Welcome Reception & Poster Session 1

Strategies for synthesizing two compound collections will be discussed. Our goal is to maximize complexity index along the reaction sequence. Photochemical cycloaddition that produces spirocyclic amines, and Norrish-Yang cyclization to make azetidinols, are the key complexity-increasing reactions we used. Selective C-H functionalization and Buchner aromatic ring expansion through carbene insertion are composed onto initially prepared scaffolds. 

The discussion of development of a complementary nickel-catalyzed method for preparing spirocyclic compounds offers ways to contrast photochemistry with metal-catalyzed processes. 

Conclusions of this research are strengthened by structural characterization of important intermediates through X-ray diffraction, kinetic studies of key processes, ultrafast spectroscopy of primary photochemically-generated species, electrochemical experiments, etc.

Finally, consequences of synthetic decisions on broad aspects of biological activity of the biologically naive compounds comprising the two collections are discussed.

The activation and functionalisation of carbon–fluorine bonds represents a significant synthetic challenge, given the high thermodynamic barrier to C–F bond cleavage. Stoichiometric hydridoborane-mediated C–F functionalisation has recently emerged, but is yet to be rendered catalytic.[1–3] This talk will discuss the borane-catalysed coupling of alkyl fluorides with arenes (carbon–carbon bond formation) and carboxylic acids (carbon–oxygen bond formation) using transborylation reactions to achieve catalytic turnover.[4] Successful C–C and C–O coupling across a variety of structurally and electronically differentiated arenes and carboxylic acids was achieved using 9-borabicyclo[3.3.1]nonane (H-B-9-BBN) as the catalyst and pinacolborane (HBpin), with excellent functional group tolerance, and was highly applicable to late-stage esterification of active pharmaceutical ingredients. Experimental and computational studies suggest a mechanistic dichotomy for the carbon–carbon and carbon–oxygen coupling reactions. B–F transborylation (B–F/B–H metathesis) between F-B-9-BBN and HBpin enabled catalytic turnover for carbon–carbon bond formation, whereas direct exchange between the alkyl fluoride and acyloxyboronic ester (C–F/B–O metathesis) was proposed for carbon–oxygen coupling, where H-B-9-BBN catalysed the dehydrocoupling of the carboxylic acid with HBpin, representing a novel C‒F activation pathway for organoboranes.

References

[1] K.L. Bamford, S.S. Chitnis, Z. Qu, D.W. Stephan, Chem. – A Eur. J. 24 (2018) 16014–16018.

[2] J. Guo, K.L. Bamford, D.W. Stephan, Org. Biomol. Chem. 17 (2019) 5258–5261.

[3] N.A. Phillips, J. O’Hanlon, T.N. Hooper, A.J.P. White, Org. Lett. 21 (2019) 7289–7293.

[4] D.R. Willcox, G.S. Nichol, S.P. Thomas, ACS Catal. 11 (2021) 3190–3197.

Herein, we synthesis, characterization and investigation the physicochemical properties and antimicrobial activity of both a series of new peptide analogues of hemorphins and functionalized cotton, as well as their corresponding zinc/copper complexes, aiming both to increase the antiviral activity and attached to the functional groups of the cotton fabric. The newly synthesized compounds have potential for antimicrobial protection of textile materials against different pathogens. Antimicrobial peptides are able to inhibit many pathogens, including Gram-negative and Gram-positive bacteria and fungi. Peptide scaffolds allow the introduction of desired functional groups in their structure, in order to increase biological activity or enhance other wished properties such as easier coating to textiles or other materials, for example, which may increase the possibilities for their application in biochemistry, medicine and materials chemistry. 

In this study, the solid-phase synthesis and characterization of new peptides and their zinc/copper complexes for textile dyeing has been presented. The crude antimicrobial peptides were purified on an RP-HPLC and the molecular weights were determined, using ESI-MS, and also determining of the specific angles of optical rotation. By using combined experimental approaches the structural-textile application has been investigated by UV-Vis, fluorimetric and electrochemical methods.

Acknowledgment: This work was financial supported by the Bulgarian National Scientific Fund project КП-06-ДК1/11 (title: "Textile materials to prevent the spread of SARS-CoV2 and other pathogens") of the Ministry of Education and Science, Bulgaria

Nitrogen-containing heterocycles such as quinolines, quinolones, oxindoles, and related compounds, represent an important class of natural products (Figure 1a). Their structural complexity, together with their wide range of biological activities have made these scaffolds particularly interesting to both the synthetic chemistry community—due to the challenge embedded in their synthesis—as well as to the chemical biology and drug discovery fields. The degree of complexity that these structures exhibit challenges standard chemical methods and inspires the development of novel and creative procedures in order to efficiently construct such complex frameworks. It is crucial though that these methods minimise our reliance on rare and precious metal resources as well as energy intense processes in order to ensure a sustainable future for synthetic chemistry.

This talk describes our efforts at accelerating the transition toward using small organic molecules and abundant metals as photocatalysts in the construction of biologically relevant nitrogen-containing heterocycles, with a specific focus on formal C-H arene activation (Figure 1b).

References

1. Dobah, F.; Mazodze, C. M.; Petersen, W. F. Cross-Dehydrogenative Cyclization-Dimerization Cascade Sequence for the Synthesis of Symmetrical 3,3'-Bisoxindoles. Org. Lett. 2021, 23, 5466–5470.
2. Oddy, M. J.; Kusza, D. A.; Petersen, W. F. Visible-Light Mediated Metal-Free 6π-Photocyclization of N-Acrylamides: Thioxanthone Triplet Energy Transfer Enables the Synthesis of 3,4-Dihydroquinolin-2-ones. Org. Lett. 2021, 23, 8963–8967.

Nitrate and nitrite ions represent one of the most common contaminants in surface freshwaters because of extensive usage of nitrogenous fertilizer and improper discharge of industrial, agricultural, and sanitary wastes. Therefore, the development of new sensitive methods for speciation analysis of two forms is essential for their analytical control. In this regards the diazotization-coupling reaction of nitrite with cefixime and 1-naphthylamine was studied using voltamperometric method with GC (glass carbon) electrode as working electrodes, Ag/AgCl, (3 mol L^-1) KCl electrode as a reference electrode, and a carbon electrode as an auxiliary electrode at phosphate buffer solution (pH 7.01) as an electrolyte medium. The final product that is an azo compound was used for direct determination of the nitrite ions by registration of a reduction peak obtained from the cleavage of the N=N center. The electrochemical behavior of the azo group in different solutions was also investigated at distinctive techniques as cyclic (CV) and differential pulse polarography (DPP) to evaluate the effect of medium and substituent on the reduction process and suggestion of the electrode reaction mechanism. The proposed redox reaction was applied for the development of a method for direct nitrite anions detection in surface water samples. The results showed that the proposed method allows selective determination of nitrate ions with detection limits: 0.315 ng ml^-1 and determination: 0.534 ng ml^-1. The method is sensitive with a coefficient of analytical function: 3.5x10⁶ µA.ml mol^-1. The precision of the determinations estimated by the relative standard deviation is Sr ≈ 2%.

Acknowledgment: This work was financially supported by the Bulgarian National Scientific Fund project КП-06-ОПР 03/3 (title: "Profiles of spatial differentiation of the quality of river waters in basins with various anthropogenic impact") of the Ministry of Education and Science, Bulgaria.

Marine algae may be used to produce fuel, food or pharmaceutical agents on large scale while absorbing the greenhouse gas carbon dioxide.¹ (˗)-Thallusin, a terpenoid-hybrid metabolite, was isolated from epiphytic marine bacteria Maribacter sp. It triggers the differentiation of algal tissue.² For example, (˗)-thallusin is essential for the development of cell walls and rhizoids in the green macroalgae Ulva mutabilis.³ However, (˗)-thallusin is not accessible by fermentation. Thus, synthetic access to this chemical mediator is highly desirable in order to study its modulation of algae development.

After completing a stereoselective total synthesis of (˗)-thallusin using chiral auxiliaries,⁴ we present here an advanced second generation synthesis of thallusin relying on an iridium-catalyzed, enantioselective polyene cylization⁵ as the key step (ee = 98 %). In addition, first biological data regarding the morphological activity will be presented. (˗)-Thallusin was found by us to be a highly potent morphogen (EC₅₀ = 5 pM) in Ulva, while different structural elements seem to be responsible for separate morphological effects.

[1] C. H. Greene et al., Oceanography 2016, 29, 10. [2] Y. Matsuo et al., Science 2005, 307, 1598. [3] T. Alsufyani et al., J. Exp. Bot. 2020, 71, 3340. [4] S. Rani et al., manuscript in preparation. [5] Schafroth et al., J. Am. Chem. Soc. 2012, 134, 20276.

The Orai calcium channels control Ca²⁺ influx in lymphocytes and are crucial for store-operated Ca²⁺ entry (SOCE). A recessive loss-of-function mutation in Orai1 results in severe combined immunodeficiency (SCID) syndrome, supporting Orai as an attractive target for the development novel immune modulators. We describe in this report the discovery of novel indole-3-carboxamides, and the structure-activity relationship study of their inhibition of Ca²⁺ entry via Orai channels and expression of inflammatory cytokines in immune cells. One unique feature of this class of blockers is that they demonstrate a fast-onset mode of action and elicit complete blockade of Ca²⁺ influx without preincubation. Furthermore, washout experiments indicate their inhibitory activity is completely reversible. In HEK293 cells transfected with the constitutively active human Orai variant (G98S), patch-clamp electrophysiological measurement of calcium currents determined the IC₅₀ of Cpd-10 (Figure) as 4.8 µM. Unlike the commonly used pharmacological tool compound BTP2 (YM-58483) that was shown to affect the function of TRPM4 ion channel, Cpd-10 did not affect this channel at concentrations as high as 100 µM. TRPM7 channels, highly expressed in immune cells, were also not affected by Cpd-10. Cpd-10 dose-dependently inhibited the nuclear translation of NFAT and the expression of IL-2 In Jurkat T cell line, as well as IL2 and IL-17 in primary human PBMC cells. Together, our data suggest the indole-3-carboxamides are promising lead molecules for the development of selective Orai channel blockers as effective therapies for autoimmune diseases.

 Diazonamides are a structurally unique class of secondary metabolites first isolated by Fenical and coworkers from the colonial marine ascidian Diazona angulata¹. The structurally complex Diazonamide A (1) was found to be highly cytotoxic anticancer agent (IC₅₀ = 57 nM)². Studies conducted by Harran³ revealed that DZ-2384 (2), a structurally simplified analog of 1, is more potent (IC₅₀ = 0.47 nM) and it lacks neurotoxicity at effective doses. However, 2 still remains to be synthetically challenging and its preparation requires many steps with poor overall yield. 

Figure 1. Structures of diazonamide A (1), DZ-2384 (2) and analogs 3 and 4

Herein we report the less complex synthesis of oxindole-containing macrocycles 3 using diastereoselective S_NAr-type macrocyclization as the key step. In vitro cytotoxicity measurements indicated that analog 4 exhibits nanomolar activity against relevant cancer cell lines making it more cytotoxic than diazonamide A (1).

Acknowledgements

We gratefully acknowledge financial support from European Regional Development Fund (ERDF) and thank Dr.chem. Ilona Domraceva for performing in vitro experiments. 

