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Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by Naegleria fowleri with a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, N -demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)- trans - 57b which featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4a S ,13b R )- 57b ( BDGR-20237 ) with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for BDGR-20237 revealed high brain penetrance but a limited half-life which did not statistically enhance the mouse survival in a pilot efficacy study. The pharmacophoric model, supported by 88 quinazolinones, several of which exhibit subnanomolar potency, will guide further scaffold optimization.

The widely established PET isotope 18 F does not have a therapeutic partner. We have recently established that the Sc-F bond can be formed under aqueous, high yielding conditions, paving the way to providing 18 F as diagnostic partners to 47 Sc and 177 Lu radiotherapeutics. Here, we synthesized a library of tacn-based chelators comprised of 10 structurally unique permutations incorporating acetate, methyl-benzylamide and picolinate donor arms. The chelator library encompasses chelators ranging from 6- to 9-dentate, and produces complex changes ranging from +3 to -1. The corresponding Sc-F/Sc and Lu chelate complexes were characterized using computational, spectroscopic and potentiometric methods, followed by optimization of radiolabeling with 18 F, 44 Sc and 177 Lu and concluded by in vivo validation. We identify characterization benchmarks that chart the coordinative landscape of radiochelation approaches for this unusual triad. Our screening identifies two ligand systems, H 2 L 111 and H 3 L 201 as ideal, readily functionalizable constructs for prospective, targeted theranostic applications with 18 F/ 44 Sc/ 177 Lu., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The incommensurately modulated structure of (2S,3S)-2-amino-3-hydroxy-3-methyl-4-phenoxybutanoic acid dihydrate (C 11 H 15 NO 4 ·2H 2 O or I·2H 2 O) is described in the (3+1)-dimensional superspace group P2 1 2 1 2 1 (0β0)000 (β = 0.357). The loss of the three-dimensional periodicity is ascribed to the occupational modulation of one positionally disordered solvent water molecule, where the two positions are related by a small translation [ca 0.666 (9) Å] and ∼168 (5)° rotation about one of its O-H bonds, with an average 0.624 (3):0.376 (3) occupancy ratio. The occupational modulation of this molecule arises due to the competition between the different hydrogen-bonding motifs associated with each position. The structure can be very well refined in the average approximation (all satellite reflections disregarded) in the space group P2 1 2 1 2 1 , with the water molecule refined as disordered over two positions in a 0.625 (16):0.375 (16) ratio. The refinement in the commensurate threefold supercell approximation in the space group P112 1 is also of high quality, with the six corresponding water molecules exhibiting three different occupancy ratios averaging 0.635:0.365., (open access.)

Three structurally diverse 5-phenyltetrazolato (Tz) Ti, Zr, and Ta complexes, namely, (C 2 H 8 N)[Ti 2 (C 7 H 5 N 4 ) 5 (C 2 H 6 N) 4 ]·1.45C 6 H 6 or (Me 2 NH 2 )[Ti 2 (NMe 2 ) 4 (2,3-μ-Tz) 3 (2-η 1 -Tz) 2 ]·1.45C 6 H 6 , (1·1.45C 6 H 6 ), [Zr 2 (C 7 H 5 N 4 ) 6 (C 2 H 6 N) 2 (C 2 H 7 N) 2 ]·1.12C 6 H 6 ·0.382CH 2 Cl 2 or [Zr 2 (Me 2 NH) 2 (NMe 2 ) 2 (2,3-μ-Tz) 3 (2-η 1 -Tz) 2 (1,2-η 2 -Tz)]·1.12C 6 H 6 ·0.38CH 2 Cl 2 (2·1.12C 6 H 6 ·0.38CH 2 Cl 2 ), and (C 2 H 8 N) 2 [Ta 2 (C 7 H 5 N 4 ) 8 (C 2 H 6 N) 2 O]·0.25C 7 H 8 or (Me 2 NH 2 ) 2 [Ta 2 (NMe 2 ) 2 (2,3-μ-Tz) 2 (2-η 1 -Tz) 6 O]·0.25C 7 H 8 (3·0.25C 7 H 8 ), where TzH is 5-phenyl-1H-tetrazole, have been synthesized and structurally characterized. All three complexes are dinuclear; the Ti center in 1 is six-coordinate, whereas the Zr and Ta atoms in 2 and 3 are seven-coordinate. The coordination environments of the Ti centers in 1 are similar, and so are the ligations of the Ta centers in 3. In contrast, the two Zr centers in 2 bear a different number of ligands, one of which is a bidentate η 2 -5-phenyltetrazolato ligand that has not been observed previously for d-block elements. The dimethylamido ligand, present in the starting materials, remained unchanged, or was converted to dimethylamine and dimethylammonium during the synthesis. Dimethylamine coordinates as a neutral ligand, whereas dimethylammonium is retained as a hydrogen-bonded entity bridging Tz ligands., (open access.)

Azepines and their saturated azepane counterparts are important moieties in bioactive molecules but are under-represented in current drug screening libraries. Herein, we report a mild and efficient azepine formation via silver-catalyzed dearomative nitrene transfer. A 2,2,2-trichloroethoxysulfonyl (Tces)-protected carbamimidate nitrene precursor, coupled with the appropriate ligand for silver, is essential for achieving the unexpected chemoselectivity between arene dearomatization and benzylic C(sp 3 )-H amination. Potential applications in the late-stage diversification of azepines to complex molecular scaffolds and diastereoselective hydrogenations to sp 3 -rich derivatives are also highlighted.

