Kinetically E-selective macrocyclic ring-closing metathesis.

Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization-a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl-B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib-a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis-was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.

Synthesis and duplex-forming ability of oligonucleotides modified with 4'-C,5'-C-methylene-bridged nucleic acid (4',5'-BNA).

We describe herein the design and synthesis of 4'-C,5'-C-methylene-bridged nucleic acid (4',5'-BNA), a novel artificial nucleic acid with the torsion angle γ in a non-canonical +ac range. The 4',5'-BNA phosphoramidite bearing a thymine nucleobase was synthesized from a commercially available thymidine analog in 11 steps and successfully incorporated into oligonucleotides. The resulting oligonucleotides were evaluated for their duplex-forming ability toward single-stranded DNA and RNA.

Multifaceted activity of polyciclic MDR revertant agents in drug-resistant leukemic cells: Role of the spacer.

A small library of derivatives carrying a polycyclic scaffold recently identified by us as a new privileged structure in medicinal chemistry was designed and synthesized, aiming at obtaining potent MDR reverting agents also endowed with antitumor properties. In particular, as a follow-up of our previous studies, attention was focused on the role of the spacer connecting the polycyclic core with a properly selected nitrogen-containing group. A relevant increase in reverting potency was observed, going from the previously employed but-2-ynyl- to a pent-3-ynylamino moiety, as in compounds 3d and 3e, while the introduction of a triazole ring proved to differently impact on the activity of the compounds. The docking results supported the data obtained by biological tests, showing, for the most active compounds, the ability to establish specific bonds with P-glycoprotein. Moreover, a multifaceted anticancer profile and dual in vitro activity was observed for all compounds, showing both revertant and antitumor effects on leukemic cells. In this respect, 3c emerged as a "triple-target" agent, endowed with a relevant reverting potency, a considerable antiproliferative activity and a collateral sensitivity profile.

Biomimetic Total Synthesis of Enterocin.

The first chemical total synthesis of the highly oxygenated polyketide enterocin has been accomplished. The key step of the synthesis was a late-stage biomimetic reaction cascade involving two intramolecular aldol reactions in which each step proceeded in 52 % yield (averaged) and which established four of the seven stereogenic centers. The pivotal precursor for the cascade reaction was assembled from three readily available building blocks. A chiral dithioacetal with two stereogenic centers originating from L-arabinose represented the core fragment to both ends of which the other building blocks were attached by aldol reactions. The remaining stereogenic center was installed by Davis oxygenation immediately prior to the key step.

CaMn3IV O4 Cubane Models of the Oxygen-Evolving Complex: Spin Ground States S<9/2 and the Effect of Oxo Protonation.

We report the single crystal XRD and MicroED structure, magnetic susceptibility, and EPR data of a series of CaMn3IV O4 and YMn3IV O4 complexes as structural and spectroscopic models of the cuboidal subunit of the oxygen-evolving complex (OEC). The effect of changes in heterometal identity, cluster geometry, and bridging oxo protonation on the spin-state structure was investigated. In contrast to previous computational models, we show that the spin ground state of CaMn3IV O4 complexes and variants with protonated oxo moieties need not be S=9/2. Desymmetrization of the pseudo-C3 -symmetric Ca(Y)Mn3IV O4 core leads to a lower S=5/2 spin ground state. The magnitude of the magnetic exchange coupling is attenuated upon oxo protonation, and an S=3/2 spin ground state is observed in CaMn3IV O3 (OH). Our studies complement the observation that the interconversion between the low-spin and high-spin forms of the S2 state is pH-dependent, suggesting that the (de)protonation of bridging or terminal oxygen atoms in the OEC may be connected to spin-state changes.

A General Supramolecular Approach to Regulate Protein Functions by Cucurbit[7]uril and Unnatural Amino Acid Recognition.

Regulation of specific protein function is of great importance for both research and therapeutic development. Many small or large molecules have been developed to control specific protein function, but there is a lack of a universal approach to regulate the function of any given protein. We report a general host-guest molecular recognition approach involving modification of the protein functional surfaces with genetically encoded unnatural amino acids bearing guest side chains that can be specifically recognized by cucurbit[7]uril. Using two enzymes and a cytokine as models, we showed that the activity of proteins bearing unnatural amino acid could be turned off by host molecule binding, which blocked its functional binding surface. Protein activity can be switched back by treatment with a competitive guest molecule. Our approach provides a general tool for reversibly regulating protein function through molecular recognition and can be expected to be valuable for studying protein functions.

Recent progress on the total syntheses of macrocyclic diamine alkaloids.