 References

1. Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303.
2. Cardwell, C.; Wei, Q.; Zhou, M.; Hanson, G. J. Diazonamide Analogs. U.S. Patent 8153619; Apr. 10, 2012.
3. Wei, Q.; Zhou, M.; Xu, X.; Caldwell, C.; Harran, S.; Wang, L. Diazonamide Analogs. U.S. Patent 8846734; Sep. 30, 2014.
4. Suna, E.; Kalnins, T.; Kazak, M.; Vitkovska, V.; Narvaiss N.; Zelencova D.; Jaudzems K. Structurally Simplified Diazonamide Analogs as Antimitotic Agents. WO 2021/130515, Jul. 1, 2021.

Organic halides, as readily available and inexpensive compounds, are desirable starting materials in photoredox catalysis.¹ Upon the mesolytic cleavage of the C–X bond, they form carbon radicals that can participate in further chemical transformations. While the synthetic potential of organic iodides has already been widely exploited, the photocatalytic activation of bromides and chlorides remains a current challenge.

Herein, we show the key role of non-covalent interactions in C-H alkylation of heteroarenes with alkyl bromides, and the modifications of chlorinated benzamide derivatives.^2,3 Thanks to the use confined micellar media, it is possible to carry out the reaction under mild conditions, without the need for stoichiometric amounts of chemical reducing agents or radical promoters. We also demonstrate how the course of photomicellar reactions can be selectively controlled by simple adjustment of the reaction parameters.

References:

1. M. Cybularczyk-Cecotka, J. Szczepanik, M. Giedyk*, Nat. Catal., 2020, 3, 872-886.
2. M. S. Santos, M. Cybularczyk-Cecotka, B. König, M. Giedyk*, Chem. Eur. J., 2020, 26, 15323-15329.
3. M. Cybularczyk-Cecotka, J. Predygier, Stefano Crespi, J. Szczepanik, M. Giedyk*, submitted

Metabolites produced by the gut microbiome play a crucial and diverse role on host physiology. Microbiota dysbiosis has been associated with the development of diseases, however, the metabolic link has yet to be detected. The detailed and targeted analysis of these metabolites is important for the discovery of biomarkers and unknown bioactive molecules.

Mass spectrometric metabolomics is the method of choice for identification and quantification of these metabolites. Advanced methods at the interface of chemistry and biology coupled with metabolomics analysis are required but still limited. We have therefore developed a unique and multifunctional chemoselective probe with synthetic ¹³C/¹²C isotopically labelled analogues that allows for comparative and quantitative analysis of metabolites in human samples at low concentrations.^[1] We have termed this unique method quantitative Quantitative Sensitive CHEmoselective MetAbolomics (quant-SCHEMA). Coupled to magnetic beads, this method allows the straightforward chemoselective extraction of metabolites from human samples. This isolation procedure of specific classes of metabolites from sample matrices led to significantly increased mass spectrometric sensitivity by sixth orders of magnitude and facilitates the detection of metabolites at femtomole quantities. ^[1-4]

The chemoselective probe was applied for analysis of human fecal, urine and plasma samples. We have discovered several metabolites previously unreported and performed metabolic profiling in these sample types and confirmation of the presence of medically relevant gut microbiota-derived metabolites. 

[1] W. Lin, L.P. Conway, M. Vujasinovic, J.-M. Löhr, D. Globisch, Angew. Chem. Int. Ed. 2021, 60, 23232-23240.

[2] L. P. Conway, N. Garg, W. Lin, M. Vujasinovic, J.-M. Löhr, D. Globisch, Chem. Comm. 2019, 55, 9080–9083.

[3] W. Lin, L. P. Conway, A. Block, G. Sommi, M. Vujasinovic, J.-M. Löhr, D. Globisch, Analyst, 2020, 145, 3822–3831.

[4] W. Lin, Z. Yang, A. Kaur, A. Block, M. Vujasinovic, J.-M. Löhr, D. Globisch, RSC Chem. Biol. 2021, 2, 1479-1483.

Multi-responsive, also known as smart, materials are currently one of the most appealing part of the materials science.[1] Smart polymers are able to change macroscopically their structure, but also these transitions are reversible and system return to the original state after stimulus is removed. Since 1990s when smart materials appeared in literature[2] for the first time different reversible transformation was observed. Our unique design combines a simplicity of monomer (low molecular weight with well-defined primary structure) with complex properties of self-assembled architecture, with emphasis to synergism of several different responses of the architecture, what is encoded in different moieties of the monomer. Herein we present simple yet robust tetra substituted azobenzene molecule, bearing C₄ symmetry. When dissolved in polar solvent, molecule behave as a monomer and is fully molecularly dissolved. On the other hand, when in nonpolar-chlorinated solvent, supramolecular aggregation occurs, forming large aggregate via non-covalent interactions – hydrogen bonds and π-π stacking. After applied stimulus (heat and light) we are able to control the size of the aggregate. When different type of stimulus is present (chemical stimulus, concentration) even full disassembly of the aggregate is achieved. The aggregate and its behavior after applied stimuli was monitored in solution with several spectroscopic methods and on the surface by Atomic Force Microscopy.

Figure 1. Schematic representation of multi stimuli response of the aggregate

Acknowledgements: The project was funded by the National Science Centre of Poland grant SONATA BIS 2018/30/E/ST5/00032.

[1] L. Peponi, M. P. Arrieta, A. Mujica-Garcia, D. López, in Modification of Polymer Properties (Ed.: C. F. Jasso-Gastinel, Kenny J. M.), Elsevier Inc, Oxford, United Kingdom, 2017, pp. 131-154.

[2] C. Fouquey, J.-M. Lehn, A.-M. Levelut, Advanced Materials 1990, 2, 254-257.

The site-selective C-H oxidation in aliphatic ammonium chains poses a tremendous challenge, due to the similar reactivity of the different methylene CH-bonds. In particular, positions close to deactivating groups often remain inaccessible. In this work, we report a novel supramolecular catalyst which preferentially oxidizes the strongly deactivated C3/C4 carbons of aliphatic ammonium substrates. The chimeric catalyst was synthesized by linking the well-established catalytic Fe(pdp) moiety to an aliphatic ammonium-binding molecular tweezer. By using this catalyst, the selectivities for C3/C4 oxidation could be increased up to 80%.  Hence, the results of this work highlight the potential of using supramolecular host catalysts to override the intrinsic reactivity and to observe otherwise inaccessible products.

1. M. Knezevic, M. Heilmann, G. M. Piccini, K. Tiefenbacher; Angew. Chem. Int. Ed, 2020, 59, 12387-12391.

 This project aims to fill part of the gap in the literature concerning a class of organophosphorus compounds that is phosphiranium ions, the phosphorus analogs of aziridinium and oxiranium ions. Although these two classes and their reactivity are well-known for decades, the chemistry of their phosphorus counterpart has been scarcely studied. Despite their increased instability and sensitivity, these compounds are very interesting synthetic platforms, offering new opportunities for the synthesis of phosphines. In this context, our group has recently developed an original C-centered ring-opening reaction of phosphiranium salts, using anilines as nucleophiles.

Our research is now focusing on an in-depth exploration of the chemistry of these strained phosphorus cations. Herein we will present our recent efforts directed towards the synthesis of novel phosphiranium ions and to the development of their opening with an extended range of nucleophiles, generalizing their use for the rapid introduction of phospinoethylene units.

Compounds with a thiazolidinedione (TZD) functionality, so called glitazones, are known as PPARg activators and anti-diabetic drugs. The mode of action of these glitazones has extensively be investigated and is known in great structural details. PPARg is a prominent target with a key role in the regulation of glucose homeostasis and lipid metabolism. However,  PPARg is also vital to cancer cell growth regulation. Moreover, a combination treatment with histone deacetylase (HDAC) inhibitors and PPARg agonists increased cytotoxic effects against various cancer cell lines in a synergistic manner resulting in proliferation arrest and apoptosis. A closer view at the TZD group led us to conclude that TZD compounds should be in principle capable of binding to the catalytic zinc ion at the bottom of the active site of zinc-dependent members of the HDAC protein family. This hypothesis has been confirmed by molecular docking. Therefore, we investigated the inhibitory effect of 225 TZD-analogs on HDAC4 and HDAC8. Different clusters with dual acitivity against PPARg and HDAC4, or VEGFR-2 and HDAC4 were identified and mechanistically analyzed. Most potent compounds exhibit pronounced antiproliferative effects against tumor cells, and are also able to induce in-vivo tumor regression in animal xenograft tumor models.

One of the most important contributions to the development of organic synthesis during the last century has been the protection of functional groups, which involves the reversible protection/deprotection of a chemical functionality. Thus, a given group is temporarily modified in order to minimize or block its reactivity in the reaction conditions required to transform further a molecule of interest.

Among the functional groups mostly employed in protection processes stand out hydroxyl and carbonyl groups. Carbonyl groups are usually protected as ketals by reaction with alcohols under acid catalysis. The choice of the catalyst is often crucial to achieve optimum yield and selectivity. In this context, heterogeneous catalysts have shown broad scope being, in some cases, even superior to homogeneous counterparts.

A novel heterogeneous catalyst has been prepared by treating a readily available activated charcoal (Norit RX3) with concentrated sulfuric acid followed by thorough structural characterization. The sulfonated catalyst has been used in the synthesis of 1,2-O-isopropylidene derivatives obtained from a wide range of diols. Reactions have been conducted in a hermetically sealed vial using acetone, 2-methoxypropene and 2,2-dimethoxypropane as acetalization agents. Other variables such as time, temperature and load of catalyst have also been optimized. The catalytic potential of this type of carbonaceous materials has also been explored through the reutilization of the aforementioned catalyst, evidencing its applications in flow chemistry and large-scale synthesis.

Bis[1]benzothieno[1,4]thiazines (BBTT) as particularly electron-rich S,N-heteropentacenes strike as interesting contenders as charge transport materials. A deeper insight into their electronic structure was gained by chemical and electrochemical oxidation as well as by (TD)DFT examination. 

A controlled chemical oxidation by antimony pentachloride to either radical cations or dications was performed yielding their deeply colored hexachloroantimonates.

Figure 1: Chemical oxidation of syn-syn, syn-anti and anti-anti regioisomer of N-p-Fluorophenyl-BBTT.

In more detail, spectroelectrochemical measurements monitoring the in situ generation of oxidized BBTT by UV/Vis analysis revealed their bathochromic absorption maxima drastically shifting from 400 nm to over 700 nm.

This nicely depicts the drastic change of BBTT’s geometry upon oxidation likewise postulated by DFT calculations as well as consequently the electronic structure. Their butterfly conformation, due to folding at the S-N-Axis of the central 1,4-thiazine, disappears, resulting in a planar alignment of BBTT’s core with orthogonally twisted N‑Aryl substituents. Additionally, TD-DFT calculations reproduce the experimentally observed absorption bands assigning the underlying molecular orbital transitions revealing strong charge transfer contributions, stating BBTT’s high polarizability and strong acceptor character of oxidized BBTTs.

