Gold-Catalyzed 1,2-Aryl Shift and Double Alkyne Benzannulation.

The tandem intramolecular hydroarylation of alkynes accompanied by a 1,2-aryl shift is described. Harnessing the unique electron-rich character of 1,4-dihydropyrrolo[3,2-b]pyrrole scaffold, we demonstrate that the hydroarylation of alkynes proceeds at the already occupied positions 2 and 5 leading to a 1,2-aryl shift. Remarkably, the reaction proceeds only in the presence of cationic gold catalyst, and it leads to heretofore unknown π-expanded, centrosymmetric pyrrolo[3,2-b]pyrroles. The utility is verified in the preparation of 13 products that bear six conjugated rings. The observed compatibility with various functional groups allows for increased tunability with regard to the photophysical properties as well as providing sites for further functionalization. Computational studies of the reaction mechanism revealed that the formation of the six-membered rings accompanied with a 1,2-aryl shift is both kinetically and thermodynamically favourable over plausible formation of products containing 7-membered rings. Steady-state UV/Visible spectroscopy reveals that upon photoexcitation, the prepared S-shaped N-doped nanographenes undergo mostly radiative relaxation leading to large fluorescence quantum yields. Their optical properties are rationalized through time-dependent density functional theory calculations. We anticipate that this chemistry will empower the creation of new materials with various functionalities.

Role of intramolecular hydrogen bonds in promoting electron flow through amino acid and oligopeptide conjugates.

Elucidating the factors that control charge transfer rates in relatively flexible conjugates is of importance for understanding energy flows in biology as well as assisting the design and construction of electronic devices. Here, we report ultrafast electron transfer (ET) and hole transfer (HT) between a corrole (Cor) donor linked to a perylene-diimide (PDI) acceptor by a tetrameric alanine (Ala)4 Selective photoexcitation of the donor and acceptor triggers subpicosecond and picosecond ET and HT. Replacement of the (Ala)4 linker with either a single alanine or phenylalanine does not substantially affect the ET and HT kinetics. We infer that electronic coupling in these reactions is not mediated by tetrapeptide backbone nor by direct donor-acceptor interactions. Employing a combination of NMR, circular dichroism, and computational studies, we show that intramolecular hydrogen bonding brings the donor and the acceptor into proximity in a "scorpion-shaped" molecular architecture, thereby accounting for the unusually high ET and HT rates. Photoinduced charge transfer relies on a (Cor)NH…O=C-NH…O=C(PDI) electronic-coupling pathway involving two pivotal hydrogen bonds and a central amide group as a mediator. Our work provides guidelines for construction of effective donor-acceptor assemblies linked by long flexible bridges as well as insights into structural motifs for mediating ET and HT in proteins.

Bioinspired Bola-Type Peptide Dendrimers Inhibit Proliferation and Invasiveness of Glioblastoma Cells in a Manner Dependent on Their Structure and Amphipathic Properties.

(1) Background: Natural peptides supporting the innate immune system studied at the functional and mechanistic level are a rich source of innovative compounds for application in human therapy. Increasing evidence indicates that apart from antimicrobial activity, some of them exhibit selective cytotoxicity towards tumor cells. Their cationic, amphipathic structure enables interactions with the negatively-charged membranes of microbial or malignant cells. It can be modeled in 3D by application of dendrimer chemistry. (2) Methods: Here we presented design principles, synthesis and bioactivity of branched peptides constructed from ornithine (Orn) assembled as proline (Pro)- or histidine (His)-rich dendrons and dendrimers of the bola structure. The impact of the structure and amphipathic properties of dendrons/dendrimers on two glioblastoma cell lines U87 and T98G was studied with the application of proliferation, apoptosis and cell migration assays. Cell morphology/cytoskeleton architecture was visualized by immunofluorescence microscopy. (3) Results: Dimerization of dendrons into bola dendrimers enhanced their bioactivity. Pro- and His-functionalized bola dendrimers displayed cytostatic activity, even though differences in the responsiveness of U87 and T98G cells to these compounds indicate that their bioactivity depends not only on multiple positive charge and amphipathic structure but also on cellular phenotype. (4) Conclusion: Ornithine dendrons/dendrimers represent a group of promising anti-tumor agents and the potential tools to study interrelations between drug bioactivity, its chemical properties and tumor cells' phenotype.