The Paternò-Büchi reaction is the [2 + 2] photocycloaddition of a carbonyl with an alkene to afford an oxetane. Enantioselective catalysis of this classical photoreaction, however, has proven to be a long-standing challenge. Many of the best-developed strategies for asymmetric photochemistry are not suitable to address this problem because the interaction of carbonyls with Brønsted or Lewis acidic catalysts can alter the electronic structure of their excited state and divert their reactivity toward alternate photoproducts. We show herein that a triplet rebound strategy enables the stereocontrolled reaction of an excited-state carbonyl compound in its native, unbound state. These studies have resulted in the development of the first highly enantioselective catalytic Paternò-Büchi reaction, catalyzed by a novel hydrogen-bonding chiral Ir photocatalyst.

The truxillates constitute a large class of dimeric natural products featuring a central, highly substituted cyclobutane core. In principle, these structures could be efficiently synthesized via [2 + 2] photocycloaddition. However, the difficulty in controlling the high-energy electronically excited reactive intermediates in the solution state can lead to poor regio- and diastereocontrol. This has limited the use of photocycloaddition methodology toward the synthesis of this important class of natural products. Herein, we demonstrate that acid-controlled precipitation of C -acyl imidazoles promotes a highly selective solid-state photocycloaddition, and the products of this reaction can be quickly transformed into truxillate natural products.

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45 Ti for radiopharmaceutical applications. Herein, we evaluate the Ti (IV) -coordination chemistry of four catechol-based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN-CAM readily form mononuclear Ti (IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN-CAM form mononuclear complexes with the short-lived, positron-emitting radionuclide 45 Ti (IV) , and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45 Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent-DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [ 45 Ti][Ti(Ent-DUPA)] 2- complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n=5), and low off-target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45 Ti (IV) , provides a foundation for advancing the application of 45 Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45 Ti-complexing cargo for targeted nuclear imaging applications., (© 2024 Wiley‐VCH GmbH.)

A Cu II coordination polymer, catena -poly[[[aqua-copper(II)]-bis-(μ-4-amino-benz-o-ato)-κ 2 N : O ;κ 2 O : N ] monohydrate], {[Cu( p ABA) 2 (H 2 O)]·H 2 O} n ( p ABA = p -amino-benzoate, C 7 H 4 NO 2 - ), was synthesized and characterized. It exhibits a one-dimensional chain structure extended into a three-dimensional supra-molecular assembly through hydrogen bonds and π-π inter-actions. While the twinned crystal shows a metrically ortho-rhom-bic lattice and an apparent space group Pbcm , the true symmetry is monoclinic (space group P 2/ c ), with disordered Cu atoms and mixed roles of water mol-ecules (aqua ligand/crystallization water). The luminescence spectrum of the complex shows an emission at 345 nm, cf. 349 nm for p ABAH., (© Gogia et al. 2024.)

Copper-catalyzed aerobic oxidative coupling of diaryl imines provides a route for conversion of ammonia to hydrazine. The present study uses experimental and density functional theory computational methods to investigate the mechanism of N-N bond formation, and the data support a mechanism involving bimolecular coupling of Cu-coordinated iminyl radicals. Computational analysis is extended to Cu II -mediated C-C, N-N, and O-O coupling reactions involved in the formation of cyanogen (NC-CN) from HCN, 1,3-butadiyne from ethyne (i.e., Glaser coupling), hydrazine from ammonia, and hydrogen peroxide from water. The results reveal two different mechanistic pathways. Heteroatom ligands with an uncoordinated lone pair (iminyl, NH 2 , OH) undergo charge transfer to Cu II , generating ligand-centered radicals that undergo facile bimolecular radical-radical coupling. Ligands lacking a lone pair (CN and CCH) form bridged binuclear diamond-core structures that undergo C-C coupling. This mechanistic bifurcation is rationalized by analysis of spin densities in key intermediates and transition states, as well as multiconfigurational calculations. Radical-radical coupling is especially favorable for N-N coupling owing to energetically favorable charge transfer in the intermediate and thermodynamically favorable product formation.

The direct 1,2-azidoamidation of unsaturated precursors represents an advantageous approach for the facile synthesis of β-functionalized azides from readily available starting materials. In this paper, we describe a convenient and mild iron-catalyzed 1,2-azidoamidation of 1,3-dienes that shows excellent functional group compatibility to furnish versatile precursors to 1,2-diamine products with high levels of site, regio-, and stereoselectivity. The reaction is proposed to proceed via a single electron transfer/radical addition/C-N bond formation relay process.

The compositional tunability of 2D metal halide perovskites enables exploration of diverse semiconducting materials with different structural features. However, rationally tuning the 2D perovskite structures to target physical properties for specific applications remains challenging, especially for lead-free perovskites. Here, we study the effect of the interplay of the B-site (Ge, Sn, and Pb), A-site (cesium, methylammonium, and formamidinium), and spacer cations on the structure and optical properties of a new series of 2D Ruddlesden-Popper perovskites using the previously unreported spacer cation 4-bromo-2-fluorobenzylammonium (4Br2FBZ). We report eight new crystal structures and study the consequence of varying the B-site (Pb, Sn, Ge) and dimension ( n = 1, 2, vs 3D). Dimension strongly influences local distortion and structural symmetry, and the increased octahedral tilting and lone pair effects in Ge perovskites lead to a polar n = 2 perovskite that exhibits second harmonic generation, (4Br2FBZ) 2 (Cs)Ge 2 I 7 . In contrast, the analogous Sn and Pb perovskites remain centrosymmetric, but the B-site metal influences the photoluminescence properties. The Pb perovskites exhibit broad, defect-mediated emission at low temperature, whereas the Sn perovskites show purely excitonic emission over the entire temperature range, but the carrier recombination dynamics depend on dimensionality and dark excitonic states. Wholistic understanding of these differences that arise based on cations and dimensionality can guide the rational materials design of 2D perovskites for targeting physical properties for optoelectronic applications based on the interplay of cations and the connectivity of the inorganic framework.

