Harnessing Multistep Chalcogen Bonding Activation in the α-Stereoselective Synthesis of Iminoglycosides.

The use of noncovalent interactions (NCIs) has received significant attention as a pivotal synthetic handle. Recently, the exploitation of unconventional NCIs has gained considerable traction in challenging reaction manifolds such as glycosylation due to their capacity to facilitate entry into difficult-to-access sugars and glycomimetics. While investigations involving oxacyclic pyrano- or furanoside scaffolds are relatively common, methods that allow the selective synthesis of biologically important iminosugars are comparatively rare. Here, we report the capacity of a phosphonochalcogenide (PCH) to catalyze the stereoselective α-iminoglycosylation of iminoglycals with a wide array of glycosyl acceptors with remarkable protecting group tolerance. Mechanistic studies have illuminated the counterintuitive role of the catalyst in serially activating both the glycosyl donor and acceptor in the up/downstream stages of the reaction through chalcogen bonding (ChB). The dynamic interaction of chalcogens with substrates opens up new mechanistic opportunities based on iterative ChB catalyst engagement and disengagement in multiple elementary steps.

Tuning Reactivities of tert-Butyllithium by the Addition of Stoichiometric Amounts of Tetrahydrofuran.

In alkyllithium chemistry the highest reactivity has historically been linked to the smallest degree of aggregation possible. Since tert-butyllithium is known to form a monomer in tetrahydrofuran solution, using just stoichiometric amounts of the lewis base to selectively form a dimeric species seemed irrational. In this study, we showed a considerable increase of the reactivity of t-BuLi when using stoichiometric amounts of THF in the non-polar solvent n-pentane in order to enable the deprotonation of simple methyl silanes and other low C-H-acidic substrates. In this context, we were able to obtain the corresponding aggregates of t-BuLi with the ligand THF in suspension and as crystalline solids and investigate them by single crystal X-ray structural analysis, in situ FTIR spectroscopy and quantum chemical calculations. Furthermore, we were able to explain the enhanced reactivity of t-BuLi with stoichiometric amounts of THF on the basis of structural features of the bridged dimer obtained under these conditions. With these findings, we present a new target in the aggregation of alkyllithium reagents: the selectively formed "frustrated" aggregates!

Collective Synthesis of Sarpagine and Macroline Alkaloid-Inspired Compounds.

Design strategies that can access natural-product-like chemical space in an efficient manner may facilitate the discovery of biologically relevant compounds. We have employed a divergent intermediate strategy to construct an indole alkaloid-inspired compound collection derived from two different molecular design principles, i.e. biology-oriented synthesis and pseudo-natural products. The divergent intermediate was subjected to acid-catalyzed or newly discovered Sn-mediated conditions to selectively promote intramolecular C- or N-acylation, respectively. After further derivatization, a collection totalling 84 compounds representing four classes was obtained. Morphological profiling via the cell painting assay coupled with a subprofile analysis showed that compounds derived from different design principles have different bioactivity profiles. The subprofile analysis suggested that a pseudo-natural product class is enriched in modulators of tubulin, and subsequent assays led to the identification of compounds that suppress in vitro tubulin polymerization and mitotic progression.

Enantioselective Synthesis of Phosphine Boranes via Crystallization-Induced Dynamic Resolution of Lithiated Intermediate by Understanding the Underlying Epimerization Process.

Described herein is the successful crystallization-induced dynamic resolution (CIDR) of an α-lithiated phosphine borane utilizing the easily accessible and inexpensive ligand (R,R)-TMCDA. Starting from the essential P-prochiral building block dimethyl phenyl phosphine borane we were able to obtain phosphine boranes in yields up to 80 % and e.r. up to 98 : 2 by crystallization of the lithiated intermediate prior to the trapping reaction. NMR-based deuterium labeling experiments indicate that the epimerization in solution is based on the intermolecular proton transfer between nonlithiated phosphine borane and the corresponding lithiated intermediate, rendering the presence of the remaining starting compound in an optimized solvent mixture the main factor for successful enantioselective synthesis. Quantum chemical calculations using different model systems based on solid state structures confirm these experimental results. By gaining insights into the epimerization mechanism, essential principles for CIDR of lithiated phosphine boranes are elucidated that may be expanded to other important P-stereogenic compounds and simple chiral amines.

Stereoselective Entry into α,α'-C-Oxepane Scaffolds through a Chalcogen Bonding Catalyzed Strain-Release C-Septanosylation Strategy.

