Computational planning of the synthesis of complex natural products.

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years1-7. However, the field has progressed greatly since the development of early programs such as LHASA1,7, for which reaction choices at each step were made by human operators. Multiple software platforms6,8-14 are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary15,16 and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships17,18, allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization.

A Platform for the Synthesis of Corynantheine-Type Corynanthe Alkaloids.

Corynantheine-type alkaloids are major components of the Mitragyna speciosa, also known as kratom, that exhibit unique pharmacological activity. However, no universal method to prepare these alkaloids has been reported. Disclosed herein is a catalytic, asymmetric platform that enables rapid access to corynantheine alkaloids. The first enantioselective total synthesis of (-)-corynantheidine pseudoindoxyl is described. The first asymmetric syntheses of (+)-corynoxine and (-)-corynoxine B were also achieved, along with enantioselective syntheses of (-)-corynantheidol and (-)-corynantheidine. Through this work, all series of corynantheine alkaloids including indole, spirooxindole, and pseudoindoxyl can now be accessed in the laboratory, enabling comprehensive biological investigation of kratom alkaloids to be undertaken.

Hemin-Induced Death Models Hemorrhagic Stroke and Is a Variant of Classical Neuronal Ferroptosis.

Ferroptosis is a caspase-independent, iron-dependent form of regulated necrosis extant in traumatic brain injury, Huntington disease, and hemorrhagic stroke. It can be activated by cystine deprivation leading to glutathione depletion, the insufficiency of the antioxidant glutathione peroxidase-4, and the hemolysis products hemoglobin and hemin. A cardinal feature of ferroptosis is extracellular signal-regulated kinase (ERK)1/2 activation culminating in its translocation to the nucleus. We have previously confirmed that the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor U0126 inhibits persistent ERK1/2 phosphorylation and ferroptosis. Here, we show that hemin exposure, a model of secondary injury in brain hemorrhage and ferroptosis, activated ERK1/2 in mouse neurons. Accordingly, MEK inhibitor U0126 protected against hemin-induced ferroptosis. Unexpectedly, U0126 prevented hemin-induced ferroptosis independent of its ability to inhibit ERK1/2 signaling. In contrast to classical ferroptosis in neurons or cancer cells, chemically diverse inhibitors of MEK did not block hemin-induced ferroptosis, nor did the forced expression of the ERK-selective MAP kinase phosphatase (MKP)3. We conclude that hemin or hemoglobin-induced ferroptosis, unlike glutathione depletion, is ERK1/2-independent. Together with recent studies, our findings suggest the existence of a novel subtype of neuronal ferroptosis relevant to bleeding in the brain that is 5-lipoxygenase-dependent, ERK-independent, and transcription-independent. Remarkably, our unbiased phosphoproteome analysis revealed dramatic differences in phosphorylation induced by two ferroptosis subtypes. As U0126 also reduced cell death and improved functional recovery after hemorrhagic stroke in male mice, our analysis also provides a template on which to build a search for U0126's effects in a variant of neuronal ferroptosis.SIGNIFICANCE STATEMENT Ferroptosis is an iron-dependent mechanism of regulated necrosis that has been linked to hemorrhagic stroke. Common features of ferroptotic death induced by diverse stimuli are the depletion of the antioxidant glutathione, production of lipoxygenase-dependent reactive lipids, sensitivity to iron chelation, and persistent activation of extracellular signal-regulated kinase (ERK) signaling. Unlike classical ferroptosis induced in neurons or cancer cells, here we show that ferroptosis induced by hemin is ERK-independent. Paradoxically, the canonical MAP kinase kinase (MEK) inhibitor U0126 blocks brain hemorrhage-induced death. Altogether, these data suggest that a variant of ferroptosis is unleashed in hemorrhagic stroke. We present the first, unbiased phosphoproteomic analysis of ferroptosis as a template on which to understand distinct paths to cell death that meet the definition of ferroptosis.

Cooperative Carbene Photocatalysis for ß-Amino Ester Synthesis.

ß-Amino acids are useful building blocks of bioactive molecules, including peptidomimetics and pharmaceutical compounds. The current limited accessibility to ß2,2-type amino acids which bear an α-quaternary center has limited their use in chemical synthesis and biological investigations. Disclosed herein is the development of a new N-heterocyclic carbene/photocatalyzed aminocarboxylation of olefins, affording ß2,2-amino esters with high regioselectivity. The generation of nitrogen-centered radicals derived from simple imides via a sequence of deprotonation and single-electron oxidation allows for the subsequent addition to geminal-disubstituted olefins regioselectively. The intermediate tertiary radicals then cross-couple with a stabilized azolium-based radical generated in situ to efficiently construct the quaternary centers. Mechanistic studies, including Stern-Volmer fluorescence quenching experiments, support the proposed catalytic cycle.