Transition metal-catalyzed asymmetric nitrene transfer is a powerful method to generate enantioenriched amines found in natural products and bioactive molecules. A highly chemo- and enantioselective intramolecular silver-catalysed aziridination of 2,2,2-trichloroethoxysulfonyl (Tces)-protected carbamimidates gives [4.1.0]-bicyclic aziridines in good yields and up to 99% ee.

The solution chemistry of the hydrolytic, early-transition-metal ions Ti 4+ and Sc 3+ represents a coordination chemistry challenge with important real-world implications, specifically in the context of 44 Ti/ 44 Sc and 45 Ti/ Nat Sc radiochemical separations. Unclear speciation of the solid and solution phases and tertiary mixtures of mineral acid, organic chelators, and solid supports are common confounds, necessitating tedious screening of multiple variables. Herein we describe how thermodynamic speciation data in solution informs the design of new solid-phase chelation approaches enabling separations of Ti 4+ and Sc 3+ . The ligands catechol (benzene-1,2-diol) and deferiprone [3-hydroxy-1,2-dimethyl-4(1 H )-pyridone] bind Ti 4+ at significantly more acidic conditions (2-4 pH units) than Sc 3+ . Four chelating resins were synthesized using either catechol or deferiprone with two different solid supports. Of these, deferiprone appended to carboxylic acid polymer-functionalized silica (CA-Def) resin exhibited excellent binding affinity for Ti 4+ across a wide range of HCl concentrations (1.0-0.001 M), whereas Sc 3+ was only retained in dilute acidic conditions (0.01-0.001 M HCl). CA-Def resin produced separation factors of >100 (Ti/Sc) in 0.1-0.4 M HCl, and the corresponding K d values (>1000) show strong retention of Ti 4+ . A model 44 Ti/ 44 Sc generator was produced, showing 65 ± 3% yield of 44 Sc in 200 μL of 0.2 M HCl with a significant 44 Ti breakthrough of 0.1%, precluding use in its current form. Attempts, however, removed nat Sc in loading fractions and a dilute (0.4 M HCl) wash and recovered 80% of the loaded 45 Ti activity in 400 μL of 6 M HCl. The previously validated 45 Ti chelator TREN-CAM was used for comparative proof-of-concept reactions with the CA-Def eluent (in HCl) and literature-reported hydroxamate-based resin eluents (in citric acid). CA-Def shows improved radiolabeling efficiency with an apparent molar activity (AMA) of 0.177 mCi nmol -1 , exceeding the established methods (0.026 mCi nmol -1 ) and improving the separation and recovery of 45 Ti for positron emission tomography imaging applications.

Photochemical electrocyclization reactions are valued for both their ability to produce structurally complex molecules and their central role in elucidating fundamental mechanistic principles of photochemistry. We present herein a highly enantioselective 6π photoelectrocyclization catalyzed by a chiral Ir(III) photosensitizer. This transformation was successfully realized by engineering a strong hydrogen-bonding interaction between a pyrazole moiety on the catalyst and a basic imidazolyl ketone on the substrate. To shed light on the origin of stereoinduction, we conducted a comprehensive investigation combining experimental and computational mechanistic studies. Results from density functional theory calculations underscore the crucial role played by the prochirality and the torquoselectivity in the electrocyclization process as well as the steric demand in the subsequent [1,4]-H shift step. Our findings not only offer valuable guidance for developing chiral photocatalysts but also serve as a significant reference for achieving high levels of enantioselectivity in the 6π photoelectrocyclization reaction.

We explored trans - and cis -2-aminocycloheptanecarboxylic acid (ACHpC) as potential building blocks for helical foldamers. trans -ACHpC does not show sufficient folding propensity in unnatural peptides. cis -ACHpC promotes nontraditional helices of two unnatural peptide backbones: the 11/9-helix for 1:1 α/β-peptides and the 12/10-helix for β-peptides with interconvertible handedness. The two opposite-handed 12/10-helices rapidly interconvert in solution by pseudorotation of the two twist chair forms of the cycloheptane moiety in each cis -ACHpC residue.

Cyclopropanes are desirable structural motifs with valuable applications in drug discovery and beyond. Established alkene cyclopropanation methods give rise to cyclopropanes with a limited array of substituents, are difficult to scale, or both. Herein, we disclose a new cyclopropane synthesis through the formal coupling of abundant carbon pronucleophiles and unactivated alkenes. This strategy exploits dicationic adducts derived from electrolysis of thianthrene in the presence of alkene substrates. We find that these dielectrophiles undergo cyclopropanation with methylene pronucleophiles via alkenyl thianthrenium intermediates. This protocol is scalable, proceeds with high diastereoselectivity, and tolerates diverse functional groups on both the alkene and pronucleophile coupling partners. To validate the utility of this new procedure, we prepared an array of substituted analogs of an established cyclopropane that is en route to multiple pharmaceuticals., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Carbon-heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments because carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, C-N and C-O linkages are often a metabolic liability because they are prone to hydrolysis. While C(sp 2 )-C(sp 3 ) linkages are preferable in many cases, methods to make them require different starting materials or are less functional-group-compatible. We show here a new, decarbonylative reaction that forms C(sp 2 )-C(sp 3 ) bonds from the reaction of activated carboxylic acids (via 2-pyridyl esters) with activated alkyl groups derived from amines (via N -alkyl pyridinium salts) and alcohols (via alkyl halides). Key to this process is a remarkably fast, reversible oxidative addition/decarbonylation sequence enabled by pyridone and bipyridine ligands that, under reaction conditions that purge CO (g) , lead to a selective reaction. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug development, and this is demonstrated in the coupling of a typical Proteolysis Targeting Chimera (PROTAC) anchor with common linkers via C-C linkages.