Characterization of hexachloroantimonates of the radical cations by EPR spectroscopy unambiguously proved the radical character, indicating the predominant localization of the unpaired spin on the central 1,4-thiazine aligning with the calculated electron spin density distribution.  Dications as their thermodynamically favored singlet species were characterized by NMR spectroscopy with peaks shifting to lower field, underlining the electron-deficient dicationic nature. Syn-anellated wings place BBTT’s benzo protons into the anisotropy cone of the N-Aryl substituent's diamagnetic ring current therefore shifting to higher field, directly supporting the DFT calculated geometries. 

 [1] S. T. Hauer, A. P. W. Schneeweis, S. D. Waniek, L. P. Sorge, K. Heinze, T. J. J. Müller, Org. Chem. Front. 2021, 8, 5744-5755.

Dyes are important functional constituents in molecular electronics and photonics, which, in addition to a steady miniaturization, can also avail and realize the efficient conversion of energy.^[1] Diversity-oriented syntheses of functional dyes as well as systematic structure-property relationships in principle set the stage for the production of these components with sustainable one-pot processes.^[2] The polyfunctional, renewable material 5‑(hydroxymethyl)furfural (HMF) as a starting material has been chosen for the development of a sustainable catalytic one-pot synthesis yielding functionalized pyrroles.

Figure 1: Sustainable one-pot synthesis of substituted pyrroles based on HMF.

A compound library of 18 examples has been constructed in yields ranging from 15 to 78 % including electronically diverse substituents on the pyrrole core. Moreover, beyond the novel green one-pot synthesis, these particular pyrroles are novel in literature. Photophysical characterization of all compounds by absorption and emission spectroscopy reveals a tunable fluorescence from blue to yellowish upon photonic excitation with quantum yields up to 95 %, while solid state studies show quantum yields up to 16 %. Furthermore, a weak positive solvatochromism with a bathochromic shift of emission maxima is observed in solution.

Figure 2: Emission in different solvents (from left to right: unpolar to polar).

[1] J. Griffiths, Chem. Unserer Zeit 1993, 27, 21-31.

[2] M. Marson, Chem. Soc. Rev. 2012, 41, 7712-7722.

Electrophiles are key parts in innumerable catalytic reactions and serve almost exclusively two general purposes through their functional group: first, locating the bond-forming site at the corresponding substrate and second, providing the electronic bias for the initiation of the catalytic cycle. Apart from that, such conventional electrophiles (CE) are passive throughout the reaction rendering the functional group and the corresponding prior synthetic efforts to install it highly sacrificial. This work introduces the concept of non-innocent electrophiles (NIE). In contrast to CEs, NIEs actively participate in the reaction beyond the classical paradigm, thus providing extended reactive opportunities. This concept was used to perform exogenous base-free coupling reactions in a general fashion. Considered an inherent requisite for catalytic turnover in numerous transition metal-catalyzed coupling reactions, the use of (super)stoichiometric bases simultaneously limits the accessible chemical space, generates additional waste, and typically renders reaction conditions heterogeneous. In summary, diisopropylcarbamates as well as tert-butyl carbonates were found to release a competent base after oxidative addition. Notably, this catalytic release mechanism generates the base on-demand, establishing self-sustaining catalytic systems with intrinsic self-regulation and efficiently overrides the deleterious effects caused by exogenous bases. As a result, multiple coupling reactions (8 distinct reactions) which traditionally rely on the addition of (super)stoichiometric base could be turned into exogenous base-free, homogeneous processes, that were compatible with base-sensitive moieties. Importantly, C‒H/C‒O coupling scenarios proved feasible representing a promising avenue for sustainable catalysis. Furthermore, the advantageous features of NIEs were used in several relevant applications, such as a newly developed micromole-scale fluorescence-based assay that reliably and rapidly detects reactivity without the need for specialized equipment and only requires minimal amounts of materials. As a result, a novel Ni-catalyzed deoxygenation reaction of aryl carbamates making use of isopropanol as a benign reductant was discovered.

Selective bioconjugation remains a significant challenge for the synthetic chemist due to the stringent reaction conditions required by biomolecules along with their high degree of functionality. Recent work by Buchwald et al. has seen the emergence of Pd(II) complexes prepared via oxidative addition for bioconjugation.¹ Despite using superstoichiometric palladium, these complexes have shown excellent selectivity with the ability to arylate cysteine, lysine, and p-aminophenylalanine under mild conditions.

This work describes the use of both isolated and in situ generated Pd(II) complexes produced via C-H activation.² Examples include Pd(II) complexes based around a N,N-dimethylbenzylamine or acetanilide core, thanks to their ability to undergo facile ortho- cyclopalladation. These complexes showed bioconjugation efficiency competitive with the current literature, complemented by a user-friendly synthesis and use of stable, readily-available Pd(II) sources. An optimised protocol which generates Pd(II) complexes in situ enabled assessment of a wide substrate scope, which included biologically-relevant functionality such as (poly)ethylene glycol and an electrochemical tag. Moderate to excellent conversions of a model cysteine-containing tripeptide, glutathione, to the S-arylated species was observed.

This facile in situ method was applied to the selective arylation of the single surface cysteine residue (Cys-43) on Bovine Serum Albumin (BSA). Following trypsin digest, excellent selectivity for this transformation was observed, with Cys-34 being the only arylated residue. Overall, this work demonstrates that cyclopalladated Pd(II) complexes are promising reagents for facile bioconjugation. The entire protocol may be completed in just over two hours, with the only specialist equipment required being a balance and micropipettes.

1. Vinogradova, E. V.; Zhang, C.; Spokoyny, A. M.; Pentelute, B. L.; Buchwald, S. L. Nature 2015, 526 (7575), 687–691.
2. Tilden, J. A. R.; Lubben, A. T.; Reeksting, S. B.; Kociok-Köhn, G.; Frost, C. G.; Chem. Eur. J. 2022, e202104385.

The Suzuki reaction has become a mainstay of the pharmaceutical industry for the formation of planar “2D” biaryl structures. In some cases, chiral alkyl nucleophiles can be used to access “3D” benzylic stereocentres. However, this approach is compromised by slow transmetallation and competing β-hydride elimination, which leads to isomeric side-products. An “ideal” (but poorly developed) alternate approach is to form benzylic stereocentres directly via the enantioselective addition of aryl C-H bonds across alkenes. This approach has been pursued by the Bower group, who recently reported enantioselective Ir-catalysed hydroarylations of alkenes with acetanilides to provide tertiary benzylic stereocenters. The focus of my work has been to broaden the scope of this methodology by designing new chiral catalyst systems. I have developed enantioselective protocols that provide tertiary benzylic stereocentres via the hydroarylation of mono-substituted alkenes with a wide range of benzenoid and heterocyclic arenes. I have also achieved exciting preliminary results which show that enantioenriched quaternary stereocentres can be accessed by hydroarylation of 1,1-disubstituted alkenes.

The ubiquitous use of antifungal agents in agriculture, veterinary, and human healthcare has resulted in the development of drug-resistant fungal pathogens such as Candida auris.^1,2 The limited variety of treatments alongside a changing climate has exacerbated the problem.³ Natural products, such as the ambruticins, are a source of inspiration for new antimycotics.

Gene knockout experiments are in accord with the proposal that the tetrahydropyran ring of the ambruticins is formed via the AmbJ-catalysed epoxidation of the unsaturated 3,5-dihydroxy acid, ambruticin J, followed by regioselective cyclisation to ambruticin F.⁴ Investigations towards understanding this biosynthetic transformation may facilitate the exploitation of nature’s biological machinery to generate variants of the ambruticins. Furthermore, this could lead to novel biocatalysts to perform challenging synthetic transformations cleanly and efficiently.

To investigate THP ring formation in ambruticin biosynthesis, we have conducted model studies involving chemical epoxidation and cyclisation of unsaturated hydroxy esters. These studies indicate that both the C-5 alcohol and 8,9-alkene of epoxy-ambruticin J may be responsible for selective cyclisation to give ambruticin F. Furthermore, we have accessed the putative biosynthetic intermediate, ambruticin J, through a highly modular total synthesis, where four fragments are united via a thallium-accelerated Suzuki-Miyaura cross-coupling and two olefinations.⁵ In vitro and in vivo investigations using heterologously expressed AmbJ are currently underway for the selective oxidation of ambruticin J.

References:

1. A. Casadevall, Pathog. Immun. 2018, 3, 183.
2. K. Forsberg et al., S. Med. Mycol. 2019, 57, 1.
3. M. C. Fisher et al., Nature 2012, 484, 186.
4. C. D. Reeves et al., Chem. Biol. 2006, 13, 1277.
5. J. I. Bowen et al., Org. Biomol. Chem. 2021, 19, 6210.

Bastimolide B is a polyhydroxy macrolide isolated from marine cyanobacteria displaying antimalarial activity.^[1] It features a dense array of hydroxylated stereogenic centers in 1,5-relative configuration. These 1,5-polyols represent a particularly challenging motif for synthesis, as the remote position of the stereocenters in acyclic systems hampers stereocontrol.^[2]  Herein, we present a strategy for 1,5-polyol stereocontrolled synthesis based on iterative boronic ester homologation with enantiopure magnesium carbenoids.^[3] By merging boronic ester homologation and transition metal-catalyzed alkene hydroboration and diboration, the acyclic backbone of bastimolide B was rapidly assembled from readily available building blocks with full stereochemical control over the remote stereocenters. ^[4] 

References:

1. C.-L Shao, X.-F. Mou, F. Cao, C. Spadafora, E. Glukhov, L. Gerwick, C.-Y. Wang, W. H. Gerwick, J. Nat. Prod. 2018, 81, 211.
2. R. M. Friedrich, G. K. Friestad, Nat. Prod. Rep. 2020, 37, 1229.
3. G. Casoni, M. Kucukdisli, J. M. Fordham, M. Burns, E. L. Myers, V. K. Aggarwal, J. Am. Chem. Soc. 2017, 139, 11877.
4. D. Fiorito, S. Keskin, J. Bateman, M. George, A. Noble, V. K. Aggarwal, submitted

Multicomponent reactions constitute powerful tools for the preparation of complex scaffolds in one step. Since the mid-2000s, our group focuses on the development of organometallic Mannich reactions involving organozinc reagents as nucleophiles. These organometal species do not solely exhibit a greater functional group compatibility compared to Grignard or organolithium reagents[1] but also allow easier preparation under mild conditions. This approach therefore results in an original access to densely substituted amines by the formation of both C-C and C-N bonds in only one step. 

The state-of-the-art reveals that whereas organometallic multicomponent Mannich reactions have been extensively studied using sp- or sp² hybridized organometallic reagent,[2] sp3- hybridized reagents have been less described and only processes involving resonance stabilized organozinc species have been yet disclosed[3]. In this communication we describe the implementation of Mannich reactions involving sp3- hybridized mixed organozinc reagents. Key to the success was their preparation in acetonitrile by insertion of activated zinc dust in the Csp3-I bond alkyl iodides and their subsequent three-component coupling with amines and aldehydes.

[1] Knochel, P.; Millot, N.; Rodriguez, A.; Tucker, C. E.; "Preparations and Applications of Functionalized Organozinc Compounds" Organic Reactions 2001, 58, 417-731.

[2] Paul, J. ; Presset, M. ; Le Gall, E. ; “Multicomponent Mannich-Like Reactions of Organometallic Species” EurJOC, 2017, 17, 2386-2406

[3] R. Fan, D. Pu, L. Qin, F. Wen, G. Yao, J. Wu, J. Org. Chem. 2007, 72, 3149–3151.

