Rh(I)-Catalyzed Regio- and Enantioselective Ring Opening of Vinyl Cyclopropanes.

We describe a Rh(I) catalyzed asymmetric ring opening of racemic vinyl cyclopropanes using aryl boronic acids as C-nucleophiles. When ferrocene-based chiral bisphosphines are used as ligands, the products are obtained with regioselectivities typically 99:1 r.r. and ee's generally between 88 and 96%. A wide range of aryl boronic acids can be used, and the products can be converted into a variety of targets. Preliminary mechanistic studies indicate that Zn(OTf)2 plays a significant role in the reaction by promoting rhodium-ligand complex formation and accelerating the reaction. We expect this method and these mechanistic insights to be useful in the development of new asymmetric methods.

Widespread horse-based mobility arose around 2200 BCE in Eurasia.

Horses revolutionized human history with fast mobility1. However, the timeline between their domestication and their widespread integration as a means of transport remains contentious2-4. Here we assemble a collection of 475 ancient horse genomes to assess the period when these animals were first reshaped by human agency in Eurasia. We find that reproductive control of the modern domestic lineage emerged around 2200 BCE, through close-kin mating and shortened generation times. Reproductive control emerged following a severe domestication bottleneck starting no earlier than approximately 2700 BCE, and coincided with a sudden expansion across Eurasia that ultimately resulted in the replacement of nearly every local horse lineage. This expansion marked the rise of widespread horse-based mobility in human history, which refutes the commonly held narrative of large horse herds accompanying the massive migration of steppe peoples across Europe around 3000 BCE and earlier3,5. Finally, we detect significantly shortened generation times at Botai around 3500 BCE, a settlement from central Asia associated with corrals and a subsistence economy centred on horses6,7. This supports local horse husbandry before the rise of modern domestic bloodlines.

Enantioselective Synthesis of Sealutomicin C.

The sealutomicins are a family of anthraquinone antibiotics featuring an enediyne (sealutomicin A) or Bergman-cyclized aromatic ring (sealutomicins B-D). Herein we report the development of an enantioselective organocatalytic method for the synthesis of dihydroquinolines and the use of the developed method in the total synthesis of sealutomicin C which features a transannular cyclization of an aryllithium onto a γ-lactone as a second key step.

Routes to Advanced Intermediates in the Synthesis of Tetracarbocyclic Sesquiterpenoids Daphnenoid A and Artatrovirenols A and B.

A short route from dihydrocarvone is described, which led to the tetracarbocyclic core common to artatrovirenol A and B and daphnenoid A. A variant of this route afforded guaia-4,6-dien-3-one (from Enterospermum madagascarensis) and its epimer. From 2-(2-oxoethyl)furan, a 15-step sequence then delivered the complete carbon skeleton and all functionality necessary for daphnenoid A. Key steps in the route include diastereoselective intramolecular oxidopyrylium cycloaddition, oxa-bridge cleavage under "push-pull" conditions, and intramolecular Diels-Alder cycloaddition.

Taming nonclassical carbocations to control small ring reactivity.

Prediction of the outcome of ring opening of small organic rings under cationic conditions can be challenging due to the intermediacy of nonclassical carbocations. For example, the solvolysis of cyclobutyl or cyclopropylmethyl derivatives generates up to four products on nucleophilic capture or elimination via cyclopropylcarbinyl and bicyclobutonium ions. Here, we show that such reaction outcomes can be controlled by subtle changes to the structure of nonclassical carbocation. Using bicyclo[1.1.0]butanes as cation precursors, the regio- and stereochemistry of ring opening is shown to depend on the degree and nature of the substituents on the cationic intermediates. Reaction outcomes are rationalized using computational models, resulting in a flowchart to predict product formation from a given cation precursor.

A comparison of retrospectively reported and ecological momentary assessment-reported perceived social support in predicting ecological momentary assessment-reported non-suicidal self-injury.

INTRODUCTION: Non-suicidal self-injury (NSSI) urges and behaviors are associated with lower perceived social support and related constructs (e.g., perceived rejection). However, no studies have examined the concordance of retrospective (baseline) and ecological momentary assessment (EMA) perceived social support assessments. Retrospective and EMA reports are often only weakly to moderately correlated; measurement approaches may, therefore, impact observed associations between variables. We tested whether average EMA-reported perceived emotional social support uniquely predicts EMA-reported NSSI urges and behaviors above baseline-reported retrospective self-report of perceived emotional social support alone. METHODS: 93 young adults (ages 18-34) with past-month NSSI urges or behaviors and lifetime NSSI behaviors completed a semi-structured interview, self-report surveys, and a 2-week EMA protocol. RESULTS: Baseline- and EMA-reported perceived emotional social support were positively correlated (Kendall's tau-b = 0.51). Average EMA-reported social support was uniquely associated with EMA-reported NSSI urges but not NSSI behaviors. CONCLUSIONS: EMA-reported perceived emotional social support captured information not represented by baseline reports alone, but improvement in model fit was modest. EMA-reported social support may further improve the estimation of EMA-reported NSSI urges if modeled as a proximal predictor of NSSI. Further work is needed to clarify temporal directions between social support and NSSI urges. Limitations are discussed.