Covering: 2006 to 2019Macrocyclic diamine alkaloids derived from 3-alkyldihydropyridine dimers comprise a diverse and highly complex family of natural products. The macrocyclic and caged structural features of these alkaloids have inspired many creative solutions from the synthetic organic community over the past 30 years. This review will cover the successful synthetic campaigns over the past decade, with a focus on (1) key bond disconnections and advances and (2) remaining challenges and opportunities for innovation within this natural product class.

Occurrence, synthesis and applications of natural and designed [3.3.3]propellanes.

Covering: 1978 to 2019 The synthetically challenging [3.3.3]propellane core has caught a lot of attention over the last 50 years. This comprehensive review details all synthetic strategies reported in the period 1978-2019 to facilitate the synthesis of carbocyclic [3.3.3]propellanes. The described strategies span from acid-catalyzed rearrangements and photo-mediated cycloadditions of ketones, heteropropellanes and dispiroundecanes to thermal rearrangements of acetylenes and alkenes. Other approaches, such as radical reactions with halogenated alkenes, domino cyclizations, the smart use of epoxide-carbonyl rearrangements and intramolecular palladium-catalyzed ring contractions are discussed as well. A special section is dedicated to triptindanes, a subclass of [3.3.3]propellanes which are of interest to material sciences.

Cyclophanes as Platforms for Reactive Multimetallic Complexes.

Multimetallic cofactors supported by weak-field donors frequently function as reaction centers in metalloproteins, and many of these cofactors catalyze small molecule activation (e.g., N2, O2, CO2) with prominent roles in geochemical element cycles or detoxification. Notable examples include the iron-molybdenum cofactor of the molybdenum-dependent nitrogenases, which catalyze N2 fixation, and the NiFe4S4 cluster and the Mo(O)SCu site in various carbon monoxide dehydrogenases. The prevailing proposed reaction mechanisms for these multimetallic cofactors relies on a cooperative pathway, in which the oxidation state changes are distributed over the aggregate coupled with orbital overlap between the substrate and more than one metal ion within the cluster. Such cooperativity has also been proposed for chemical transformations at the surfaces of heterogeneous catalysts. However, the design details that afford cooperative effects and allow such reactivity to be harnessed effectively in homogeneous synthetic systems remain unclear. Relatedly, hydride donors ligated to these metal cluster cofactors are suggested as precursors to the state that reacts with substrates; here too, however, the reactivity of hydride-decorated clusters supported by weak-field ligands is underexplored. Inspired by the reactivity potential of multimetallic assemblies evidenced in biological systems, approaches to design, synthesize, and evaluate reactivity of polynuclear metal compounds have been actively explored. In a similar vein to the templating function afforded by enzyme active sites, a carefully engineered organic ligand can be employed to control metal nuclearity of the complex and the local coordination environment of each metal center. This Account presents our efforts within this field, beginning with ligand design considerations followed by a survey of observed small molecule activation by trimetallic cyclophanates. We highlight the distinct reactivity outcomes accessed by multimetallic compounds as compared to aggregates that assemble in reaction mixtures from monometallic precursors. Contributing to the opportunity for programmed cooperativity in these designed multimetallic compounds, the cyclophane also dictates the orientation of substrate binding and metal-substrate interactions, which has a prominent influence on reactivity. For example, the dinitrogen-tricopper(I) cyclophanate reacts with dioxygen with markedly different results as compared to monocopper compounds. As an unexpected outcome, one series of tricopper compounds were discovered to be competent catalysts for carbon dioxide reduction to oxalate-a formally one-electron process-hinting at an inherently broader reaction scope for weak-field clusters at lowering the barrier for one-electron pathways as well as multielectron redox transformations. Further reflecting the role of the ligand in tuning reactivity, the trimetallic trihydride cluster compounds, [M3(µ-H)3]3+ (M = FeII, CoII, ZnII), demonstrate substrate specificity for CO2 over various other unsaturated molecules and surprising stability toward water. This series reflects the role of the local environment of a shallow ligand pocket to control substrate access. Summed together, the systems described here evidence the anticipated cooperative reactivity accessed in designed multimetallic species vs self-assembled monometallic systems (e.g., O2 activation and O atom transfer) as well as control of substrate access by seemingly subtle structural effects. Indeed, future efforts aim to interrogate the limits of cooperativity in these systems as well as the role of ligand dynamics and sterics on reactivity.

Synthesis and biological activity of C-7, C-9 and C-10 modified taxane analogues from 1-deoxybaccatin VI.

A series of C-7, C-9 and C-10 modified taxane analogues were synthesized and their in vitro anticancer activities against three human cancer cell lines: A-549 (human lung cancer cell line), MDA-MB-231 (human breast cancer cell line), A-549/T (human lung cancer resistant cell line) were studied. The novel 1-deoxybaccatin VI derivatives modified with carbonate group at C-9 and C-10 positions enable the behavior of these compounds to be evidently distinct from other similar compounds. The strong cytotoxicity in the three cell lines, especially in drug-resistant cell line, showed by the newly synthesized taxane analogues indicated them as potential lead compounds for anticancer drug design.