One of the most challenging research fields of recent years has been the investigation of efficient systems able to replace fossil fuels with more sustainable energy sources. In search of more flexible and efficient options, several alternative technologies have been developed to overcoming some of the drawbacks connected with the use of traditional PVs. Recently, luminescent solar concentrator (LSC) technology has received considerable attention as an alternative approach to lower the costs of PV and facilitate the integration of solar-harvesting devices into buildings. The development of the LSC was initially limited by the performance of the luminescent dyes available; in fact, luminophores are one of the most important components of an LSC, as they are the key elements that allow the concentration of light through the absorption and re-emission of photons. 

In this context, aimed at identifying effective substitutes of perylene-based fluorophores in LSCs, we designed new Y-shaped alkynylimidazole-based fluorophores end-capped with electron-donating (EDG) and electron-acceptor (EWG) groups (“push-pull” systems) (Figure 1).

This “EDG−π−EWG” arrangement of functionalities usually provides considerable intramolecular charge transfer between the donor and acceptor moieties during electronic transitions and generates low-energy intense absorption. Furthermore, the inclusion of heteroaromatic rings in these structures often gives interesting properties to the whole system, such as high polarizability, intense charge transfer upon electronic excitation, chemical inertness, and thermal stability; moreover, heteroatoms may act as auxiliary donors or acceptor moieties, and the triple carbon-carbon bond acts as an excellent π-spacer as well as extending conjugation. 

These novel Y-shaped imidazole-based fluorophores were easily assembled in good chemical yields through a three-step synthetic sequence involving a dehydrogenative alkynylation procedure discovered by us. Their optical and spectroscopic properties were analyzed both in solution and in poly(methylmethacrylate) (PMMA) films.

Atypical protein kinase, PKMzeta lacks the regulatory domain and is often found to be associated with various disease states including addiction, chronic pain, cancer and long term potentiation. Therefore, we took an effort to design non-peptidic inhibitors based on structure-based design techniques with biological proof of concept and pharmacological screening. In this study, small molecule inhibitors were designed and evaluated their potential to attenuate neuroinflammation. The inhibitors were screened based on virtual screening of our in-house compound library with the homology models of PKMzeta. Enzymatic and cell based assays revealed about five leads with good PKMzeta IC50s less than 4 µM. Further, a protypical lead compound (BO5) with highest selectivity index and ROS IC50 0.03 μM was selected for further neuropharmacological screening to check their neuroprotective effect in MeHg treated mouse and in chronic pain models. Lead BO5 was found to reverse spontaneous pain, cold allodynia and tactile allodynia with an ED50 of 48.53 mg/kg, 9.25 mg/kg and 25.96 mg/kg, respectively in chronic pain studies. Thus the study revealed the importance of PKMzeta inhibition to be an attractive strategy to treat neuroinflammation related to neurodegeneration and neuropathic pain.

Structural diversity and functional versatility of amino acids makes them inevitable in the progress of various research areas, from drug discovery and life sciences to materials research. Presence of unusual side chains, multiple chiral centers, hydrogen-bond donors and acceptors or atypical backbones impart distinct chemical and biological properties of peptides and peptidomimetics. The main challenge in the design of novel, functional peptide-based materials is to design monomers, either non-natural amino acids or other repeating units, able to adopt distinct secondary structures and consequently exhibit favorable properties.

C-glycosyl amino acids represent a group of C-glycosides in which a carbohydrate molecule is linked by a C-C bond to the amino acid side chain or backbone. Because C-glycosides are metabolically more stable compared to their O- or N- counterparts, they are widely utilized in biomedical and drug discovery studies. Many methodologies are developed for the amino acid side-chain modifications or synthesis of C-glycosyl β-amino acids, however, routs for the synthesis of C-glycosyl α-amino acids are rare. We developed robust, stereoselective, multicomponent approach towards C-glycosyl amino acids in which the carbohydrate unit is attached directly to the α atom of the amino acid. We  utilized a three-component Passerini reaction to convert carbohydrate-derived carbonyl compounds to α-acyloxyamides. Hydrolysis of Passerini products under basic conditions afforded α-hydroxy C-glycosyl derivatives, transformed in further steps to C-glycosyl α-amino acid. Various carbohydrates were explored and the utility of novel amino acids in peptidomimetic synthesis tested.

The Cope rearrangement of 2,3-divinyloxiranes, a rare example of epoxide C–C bond cleavage, results in 4,5-dihydrooxepines which are amenable to hydrolysis, furnishing 1,6-dicarbonyl compounds containing two contiguous stereocenters at the 3- and 4-positions. We employ an Ir-based alkene isomerization catalyst to form the reactive 2,3-divinyloxirane in situ with complete regio- and stereocontrol, which translates into excellent control over the stereochemistry of the resulting oxepines and ultimately to an attractive strategy towards 1,6-dicarbonyl compounds.

Abyssomicin C is a polyketide natural product isolated from the marine bacterium Micromonospora maris. The compound exhibits potent activity against a range of clinically relevant bacterial pathogens including Mycobacterium tuberculosis and MRSA.^1,2 Abyssomicin C possesses an unusual polycyclic structure and of particular note is the ether-bridged core, which has been shown to be critical to its unique mechanism of action as a substrate mimetic of chorismate, an intermediate in bacterial folate metabolism.³ This key pharmacophore has been proposed to be installed via epoxidation of 1, followed by intramolecular ring opening of the oxirane to give abyssomicin C.⁴ With a view to harnessing this enzymatic process, we sought to identify the enzymes responsible for these key final steps in abyssomicin C biosynthesis. Our studies led to the characterisation of AbyV, a cytochrome P450 enzyme from the aby biosynthetic gene cluster. 

Precursor 1 was synthesised in 12 steps and was employed with recombinant AbyV to develop a functional in vitro assay. LC-MS data from these assays allowed us to assign the function of AbyV as an epoxidase and further support for our functional proposals were gained through the synthesis of a ¹³C labelled substrate analogue which allowed the epoxidation process to be monitored by NMR. We went on to solve the AbyV X-ray crystal structure and computational modelling with structural data provided insights into substrate binding and enzyme selectivity. These studies, in combination with previous work on the pathway, provide the foundation to harness the abyssomicin biosynthetic machinery to deliver novel derivatives for further investigation.

References:

1. J. Riedlinger et al., J. Antibiot. (Tokyo), 2004, 57, 271–279.
2. J. Freundlich et al., Tuberculosis, 2010, 90, 298–300.
3. S. Keller et al., Angew. Chemie Int. Ed., 2007, 46, 8284–8286.
4. E. M. Gottardi et al., ChemBioChem, 2011, 12, 1401–1410.

The Pummerer rearrangement has been applied extensively in the formation of new carbon-carbon or carbon-heteroatom bonds since its discovery in 1909.  While it is compatible with a broad range of nucleophiles, phosphines have previously been unusable as nucleophiles due to the propensity of competing redox chemistry with sulfoxides. Here we report a simple procedure that circumvents this problem and facilitates formal phosphine Pummerer reactions. This method is employed in the preparation of thioalkyl phosphonium salts which gives rise to a wide range of vinyl sulfides via Wittig olefination chemistry with aldehydes. Subsequent hydrolysis of these vinyl sulfides under mild conditions offers an efficient and versatile two-step one-carbon homologation of aldehydes to ketones. This presentation will detail our discovery, development, and scope of this chemistry and highlight related method development that is ongoing in our lab.

Transformations with complete atom economy, which enable the rapid construction of several new bonds in a single step, are highly desirable in synthetic organic chemistry. Since no stoichiometric waste is generated, the reaction becomes more environmentally benign and cost-efficient while the complexity of a given molecule is increased drastically at the same time. One class of reactions that can overcome the challenges to achieve such transformations is the difunctionalization of alkynes and alkenes. Especially the carbofunctionalization is of interest since it results in the formation of a new C–C and C–FG bond in only one step.

Extending previous pioneering works on carbocyanation and carbohalogenation, we envisioned a carbothiolation of alkenes with complete atom economy. Initial focus was laid on the synthesis of heterocyclic compounds, which represent common motifs in naturally occurring thioether derivatives. Compared to other synthetic pathways, our method does not require the employment of odorous or potentially toxic thiols and exhibits a superior step- and atom economy. Finally, through serendipitous findings, we were able to discover two new chemodivergent transformations that give access to quinolones and pyridinones, two common scaffolds in pharmaceutical chemistry.

Based on a 2019 report from WHO 55% of deaths worldwide are accounted for 10 diseases. The top two diseases are connected to ischaemic conditions and neurodegenerative diseases take number 7 on this list with lung cancer at number 6.

In the past few years the University of Szeged focused aimed toward the treatment of these conditions. In one of the still in progress research the main aim is on the derivatives of kynurenic acidy (KYNA). In the last two decades it has been proven that loss of KYNA can be connected to neurodegenerative conditions such as Parkinson’s or Huntington’s disease. It has also been shown that it can also contribute to alleviate the symptoms of ischaemic conditions. However, the direct medical usage of KYNA is inhibited because of its poor penetration through the blood-brain-barrier (BBB). There have already been several attempts trying to solve this problem, with the synthesis of derivatives through the alteration of the quinoline structure.

In 2016 Deb et al. described the synthesis of new, triaryl-methane (TRAM) derivatives containing indole skeleton. The synthesis of these TRAM compounds can be achieved through two synthetic routes: i) the reaction of 2-naphthole and the aminoalkyl derivative of indole; ii) reaction of indole and the ortho-quinone methide intermediate of 2-naphthole.

As KYNA can be considered a hydroxylated naphthalene we set out to investigate the reactivity of KYNA and its Mannich bases in similar fashion, thus synthesizing new bioconjugate TRAMs. We hope that through their KYNA skeleton the newly formed conjugates may have similar CNS and anti-ischaemic effects as KYNA. Nonetheless through their indole and phenyl functions, these TRAMS may also have anti-tumour effects as well.

Since the early discovery of palladium-catalysed aminocarbonylation [1], several N-nucleophiles have been tested. In this work, prompted by the seminal work of Grushin on the azidocarbonylation of iodoarenes [2], palladium-catalysed azidocarbonylation of iodoalkenes will be presented.

Iodoalkenes (1-iodocyclopentene, 1-iodocyclohexene, 1-iodo-4-tert-butylcyclohexene, iodobornene, alpha-iodostyrene, 17-iodo-5alpha-androst-16-ene, 17-iodo-3-methoxyestra-1,3,5(10),16-tetraene, 20-iodo-5alpha-pregn-20-ene, 20-iodo-3beta-hydroxypregn-5,20-diene and 12-iodo-3beta-hydroxy-5α-spirost-11-ene) were synthesised from ketones via their hydrazones.

The expected acyl azide products, obtained as primary products in azidocarbonylation, underwent consecutive reactions resulting in the formation of primary amides. Their formation can be rationalised by the conversion of the primarily formed acyl azide into an acyl isocyanate that hydrolyses to the primary amide in the presence of water used as a component of the solvent mixture.

’Direct’ aminocarbonylation of the above iodoalkenes was also carried out by using ammonium carbamate as ammonia source under mild conditions. In this way, the corresponding alpha,beta-unsaturated primary amides, detected above as products of azidocarbonylation, were synthesised in an independent high-yielding chemoselective reaction.