Computational planning of the synthesis of complex natural products.

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

Synthesis of ß-lactams via diastereoselective, intramolecular Kinugasa reactions.

Intramolecular Kinugasa reactions on in situ generated carbohydrate-derived alkynylnitrones are described. The effects of the length of chains, their mutual configuration, influence of experimental conditions on product distribution and feasibility of the ß-lactam ring construction were studied. Intramolecular reactions proceed with high stereoselectivity to provide in each case one product only. The cycloadducts from tartaric acid were converted into the corresponding non-racemic 4-acetoxy azetidinones in good yields.

Interplay of Aromaticity and Antiaromaticity in N-Doped Nanographenes.

The aromaticity of three nonplanar, fully conjugated aza-nanographenes built around a pyrrolo[3,2-b]pyrrole core is assessed through the application of two different computational procedures-GIMIC and NICS. We examine the calculated magnetically induced current densities (GIMIC) and nucleus-independent chemical shifts (NICS). The structural differences between these three apparently similar molecules lead to significantly different aromatic properties. GIMIC analysis indicates that the peripheral diatropic ring current of 3.9 nA/T for the studied bowl-shaped diaza-nanographene is the strongest, followed by the double [6]helicene which lacks seven-membered rings, and is practically nonexistent for the double [5]helicene possessing seven-membered rings. The biggest difference however is that in the two not-fully-fused molecules, the central pyrrole rings possess a significant diatropic current of about 4.1 nA/T, whereas there is no such current in the diaza-nanographene. Moreover, the antiaromaticity of the seven-membered rings is increasing while moving from double [5]helicene to diaza-nanographene (from -2.4 to -6.0 nA/T). The induced currents derived from NICSπ,zz-XY-scan analysis for all of the studied systems are in qualitative agreement with the GIMIC results. Subtle differences may originate from σ-electron currents in GIMIC or inaccuracy of NICSπ,zz values due to the nonplanarity of the systems, but the general picture is similar.

Bypassing the stereoselectivity issue: transformations of Kinugasa adducts from chiral alkynes and non-chiral acyclic nitrones.

An approach to ß-lactams via a reaction between chiral copper acetylides and acyclic nitrones is reported. Electronic circular dichroism (ECD) in combination with NMR spectroscopy was used to determine the absolute configuration of all components of complex mixtures of azetidinones. Stereochemical preferences observed in the studied reactions are discussed and a model of a new reaction pathway supported by DFT conformational analysis is proposed. Subsequent transformations of the synthesized Kinugasa adducts followed by epimerization at the C-3 carbon atom led to trans-substituted azetidinones with improved stereoselectivity, mimicking a variety of important ß-lactam structures. On the other hand, the oxidation of the furyl residue to the carboxylic group followed by oxidative decarboxylation with lead tetraacetate afforded the more thermodynamically stable trans-substituted 4-acetoxy azetidinone. The latter strategy is particularly attractive for the diastereomeric mixture in which isomers with the same configuration at the C-3 carbon atom dominate.

Covalently Linked Bis(Amido-Corroles): Inter- and Intramolecular Hydrogen-Bond-Driven Supramolecular Assembly.