Contiguous Quaternary Carbons: A Selection of Total Syntheses.

Contiguous quaternary carbons in terpene natural products remain a major challenge in total synthesis. Synthetic strategies to overcome this challenge will be a pivotal prerequisite to the medicinal application of natural products and their analogs or derivatives. In this review, we cover syntheses of natural products that exhibit a dense assembly of quaternary carbons and whose syntheses were uncompleted until recently. While discussing their syntheses, we not only cover the most recent total syntheses but also provide an update on the status quo of modern syntheses of complex natural products. Herein, we review (±)-canataxpropellane, (+)-waihoensene, (-)-illisimonin A and (±)-11-O-debenzoyltashironin as prominent examples of natural products bearing contiguous quaternary carbons.

Stereodivergent Synthesis of Camphor-Derived Diamines and Their Application as Thiourea Organocatalysts.

A series of 18 regio- and stereo-chemically diverse chiral non-racemic 1,2-, 1,3-, and 1,4-diamines have been synthesized from commercial (1S)-(+)-ketopinic acid and (1S)-(+)-10-camphorsulfonic acid. The structures of the diamines are all based on the d-(+)-camphor scaffold and feature isomeric diversity in terms of regioisomeric attachment of the primary and the tertiary amine function and the exo/endo-isomerism. Diamines were transformed into the corresponding noncovalent bifunctional thiourea organocatalysts, which have been evaluated for catalytic activity in the conjugative addition of 1,3-dicarbonyl nucleophiles (dimethyl malonate, acetylacetone, and dibenzoylmethane) to trans-ß-nitrostyrene. The highest enantioselectivity was achieved in the reaction with acetylacetone as nucleophile using endo-1,3-diamine derived catalyst 52 (91.5:8.5 er). All new organocatalysts 48-63 have been fully characterized. The structures and the absolute configurations of eight intermediates and thiourea derivative 52 were also determined by X-ray diffraction.

Biomimetic Approach Toward Enterocin and Deoxyenterocin.

Enterocin (vulgamycin) is a structurally remarkable natural product with significant antibiotic activity. The synthesis of a linear polyketide resembling a biosynthetic precursor was achieved using an unusual acyloin reaction. A diazo group was introduced as a protecting group for an enolizable ketone. We were unable to bring about the envisioned biomimetic aldol addition cascade and gained insights into the feasibility of this process by DFT calculations. As an alternative approach to enterocin, we developed a Cu-catalyzed intramolecular cyclopropanation followed by a MgI2-induced fragmentation to install the 2-oxabicyclo[3.3.1]nonane core of the natural product.

Design, synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives: Potential anticancer agents.

A large number of natural products containing the propellane scaffold have been reported to exhibit cytotoxicity against several cancers; however, their mechanism of action is still unknown. Anticancer drugs targeting DNA are mainly composed of small planar molecule/s that can interact with the DNA helix, causing DNA malfunction and cell death. The aim of this study was to design and synthesize propellane derivatives that can act as DNA intercalators and/or groove binders. The unique structure of the propellane derivatives and their ability to display planar ligands with numerous possible geometries, renders them potential starting points to design new drugs targeting DNA in cancer cells. New substituted furo-imidazo[3.3.3]propellanes were synthesized via the reaction of substituted alkenylidene-hydrazinecarbothioamides with 2-(1,3-dioxo-2,3-dihydro-1H-2-ylidene)propanedinitrile in tetrahydrofuran at room temperature. The structures of the products were confirmed by a combination of elemental analysis, NMR, ESI-MS, IR and single crystal X-ray analysis. Interestingly, 5c, 5d and 5f showed an ability to interact with Calf Thymus DNA (CT-DNA). Their DNA-binding mode was investigated using a combination of absorption spectroscopy, DNA melting, viscosity, CD spectroscopy measurements, as well as competitive binding studies with several dyes. Their cytotoxicity was evaluated against the NCI-60 panel of cancer cell lines. 5c, 5d and 5f exhibited similar anti-proliferative activity against the A549 non-small cell lung cancer (NSCLC) cell line. Further mechanistic studies revealed their ability to induce DNA damage in the A549 cell line, as well as apoptosis, evidenced by elevated Annexin V expression, enhanced caspase 3/7 activation and PARP cleavage. In this study, we present the potential for designing novel propellanes to provoke cytotoxic activity, likely through DNA binding-induced DNA damage and apoptosis.

Synthesis and Cytotoxicity of 7,9-O-Linked Macrocyclic C-Seco Taxoids.