The utility of unconventional noncovalent interactions (NCIs) such as chalcogen bonding has lately emerged as a robust platform to access synthetically difficult glycosides stereoselectively. Herein, we disclose the versatility of a phosphonochalcogenide (PCH) catalyst to facilitate access into the challenging, but biologically interesting 7-membered ring α,α'-C-disubstituted oxepane core through an α-selective strain-release C-glycosylation. Methodically, this strategy represents a switch from more common but entropically less desired macrocyclizations to a thermodynamically favored ring-expansion approach. In light of the general lack of stereoselective methods to access C-septanosides, a remarkable palette of silyl-based nucleophiles can be reliably employed in our method. This include a broad variety of useful synthons, such as easily available silyl-allyl, silyl-enol ether, silyl-ketene acetal, vinylogous silyl-ketene acetal, silyl-alkyne and silylazide reagents. Mechanistic investigations suggest that a mechanistic shift towards an intramolecular aglycone transposition involving a pentacoordinate silicon intermediate is likely responsible in steering the stereoselectivity.

Exploiting π and Chalcogen Interactions for the ß-Selective Glycosylation of Indoles through Glycal Conformational Distortion.

Harnessing unconventional noncovalent interactions (NCIs) is emerging as a formidable synthetic approach in difficult-to-access glycosidic chemical space. C-Glycosylation, in particular, has gained a flurry of recent attention. However, most reported methods are restricted to the relatively facile access to α-C-glycosides. Herein, we disclose a ß-stereoselective glycosylation of indoles by employing a phosphonoselenide catalyst. The robustness of this protocol is exemplified by its amenability for reaction at both the indolyl C- and N- reactivity sites. In contrast to previous reports, in which the chalcogens were solely involved in Lewis acidic activation, our mechanistic investigation unraveled that the often neglected flanking aromatic substituents of phosphonoselenides can substantially contribute to catalysis by engaging in π-interactions. Computations and NMR spectroscopy indicated that the chalcogenic and aromatic components of the catalyst can be collectively exploited to foster conformational distortion of the glycal away from the usual half-chair to the boat conformation, which liberates the convex ß-face for nucleophilic attack.

Asymmetric Pd/Organoboron-Catalyzed Site-Selective Carbohydrate Functionalization with Alkoxyallenes Involving Noncovalent Stereocontrol.

Herein, we demonstrate the robustness of a synergistic chiral Pd/organoboron system in tackling a challenging suite of site-, regio-, enantio- and diastereoselectivity issues across a considerable palette of biologically relevant carbohydrate polyols, when prochiral alkoxyallenes were employed as electrophiles. In view of the burgeoning role of noncovalent interactions (NCIs) in stereoselective carbohydrate synthesis, our mechanistic experiments and DFT modeling of the reaction path unexpectedly revealed that NCIs such as hydrogen bonding and CH-π interactions between the resting states of the Pd-π-allyl complex and the borinate saccharide are critically involved in the stereoselectivity control. Our strategy thus illuminates the untapped potential of harnessing NCIs in the context of transition metal catalysis to tackle stereoselectivity challenges in carbohydrate functionalization.

Cooperative Bifurcated Chalcogen Bonding and Hydrogen Bonding as Stereocontrolling Elements for Selective Strain-Release Septanosylation.

The exploitation of noncovalent interactions (NCIs) is emerging as a vital handle in tackling broad stereoselectivity challenges in synthesis. In particular, there has been significant recent interest in the harnessing of unconventional NCIs to surmount difficult selectivity challenges in glycosylations. Herein, we disclose the exploitation of an unconventional bifurcated chalcogen bonding and hydrogen bonding (HB) network, which paves the way for a robust catalytic strategy into biologically useful seven-membered ring sugars. Through 13C nuclear magnetic resonance (NMR) in situ monitoring, NMR titration experiments, and density functional theory (DFT) modeling, we propose a remarkable contemporaneous activation of multiple functional groups consisting of a bifurcated chalcogen bonding mechanism working hand-in-hand with HB activation. Significantly, the ester moiety installed on the glycosyl donor is critical in the establishment of the postulated ternary complex for stereocontrol. Through the 13C kinetic isotopic effect and kinetic studies, our data corroborated that a dissociative SNi-type mechanism forms the stereocontrolling basis for the excellent α-selectivity.