Bifunctional Iminophosphorane Catalyzed Amide Enolization for Enantioselective Cyclohexadienone Desymmetrization.

The organocatalytic enolization of 2-arylacetamides, followed by an enantioselective intramolecular conjugate addition to tethered 2,5-cyclohexadienones, yielding 3D fused N-heterocycles, is described. The transformation represents the first strong activating group-free activation of carboxamides via α-C-H deprotonation in a metal-free, catalytic, and enantioselective reaction, and is achieved by employing a bifunctional iminophosphorane (BIMP) superbase.

Bridge Cross-Coupling of Bicyclo[1.1.0]butanes.

Bicyclo[1.1.0]butanes (BCBs) have gained growing popularity in "strain release" chemistry for the synthesis of four-membered-ring systems and para- and meta-disubstituted arene bioisosteres as well as applications in chemoselective bioconjugation. However, functionalization of the bridge position of BCBs can be challenging due to the inherent strain of the ring system and reactivity of the central C-C bond. Here we report the first late-stage bridge cross-coupling of BCBs, mediated by directed metalation/palladium catalysis.

Stereoselective Alder-Ene Reactions of Bicyclo[1.1.0]butanes: Facile Synthesis of Cyclopropyl- and Aryl-Substituted Cyclobutenes.

Bicyclo[1.1.0]butanes (BCBs), strained carbocycles comprising two fused cyclopropane rings, have become well-established building blocks in organic synthesis, medicinal chemistry, and chemical biology due to their diverse reactivity profile with radicals, nucleophiles, cations, and carbenes. The constraints of the bicyclic ring system confer high p-character on the interbridgehead C-C bond, leading to this broad reaction profile; however, the use of BCBs in pericyclic processes has to date been largely overlooked in favor of such stepwise, non-concerted additions. Here, we describe the use of BCBs as substrates for ene-like reactions with strained alkenes and alkynes, which give rise to cyclobutenes decorated with highly substituted cyclopropanes and arenes. The former products are obtained from highly stereoselective reactions with cyclopropenes, generated in situ from vinyl diazoacetates under blue light irradiation (440 nm). Cyclobutenes featuring a quaternary aryl-bearing carbon atom are prepared from equivalent reactions with arynes, which proceed in high yields under mild conditions. Mechanistic studies highlight the importance of electronic effects in this chemistry, while computational investigations support a concerted pathway and rationalize the excellent stereoselectivity of reactions with cyclopropenes.

Fullerene-Functionalized Halogen-Bonding Heteroditopic Hosts for Ion-Pair Recognition.

Despite their hydrophobic surfaces with localized π-holes and rigid well-defined architectures providing a scaffold for preorganizing binding motifs, fullerenes remain unexplored as potential supramolecular host platforms for the recognition of anions. Herein, we present the first example of the rational design, synthesis, and unique recognition properties of novel fullerene-functionalized halogen-bonding (XB) heteroditopic ion-pair receptors containing cation and anion binding domains spatially separated by C60. Fullerene spatial separation of the XB donors and the crown ether complexed potassium cation resulted in a rare example of an artificial receptor containing two anion binding sites with opposing preferences for hard and soft halides. Importantly, the incorporation of the C60 motif into the heteroditopic receptor structure has a significant effect on the halide binding selectivity, which is further amplified upon K+ cation binding. The potassium cation complexed fullerene-based receptors exhibit enhanced selectivity for the soft polarizable iodide ion which is assisted by the C60 scaffold preorganizing the potent XB-based binding domains, anion-π interactions, and the exceptional polarizability of the fullerene moiety, as evidenced from DFT calculations. These observations serve to highlight the unique properties of fullerene surfaces for proximal charged guest binding with potential applications in construction of selective molecular sensors and modulating the properties of solar cell devices.

Selective P450BM3 Hydroxylation of Cyclobutylamine and Bicyclo[1.1.1]pentylamine Derivatives: Underpinning Synthetic Chemistry for Drug Discovery.