References:

[1] (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318-3326.; (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327-3331.; (c) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761-7764.

[2] (a) Miloserdov, F. M.; Grushin, V. V. Angew. Chem. Int. Ed. 2012, 51, 3668-3672.; (b) Miloserdov, F. M.; McMullin, C. L.; Belmonte, M. M.; Benet-Buchholz, J.; Bakhmutov, V. I.; Macgregor, S. A.; Grushin, V. V. Organometallics 2014, 33, 736−752.

The emerging field of electron donor-acceptor (EDA) complex photoactivation has led to the development of sustainable, selective and versatile alternatives to photoredox catalysis, for the generation of radical species.¹ Rather than relying on precious photocatalysts, EDA complexes take advantage of charge transfer interactions between electron-rich donors and electron-deficient acceptors – which alone are colourless – to generate visible-light absorbing aggregates. Photoexcitation of EDA complexes induces an intracomplex single electron transfer (SET), which drives the formation of radical species.¹ However, for aryl radical formation, EDA photoactivation has been held back by limitations with regard to the aromatic radical precursor, with electron-deficient aryl halide acceptors being required.² Thus, general strategies for aryl radical generation via EDA complex photoactivation have so far proved elusive. 

Recently, our group disclosed that triarylsulfonium salts, readily synthesised by C–H sulfenylation of native arene precursors, can be reduced by photoexcited organic photocatalysts to efficiently produce aryl radicals.³ We now introduce triarylsulfonium salts as acceptors in photoactive EDA-complexes, used in combination with catalytic amounts of newly-designed amine donors. The sulfonium salt tag renders inconsequential the electronic features of the aryl radical precursor and, more importantly, it is installed regioselectively in native aromatic compounds by C–H sulfenylation. Using this general synthetic platform for aryl radical formation, we have developed site-selective, metal-free protocols for the aromatic C–H alkylation and cyanation of arenes, and showcased their application in both the synthesis and the late-stage modification of pharmaceuticals and agrochemicals.⁴

1 – Melchiorre, P., et al. J. Am. Chem. Soc. 142, 5461−5476 (2020).

2 – (a) Miyake, G. M., et al. J. Am. Chem. Soc. 139, 13616−13619 (2017); (b) Xia, C., et al. Chem. Sci. 10, 3049-3053 (2019).

3 – Procter, D. J., et al. Nat. Catal. 3, 163−169 (2020).

4 – Procter, D. J., et al. ChemRxiv (2021). doi:10.26434/chemrxiv-2021-xbn7k.

Fluorine has been considered one of the most interesting atoms in medicinal chemistry because of its unique physicochemical properties. Fluorine substituents have been widely used in a variety of fields, including pharmaceuticals, agrochemicals, materials, and positron emission tomography. As a result, various late-stage fluorination methods have been intensively studied in the field of organic chemistry. Among them, regioseletive alkylfluorinations of olefins have been considered one of most powerful methods because of their ability of incorporating three dimensional structures as well as fluorine atom in a single protocol.

Herein, we disclose the three components alkylfluorination of olefin via oxidative radical-polar crossover. This process utilizes easily available N-hydroxyphthalimide as alkyl group and cost-efficient hydrogen fluoride as fluorine source. We demonstrated the versatility and feasibility of this protocol with a one-step procedure from commercially available carboxylic acids. In this presentation, the details and possible application of this reaction will be discussed.

Flavin-dependent ene-reductases (EREDs), such as those of the Old Yellow Enzyme (OYE) family, are a well described class of enzymes, mostly applied for the enantioselective reduction of activated C=C double bonds. While a wide substrate scope has been established [1-3], the enzymes are not known for the reduction of C=heteroatom bonds. Recent work in our group has shown that several ene-reductases reduce the oxime functionality of β-keto-α-oximo esters to the corresponding amino group yielding tetrasubstituted pyrazines after non-enzymatic cyclisation and oxidation [4].

The oxime reduction has been tested using a small substrate library (8 oximes) and six EREDs. This has shown that various oximes are transformed with high efficiency (up to 77% product formation within 24 hours), and that the experiments can easily be scaled up to preparative scale. Typical experiments using 2 mmol oxime yield 150-250 mg pyrazine, corresponding to isolated yields of up to 62% [2]. 

Furthermore, the biotransformation is highly enantioselective as shown by cascade reactions using an ADH in addition to the ene-reductase. This yields the aminoalcohol products in high ee and de, showing highly selective binding of the substrate. By combining computational studies, substrate docking and mutant screening, we are elucidating the enzymatic mechanism by identifying catalytically active amino acid residues and reaction intermediates. This, in turn, also rationalises the found substrate scope and enantioselectivity.

References

[1] R. Stuermer, B. Hauer, M. Hall, K. Faber, Curr. Opin. Chem. Biol. 2007, 11:203-213.

[2] H. S. Toogood; J. M. Gardiner; N. S. Scrutton, ChemCatChem 2010, 2, 892–914.

[3] K. Durchschein, M. Hall, K. Faber, Green Chem. 2013, 15, 1764-1772.

[4] S. Velikogne; W. B. Breukelaar; F. Hamm; R. A. Glabonjat; W. Kroutil, ACS Catal. 2020, 10, 13377–13382.

Polycyclic natural products (PNP) show vast potential in drug discovery and exhibit certain challenges to the synthetic chemist. Examples for PNPs are the spinosyns or clifednamides. Whereas the first ones are part of an environmentally benign insecticide the latter displays anti-cancer activities. Both natural products share 5/6/5-tricylcic core scaffolds which proved to be difficult to obtain in previous and ongoing synthetic endeavours. Consequently, we developed a synthetic sequence to access these core scaffolds using chiral trans-hydrindanes ([4,3]-bicyclononanes) as key building blocks.[1,2]

The synthesis of these hydrindanes commenced with an asymmetric 1,4-addition to cyclopentene carbaldehyde using the Hayashi-Jorgensen catalyst. The following aldol condensation under basic or acidic conditions provided the hydrindanes in enantio- and diastereoselective fashion. The third ring was then installed via Diels-Alder reaction to yield bridged tricyclic scaffolds. Surprisingly, the diastereofacial preference of the cycloaddition could be controlled by applying acidic or thermal conditions. Both diastereomers were obtained as endo-isomers and the diastereofacial preferences were rationalized by high-level quantum-chemical computations. Unfortunately, the scope of dienes applicable in the Diels-Alder reaction was rather limited although interesting side reactions were discovered within this course. In addition, analytic challenges presented by the cycloadducts were overcome by boron complexation of the 1,3-dicarbonyl moiety. Finally a ring-opening metathesis provided the desired tricyclic target scaffolds.

References

[1]        Y. Stöckl, W. Frey, J. Lang, B. Claasen, S. Laschat, A. Baro, Synthesis 2019, 51, 1123–1134.

[2]        Y. Stöckl, T. Fellmeth, F. Bauer, B. Wank, W. Frey, B. Claasen, A. Zens, A. Köhn, S. Laschat, European Journal of Organic Chemistry 2022, DOI 10.1002/ejoc.202101416.

Buchwald-Hartwig vs. Microwave-Assisted Amination of Chloroquinoline – En Route to the Pyoverdin Chromophore

Pyoverdin D 1 is a siderophore produced by Pseudomonas aeruginosa, an opportunistic human pathogen ubiquitous in nature. A subspecies of siderophores, Pyoverdins, consist of a polypeptide fragment and a tricyclic chromophore. In 1 a high preference for formation of octahedral Fe³⁺ chelating complexes is observed.^[1,2] Siderophores are shuttled into gram negative bacteria therefore presenting future application fields, especially as Trojan horses for antibiotics.^[3]

A synthetic approach towards Pyoverdins is the essential step towards future applications. Especially the chromophore unit , a 5-amino-8,9-dihydroxy-2,3-dihydro-1H-pyrimido[1,2-a]quinoline-1-carbox-ylic acid 2 displays several synthetic challenges. A metal-free synthetic approach using microwave assisted condensation and amination will be presented.^[4] Additionally steps using highly toxic and environmentally concerning Hg(OAc)₂ reported in previous routes^[5] could be completely omitted by the developed route.

The intermediate quinolone 5 was obtained by microwave-assisted condensation of ethyl-nitroacetate 3 and an amino benzaldehyde 4. After chlorination to 6, Buchwald-Hartwig-type aminations were compared to microwave-initiated condensations. The latter protocol proved superior, not only in cost but as well in yield and substrate diversity. The final cyclisation could be achieved using MsCl and NEt₃ paving the way towards Pyoverdin chromophores.

[1]        U. Bilitewski, J. A. V. Blodgett, A.-K. Duhme-Klair, S. Dallavalle, S. Laschat, A. Routledge, R. Schobert, Angew. Chem. Int. Ed. 2017, 56, 14360–14382.

[2]        C. Cezard, N. Farvacques, P. Sonnet, Curr. Med. Chem. 2014, 22, 165–186.

[3]        T. C. Johnstone, E. M. Nolan, Dalton Trans. 2015, 44, 6320–6339.

[4]        M.Freund, P. Seubert, R. Rudolf, Y. Lin, L. Altevogt, U. Bilitewski, A. Baro, S. Laschat, Synlett 2020, 31, 1177–1181.

[5]        R. Mashiach, M. M. Meijler, Org. Lett. 2013, 15, 1702–1705.

Di- and triquinanes are important subunits for a range of biologically active natural products like maltophilin.[1] We created a simplified access to annelated bi- and tricycles with different substitution patterns based on sulfur ylide mediated cyclopropanation and subsequent transition metal catalyzed vinylcyclopropane (VCP) rearrangement. To overcome the limitation to strongly activated substrates of previously reported transition metal catalyzed VCP rearrangements,[2] we investigated the Ni(NHC) catalyzed rearrangement of vinylcyclopropanes with simple alkyl or aryl substituted alkenes. Additionally, we extended the substrate scope to 1-acyl-2-vinylcyclopropanes, enabling further functionalization of the rearrangement products by introducing a carbonyl function.

Surprising effects regarding stereoselectivity and substrate scope of the Ni-NHC catalyzed VCP rearrangement of 1-acyl-2-vinylcyclopropanes to the corresponding 4-acyl-cyclopent-1-enes were observed. Only 1-methyl-, 1-phenyl-, 1,2-dialkyl- or 2-phenyl-vinylcyclopropanes could be rearranged successfully. Moreover, an endo-configuration on the cyclopropane ring was determined to be a requirement for successful rearrangement. To rationalize the reactivity of the Ni(NHC) complexes and to understand the experimental results, theoretical studies were carried out, which provided insights into mechanistic details.[3]

References
 [1] a) M. Jakobi, G. Winkelmann, D. Kaiser, C. Kempter, G. Jung, G Berg, H. Bahl, J. Antibiot. 1996, 49, 1101-1104; b) T. Hudlicky, J. W. Reed, Angew. Chem. Int. Ed. 2010, 49, 4864-4876.