Copper-catalyzed radical-relay reactions provide a versatile strategy for selective C-H functionalization; however, reactions with peroxide-based oxidants often require excess C-H substrate. Here, we report a photochemical strategy to overcome this limitation by using a Cu/2,2'-biquinoline catalyst that supports benzylic C-H esterification with limiting C-H substrate. Mechanistic studies indicate that blue-light irradiation promotes carboxylate-to-copper charge transfer, reducing resting-state Cu II to Cu I , which activates the peroxide to generate an alkoxyl radical hydrogen-atom-transfer species. This "photochemical redox buffering" introduces a unique strategy to sustain the activity of Cu catalysts in radical-relay reactions.

Modular strategies to rapidly increase molecular complexity have proven immensely synthetically valuable. In principle, transformation of an alkene into a dielectrophile presents an opportunity to deliver two unique nucleophiles across an alkene. Unfortunately, the selectivity profiles of known dielectrophiles have largely precluded this deceptively simple synthetic approach. Herein, we demonstrate that dicationic adducts generated through electrolysis of alkenes and thianthrene possess a unique selectivity profile relative to more conventional dielectrophiles. Specifically, these species undergo a single and perfectly regioselective substitution reaction with phthalimide salts. This observation unlocks an appealing new platform for aminofunctionalization reactions. As an illustrative example, we implement this new reactivity paradigm to address a longstanding synthetic challenge: alkene diamination with two distinct nitrogen nucleophiles. Studies into the mechanism of this process reveal a key alkenyl thianthrenium salt intermediate that controls the exquisite regioselectivity of the process and highlight the importance of proton sources in controlling the reactivity of alkenyl sulfonium salt electrophiles.

Compared with their 3D counterparts, 2D hybrid organic-inorganic halide perovskites (HOIPs) exhibit enhanced chemical stabilities and superior optoelectronic properties, which can be further tuned by the application of external pressure. Here, we report the first high-pressure study on CMA 2 PbI 4 (CMA = cylcohexanemethylammonium), a 2D HOIP with a soft organic spacer cation containing a flexible cyclohexyl ring, using UV-visible absorption, photoluminescence (PL) and vibrational spectroscopy, and synchrotron X-ray microdiffraction, all aided with density functional theory (DFT) calculations. Substantial anisotropic compression behavior is observed, as characterized by unprecedented negative linear compressibility along the b axis. Moreover, the pressure dependence of optoelectronic properties is found to be in strong contrast with those of 2D HOIPs with rigid spacer cations. DFT calculations help to understand the compression mechanisms that lead to pressure-induced bandgap narrowing. These findings highlight the important role of soft spacer cations in the pressure-tuned optoelectronic properties and provide guidance to the design of new 2D HOIPs.

Although microbial genomes harbor an abundance of biosynthetic gene clusters, there remain substantial technological gaps that impair the direct correlation of newly discovered gene clusters and their corresponding secondary metabolite products. As an example of one approach designed to minimize or bridge such gaps, we employed hierarchical clustering analysis and principal component analysis ( hcapca , whose sole input is MS data) to prioritize 109 marine Micromonospora strains and ultimately identify novel strain WMMB482 as a candidate for in-depth "metabologenomics" analysis following its prioritization. Highlighting the power of current MS-based technologies, not only did hcapca enable the discovery of one new, nonribosomal peptide bearing an incredible diversity of unique functional groups, but metabolomics for WMMB482 unveiled 16 additional congeners via the application of Global Natural Product Social molecular networking (GNPS), herein named ecteinamines A-Q ( 1 - 17 ). The ecteinamines possess an unprecedented skeleton housing a host of uncommon functionalities including a menaquinone pathway-derived 2-naphthoate moiety, 4-methyloxazoline, the first example of a naturally occurring Ψ[CH 2 NH] "reduced amide", a methylsulfinyl moiety, and a d-cysteinyl residue that appears to derive from a unique noncanonical epimerase domain. Extensive in silico analysis of the ecteinamine ( ect ) biosynthetic gene cluster and stable isotope-feeding experiments helped illuminate the novel enzymology driving ecteinamine assembly as well the role of cluster collaborations or "duets" in producing such structurally complex agents. Finally, ecteinamines were found to bind nickel, cobalt, zinc, and copper, suggesting a possible biological role as broad-spectrum metallophores.

Molecules at a liquid/vapor interface have different organizations and mobilities from those in the bulk. These differences potentially influence the rate of crystal nucleation, but the effect remains imperfectly understood. We have measured the crystal nucleation rates at the surface and in the bulk of amorphous poscaconazole, a rod-like molecule known to have a preferred interfacial orientation. We find that surface nucleation is vastly enhanced over bulk nucleation, by ∼9 orders of magnitude, and selects a different polymorph (II) from bulk nucleation (I). This phenomenon mirrors the recently reported case of D-arabitol and stems from the similarity of anisotropic surface molecular packing to the structure of the surface-nucleating polymorph. In contrast to these two systems, the surface enhancement of nucleation is weaker (though still significant) in acetaminophen and in water and does not select a different polymorph. Together, the systems investigated to date all feature surface enhancement, not suppression, of crystal nucleation, and those showing a polymorphic change feature (1) structural reconstruction at the surface relative to the bulk and (2) existence of a different polymorph that can take advantage of the surface environment to nucleate. These results help predict the effect of a liquid/vapor interface on crystal nucleation and polymorph selection, especially in systems with a large surface/volume ratio, such as atmospheric water and amorphous particles.