Four bis-corroles linked by diamide bridges were synthesized through peptide-type coupling of a trans-A2 B-corrole acid with aliphatic and aromatic diamines. In the solid state, the hydrogen-bond pattern in these bis-corroles is strongly affected by the type of solvent used in the crystallization process. Although intramolecular hydrogen bonds play a decisive role, they are supported by intermolecular hydrogen bonds and weak N-H⋅⋅⋅π interactions between molecules of toluene and the corrole cores. In an analogy to mono(amido-corroles), both in crystalline state and in solutions, the aliphatic or aromatic bridge is located directly above the corrole ring. When either ethylenediamine or 2,3-diaminonaphthalene are used as linkers, incorporation of polar solvents into the crystalline lattice causes a roughly parallel orientation of the corrole rings. At the same time, both NHCO⋅⋅⋅NH corrole hydrogen bonds are intramolecular. In contrast, solvation in toluene causes a distortion with one of the hydrogen bonds being intermolecular. Interestingly, intramolecular hydrogen bonds are always formed between the -NHCO- functionality located further from the benzene ring present at the position 10-meso. In solution, the hydrogen-bonds pattern of the bis(amido-corroles) is strongly affected by the type of the solvent. Compared with toluene (strongly high-field shifted signals), DMSO and pyridine disrupt self-assembly, whereas hexafluoroisopropanol strengthens intramolecular hydrogen bonds.

Asymmetric total synthesis of (+)-asenapine.

Asymmetric total synthesis of (+)-asenapine, an atypical antipsychotic drug, used for treating schizophrenia and acute mania associated with bipolar disorder, is reported. The key steps are the organocatalytic Michael addition of aldehydes to trans-nitroalkenes and subsequent reductive cyclization.

Unprecedented rearrangement of diketopyrrolopyrroles leads to structurally unique chromophores.

Diketopyrrolopyrroles possessing thienyl, furyl and benzofuryl substituents undergo unprecedented skeletal rearrangement in the presence of trimethylsilyl bromide resulting in the formation of thieno[2,3-f]isoindole-5,8-diones and furo[2,3-f]isoindole-5,8-diones. These relatively small dyes possess favorable photophysical properties with the emission maxima within the range of 573-624 nm, large fluorescence quantum yields, moderate sensitivity of emission to solvent polarity and a HOMO-LUMO gap of ca. 1.8 eV.

Synthesis and antimicrobial activity of chiral quaternary N-spiro ammonium bromides with 3',4'-dihydro-1'H-spiro[isoindoline-2,2'-isoquinoline] skeleton.

A new class of highly functionalized tetrahydroisoquinolines with a quaternary carbon stereocenter was synthesized starting from an easily accessible L-tartaric acid. Nine strains of bacteria (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus mutans, Streptococcus salivarius, Bacillus subtilis, Enterococcus faecalis, Moraxella catarrhalis, Escherichia coli, Campylobacter jejuni) were used for the determination of minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of synthesized compounds. The influence of analyzed compounds on viability and induction of apoptosis in human skin fibroblasts was determined. A majority of the synthesized compounds showed the strongest antibacterial properties toward some gram-negative bacteria (M. catarrhalis and C. jejuni) with a high level of selectivity. High antibacterial compounds have bactericidal activity ratio MBC/MIC ≤4. Our studies also proved that the novel compounds do not possess cytotoxic and proapoptotic potential in normal cells.

Pd-Catalyzed Carbonylative Carboperfluoroalkylation of Alkynes. Through-Space 13C-19F Coupling as a Probe for Configuration Assignment of Fluoroalkyl-Substituted Olefins.

A four-component Pd-catalyzed protocol for direct synthesis of perfluoroalkyl-substituted enones is reported. Under mild conditions and low catalyst loading, alkynes, iodoperfluoroalkanes, (hetero)arylboronic acids, and carbon monoxide are assembled into highly elaborate products with good yields and excellent regio- and stereoselectivities. The configuration of the products was confirmed by the observation of through-space 13C-19F couplings, accessible through the analysis of routine 13C NMR spectra.

Biological evaluation of octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives as potent anticancer agents.

In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.