[2] a) S. C. Wang, D. J Tantillo, J. Organomet. Chem. 2006, 691, 4386-4392; b) Y. Morizawa, K. Oshima, H. Nozaki, Tetrahedron Lett. 1982, 23, 2871-2874; c) T. Hudlicky, F. J. Koszyk, T. M. Kutchan, J. P. Sheth, J. Org. Chem. 1980, 45, 5020-5027; d) M. Hayashi, T. Ohmatsu, Y.-P. Meng, K. Saigo, Angew. Chem. Int. Ed. 1998, 37, 837-839.

[3] A. Zens, F. Bauer, B. Kolb, F. Mannchen, P.Seubert, R. Forschner, K. S. Flaig, A. Köhn, D. Kunz, S. Laschat, Eur. J. Org. Chem. 2019, 6285–6295.

FaDu and 4T1 express high drug resistance and most surfactants (e.g, sodium dodecyl sulphate, cetyltrimethylammonium bromide) currently being used for advanced imaging and therapeutic purposes are toxic and can cause serious harmful effects on living systems. Besides,the cytotoxic consequences of utilizing inorganic imaging agents (e.g. gold nanoparticles, quantum dots, copper chalcogenides, etc.) still need thorough investigation. On the other hand, organic therapeutic agents like doxorubicin exhibit hydrophobic and rigid planar structure and cause aggregation-induced quenched emission (ACQ) with the reduced treatment efficiency.[1] In this context, we have designed indole based anthracenyl π-conjugates with very less cytotoxic effect but with the potency to act as an anticancer agent with the self-bioimaging ability. Fast and facile, metal-free pathway-based synthesis of the molecules claims a low preparation cost. The newly derived structures/molecules exhibit aggregation induced emission (AIE) properties while possessing biocompatibility and anticancer properties too.  A trimethoxy benzene-linked AIE-gen is found to be the lead with decent anticancer activity [IC50: 20.76 μM for 4T1 and 24.94 μM for FaDu] but with ~230 times less cytotoxicity than doxorubicin. Further, this lead molecule can facilitate ROS (Reactive Oxygen Species) generation and exhibits almost three times less hemolyzing tendency in comparison to doxorubicin at their respective IC50 values. Also, this probe can monitor the cancer cell death at its IC50 concentration while applied as a bio-marking agent and behave as a self-bioimaging anticancer agent with a minimum photobleaching.

Hexokinase 2 (HK2) is mitochondrial protein responsible for phosphorylation of glucose to glucose 6-phosphate. HK2 controls the rate limiting step of glycolysis and plays a key role in maintaining the integrity of the outer mitochondrial membrane by preventing release of apoptotic markers. Overexpression of HK2 has been linked with the progression of oral cancer. 3-bromo pyruvic acid (3BP) and 2-deoxy glucose (2DG) are HK2 enzymatic inhibitors and hence effective glycolytic inhibitors. 3BP is also known to inhibit mitochondrial OXPHOS in tumour cells. We observed that 3BP treated FaDu and Cal27 cells undergo delocalization of mitochondrial HK2 to cytosolic compartments as observed in western blot fractionation experiments. 3BP also showed growth inhibition of FaDu cells with a GI50 value of 23.85 ±1.01 µM (72 h post treatment). A novel benzothiazole-3-(2-methoxy-phenyl) urea based inhibitor (H10) which inhibited both the EGFR and HK2 cellular kinases in enzyme-based and cell-based assays was discovered (via structure-based and ligand-based drug design strategies) which showed growth inhibition of FaDu and Cal27 cells with GI50 of 65.92 ± 0.79 µM and 28.29 ± 2.25 µM respectively. Further, cell cycle analysis revealed that post treatment with H10 for 72 h, there is an induction of G2/M phase cell cycle arrest and apoptosis in FaDu cells indicating inhibition of HKII may be an alternative therapeutic option for oral cancer.

Isoindolinones have attracted much attention among synthetic chemists, as they are integral structural parts of a number of natural products and biologically active compounds. In most cases, only a single enantiomer is effective, or has a better activity profile than the other. Consequently, the synthesis of these structural motifs and the natural products that contain them has been the subject of much elegant and effective research. The most straightforward way to functionalize isoindolinones includes transformations of easily accessible 3-hydroxyisoindolinone precursors. Their ability to form highly reactive species under mild conditions renders them as an attractive substrates in various catalytic reactions.

The overview of our recent achievements in the construction of isoindolinone derivatives comprising quaternary stereogenic centers will be presented. The focus will be given on chiral Brønsted acid-catalyzed additions of aromatic and non-aromatic carbon nucleophiles to in situ generated isoindolinone-derived ketimines. Generally, transformations proceed smoothly and the corresponding products are isolated predominantly in high yields and enantioselectivities.

One of the constant challenges of modern organic synthesis is the formation of a new C-C and C-heteroatom bond in a single step while maintaining the latest ecological and economic requirements of sustainable chemistry. A crucial part of the process is often represented by selecting an appropriate, environmentally friendly, and inexpensive product isolation method. Crystallization belongs to the oldest and most popular separation techniques, and its thermodynamic driving forces of the reaction system could empower the course of chemical transformation. 

A common choice for the simultaneous C-C and C-N bond formation in the preparation of potentially biologically active molecules is the versatile Mannich reaction employing classical procedures or even asymmetric metal-catalyzed protocols.^1,2 Equally interesting is the possibility of Mannich bases derivatizations providing 1,3-amino alcohols, substituted carbonyl compounds, Michael acceptors or interesting β-lactams.

Figure 1: Stereoselective preparation of α-substituted Mannich salts

Our research is focused on the stereoselective synthesis of α-substituted Mannich salts. In the first step, the direct three-component Mannich reaction is performed using commercially available reagents in almost stoichiometric ratio. After the crystallization controlled epimerization, desired aromatic, aliphatic and cyclic α-substituted Mannich salts are isolated in high enantio- and diastereomeric purities by simple filtration. The effective chromatography-free protocol is readily scalable (5-110 mmol) and predetermines it for industrial applications.³

The research was supported by the Slovak Research and Development Agency under contract No. APVV-20-0298.

1. Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647–667.
2. Cai, X.-h.; Xie, B., Recent advances on organocatalysed asymmetric Mannich reactions. ARKIVOC 2013, 2013 (1), 264-293.
3. Čierna, M., Markus, J., Doháňošová, J., Moncoľ, J., Jakubec, P., Berkeš, D. and Caletková, O. Eur. J. Org. Chem. 2020, 5685-5689.

Cross-coupling reactions stand among the most important synthetic transformations in the field of organic chemistry.¹ For decades, transition-metal catalyzed reactions dominated the coupling scene, however that changed due to the rapid progress in photoredox catalysis,² electrochemical transformations,³ and the long-sustainability demands.⁴ Novel reactions employing various new cross-coupling partners were also developed. Particularly popular became β-nitrostyrenes, typically bench-stable solids easily accessible via the Henry reaction−dehydration sequence.⁵ We have envisaged that a general and catalyst-free radical denitrative C−C cross-coupling of nitrostyrenes operating under mild conditions would significantly enhance the rapidly expanding field of new sustainable cross-couplings (Scheme 1).⁶

                          Scheme 1. Visible-light-mediated denitrative cross-coupling.

 The stereoselective visible-light-induced reaction of nitrostyrenes and Katritzky salts proceeds without any catalyst at ambient temperature. Broad in scope and tolerant to multiple functional groups, the moderately yielding transformation is orthogonal to several traditional metal-catalyzed cross-couplings.

This research was supported by the Slovak Research and Development Agency under contract no. APVV-20-0298.

References:

1. Johansson Seechurn, C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062-5085.

2. Cavalcanti, L. N.; Molander, G. A. Top. Curr. Chem. 2016, 374, 39.          

3. Wang, H.; Gao, X.; Lv, Z.; Abdelilah, T.; Lei, A. Chem. Rev. 2019, 119, 6769−6787.

4. Vásquez-Céspedes, S.; Betori, R. C.; Cismesia, M. A.; Kirsch, J. K.; Yang, Q. Org. Process Res. Dev. 2021, 25, 740−753.

5. Worrall, D. E. Org. Synth. 1929, 9, 66.

6. Ferko B.; Marčeková M.; Detková K. R.; Doháňošová J.; Berkeš D.; Jakubec P.; Org. Lett. 2021, 23, 8705-8710.

Sensing double-stranded DNA (dsDNA) in cytoplasm is one of the innate immunity mechanisms that protects an organism from pathogens and cell damage.¹ The cGAS-STING pathway is crucial for detection of dsDNA in cytoplasm. Synthetic STING agonists with druglike properties are currently being studied as potential immunotherapy or antitumor agents. For successful drug design, the negative charges of CDNs need to be masked to increase their ability to enter cells. Phosphate and phosphonate prodrug strategies were successfully developed and used in the clinic.² Several phosphorothioate prodrugs of CDNs were exemplified in the patent literature, however, to the best of our knowledge, no prodrugs of phosphodiester CDNs have been published so far.

In our work, we describe a synthesis of various acyloxymethyl (POM-like) and POC prodrugs of the 3’,3’-c-di(2’F,2’dAMP) and their phosphorothioate analogues. Masking the negative charges of CDNs results in up to a 1000-fold improvement of prodrugs activity relative to their parent CDNs in reporter cell lines and PBMCs. Finally, we prepared tritium-labeled 3’,3’-c-di(2’F,2’dAMP) and its corresponding prodrug and described their cellular uptake and intracellular cleavage.³

Acknowledgment: This work was supported by the Institute of Organic Chemistry and Biochemistry CAS (RVO 61388963) and by European Regional Development Fund, OP RDE; Project “Chemical biology for drugging undruggable targets” (ChemBioDrug, No. CZ.02.1.01/0.0/0.0/16_019/0000729).

 References:

1. Motwani, M. et al. K. A. DNA Sensing by the cGAS-STING Pathway in Health and Disease. Nat. Rev. Genet. 2019, 20 (11), 657–674.
2. Pradere, U. et al. Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs. Chem. Rev. 2014, 114 (18), 9154–9218. 
3. Pimková Polidarová, M.; Břehová, P. et al. Synthesis and Biological Evaluation of Phosphoester and Phosphothioate Prodrugs of STING Agonist 3’,3’-c-Di(2’F,2’dAMP). J. Med. Chem. 2021, 64, 7596–7616.

Trihaloacetaldehydes represent useful electrophiles in many asymmetric processes that can grant access to a large number of biologically active compounds containing CX₃ groups. One of the possibilities to obtain aromatic trihaloethanols is the asymmetric organocatalyzed Friedel-Crafts reaction between phenol and trihaloacetaldehyde, which represented the subject of our current research. As such, we started with the extensive three-phase catalyst screening. Sesamol and chloral were used as substrates in the model reaction. Cinchona alkaloid-based amide derivatives showed the best enantioselectivity in the initial stage of catalyst testing. Improvement of the catalyst structure revealed 3,5-dinitrobenzamide of 9-aminoepicinchonidine as the lead catalytic molecule. Next, a series of optimizations were performed to establish the most suitable reaction conditions (catalyst load, solvent type, amount of chloral, temperature, and reaction time). Having the optimal parameters in hand, the reaction between electron-rich phenols and trihaloacetaldehydes or their hemiacetals conveniently provided enantioenriched adducts with good to excellent enantiomeric ratios (up to 99:1) within 12–24 h at 25 °C. The substrate scope included 27 derivatives containing –CF₃, –CCl₃, –CF₂Cl, and –CF₂Br groups, which suggests a reasonable generality of the developed process. Additionally, several stereoretentive downstream transformations of products were identified. This work constitutes the first organocatalyzed method for the synthesis of chiral non-racemic 2,2,2-trihalo-1-hydroxyalkylphenols.