Strained rings are increasingly important for the design of pharmaceutical candidates, but cross-coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all-carbon quaternary centers is the coupling of abundant strained-ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel-catalyzed cross-electrophile approach that couples a variety of strained ring N-hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that t-Bu BpyCam CN , an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96-well plates., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Stereoinduction in complex organic reactions often involves the influence of multiple stereocontrol elements. The interaction among these can often result in the observation of significant cooperative effects that afford different rates and selectivities between the matched and mismatched sets of stereodifferentiating chiral elements. The elucidation of matched/mismatched effects in ground-state chemical reactions was a critically important theme in the maturation of modern stereocontrolled synthesis. The development of robust methods for the control of photochemical reactions, however, is a relatively recent development, and similar cooperative stereocontrolling effects in excited-state enantioselective photoreactions have not previously been documented. Herein, we describe a tandem chiral photocatalyst/Brønsted acid strategy for highly enantioselective [2 + 2] photocycloadditions of vinylpyridines. Importantly, the matched and mismatched chiral catalyst pairs exhibit different reaction rates and enantioselectivities across a range of coupling partners. We observe no evidence of ground-state interactions between the catalysts and conclude that these effects arise from their cooperative behavior in a transient excited-state assembly. These results suggest that similar matched/mismatched effects might be important in other classes of enantioselective dual-catalytic photochemical reactions.

A green and optimized protocol has been developed for the preparation of symmetric 1,7-bis(aryl)-1,6-heptadiene-3,5-diones and asymmetric 2-aryl-6-arylidenecyclohexanones with modified substrate scope and good functional group tolerance. Syntheses proceed smoothly under solvent-free conditions, providing moderate to excellent product yields with a minimal workup procedure. Control experiments, spectroscopic, and computational studies support a mechanism involving the boron-assisted in situ generation of imine intermediates. Crystal structures of three curcuminoids and isolated mechanistic intermediates are reported. The data provide insight for the further development of solvent-free protocols toward diverse curcumin derivatives in the fields of pharmaceutical and synthetic chemistries., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Methods for rapid preparation of densely functionalized and stereochemically complex N -heterocyclic scaffolds are in demand for exploring potential bioactive chemical space. This work describes experimental and computational studies to better understand the features of aziridinium ylides as intermediates for the synthesis of highly substituted dehydromorpholines. The development of this chemistry has enabled the extension of aziridinium ylide chemistry to the concomitant formation of both a C-N and a C-O bond in a manner that preserves the stereochemical information embedded in the substrate. Additionally, we have uncovered several key insights that describe the importance of steric effects, rotational barriers around the C-N bond of the aziridinium ylide, and non-covalent interactions (NCIs) on the ultimate reaction outcome. These critical insights will assist in the further development of this chemistry to generate N -heterocycles that will further expand complex amine chemical space.

Control over the stereochemistry of excited-state photoreactions remains a significant challenge in organic synthesis. Recently, it has become recognized that the photophysical properties of simple organic substrates can be altered upon coordination to Lewis acid catalysts, and that these changes can be exploited in the design of highly enantioselective catalytic photoreactions. Chromophore activation strategies, wherein simple organic substrates are activated towards photoexcitation upon binding to a Lewis acid catalyst, rank among the most successful asymmetric photoreactions. Herein, we show that chiral Brønsted acids can also catalyze asymmetric excited-state photoreactions by chromophore activation. This principle is demonstrated in the context of a highly enantio- and diastereoselective [2+2] photocycloaddition catalyzed by a chiral phosphoramide organocatalyst. Notably, the cyclobutane products arising from this method feature a trans-cis stereochemistry that is complementary to other enantioselective catalytic [2+2] photocycloadditions reported to date., (© 2021. The Author(s).)

An expedient route to enantiopure, diastereomeric pyrrolopyrazinoquinazolinones was developed following the discovery of a domino quinazolinone rearrangement-intramolecular cyclization of N-H benzamidines. A Ugi-Mumm-Staudinger sequence employing an optically pure proline derivative gave quinazolinones that, upon N -Boc deprotection, rearranged to tautomeric Z -benzamidines. Subsequent spontaneous cyclization afforded 15 diastereomeric pyrazinoquinazolinone pairs in up to 83% overall yield and 89:11 d.r which were separated easily via routine chromatographic purification-the only one required in the entire process.

Aziridines-three-membered nitrogen-containing cyclic molecules-are important synthetic targets. Their substantial ring strain and resultant proclivity towards ring-opening reactions makes them versatile precursors of diverse amine products 1-3 , and, in some cases, the aziridine functional group itself imbues important biological (for example, anti-tumour) activity 4-6 . Transformation of ubiquitous alkenes into aziridines is an attractive synthetic strategy, but is typically accomplished using electrophilic nitrogen sources rather than widely available amine nucleophiles. Here we show that unactivated alkenes can be electrochemically transformed into a metastable, dicationic intermediate that undergoes aziridination with primary amines under basic conditions. This new approach expands the scope of readily accessible N-alkyl aziridine products relative to those obtained through existing state-of-the-art methods. A key strategic advantage of this approach is that oxidative alkene activation is decoupled from the aziridination step, enabling a wide range of commercially available but oxidatively sensitive 7 amines to act as coupling partners for this strain-inducing transformation. More broadly, our work lays the foundations for a diverse array of difunctionalization reactions using this dication pool approach., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

A series of nylon-like oligomers was synthesized, which consisted of alternating cyclic 1,2-diamine and 1,2-dicarboxylic acid building blocks with a five-membered ring constraint. The nylon 2 4 oligomers are symmetric and display helical structures similar to the β-peptide 12-helix with intramolecular 12-membered ring hydrogen bonds. The cyclopentane moiety allows each building block to promote 12-helical folding. In addition, a tartaric acid derivative with the acetonide moiety increases the solubility of oligomers in common organic solvents and promotes helical folding., (© 2021 Wiley-VCH GmbH.)