A Silicon-Stereogenic Silanol - 18 O-Isotope Labeling and Stereogenic Probe Reveals Hidden Stereospecific Water Exchange Reaction.

A silicon-stereogenic aminosilanol was isolated in excellent diastereomeric ratio and the absolute configuration was determined. The silanol is configurative and condensation stable in solution and shows stereoselective transformations with a clean stereospecific pathway in follow-up reactions, which leads to the isolation of a silicon-stereogenic zinc complex and siloxane compounds. Investigations with 18 O-labelled water and mass spectrometry analysis revealed an otherwise hidden exchange of oxygen atoms of silanol and water in solution that proceeds with retention of the configuration at the silicon center. This novel combination of a stereochemical probe and isotopic labeling in a silicon-stereogenic compound opens new analytic possibilities to study stereochemical courses of reactions with the aid of chiral silanols mechanistically.

Simultaneous observation of halogen-lone pair and halogen-π interactions of ferrocene derivatives under cryogenic conditions.

Contrasting cryosolutions and matrix isolation infrared spectroscopy, we investigate weak intermolecular interactions in complexes of iodo trifluoroethene (C2F3I) and N,N-dimethyl ferrocenyl amine as well as the parent ferrocene. In liquid xenon, solely the C-I⋯N halogen bond can be observed, while the confined environment in solid argon allows for the characterization of C-I⋯π and π⋯π bonded complexes.

Synthesis of Tetracyclic Spirooxindolepyrrolidine-Engrafted Hydantoin Scaffolds: Crystallographic Analysis, Molecular Docking Studies and Evaluation of Their Antimicrobial, Anti-Inflammatory and Analgesic Activities.

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out.

Comprehensive Study of the Enhanced Reactivity of Turbo-Grignard Reagents.

Since its introduction in 2004, Knochel's so called Turbo-Grignard reagents revolutionized the usage of Grignard reagents. Through the simple addition of LiCl to a magnesium alkyl an outstanding increase in reactivity can be achieved. Though the exact composition of the reactive species remained mysterious, the reactive mixture itself is readily used not only in synthesis but also found its way into more distant fields like material science. To unravel this mystery, we combined single-crystal X-ray diffraction with in-solution NMR-spectroscopy and closed our investigations with quantum chemical calculations. Using such a variety of methods, we have gained insight into and an explanation for the extraordinary reactivity of this extremely convenient reagent by determining the structure of the first bimetallic reactive species [t-Bu2 Mg ⋅ LiCl ⋅ 4 thf] with two tert-butyl anions at the magnesium center and incorporated lithium chloride.

Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles.

Oxindoles and iso-oxindoles are natural product-derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso-oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective RhIII -catalyzed scaffold-divergent synthesis of spirooxindole-isooxindoles and spirooxindole-oxindoles from differently protected diazooxindoles and N-pivaloyloxy aryl amides which includes a functional group-controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space.

Monoterpene indole alkaloids (MIAs) are endowed with high structural and spatial complexity and characterized by diverse biological activities. Given this complexity-activity combination in MIAs, rapid and efficient access to chemical matter related to and with complexity similar to these alkaloids would be highly desirable, since such compound classes might display novel bioactivity. We describe the design and synthesis of a pseudo-natural product (pseudo-NP) collection obtained by the unprecedented combination of MIA fragments through complexity-generating transformations, resulting in arrangements not currently accessible by biosynthetic pathways. Cheminformatic analyses revealed that both the pseudo-NPs and the MIAs reside in a unique and common area of chemical space with high spatial complexity-density that is only sparsely populated by other natural products and drugs. Investigation of bioactivity guided by morphological profiling identified pseudo-NPs that inhibit DNA synthesis and modulate tubulin. These results demonstrate that the pseudo-NP collection occupies similar biologically relevant chemical space that Nature has endowed MIAs with.

Towards Substrate-Reagent Interaction of Lochmann-Schlosser Bases in THF: Bridging THF Hides Potential Reaction Site of a Chiral Superbase.

The metalation of N,N-dimethylaminomethylferrocene in THF by the superbasic mixture of n BuLi/KOt Bu proceeds readily at low temperatures to afford a bimetallic Li2 K2 aggregate containing ferrocenyl anions and tert-butoxide. Starting from an enantiomerically enriched ortho-lithiated aminomethylferrocene, an enantiomerically pure superbase can be prepared. The molecular compound exhibits superbasic behavior deprotonating N,N-dimethylbenzylamine in the α-position and is also capable of deprotonating toluene. Quantum chemical calculations provide insight into the role of the bridging THF molecule to the possible substrate-reagent interaction. In addition, a benzylpotassium alkoxide adduct gives a closer look into the corresponding reaction site of the Lochmann-Schlosser base that is reported herein.