Cutaneous leishmaniasis (CL) is a group of skin infections caused by intracellular protozoa belonging to the genus Leishmania and transmitted by Lutzomyia and Phlebotomus sand flies. CL is a poverty-associated disease considered by theWorld Health Organization as one of the 17 neglected diseases due to a lack of interest by the pharmaceutical industry to develop new drugs and a wide distribution around the world. More than 310 million people at risk, and about one million new cases are occurring annually. 

 A few drugs are available against leishmaniasis, including pentavalent antimonials, amphotericin B, and miltefosine. However, existing treatments are unsatisfactory because of their high cost, toxicity, need for prolonged treatment, and reduced efficacy, therefore, there is an urgent need to develop new molecules with novel modes of action against this disease.

 The chroman (benzopyran) moiety is considered a privileged scaffold in medicinal chemistry since it exhibits a broad range of biological activities such as antiemetic, anti-hypertensive, anti-malarial, and insecticidal activities, among others. From a bioisosteric point of view, replacement of the oxygen atom (O) by a sulfur atom (S) it may cause significant changes in the pharmacology activity since the changes in electron-donating potential and the size of sulfur cause solubility, polarity, hydrogen bonding and metabolism modifications

 In continuation of our efforts to identify promising antileishmanial agents based on the chroman scffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, and evaluated against intracellular amastigotes of Leishmania (V) panamensis. Twelve compounds were active, with EC50 values lower than 40 mM, but only four compounds displayed the highest antileishmanial activity, with EC50 values below 10 mM.

Acknowledgments: Authors thank to Universidad de Antioquia (CODI) for funding the project ES84200136 - 10410023

Protein-protein interactions (PPIs) are responsible for regulating many biological processes in our bodies. Due to the large binding site, often involving an α-helix, inhibition of PPIs can be difficult using small molecules.^[1] In contrast, short helical peptides have a potential to bind to the protein targets. Nevertheless, isolated helical sequences lack the necessary structural rigidity, binding affinity and cell-permeability. Peptide stapling - covalent cross-linking of two amino acid side chains, can be used to improve these properties of helices. Therefore, an easy access to a wide range of structurally varied stapled peptides is crucial for the development of efficient inhibitors of PPIs. Alkynylation of cysteines has been previously developed in our group using various hypervalent iodine reagents.^[2] Their high reactivity and selectivity towards thiols was now used to development novel bifunctional tools for two-component cysteine-cysteine and cysteine-lysine peptide stapling.^[3] This metal free method utilises unprotected peptides, providing excellent functional group tolerance, as well as, proximity driven selectivity. The obtained structurally diverse products can undergo post-stapling modifications via amidation of an activated ester, or via Ru "click" cycloaddition with the unique thioalkyne group present on the linker. Stapling of a peptide, derived from p53 protein, showed significant increase in helicity and binding affinity to MDM2 protein, a known cancer target.

^[1] Y. H. Lau, P. de Andrade, Y. Wu, D. R. Spring, Chem. Soc. Rev., 2015, 44, 91-102.

^[2] E. M. D. Allouche, E. Grinhagena, J. Waser, Angew. Chem. Int. Ed., doi.org/10.1002/anie.202112287.

^[3] J. Ceballos, E. Grinhagena, G. Sangouard, C. Heinis, J. Waser, Angew. Chem. Int. Ed., 2021, 60, 9022-9031.

The absolute configuration of a series of terpenes, terpenoids and cannabinoids was explored using both experimental and theoretical IR and VCD spectra.  These classes of natural products are of increasing interest in therapeutic and commercial applications, yet there are very few methods available for analysis or quality control of absolute stereochemistry.  In this study, we selected a number of examples to investigate the difficulty level and time requirements for proving absolute configuration using VCD.  In order to cut down on computing resources, we modeled full and truncated versions of the ubiquitous cannabinoid CBD – ultimately finding a good balance between speed and accuracy.  We also discovered a mistake in the Sigma-Aldrich catalog for the terpene camphene: samples from bottles of both (+) and (-) camphene had the same absolute configuration.   Finally, a theoretical study of D-8 and D-9 THC was performed to see if it would be possible to discriminate between these very similar compounds.  Overall, the comparison of DFT calculated IR and VCD spectra to experimental measurements for determination of absolute configuration for terpenes, terpenoids and cannabinoids was efficient, with clear-cut results.  

Protein tyrosine phosphatases (PTPs) are a class of enzymes whose dysregulation is key in the development of various diseases and disorders; however, much remains unknown about this class of enzymes due to a lack of chemical tools. The leukocyte antigen related (LAR) subfamily of PTPs is particular interest due to their involvement in diabetes and insulin resistance, substance abuse and neurogenesis, and cardiac reinnervation. The development of small molecule inhibitors for PTPs has historically been problematic due to their highly conserved positively charged active site making selectivity and bioavailability difficult. These challenges have resulted in a shortage of chemical probes and therapeutics targeted towards PTPs. Over a decade ago, the fungal natural product illudalic acid was reported as a novel inhibitor of LAR PTP activity and recent advances in the synthesis of illudalic acid have provided ready access to both illudalic acid and a small library of analogs. Here we will present evidence that illudalic acid and its analogs can be potent and selective inhibitors of LAR PTP activity and will also summarize recent advances in understanding the mechanism of inhibition for illudalic acid and its analogs against the LAR family of PTPs.

A diverse reactivity of diazo compounds with nitrosoarene in an oxygen-transfer process and a formal [2 + 2] cycloaddition is reported. Nitosoarene has been exploited as a mild oxygen source to oxidize an in situ generated carbene intermediate under visible-light irradiation. UV-light-mediated in situ generated ketenes react with nitosoarenes to deliver oxazetidine derivatives. These operationally simple processes exemplify a transition-metal-free and catalyst-free protocol to give structurally diverse α-ketoesters or oxazetidines.

Group transfer reactions, also known as shuttle catalysis, enable the transfer of hazardous reagents (e.g. HCN, CO, HCl) from a donor molecule to an acceptor molecule. Applying this strategy to the transfer of extremely toxic HCN, Morandi and co-workers were able to develop a transfer hydrocyanation reaction for the functionalization of alkenes and alkynes using Ni-catalysis in combination with co-catalytic Lewis acid.¹ Here, commercially available isovaleronitrile served as the sacrificial HCN donor molecule. To achieve a regioselective transfer hydrocyanation protocol, a second generation HCN donor molecule was developed. Isopropylmalononitrile was shown to irreversibly transfer HCN to the nickel catalyst in the absence of co-catalytic Lewis acid, thereby allowing selective access to the less thermodynamically stable, branched product in the hydrocyanation of styrenes and Lewis acid sensitive functional group tolerance.²

Intrigued by the inherent reactivity of the novel HCN donor, the activation of the malononitrile derivative by the nickel catalyst was investigated. Initial rate kinetic studies as well as deuterium labelling experiments suggest that activation of the C–CN bond by the nickel catalyst, followed by subsequent β-hydride elimination leads to the key H–Ni–CN intermediate, which was shown to be the active species in hydrocyanation reactions. ¹³C kinetic isotope effects at natural abundance were evaluated by NMR techniques and DFT calculations are currently being pursued in order to support our proposed activation pathway. We consider that the gained insights will allow us to further improve the hydrocyanation protocol and inspire the development of other donor reagents to enable the transfer of otherwise highly hazardous reagents.

1.  Fang, X.; Yu, P.; Morandi, B. Science 2016, 832–836
2.  Bhawal, B. N.; Reisenbauer, J. C.; Ehinger, C.; Morandi, B. J. Am. Chem. Soc. 2020, 142 (25), 10914–10920.

Chlorosulfonyl isocyanate (CSI), discovered by R.Graf, is the most chemically reactive isocyanate reagent, which has beem used in three representative reactions according to the probable sites of it. The CSI molecules has two electrophilic sites to be attacked by nucleophilic reagents, namely the carbonyl carbon (type 1) and the sulfur of the sulfonyl chloride group (type 2) and has isocyanate moiety used in the [2+2] cycloaddition reaction (type 3) N-allycarbamates formation from benzyl protected allyl ethers using CSI, which we developed, belongs to the reaction of type 1.1 By using this CSI reaction, various biologically active pyrrolidine, piperidine, pyrrolizidine, indolizidine alkaloids have been synthesized.

In a previous study, we applied our CSI reaction to benzyl ether at p-methoxybenzyl or cinnamyl position to afford the corresponding benzylcarbamate with excellent regio- and stereo-selectivity. Carbamate formation at p-methoxybenzyl position has been used for the synthesis of cytoxazone, codonopsinine, deoxynojirimycine, etc. And carbamate formation at cinnamyl position has been used for the synthesis of aminocyclopentitiols, swainsonine, fagomine, hyacinthacine, D-ribo-phytosphingosine, L-ribo-phytosphingosine, etc.

In this study, we applied our noble CSI reaction to anomeric acetal of sugars directly to afford the corresponding protected 6-amino-2H-pyran or 5-aminotetrahydrofuran, which can be converted into an important building block for the synthesis of various azasugars such as Indolizidine and Nojirimycin derivatives. We will describe the results of this reaction according to the starting materials (6-membered sugars), reaction solvents and temperature, protecting groups of acetals and their sterochemistry. We belive that this synthetic protocol can be applied to the preparation of various azasugars very efficiently due to the lack of formation of p-methoxybenzyl or cinnamyl moiety, which is necessary substrare for our previous CSI reaction.

(KLAKLAK)₂ is an antimicrobial peptide with established anticancer properties as on internalization it causes mitochondrial swelling and destruction of the mitochondrial membrane leading to apoptosis [1]. Introducing of unnatural amino acids in the primary structures of peptides often influence positively pharmacodinamic and pharmacokinetic properties of obtained compounds. Our previous investigations reveal that replacement of natural amino acid Ala in the primary structure of (KLAKLAK)₂ with unnatural analogue beta-Ala leads to good antiproliferative properties against panel of tested cell lines as well as good antimicrobial activity against model strains G+, G- microorganisms and fungi and also perfect hydrolytic stability at different pH values for 72 hours. Herein, we report synthesis, antiproliferative properties and antimicrobial activity of (KLAKLAK)₂-NH₂ analogues containing unnatural amino acid nor-Leu and conjugates with second pharmacophore with proven anticancer properties such as caffeic acid and 1,8-naphtalimide. Some structure-activity relationships will be also discussed. 

[1] Thundimadathil, J. Cancer Treatment Using Peptides: Current Therapies and Future Prospects. J. Amino Acids 2012, 2012, 967347, doi:10.1155/2012/967347

 Acknowledgements: This research is realized in a frame of National Program “EUROPEAN SCIENTIFIC NETWORKS” of Ministry of Science and Education of Bulgaria, project D01-278/05.10.2020 “Drug Molecule”.