1,2-Bis{(3,5-dimethylpyrazol-1-yl)methyl}benzene (L) reacts with [Cu(OAc) 2 ] and C 6 H 5 COOH, 4-OH-C 6 H 4 COOH, 2-Cl-C 6 H 4 COOH and (3,5-NO 2 ) 2 -C 6 H 3 COOH to afford the copper complexes [Cu 2 (C 6 H 5 COO) 4 (L) 2 ] (1), [Cu 2 (4-OH-C 6 H 4 COO) 4 (L) 2 ] (2), [Cu 2 (2-Cl-C 6 H 4 COO) 4 (L) 2 ] n (3) and [Cu{(3,5-NO 2 ) 2 -C 6 H 3 COO} 2 L] n (4) which are characterised by IR, mass spectrometry, elemental analyses, and X-ray crystallography. The structural data revealed two geometries that are adopted by the complexes: (i) paddle wheel in 1, 2·7H 2 O, 3 and (ii) regular chains in 3 and 4. Magnetic studies show strong antiferromagnetic couplings in the paddle wheel complexes and a weak antiferromagnetic coupling in the monometallic chain one. Catalysis studies performed with these complexes (1-4) showed that they initiate ring opening polymerization (ROP) of ε-caprolactone (ε-CL) under solvent-free conditions and d,l-lactide in toluene at elevated temperatures. Polycaprolactone (PCL) and poly(d,l-lactide) (PLA) obtained from the polymerization reactions are of low molecular weights (858 for PCL and 602 Da for PLA for initiator 1) and polydispersity indices (typically 2.16 for PCL and 1.64 for PLA with 1 as the initiator). End group analysis of the polymers, determined by MALDI-ToF MS, indicates that the polymers have benzoate, hydroxyl, methoxy and cyclic end groups., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug-resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Layered two-dimensional Ruddlesden-Popper (RP) halide perovskites are an intriguing class of semiconductors being explored for their linear and nonlinear optical and ferroelectric properties. Second harmonic generation (SHG) is commonly used to screen for noncentrosymmetric and ferroelectric materials. However, SHG measurements of perovskites can be obscured by their intense multiphoton photoluminescence (mPL). Here, we apply multidimensional harmonic generation as a method to eliminate the complications from mPL. By scanning and correlating both excitation and emission frequencies, we unambiguously assess whether a material supports SHG by examining if an emission feature scales as twice the excitation frequency. Measurements of a series of n = 2, 3 RP perovskites reveal that, contrary to previous belief, n -butylammonium (BA) RP perovskites are not SHG-active and thus centrosymmetric, but RP perovskites with phenylethylammonium (PEA) and 2-thiophenemethylammonium (TPMA) spacer cations display SHG. This work establishes multidimensional harmonic generation as a definitive method to measure SHG in halide perovskites.

Asymmetric C-H amination via nitrene transfer is a powerful tool to prepare enantioenriched amine precursors from abundant C-H bonds. Herein, we report a regio- and enantioselective synthesis of γ-alkynyl γ-aminoalcohols via a silver-catalyzed propargylic C-H amination. The protocol was enabled by a new bis(oxazoline) (BOX) ligand designed via a rapid structure-activity relationship (SAR) analysis. The method utilizes accessible carbamate esters bearing γ-propargylic C-H bonds and furnishes versatile products in good yields and excellent enantioselectivity (90-99% ee ). The putative Ag-nitrene is proposed to undergo enantiodetermining hydrogen-atom transfer (HAT) during the C-H amination event. Density functional theory calculations shed insight into the origin of enantioselectivity in the HAT step.

Copper(I) iodide complexes are well known for displaying a diverse array of structural features even when only small changes in ligand design are made. This structural diversity is well displayed by five copper(I) iodide compounds reported here with closely related piperidine-2,6-di-thione (SNS), isoindoline-1,3-di-thione (SNS6), and 6-thioxopiperidin-2-one (SNO) ligands: di-μ-iodido-bis-[(aceto-nitrile-κ N )(6-sulfanylidenepiperidin-2-one-κ S )copper(I)], [Cu 2 I 2 (CH 3 CN) 2 (C 5 H 7 NOS) 2 ] ( I ), bis-(aceto-nitrile-κ N )tetra-μ 3 -iodido-bis-(6-sulfanylidenepiperidin-2-one-κ S )- tetra-hedro -tetra-copper(I), [Cu 4 I 4 (CH 3 CN) 4 (C 5 H 7 NOS) 4 ] ( II ), catena -poly[[(μ-6-sulfanylidenepiperidin-2-one-κ 2 O : S )copper(I)]-μ 3 -iodido], [CuI(C 5 H 7 NOS)] n ( III ), poly[[(piperidine-2,6-di-thione-κ S )copper(I)]-μ 3 -iodido], [CuI(C 5 H 7 NS 2 )] n ( IV ), and poly[[(μ-isoindoline-1,3-di-thione-κ 2 S : S )copper(I)]-μ 3 -iodido], [CuI(C 8 H 5 NS 2 )] n ( V ). Compounds I and II crystallize as discrete dimeric and tetra-meric complexes, whereas III , IV , and V crystallize as polymeric two-dimensional sheets. To the best of our knowledge, compound III is the first instance of an extended hexa-gonal [Cu 3 I 3 ] structure that is not supported by bridging ligands. Structures I , II , and IV display weak to moderately strong Cu⋯Cu cuprophilic inter-actions [Cu⋯Cu inter-nuclear distances range between 2.5803 (10) and 2.8485 (14) Å]. All structures except III display weak hydrogen-bonding inter-actions between the N-H of the ligand and the μ 2 and μ 3 -I - atoms. Structure III contains classical N-H⋯O inter-actions between the SNO ligands that connect the mol-ecules in a three-dimensional framework. Complex V features π-π stacking inter-actions between the aryl rings of the SNS6 ligands within the same polymeric sheet. In structure IV , there were three partially occupied solvent mol-ecules of di-chloro-methane and one partially occupied mol-ecule of aceto-nitrile present in the asymmetric unit. The SQUEEZE routine [Spek (2015 ▸). Acta Cryst . C 71 , 9-18] was used to correct the diffraction data for diffuse scattering effects and to identify the solvent mol-ecules. The given chemical formula and other crystal data do not take into account the solvent mol-ecules., (© Wheaton et al. 2020.)