Photoinduced Acylations Via Azolium-Promoted Intermolecular Hydrogen Atom Transfer.

Photoinduced hydrogen atom transfer (HAT) has been developed as a powerful tool to generate synthetically valuable radical species. The direct photoexcitation of ketones has been known to promote HAT or to generate acyl radicals through Norrish-type pathways, but these modalities remain severely limited by radical side reactions. We report herein a catalyst- and transition metal-free method for the acylation of C-H bonds that leverages the unique properties of stable, isolable acyl azolium species. Specifically, acyl azolium salts are shown to undergo an intermolecular and regioselective HAT upon LED irradiation with a range of substrates bearing active C-H bonds followed by C-C bond formation to afford ketones. Experimental and computational studies support photoexcitation of the acyl azolium followed by facile intersystem crossing to access triplet diradical species that promote selective HAT and radical-radical cross-coupling.

Photocatalyzed Direct α-Alkylation of Esters Using Styrenes.

A mild photocatalyzed approach to achieve the α-alkylation of esters via formation of an α -radical is disclosed here. Cesium enolates of esters were generated in situ using Cs2CO3 as a base. A subsequent photocatalyzed oxidation at the α-carbon of these enolates produced an α-radical that was added into activated alkenes. This is the first example accessing the α-carbon radical of esters in photoredox catalyed transformations.

High-throughput photocapture approach for reaction discovery.

Modern organic reaction discovery and development relies on the rapid assessment of large arrays of hypothesis-driven experiments. The time-intensive nature of reaction analysis presents the greatest practical barrier for the execution of this iterative process that underpins the development of new bioactive agents. Toward addressing this critical bottleneck, we report herein a high-throughput analysis (HTA) method of reaction mixtures by photocapture on a 384-spot diazirine-terminated self-assembled monolayer, and self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) analysis. This analytical platform has been applied to the identification of a single-electron-promoted reductive coupling of acyl azolium species.

Light-Driven Enantioselective Carbene-Catalyzed Radical-Radical Coupling.

An enantioselective carbene-catalyzed radical-radical coupling of acyl imidazoles and racemic Hantzsch esters is disclosed. This method involves the coupling of an N-heterocyclic carbene-derived ketyl radical and a secondary sp3 -carbon radical and allows access to chiral α-aryl aliphatic ketones in moderate-to-good yields and enantioselectivities without any competitive epimerization. The utility of this protocol is highlighted by the late-stage functionalization of various pharmaceutical compounds and is further demonstrated by the transformation of the enantioenriched products to biologically relevant molecules. Computational investigations reveal the N-heterocyclic carbene controls the double-facial selectivity of the ketyl radical and the alkyl radicals, respectively.

Synthesis of Cyclohexanones by a Tandem Photocatalyzed Annulation.

The rapid synthesis of cyclic scaffolds is of high importance to the chemistry community. Strategies for the convergent synthesis of substituted carbocycles and heterocycles remain underexplored despite the plethora of applications that these cyclic motifs have in the pharmaceutical and materials industries. Reported herein is a tandem carbene and photoredox-catalyzed process for the convergent synthesis of substituted cycloalkanones via a formal [5 + 1] cycloaddition. Featuring two distinct photoredox cycles and a novel α-oxidation of benzylic ketones, this reaction offers a mild approach to construct two contiguous C-C bonds and eliminates the need for strong bases or expensive metal catalysts. The utility of this method is highlighted through various product diversification reactions that allow access to a range of important cyclic scaffolds.

Enantioselective Copper-Catalyzed Borylative Amidation of Allenes.

An approach for the copper-catalyzed synthesis of enantioenriched amides bearing an α-stereogenic center is disclosed. This method involves the addition of an allyl copper species to an isocyanate and allows access to α-substituted chiral amides in high yields and high-to-excellent enantioselectivities. The utility of α-vinyl ß-boryl amides in synthesis is highlighted by the diversification of products to afford highly useful scaffolds. DFT calculations reveal that the catalyst preferentially coordinates to the oxygen of the isocyanate. Enantiocontrol arises from the steric repulsion between the boryl group and the stereodirecting phenyl of the chiral ligand.

Combined Photoredox and Carbene Catalysis for the Synthesis of γ-Aryloxy Ketones.

N-heterocyclic carbenes (NHCs) have emerged as catalysts for the construction of C-C bonds in the synthesis of substituted ketones under single-electron processes. Despite these recent reports, there still remains a need to increase the utility and practicality of these reactions by exploring new radical coupling partners. Herein, we report the synthesis of γ-aryloxyketones via combined NHC/photoredox catalysis. In this reaction, an α-aryloxymethyl radical is generated via oxidation of an aryloxymethyl potassium trifluoroborate salt, which is then added into styrene derivatives to provide a stabilized benzylic radical. Subsequent radical-radical coupling reaction with an azolium radical affords the γ-aryloxy ketone products.

