Therefore, their application to drug discovery and development requires the challenging preparation of single enantiomers rather than racemic mixtures. Here, we report a general and fundamentally new asymmetric synthesis of sulfoximines. The first S-alkylation of sulfenamides, which are readily accessible sulfur compounds with one carbon and one nitrogen substituent, represents the key step. A broad scope for S-alkylation was achieved by rhodium-catalyzed coupling with diazo compounds under mild conditions. When a chiral rhodium catalyst was utilized with loadings as low as 0.1 mol %, the S-alkylation products were obtained in high yields and with enantiomeric ratios up to 98:2 at the newly generated chiral sulfur center. The S-alkylation products were efficiently converted to a variety of sulfoximines with complete retention of stereochemistry. The utility of this approach was further demonstrated by the asymmetric synthesis of a complex sulfoximine agrochemical.

Rhodium-Catalyzed C-H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles.

Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C-H bond alkenylation/electrocyclization cascade from readily available α,ß-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxy-substituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity.When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C-H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3 + 2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements.The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric syntheses of morphinan drugs, including the opioid antagonist (-)-naltrexone, which is extensively used for the treatment of drug abuse.

Stereoselective Synthesis of Allenyl Alcohols by Cobalt(III)-Catalyzed Sequential C-H Bond Addition to 1,3-Enynes and Aldehydes.

An efficient and stereoselective CoIII -catalyzed sequential C-H bond addition to 1,3-enynes and aldehydes is disclosed. This transformation represents the first example of sequential C-H bond additions to 1,3-enynes and a second coupling partner and provides the first example of preparing allenes by C-H bond addition to 1,3-enynes. A wide range of aldehydes, C-H bond substrates and 1,3-enynes with large substituents on the alkynes are effective substrates. The allenyl alcohol products can be further converted to dihydrofurans with high stereoselectivity either in situ or under Ag-mediated cyclization conditions. The allenyl silyl group can also be transferred to the adjacent alcohol by a Brook rearrangement. Moreover, a mechanism for the transformation is proposed supported by X-ray structural characterization of a cobaltacycle intermediate.

General Light-Mediated, Highly Diastereoselective Piperidine Epimerization: From Most Accessible to Most Stable Stereoisomer.

We report a combined photocatalytic and hydrogen atom transfer (HAT) approach for the light-mediated epimerization of readily accessible piperidines to provide the more stable diastereomer with high selectivity. The generality of the transformation was explored for a large variety of di- to tetrasubstituted piperidines with aryl, alkyl, and carboxylic acid derivatives at multiple different sites. Piperidines without substitution on nitrogen as well as N-alkyl and aryl derivatives were effective epimerization substrates. The observed diastereoselectivities correlate with the calculated relative stabilities of the isomers. Demonstration of reaction reversibility, luminescence quenching, deuterium labeling studies, and quantum yield measurements provide information about the mechanism.

Synthesis of Nitrile Bearing Acyclic Quaternary Centers through Co(III)-Catalyzed Sequential C-H Bond Addition to Dienes and N-Cyanosuccinimide.

Herein we disclose a three-component strategy to access quaternary centers bearing nitriles by cobalt-catalyzed C-H bond activation and sequential addition to internally substituted 1,3-dienes and an electrophilic cyanating reagent with high regio and stereocontrol. 2-Aryl and alkyl monosubstituted dienes provide α-aryl and α-alkyl α-methyl-substituted nitriles, respectively. An even wider variety of functionality can be installed at the quaternary carbon by using 1,2-disubstituted dienes. The synthetic utility of the nitrile products was successfully demonstrated by various transformations, including conversions to γ-lactones and tetrazoles. The observed connectivity in the products along with studies with deuterium labeled reactants provide insight into the mechanism. Formation of a 7-membered cobaltacycle by C-H activation and migratory insertion of the diene is followed by ß-hydride elimination and hydride reinsertion to give a 6-membered cobaltacycle that then reacts with the cyanating agent.

Highly Diastereoselective Functionalization of Piperidines by Photoredox-Catalyzed α-Amino C-H Arylation and Epimerization.

We report a photoredox-catalyzed α-amino C-H arylation reaction of highly substituted piperidine derivatives with electron-deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. To probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used to investigate the reaction. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer processes associated with radical formation beyond the initial excited-state Ir(ppy)3 oxidation. Following the rapid and unselective C-H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a majority of the products. Several stereoisomerically pure products were resubjected to the reaction conditions, each of which converged to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermodynamic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).

Cobalt(III)-Catalyzed C-H Amidation of Dehydroalanine for the Site-Selective Structural Diversification of Thiostrepton.

Thiostrepton is a potent antibiotic against a broad range of Gram-positive bacteria, but its medical applications have been limited by its poor aqueous solubility. In this work, the first C(sp2 )-H amidation of dehydroalanine (Dha) residues was applied to the site selective modification of thiostrepton to prepare a variety of derivatives. Unlike all prior methods for the modification of thiostrepton, the alkene framework of the Dha residue is preserved and with complete selectivity for the Z-stereoisomer. Additionally, an aldehyde group was introduced by C-H amidation, enabling oxime ligation for the installation of an even greater range of functionality. The thiostrepton derivatives generally maintain antimicrobial activity, and importantly, eight of the derivatives displayed improved aqueous solubility (up to 28-fold), thereby addressing a key shortcoming of this antibiotic. The exceptional functional group compatibility and site selectivity of CoIII -catalyzed C(sp2 )-H Dha amidation suggests that this approach could be generalized to other natural products and biopolymers containing Dha residues.