Site selectivity represents a key challenge for non-directed C-H functionalization, even when the C-H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C-H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a Cu II -azide species via a radical-polar crossover pathway. Comparison of this method with other C-H azidation methods highlights its unique site selectivity, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.

Mono-N-protected amino acids (MPAAs) are increasingly common ligands in Pd-catalyzed C-H functionalization reactions. Previous studies have shown how these ligands accelerate catalytic turnover by facilitating the C-H activation step. Here, it is shown that MPAA ligands exhibit a second property commonly associated with ligand-accelerated catalysis: the ability to support catalytic turnover at substoichiometric ligand-to-metal ratios. This catalytic role of the MPAA ligand is characterized in stoichiometric C-H activation and catalytic C-H functionalization reactions. Palladacycle formation with substrates bearing carboxylate and pyridine directing groups exhibit a 50-100-fold increase in rate when only 0.05 equivalents of MPAA are present relative to Pd II . These and other mechanistic data indicate that facile exchange between MPAAs and anionic ligands coordinated to Pd II enables a single MPAA to support C-H activation at multiple Pd II centers., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses. Methods that introduce significant stereochemical complexity are attractive for identifying new bioactive amine chemical space. Here, we report a [3 + 3] ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate that the reaction proceeds through formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a pseudo-[1,4]-sigmatropic rearrangement to directly furnish heterocyclic products with net retention at the new C-C bond. In combination with asymmetric silver-catalyzed aziridination, enantioenriched scaffolds with up to three contiguous stereocenters are rapidly delivered. The mild reaction conditions, functional group tolerance, and high stereospecificity of this method are well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates for converting small, strained rings to larger N-heterocycles.

Forazoline A is a structurally complex PKS-NRPS hybrid produced by marine-derived Actinomadura sp. During the course of studies highlighting the application of IFS analysis as a powerful tool for natural products analysis, we were alerted to an earlier misinterpretation with respect to forazoline A structure elucidation. In particular, IFS reveals that forazoline A contains a thioketone moiety rarely seen in secondary metabolites and, thus, constitutes an even more intriguing structure than originally thought.

A highly efficient 2-chloroquinazolin-4(3H)-one rearrangement was developed that predictably generates either twisted-cyclic or ring-fused guanidines in a single operation, depending on the presence of a primary versus secondary amine in the accompanying diamine reagent. Exclusive formation of twisted-cyclic guanidines results from pairing 2-chloroquinazolinones with secondary diamines. Use of primary amine-containing diamines permits a domino quinazolinone rearrangement/intramolecular cyclization, gated through (E)-twisted-cyclic guanidines, to afford ring-fused N-acylguanidines. This scalable, structurally tolerant transformation generated 55 guanidines and delivered twisted-cyclic guanidines with robust plasma stability and an abbreviated total synthesis of an antitumor ring-fused guanidine (4 steps, 55 % yield)., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Conjugate addition of thiols to benzoquinones has been coupled to in situ electrochemical oxidation of the resulting hydroquinone to enable full substitution of quinone C-H bonds. The sulfonated thioether-substituted quinones exhibit high solublity and stability in aqueous solution and have redox potentials ranging from 440-750 mV vs. SHE. The electrosynthetic protocol is effective on >100 g scale.

Carbohydrates are synthetically challenging molecules with vital biological roles in all living systems. Selective synthesis and functionalization of carbohydrates provide tremendous opportunities to improve our understanding on the biological functions of this fundamentally important class of molecules. However, selective functionalization of seemingly identical hydroxyl groups in carbohydrates remains a long-standing challenge in chemical synthesis. We herein describe a practical and predictable method for the site-selective and stereoselective alkylation of carbohydrate hydroxyl groups via Rh(II)-catalyzed insertion of metal carbenoid intermediates. This represents one of the mildest alkylation methods for the systematic modification of carbohydrates. Density functional theory (DFT) calculations suggest that the site selectivity is determined in the Rh(II)-carbenoid insertion step, which prefers insertion into hydroxyl groups with an adjacent axial substituent. The subsequent intramolecular enolate protonation determines the unexpected high stereoselectivity. The most prevalent trans- 1,2-diols in various pyranoses can be systematically and predictably differentiated based on the model derived from DFT calculations. We also demonstrated that the selective O -alkylation method could significantly improve the efficiency and stereoselectivity of glycosylation reactions. The alkyl groups introduced to carbohydrates by OH insertion reaction can serve as functional groups, protecting groups, and directing groups.