Photocatalytic acyl azolium-promoted alkoxycarbonylation of trifluoroborates.

Despite recent advancements in the selective generation and coupling of organic radical species, the alkoxycarbonyl radical remains underexplored relative to other carbon-containing radical species. Drawing inspiration from new strategies for generating acyl radical equivalents utilizing dual N-heterocyclic carbene catalysis and photocatalysis, we have prepared dimethylimidazolium esters that can function as an alkoxycarbonyl radical surrogate under photocatalytic conditions. We demonstrate the synthetic utility of these azolium-based partners through the preparation of esters arising from the coupling of this radical surrogate with an oxidatively generated alkyl radical.

Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones.

Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C-C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.

A Concise, Enantioselective Approach for the Synthesis of Yohimbine Alkaloids.

We report a concise, enantioselective synthesis of the yohimbine alkaloids (-)-rauwolscine and (-)-alloyohimbane. The key transformation involves a highly enantio- and diastereoselective NHC-catalyzed dimerization and an amidation/N-acyliminium ion cyclization sequence to furnish four of the five requisite rings and three of the five stereocenters in two operations. This route also provides efficient access to all four diastereomeric arrangements of the core stereotriad of the yohimbine alkaloids from a common intermediate. This platform approach in combination with the ability to access both enantiomers from the carbene-catalyzed reaction is a powerful strategy that can produce a wide range of complex alkaloids and related structures for future biomedical investigations.

A Sequential Umpolung/Enzymatic Dynamic Kinetic Resolution Strategy for the Synthesis of γ-Lactones.

Combining biological and small-molecule catalysts under a chemoenzymatic manifold presents a series of significant advantages to the synthetic community. We report herein the successful development of a two-step/single flask synthesis of γ-lactones through the merger of Umpolung catalysis with a ketoreductase-catalyzed dynamic kinetic resolution, reduction, and cyclization. This combined approach delivers highly enantio- and diastereoenriched heterocycles and demonstrates the feasibility of integrating NHC catalysis with enzymatic processes.

Non-'classical' MEKs: A review of MEK3-7 inhibitors.

The MAPK pathways are an enduring area of interest due to their essential roles in cell processes. Increased expression and activity can lead to a multitude of diseases, sparking research efforts in developing inhibitors against these kinases. Though great strides have been made in developing MEK1/2 inhibitors, there is a notable lack of chemical probes for MEK3-7, given their central role in stimuli response, cell growth, and development. This review summarizes the progress that has been made on developing small molecule probes for MEK3-7, the specific disease states in which they have been studied, and their potential to become novel therapeutics.

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids.

As a key element in the construction of complex organic scaffolds, the formation of C-C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single-electron chemistry have enabled new methods for the formation of various C-C bonds. Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical-radical coupling was made possible merging N-heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late-stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.

Synthesis and Evaluation of Azolium-Based Halogen-Bond Donors.

A method for the synthesis of iodinated imidazolium and triazolium N-heterocyclic halogen-bond-donor catalysts has been developed. This approach was applied to the synthesis of a variety of 1,2,4-triazolium salts to prepare a series of novel chiral halogen-bond-donor catalysts. The counterions of the iodinated triazoliums can be readily exchanged with chiral and achiral non-coordinating counterions to produce unique scaffolds. Their ability to promote/catalyse a conjugate addition reaction with indole was investigated. Through these initial studies, a set of general guidelines and considerations for the application of these halogen-bond donors in organocatalysis have been established.

Modeling MEK4 Kinase Inhibitors through Perturbed Electrostatic Potential Charges.

MEK4, mitogen-activated protein kinase kinase 4, is overexpressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed. With advances in both computer and biological high-throughput screening, selective chemical entities can be discovered. Structure-based quantitative structure-activity relationship (QSAR) modeling often fails to generate accurate models due to poor alignment of training sets containing highly diverse compounds. Here we describe a highly predictive, nonalignment based robust QSAR model based on a data set of strikingly diverse MEK4 inhibitors. We computed the electrostatic potential (ESP) charges using a density functional theory (DFT) formalism of the donor and acceptor atoms of the ligands and hinge residues. Novel descriptors were then generated from the perturbation of the charge densities of the donor and acceptor atoms and were used to model a diverse set of 84 compounds, from which we built a robust predictive model.

A continuing challenge: N-heterocyclic carbene-catalyzed syntheses of γ-butyrolactones.

Catalytic, stereoselective N-heterocyclic carbene-catalyzed reactions facilitate efficient construction of many different heterocyclic compounds, such as the enantioenriched 5-membered (γ) lactones highlighted in this tutorial review. Herein, various strategies to enable formal [3+2] type annulations between electrophilic carbonyl equivalents and homoenolate nucleophiles for the synthesis of γ-lactones are summarized.