π-Facial Selectivities in Hydride Reductions of Hindered Endocyclic Iminium Ions.

The origins of π-facial selectivities in the borohydride reduction of endocyclic iminium ions have been elucidated by density functional theory calculations. In reductions of conjugated ("thermodynamic") iminium ions, the π-facial preference of the hydride attack was found to be due to torsional steering. Attack at the favored π-face leads to a lower-energy "half-chair"-like conformation of the tetrahydropyridine product, whereas attack at the other π-face results in an unfavorable "twist-boat" conformation. In reductions of nonconjugated ("kinetic") iminium ions, torsional distinction is small between the top- and bottom-face attacks, and the π-facial selectivity of the hydride approach is primarily due to steric hindrance.

Transition-Metal-Catalyzed C-H Bond Addition to Carbonyls, Imines, and Related Polarized π Bonds.

The transition-metal-catalyzed addition of C-H bonds to carbonyls, imines, and related polarized π bonds has emerged as a particularly efficient and powerful approach for the construction of an incredibly diverse array of heteroatom-substituted products. Readily available and stable inputs are typically employed, and reactions often proceed with very high functional group compatibility and without the production of waste byproducts. Additionally, many transition-metal-catalyzed C-H bond additions to polarized π bonds occur within cascade reaction sequences to provide rapid access to a diverse array of different heterocyclic as well as carbocyclic products. This review highlights the diversity of transformations that have been achieved, catalysts that have been used, and types of products that have been prepared through the transition-metal-catalyzed addition of C-H bonds to carbonyls, imines, and related polarized π bonds.

Synthesis of Homoallylic Alcohols with Acyclic Quaternary Centers through CoIII -Catalyzed Three-Component C-H Bond Addition to Internally Substituted Dienes and Carbonyls.

An efficient CoIII -catalyzed three-component strategy to prepare homoallylic alcohols containing acyclic quaternary centers is disclosed. This transformation enables the introduction of two C-C σ bonds through C-H bond activation and sequential addition to internally substituted dienes and a wide range of aldehydes and activated ketones. Isoprene and other internally monosubstituted dienes are effective inputs, with the reaction proceeding with high diastereoselectivity for those substrate combinations that result in more than one stereogenic center. Moreover, the opposite relative stereochemistry can be achieved by employing 1,2-disubstituted dienes. A mechanism for the transformation is proposed based upon the relative stereochemistry of the products and studies with isotopically labeled starting materials.

Synthesis of Azolo[1,3,5]triazines via Rhodium(III)-Catalyzed Annulation of N-Azolo Imines and Dioxazolones.

A wide range of azolo[1,3,5]triazines were obtained by Rh(III)-catalyzed annulation of N-azolo imines and dioxazolones. The reaction proceeds by the first catalytic C-H amidation of an imidoyl C-H bond followed by cyclodehydration. Good yields were obtained for N-azolo imines derived from aminoazoles and aromatic and heteroaromatic aldehydes. A range of dioxazolone amidating reagents were employed to introduce aryl, heteroaryl, and alkyl substituents. The reaction was also performed with a benchtop setup at 1 mmol scale using microwave heating.

Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrazolo[1,5- a]pyrimidines.

An efficient, three-component strategy for Rh(III)-catalyzed annulation of readily available 3-aminopyrazoles, aldehydes, and sulfoxonium ylides to give diverse pyrazolo[1,5- a]pyrimidines is disclosed. The reactions were performed under straightforward benchtop conditions using microwave heating with short reaction times. Good yields were obtained for many substituted aminopyrazoles and a very large variety of aromatic and heteroaromatic aldehydes, including those incorporating electron-withdrawing, electron-donating, basic nitrogen, halide and acidic functionality. Ester and methoxy functionalities could also be directly installed on the pyrimidine ring by employing ethyl glyoxylate and trimethyl orthoformate in place of the aldehyde, respectively. In addition, a range of sulfoxonium ylides provided products in good yields to establish that aryl, heteroaryl, and branched and unbranched alkyl substituents can be introduced with this reagent. Finally, the first use of a formyl sulfoxonium ylide in a chemical transformation enabled the preparation of products with only a single substituent on the pyrimidine ring as introduced by the aldehyde coupling partner. For the formyl ylide, a one-pot, stepwise reaction sequence was used to prevent competitive condensation of the formyl group with the aminopyrazole.

Rhodium(III)-catalyzed C-H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles.

The synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles via rhodium(III)-catalyzed C-H functionalization of C-alkenyl azoles with sulfoxonium ylides is disclosed. Reactions proceeded in good to high yields for a range of aryl, heteroaryl and alkyl sulfoxonium ylides. In addition, 2-alkenyl imidazoles with different substitution patterns as well as C-alkenyl triazoles were effective inputs. The reaction could also be performed under straightforward bench top conditions.