Achieving single-step syntheses of a set of related compounds divergently and selectively from a common starting material affords substantial efficiency gains when compared with preparing those same compounds by multiple individual syntheses. In order for this approach to be realized, complementary reagent systems must be available; here, a panel of engineered P450BM3 enzymes is shown to fulfill this remit in the selective C-H hydroxylation of cyclobutylamine derivatives at chemically unactivated sites. The oxidations can proceed with high regioselectivity and stereoselectivity, producing valuable bifunctional intermediates for synthesis and applications in fragment-based drug discovery. The process also applies to bicyclo[1.1.1]pentyl (BCP) amine derivatives to achieve the first direct enantioselective functionalization of the bridging methylenes and open a short and efficient route to chiral BCP bioisosteres for medicinal chemistry. The combination of substrate, enzyme, and reaction engineering provides a powerful general platform for small-molecule elaboration and diversification.

αß,α'ß'-Diepoxyketones are mechanism-based inhibitors of nucleophilic cysteine enzymes.

Epoxides are an established class of electrophilic alkylating agents that react with nucleophilic protein residues. We report αß,α'ß'-diepoxyketones (DEKs) as a new type of mechanism-based inhibitors of nucleophilic cysteine enzymes. Studies with the L,D-transpeptidase LdtMt2 from Mycobacterium tuberculosis and the main protease from SARS-CoV-2 (Mpro) reveal that following epoxide ring opening by a nucleophilic cysteine, further reactions can occur, leading to irreversible alkylation.

On-surface synthesis of a doubly anti-aromatic carbon allotrope.

Synthetic carbon allotropes such as graphene1, carbon nanotubes2 and fullerenes3 have revolutionized materials science and led to new technologies. Many hypothetical carbon allotropes have been discussed4, but few have been studied experimentally. Recently, unconventional synthetic strategies such as dynamic covalent chemistry5 and on-surface synthesis6 have been used to create new forms of carbon, including γ-graphyne7, fullerene polymers8, biphenylene networks9 and cyclocarbons10,11. Cyclo[N]carbons are molecular rings consisting of N carbon atoms12,13; the three that have been reported to date (N = 10, 14 and 18)10,11 are doubly aromatic, which prompts the question: is it possible to prepare doubly anti-aromatic versions? Here we report the synthesis and characterization of an anti-aromatic carbon allotrope, cyclo[16]carbon, by using tip-induced on-surface chemistry6. In addition to structural information from atomic force microscopy, we probed its electronic structure by recording orbital density maps14 with scanning tunnelling microscopy. The observation of bond-length alternation in cyclo[16]carbon confirms its double anti-aromaticity, in concordance with theory. The simple structure of C16 renders it an interesting model system for studying the limits of aromaticity, and its high reactivity makes it a promising precursor to novel carbon allotropes15.

Gold-Catalyzed Cyclization of Yndiamides with Isoxazoles via α-Imino Gold Fischer Carbenes.

Gold catalysis is an important method for alkyne functionalization. Here we report the gold-catalyzed formal [3+2] aminative cyclization of yndiamides and isoxazoles in a direct synthesis of polysubstituted diaminopyrroles, which are important motifs in drug discovery. Key to this process is the formation, and subsequent cyclization, of an α-imino gold Fischer carbene, which represents a new type of gold carbene intermediate. The reaction proceeds rapidly under mild conditions, with high regioselectivity being achieved by introducing a subtle steric bias between the nitrogen substituents on the yndiamide. DFT calculations revealed that the key to this regioselectivity was the interconversion of isomeric gold keteniminiun ions via a low-barrier π-complex transition state, which establishes a Curtin-Hammett scenario for isoxazole addition. By using benzisoxazoles as substrates, the reaction outcome could be switched to a formal [5+2] cyclization, leading to 1,4-oxazepines.

Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides.

sulfinamides, sulfonamides, and sulfonimidamides are in-demand motifs in medicinal chemistry, yet methods for the synthesis of alkyl variants that start from simple, readily available feedstocks are scarce. In addition, bespoke syntheses of each class of molecules are usually needed. In this report, we detail the synthesis of these three distinct sulfur functional groups, using readily available and structurally diverse alkyl carboxylic acids as the starting materials. The method harnesses alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products. Using the N-alkoxy sulfinylamine reagent t-BuO-NSO as the radical trap provides common N-alkoxy sulfinamide intermediates, which can be converted in a divergent manner to either sulfonamides or sulfonimidamides, by treatment with sodium hydroxide, or an amine, respectively. The reactions are scalable, tolerate a broad range of functional groups, and can be used for the diversification of complex biologically active compounds.