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and ßIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ßIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ßIII.

Rearrangement of Hydroxylated Pinene Derivatives to Fenchone-Type Frameworks: Computational Evidence for Dynamically-Controlled Selectivity.

An acid-catalyzed Prins/semipinacol rearrangement cascade reaction of hydroxylated pinene derivatives that leads to tricyclic fenchone-type scaffolds in very high yields and diastereoselectivity has been developed. Quantum chemical analysis of the selectivity-determining step provides support for the existence of an extremely flat potential energy surface around the transition state structure. This transition state structure appears to be ambimodal, i.e., the fenchone-type tricyclic scaffolds are formed in preference to the competing formation of a bornyl (camphor-type) skeleton under dynamic control via a post-transition state bifurcation (PTSB).

Total Synthesis of Parvineostemonine by Structure Pattern Recognition: A Unified Approach to Stemona and Sarpagine Alkaloids.

Through structure pattern recognition based total synthesis we designed a synthesis in which two biogenetically unrelated natural product families (Stemona- and Sarpagine alkaloids) share 50 % of their synthetic sequence. In this report, the efficiency of such a strategic approach is demonstrated in the total synthesis of the Stemona alkaloid parvineostemonine, proceeding through a privileged intermediate that we have previously transformed into biogenetically completely unrelated Sarpagine alkaloids. In addition, we capitalized on the symmetry properties of the privileged intermediate, which was obtained as two regioisomers. After their separation by column chromatography the two regioisomers were converted to the corresponding pair of enantiomers by one transformation. To the best of our knowledge, this feature (conversion of regioisomers to enantiomers) has never been applied to natural product synthesis, and proved to be very valuable, since it allowed to obtain both optical antipodes of parvineostemonine in a single synthetic campaign. This not only enabled the determination of the previously undisclosed absolute configuration of the natural product, but gave 60-200 mg amounts of both enantiomers of the natural product.

Characterization of a helminthosporic acid analog that is a selective agonist of gibberellin receptor.

Helminthosporol, a natural growth regulator isolated from a fungus, stimulates hypocotyl growth and seed germination, similar to gibberellin (GA). We recently reported that helminthosporic acid (H-acid), a synthetic analog of helminthosporol, acts as an agonist of GA receptor. In this study, we showed that a H-acid analog, in which the hydroxymethyl group at the C-8 position of H-acid was converted to a keto group, acts as a selective GA receptor agonist. 1) This analog shows higher hypocotyl elongation activity in Arabidopsis than H-acid does, and induces the degradation of DELLA protein and 2) leads to the formation of the GID1-DELLA complex and 3) regulates the expression of GA-related genes. In addition, 4) its hypocotyl elongation activity was not observed in a atgid1a single mutant, and 5) this analog could promote only the interaction between specific GA receptors and DELLA proteins in vitro. Taken together, our results strongly suggest that the selectivity of the reported H-acid analog depends on the specificity of its GA receptor binding activity.

Through-Space Paramagnetic NMR Effects in Host-Guest Complexes: Potential Ruthenium(III) Metallodrugs with Macrocyclic Carriers.

The potential of paramagnetic ruthenium(III) compounds for use as anticancer metallodrugs has been investigated extensively during the past several decades. However, the means by which these ruthenium compounds are transported and distributed in living bodies remain relatively unexplored. In this work, we prepared several novel ruthenium(III) compounds with the general structure Na+[ trans-RuIIICl4(DMSO)(L)]- (DMSO = dimethyl sulfoxide), where L stands for pyridine or imidazole linked with adamantane, a hydrophobic chemophore. The supramolecular interactions of these compounds with macrocyclic carriers of the cyclodextrin (CD) and cucurbit[ n]uril (CB) families were investigated by NMR spectroscopy, X-ray diffraction analysis, isothermal titration calorimetry, and relativistic DFT methods. The long-range hyperfine NMR effects of the paramagnetic guest on the host macrocycle are related to the distance between them and their relative orientation in the host-guest complex. The CD and CB macrocyclic carriers being studied in this account can be attached to a vector that attracts the drug-carrier system to a specific biological target and our investigation thus introduces a new possibility in the field of targeted delivery of anticancer metallodrugs based on ruthenium(III) compounds.

Stereo- and regioselective photocycloaddition of extended alkenes using γ-cyclodextrin.

Photoexcitation of dibenzalacetones (1a-d) in homogeneous media and solid state yields a mixture of products with poor conversions. Irradiation of the reactants complexed to γ-cyclodextrin predominantly affords a single dimer (syn adduct 6) despite the possibility for several monomeric and dimeric products. High selectivity in the cavitand-mediated reaction along with the structural characterization of the inclusion complex provides insight into the supramolecular interactions that drive the self-assembly of the host-guest system.