Despite utilizing a common cofactor binding motif, hemoproteins bearing a cysteine-derived thiolate ligand (heme-thiolate proteins) are involved in a diverse array of biological processes ranging from drug metabolism to transcriptional regulation. Though the origin of heme-thiolate functional divergence is not well understood, growing evidence suggests that the hydrogen bonding (H-bonding) environment surrounding the Fe-coordinating thiolate influences protein function. Outside of X-ray crystallography, few methods exist to characterize these critical H-bonding interactions. Electron paramagnetic resonance (EPR) spectra of heme-thiolate proteins bearing a six-coordinate, Fe(III) heme exhibit uniquely narrow low-spin ( S = 1/2), rhombic signals, which are sensitive to changes in the heme-thiolate H-bonding environment. To establish a well-defined relationship between the magnitude of g -value dispersion in this unique EPR signal and the strength of the heme-thiolate H-bonding environment, we synthesized and characterized of a series of six-coordinate, aryl-thiolate-ligated Fe(III) porphyrin complexes bearing a tunable intramolecular H-bond. Spectroscopic investigation of these complexes revealed a direct correlation between H-bond strength and g -value dispersion in the rhombic EPR signal. Using density functional theory (DFT), we elucidated the electronic origins of the narrow, rhombic EPR signal in heme-thiolates, which arises from an Fe-S p π -d π bonding interaction. Computational analysis of the intramolecularly H-bonded heme-thiolate models revealed that H-bond donation to the coordinating thiolate reduces thiolate donor strength and weakens this Fe-S interaction, giving rise to larger g -value dispersion. By defining the relationship between heme-thiolate electronic structure and rhombic EPR signal, it is possible to compare thiolate donor strengths among heme-thiolate proteins through analysis of low-spin, Fe(III) EPR spectra. Thus, this study establishes EPR spectroscopy as a valuable tool for exploring how second coordination sphere effects influence heme-thiolate protein function.

The stability and formation of a perovskite structure is dictated by the Goldschmidt tolerance factor as a general geometric guideline. The tolerance factor has limited the choice of cations (A) in 3D lead iodide perovskites (APbI 3 ), an intriguing class of semiconductors for high-performance photovoltaics and optoelectronics. Here, we show the tolerance factor requirement is relaxed in 2D Ruddlesden-Popper (RP) perovskites, enabling the incorporation of a variety of larger cations beyond the methylammonium (MA), formamidinium, and cesium ions in the lead iodide perovskite cages for the first time. This is unequivocally confirmed with the single-crystal X-ray structure of newly synthesized guanidinium (GA)-based ( n -C 6 H 13 NH 3 ) 2 (GA)Pb 2 I 7 , which exhibits significantly enlarged and distorted perovskite cage containing sterically constrained GA cation. Structural comparison with ( n -C 6 H 13 NH 3 ) 2 (MA)Pb 2 I 7 reveals that the structural stabilization originates from the mitigation of strain accumulation and self-adjustable strain-balancing in 2D RP structures. Furthermore, spectroscopic studies show a large A cation significantly influences carrier dynamics and exciton-phonon interactions through modulating the inorganic sublattice. These results enrich the diverse families of perovskite materials, provide new insights into the mechanistic role of A-site cations on their physical properties, and have implications to solar device studies using engineered perovskite thin films incorporating such large organic cations., Competing Interests: The authors declare no competing financial interest.

An efficient four-step, six-transformation protocol was developed to afford bioactive N-alkyl- or N-arylamide (E)-arylamidines featuring strategic amidine C3 modifications which were inaccessible or low yielding by previous methods. This synthetic approach, exemplified with 24 amidines and requiring only a single purification, highlights a multicomponent Ugi-Mumm rearrangement to afford highly diversified quinazolinones which undergo regiospecific rearrangement to afford new amidines. The method extensively broadens the structural scope of this new class of trisubstituted amidines and demonstrates the tolerance of regional C3 amidine steric bulk, visualized with X-ray crystallographic analysis.

We have developed the first intermolecular hetero-[5+2] cycloaddition reaction between oxidopyrylium ylides and cyclic imines with excellent control of regio- and stereoselectivity. Surprisingly, divergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide. This new reaction provides quick access to highly substituted nitrogen-containing seven-membered rings-azepanes. Notably, a broad range of oxidopyrylium ylides and cyclic imines participate in this novel hetero-[5+2] cycloaddition reaction and the cycloadducts can be readily transformed into the core skeletons of bioactive natural products. DFT calculations revealed that the cycloaddition proceeds through a stepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The synthesis of densely functionalized azetidinesin a highly stereocontrolled manner is challenging, but interest in the bioactivities of these small heterocycles has stimulated methods for their preparation. We recently reported a one-carbon ring expansion of bicyclic methylene aziridines under dirhodium catalysis capable of delivering enantioenriched azetidines. This work explores this ring expansion using computational and experimental studies. DFT computations indicate that the reaction proceeds through formation of an aziridinium ylide, which is precisely poised for concerted, asynchronous ring-opening/closing to deliver the azetidines in a [2,3]-Stevens-type rearrangement. The concerted nature of this rearrangement is responsible for the stereospecificity of the reaction, where axial chirality from the initial allene substrate is transferred to the azetidine product with complete fidelity. The computed mechanistic pathway highlights the key roles of the olefin and the rigid structure of the methylene aziridine in differentiating our observed ring expansion from competing cheletropic elimination pathways noted with ylides derived from typical aziridines., Competing Interests: The authors declare no competing financial interest.