5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5.

Jumonji-C domain-containing protein 5 (JMJD5) is a 2-oxoglutarate (2OG)-dependent oxygenase that plays important roles in development, circadian rhythm, and cancer through unclear mechanisms. JMJD5 has been reported to have activity as a histone protease, as an Nε-methyl lysine demethylase, and as an arginine residue hydroxylase. Small-molecule JMJD5-selective inhibitors will be useful for investigating its (patho)physiological roles. Following the observation that the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylic acid (2,4-PDCA) is a 2OG-competing JMJD5 inhibitor, we report that 5-aminoalkyl-substituted 2,4-PDCA derivatives are potent JMJD5 inhibitors manifesting selectivity for JMJD5 over other human 2OG oxygenases. Crystallographic analyses with five inhibitors imply induced fit binding and reveal that the 2,4-PDCA C5 substituent orients into the JMJD5 substrate-binding pocket. Cellular studies indicate that the lead compounds display similar phenotypes as reported for clinically observed JMJD5 variants, which have a reduced catalytic activity compared to wild-type JMJD5.

Synthesis of Cyclopropanes via Hydrogen-Borrowing Catalysis.

Cyclopropanes are highly useful motifs that are often incorporated into drug candidates to improve potency, metabolic stability, or pharmacokinetic properties. An expedient method for the α-cyclopropanation of ketones using hydrogen borrowing (HB) catalysis is described. The transformation occurs via HB alkylation of a hindered ketone with subsequent intramolecular displacement of a pendant leaving group affording the cyclopropanated product. The leaving group can be installed in either the ketone or alcohol component of the HB system, giving access to α-cyclopropyl ketones via two complementary approaches. Conversion to the corresponding carboxylic acids can be achieved in a simple two-step sequence to afford synthetically useful 1,1-substituted spirocyclopropyl acid building blocks.

Anthracene-Porphyrin Nanoribbons.

π-Conjugated nanoribbons attract interest because of their unusual electronic structures and charge-transport behavior. Here, we report the synthesis of a series of fully edge-fused porphyrin-anthracene oligomeric ribbons (dimer and trimer), together with a computational study of the corresponding infinite polymer. The porphyrin dimer and trimer were synthesized in high yield, via oxidative cyclodehydrogenation of singly linked precursors, using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and trifluoromethanesulfonic acid (TfOH). The crystal structure of the dimer shows that the central π-system is flat, with a slight S-shaped wave distortion at each porphyrin terminal. The extended π-conjugation causes a dramatic red-shift in the absorption spectra: the absorption maxima of the fused dimer and trimer appear at 1188 nm and 1642 nm, respectively (for the nickel complexes dissolved in toluene). The coordinated metal in the dimer was changed from Ni to Mg, using p-tolylmagnesium bromide, providing access to free-base and Zn complexes. These results open a versatile avenue to longer π-conjugated nanoribbons with integrated metalloporphyrin units.

Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters.

Molecules that contain a stereogenic phosphorus atom are crucial to medicine, agrochemistry and catalysis. While methods are available for the selective construction of various chiral organophosphorus compounds, catalytic enantioselective approaches for their synthesis are far less common. Given the vastness of possible substituent combinations around a phosphorus atom, protocols for their preparation should also be divergent, providing facile access not only to one but to many classes of phosphorus compounds. Here we introduce a catalytic and enantioselective strategy for the preparation of an enantioenriched phosphorus(V) centre that can be diversified enantiospecifically to a wide range of biologically relevant phosphorus(V) compounds. The process, which involves an enantioselective nucleophilic substitution catalysed by a superbasic bifunctional iminophosphorane catalyst, can accommodate a wide range of carbon substituents at phosphorus. The resulting stable, yet versatile, synthetic intermediates can be combined with a multitude of medicinally relevant O-, N- and S-based nucleophiles.

Synthesis of fused tetramate-oxazolidine and -imidazolidine derivatives and their antibacterial activity.

A chemoselective route which provides direct access to bicyclic tetramates, making use of Dieckmann cyclisation of functionalised oxazolidines and imidazolidines derived from an aminomalonate, is reported; calculations suggest that the observed chemoselectivity is kinetically controlled and leads to the thermodynamically most stable product. Some compounds in the library showed modest antibacterial activity against Gram-positive bacteria, and this activity is maximal in a well-defined region of chemical space (554 < Mw < 722 g mol-1; 5.78 < cLogP < 7.16; 788 < MSA < 972 Å2; 10.3 < rel. PSA < 19.08).