Hydrogen Bonds Involving Cavity NH Protons Drives Supramolecular Oligomerization of Amido-Corroles.

trans-A2 B-Corroles with amide substituents at different positions versus the macrocyclic core have been synthesized. Their self-organizing properties have been comprehensively evaluated both in solid-state and in solution. The rigid arrangement of the amide functionality with the corrole ring led to the formation of strong intramolecular interactions and precluded intermolecular interactions. Replacement of sterically hindered C6 F5 substituents at positions 5 and 15 with smaller electron-withdrawing CO2 Me groups resulted in significant changes in the self-assembly pattern. With these substituents, tetramers formed in a crystalline state, in which one of the H-pyrrole subunits is out of the corrole plane. This allows the N-H group to form a hydrogen bond with a neighboring carbonyl group of the n-butyl amide fragment. DOSY NMR studies showed that amido-corroles bearing the OCH2 CONHnBu motif formed dimers in millimolar solutions in nonpolar solvents and the dimers existed in equilibrium with monomers. However, the corroles possessing meso-ester groups did not form dimers in polar tetrahydrofuran. Comprehensive optical studies allowed the absorption and emission features of the monomer corroles to be characterized in dilute solutions.

1,3-Dipolar cycloaddition of a cyclic nitrone derived from 2-deoxy-D-ribose to α,ß-unsaturated lactones: An entry to carbapenem antibiotics.

1,3-Dipolar cycloadditions of 2-deoxy-D-ribose-derived L-threo five-membered cyclic nitrone to α,ß-unsaturated γ- and δ-lactones were investigated. Cycloadducts obtained from δ-lactones, after NO bond cleavage, opening of the lactone ring, and protection of hydroxyl groups were subjected to ß-lactam ring formation by using Mukaiyama's salt. Cycloadducts from γ-lactones subjected to the same reaction sequence undergo ß-elimination of a water molecule to provide pyrrolidine-substituted unsaturated γ-lactones.

Synthesis of Thienamycin methyl ester from 2-deoxy-D-ribose via Kinugasa reaction.

A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from D-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-D-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the ß-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.

Synthesis of polyhydroxylated quinolizidine and indolizidine scaffolds from sugar-derived lactams via a one-pot reduction/Mannich/Michael sequence.

A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartz's reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky's diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives.

Bispyrrolylbenzene anion receptor: from supramolecular switch to molecular logic gate.

We have designed anion receptor 4 based on a conformationally labile bispyrrolylbenzene framework, the conformation of which can be changed by appropriate anionic stimuli. In the absence of fluoride anion, the pyrrole moieties rotate freely at room temperature. However, when the concentration of fluoride anion exceeds 2 equivalents, the rotation of the pyrrole units slows down and the conformation of the receptor changes to anti-anti. DFT calculations have shown that this change is due to binding of a third fluoride anion through C-H interaction. Anion receptor 4 can also serve as a molecular logic gate. Anionic inputs such as fluoride and dihydrogenphosphate allow the realization of INHIBIT and NAND logic gate functions with absorption and fluorescence as readouts, respectively.

A practical preparation of the key intermediate for penems and carbapenems synthesis.

A novel, practical and stereoselective synthesis of (3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone, a key intermediate in the preparation of ß-lactam antibiotics is reported. The crucial step of the synthesis is based on the Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade between silyl protected (R)-3-butyn-2-ol and the nitrone derived from benzyl hydroxylamine and benzyl glyoxylate. The obtained adduct is subjected to debenzylation with sodium, or lithium in liquid ammonia followed by oxidation with lead tetraacetate to afford the final product.

Ferrier-Petasis rearrangement of 4-(vinyloxy)azetidin-2-ones: an entry to carbapenams and carbacephams.

Trimethylsilyl triflate promotes Ferrier-Petasis rearrangement of 4-(vinyloxy)-, 4-(propenyloxy)-, and 4-(isopropenyloxy)azetidin-2-ones to corresponding 4-(carbonylmethyl)azetidin-2-ones. The latter compounds may serve as attractive intermediates in the synthesis of carbapenem antibiotics. To illustrate the potential of this reaction, selected rearrangement products have been transformed into carbapenams.