Chain Length Effect on the Structural and Emission Properties of the CuI/Bis((4-methoxyphenyl)thio)alkane Coordination Polymers.

A systematic chain length variation of the ligand para-MeOC6H4S(CH2)mSC6H4OMe (1 ≤ m ≤ 8) was performed to study its effect on the structures and photophysical properties of the coordination polymers (CP) when reacted with CuI. Indeed, direct correlations are noted between these features and m. When m is an odd number, the secondary building unit is systematically the common closed-cubane Cu4I4 cluster, rendering the material strongly luminescent (i.e., emission quantum yield, Φe > 20%), and the CP is one-dimensional (1D). However, when m is 2, 4, and 6, the SBUs exhibit rare polymeric motifs of (Cu2I2)n: staircase ribbon, fused poly(rhombic pseudo-dodecahedron), and accordion ribbon, respectively, and the emission intensities are either very weak (Φe < 0.001%) or of medium intensity (Φe ∼ 10% when m = 6). When m = 8 (i.e. the most flexible chain), the SBU is a closed-cubane Cu4I4 and the emission intensity is medium (Φe ∼ 10%). A special case was observed for m = 3, where a co-crystallization of the molecular cluster Cu4I4(NCCH3)4 is observed in the lattice, which turns out to be quite important for the stability of the network.

Design of Novel Enantiopure Dispirooxindolopyrrolidine-Piperidones as Promising Candidates toward COVID-19: Asymmetric Synthesis, Crystal Structure and In Silico Studies.

Despite the effectiveness of COVID-19 vaccines, there is still an urgent need for discovering new anti-viral drugs to address the awful spread and transmission of the rapidly modifiable virus. In this study, the ability of a small library of enantiomerically pure spirooxindolopyrrolidine-grafted piperidones to inhibit the main protease of SARS-CoV-2 (Mpro) is evaluated. These spiroheterocycles were synthesized by 1,3-dipolar cycloaddition of various stabilized azomethine ylides with chiral dipolarophiles derived from N-[(S)-(-)-methylbenzyl]-4-piperidone. The absolute configuration of contiguous carbons was confirmed by a single crystal X-ray diffraction analysis. The binding of these compounds to SARS-CoV-2 Mpro was investigated using molecular docking and molecular dynamics simulation. Three compounds 4a, 4b and 4e exhibited stable binding modes interacting with the key subsites of the substrate-binding pocket of SARS-CoV-2 Mpro. The synthesized compounds represent potential leads for the development of novel inhibitors of SARS-CoV-2 main protease protein for COVID-19 treatment.

Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds.

A novel series of 14 spiropyrrolidines bearing thiochroman-4-one/chroman-4-one, and oxindole/acenaphthylene-1,2-dione moieties were synthesized and characterized by spectroscopic techniques, as well as by three X-ray diffraction studies, corroborating the stereochemistry. Quantum chemical calculations studies, using the DFT approach, were performed to rationalize the stereochemical outcome. These N-heterocycles were evaluated for their antibacterial and antifungal activities against some pathogenic organisms. Several compounds displayed moderate to excellent activity towards the screened microbe strains in the study compared to Amoxicillin (AMX), Ampicillin (AMP), and Amphotericin B. Furthermore, a structural activity relationship (SAR) was established considering the synthesized compounds. Pharmacokinetic studies reveal that these derivatives exhibit an acceptable predictive ADMET profile (Absorption, Distribution, Metabolism, Excretion and Toxicity) and good drug-likeness.

Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype.

Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.

The Pseudo-Natural Product Rhonin Targets RHOGDI.

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment-based design. We describe the de novo combination of different 5-membered NP-derived N-heteroatom fragments to structurally unprecedented "pseudo-natural products" in an efficient complexity-generating and enantioselective one-pot synthesis sequence. The pseudo-NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP-derived chemotypes, and may have novel biological targets. Investigation of the pseudo-NPs in unbiased phenotypic assays and target identification led to the discovery of the first small-molecule ligand of the RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP-bound RHO GTPases and alters the subcellular localization of RHO GTPases.