Polynuclear systems, where multiple catalytic sites are present, are an important development in the design of new catalysts. In the majority of catalysed processes, a growing number of active centres in the individual molecule of a catalyst induces a positive effect observed as increase in efficiency.¹ Despite a number of systems based on dendritic architectures or nanoparticles having exhibited the local concentration effect in catalysis, molecular systems displaying this phenomenon are very limited.² Therefore, a series of cationic metallosupramolecular Pd(II) complexes based on polyketonate ligands allied with 2,2'-bipyridine has been designed, synthesized and fully characterized. The differences in charge, composition and morphology between the compounds resulting from the employment of mono-, bi- and tritopic β-diketonate ligands diversify significantly their catalytic properties. Application of the complexes as catalysts in Suzuki-Miyaura cross-coupling as a model reaction has revealed noticeable differences in reaction yields and a trend in reactivity reflecting their nuclearity. Under the same reaction conditions and an identical total Pd(II) loading, the reaction yields were enhanced as the number of Pd(II) ions per complex molecule increased. Thus, it provides a basis for regarding simple coordination compounds with a well-defined structure as an alternative to macromolecular systems, through a significant enhancement of catalytic activity of individual units due to the embedding several active centres on a properly designed multivalent core without increasing the catalyst metal loading.

Fig. 1. The effect of local concentrations in the Suzuki-Miyaura cross-coupling catalyzed by mono- and polynuclear Pd(II) complexes.

The financial support was provided by the National Science Centre (ARS, grant SONATA BIS 2018/30/E/ST5/00032).  

¹ P. Neumann, H. Dib, A. M. Caminade, E. Hey-Hawkins, Angew. Chem. Int. Ed. 2015, 54, 311-314.

² G. Zhang, G. Proni, S. Zhao, E. C. Constable, C. E. Housecroft, M. Neuburger, J. A. Zampese, Dalton Trans. 2014, 43, 12313-12320.

Introducing of unnatural amino acids in the primary structures of peptides often influence positively pharmacodinamic and pharmacokinetic properties of obtained compounds. Our previous studies reveal that analogue of BIM-23052, a linear derivative of somatostatin, which contain unnatural amino acid aminoisobutanoic acid (Aib) in the structure, has very good antiproliferative activity in nM range against panel of tested tumor cell lines [1]. On the other hand peptides are often used as cargo for transportation of second pharmacophore as diagnostic tool, vectors for delivery at specific cells or tissues or to create molecules with two pharmacophors with synergic effect. Herein, we will present synthesis and biological investigations of bioconjugates of analogue of BIM-23052 D-Phe-Phe-Phe-D-Trp-Lys-Aib-Phe-Thr-NH2 with second pharmacophore with well established anticancer properties such as caffeic acid, 1,8-naphtalimide and tripeptide Arg-Gly-Asp. Some docking calculations and structure-activity relationships will be also discussed. 

[1] E.D. Naydenova,   D. Wesselinova, S.Ts. Staykova, D.L. Danalev, T.A. Dzimbova, Synthesis, in vitro biological activity and docking of new analogs of BIM-23052 containing unnatural amino acids, Amino acids, 2019, 51 (9):1247–1257.

 Acknowledgements: Some parts of this research is funded by Bulgarian National Fund of Scientific Research at the Ministry of Education and Science, Grant No. DN 19/17, 20.12.2017. Another part of the work is realized in a frame of National Program “EUROPEAN SCIENTIFIC NETWORKS” of Ministry of Science and Education of Bulgaria, project D01-278/05.10.2020, “Drug Molecule”.

Indazoles are a privilege class of heterocycles present in numerous natural products, commercially available drugs, and bioactive compounds. They are used as antimicrobial, anti-depressant and antihypertensive agents among other uses.¹ These scaffolds have also incorporated as ligands in copper (I) complexes which present a high interest due to their luminiscent and photoredox properties with α-diimine ligands and diphosphine.² Many methods have been reported to synthesize these scaffolds using copper, rhodium, cobalt or palladium needing most of them high temperatures and long reaction times.³ 

In this work, we describe a new visible light mediated methodology for the synthesis of indazoles from alkynylazobenzene derivatives. In contrast with other methods already reported, this approach works under soft conditions using gold and a photocatalyst at room temperature. 

[1] a) Thangadurai, A., Minu, M., Wakode, S. et al., Med. Chem. Res. 2012, 21, 1509. b) Digambar D. Gaikwad, Archana D. Chapolikar, Chandrashekhar G. Devkate, Khandu D. Warad, Amit P. Tayade, Rajendra P. Pawar, Abraham J. Domb, Eur. J. Med. Chem. 2015, 90, 707.

[2] M. A. Escobar, D. H. Jara, R. A. Tapia, L. Lemus, R. Fröhlich, J. Guerrero, R. S. Rojas, Polyhedron, 2013, 62, 66-74.

[3] a) D. B. Kimball, T. J. R. Weakley, R. Herges, M. M. Haley, J. Am. Chem. Soc., 2002, 124, 13463-13473. b) J. R. Hummel, J. A. Ellman, J. Am. Chem. Soc., 2015, 137, 1, 490. c) J. Zhu, S. Sung, J. Cheng, Tetrahedron Lett., 2018, 59, 23, 2284. d) X. Li, X. Ye, C. Wei, C. Shan, L. Wojtas, Q. Wang, and X. Shi, Org. Lett., 2020, 22, 11, 4151. e) M. Angelis, F. Stossi, K. A. Carlson, B. S. Katzenellenbogen, and J. A. Katzenellenbogen, J. Med. Chem., 2005, 48, 1132.

With the emergence of organocatalysts, over 20 years ago, the interest in thioureas has resurfaced.^[1,2] Their ability of being strong hydrogen bond donors makes them a prime functionality for catalysis, however, to introduce chirality in the products a second functionality is needed and found in amines. Efficient chiral catalysts, such as Takemoto’s (bifunctional chiral thiourea) or Soos, Connon and Dobson’s (Cinchona alkaloid thiourea), combine the thiourea moiety with a second amine function connected over two stereogenic carbon atoms. Based on that well organised structure we developed new efficient catalysts with intrinsically chiral 2-azabicycloalkanes skeleton.^[3] The set of organocatalysts was tested in the asymmetric Michael addition; optimisation of the reaction led to good yields and enantiomeric excess.

1. O. V. Serdyuk et al. Org. Biomol. Chem. 2013, 11, 7051.
2. F. Steppeler et al. Molecules 2020, 25, 401.
3. E. Wojaczyńska et al. Org. Biomol. Chem. 2015, 13, 6116.

The regioselectivity of ring-closure reactions can be easily predicted by the iconic Baldwin rules.¹ While many examples have been reported over the years for most cyclic systems, cyclization reactions yielding to small rings, such as 4-exo-dig cyclizations, remain however poorly documented, despite their obvious strong synthetic potential. Radical 4-exo-dig cyclizations were originally predicted as unfavorable by Baldwin but were later on suggested to be possible by Beckwith and Alabugin:² this cyclization therefore still remains controversial. Based on our long-standing interest in the chemistry of ynamides,³ we hypothesized that these nitrogen-substituted alkynes could behave as excellent substrates to develop a new radical 4-exo-dig cyclization as the nitrogen atom should favor the cyclization by bringing the reacting centers closer, polarizing the triple bond and stabilizing the resulting vinylic radical species. In addition to developing the first general anti-Baldwin 4-exo-dig cyclization, this process would moreover afford a straightforward entry to highly substituted azetidines, four-membered nitrogen heterocycles of growing importance in chemical synthesis and medicinal chemistry.

This cyclization could actually be efficiently performed from N-iodoethyl-ynamides that were shown to be readily activated by our previously reported copper-based photoredox catalyst, [Cu(bcp)(DPEPhos)]PF₆,⁴ under blue light irradiation in the presence of a sacrificial reductant. The scope of the reaction was found to be quite broad as a series of azetidines substituted at all positions could be readily obtained in fair-to-excellent yields and under mild conditions. The development of this reaction, its application to the synthesis of complex and/or biologically relevant azetidines, their chemical diversification and mechanistic studies will be presented and discussed.⁵

References

¹ J. Chem. Soc., Chem. Commun. 1976, 734; Chem. Rev. 2011, 111, 6513.

² J. Chem. Soc., Chem. Commun. 1980, 482.

³ For a review, see: Aldrichimica Acta 2015, 48, 59.

⁴ Org. Lett. 2017, 19, 3576. 

⁵ Nat. Commun. 2022, DOI: 10.1038/s41467-022-28098-x.

Chiral lactams are a key molecular unit present in a wide variety of natural products and pharmaceuticals. In addition to β-lactams found in ground-breaking antibiotics [1], thehigher-membered cyclic amides have been known as an essential structural motif in clinical drugs and their candidates, including antitumor drugs. [2]

Despite many efforts to develop efficient and selective methods of synthesizing this building block [3], the preparation of chiral analogs remains a significant synthetic challenge. In addition to tedious derivatization methods [4], several asymmetric protocols have been developed to allow the synthesis of optically pure cyclic amides.

In our study we have developed a new methodology for the synthesis of functionalized chiral lactams using l-cysteine and other low cost and commercially available starting materials under mild conditions. Our protocol is based on a stereospecific rearrangement of thiazolidine containing esters with hydroxyl functionality under basic conditions leading to optically pure ɣ-lactams equipped with a protected thiol and a hydroxyl group (1,3-oxathiane unit; Figure 1). This procedure is useful for preparation of other lactams: β-lactams, ẟ-lactams and Ɛ-lactams.

Figure 1. General structure of chiral, functionalized ɣ-lactam.

Amines are a widely represented substance class in a variety of compounds ranging from materials science to biology. They make up the vast majority of biologically active substances, which is manifested in their application in agrochemicals and pharmaceuticals. Moreover, the ample representation of amines in materials such as dyes and organic electronics underlines the ever-present demand to develop new methodologies and innovative strategies for C–N bond formation. In recent years, some remarkable progress has been made regarding the development of mild methods to directly obtain unprotected amines from alkenes and arenes. Morandi and co-workers reported the direct synthesis of unprotected primary anilines through the Fe-catalyzed C–H amination of arenes, using a bench-stable aminating reagent.¹ This offers an economical alternative to the established methodology using a Rh-catalyst.

Extending this methodology by employing a novel, highly electrophilic N-alkyl aminating reagent (NsONHMe·TfOH) and catalytic amounts of an iron salt, provided access to a wide variety of unprotected N-methyl anilines.² A broad functional group tolerance and selective mono-amination allowed for the late-stage derivatization of two drugs, namely Nimesulide and ibuprofen methyl ester. A modified protocol was used for the intramolecular C–H amination of electron-poor arenes to generate tetrahydroquinolines.

¹Legnani, L.; Prina Cerai, G.; Morandi, B. ACS Catal. 2016, 6, 8162–8165.

²Falk, E.; Gasser, V. C. M.; Morandi, B. Org. Lett. 2021, 23, 1422–1426.

The fluorescent alkaloid ageladine A (1) was isolated from the marine sponge Agelas nakamurai by the Fusetani group.^[1] Interestingly, pH-dependent fluorescence of 1 was observed with a maximum at pH 3–4.^[2] In the light of the chemoselective photoreactivity of 2-azidobenzimidazole derivatives towards amino acids and peptides, we wondered whether it is possible to design an azido analog of ageladine A (1) that would become fluorescent on binding to target molecules. In the first phase of the project, a synthesis of ageladine A (1) was to be developed that would also provide a "photoageladine" 2 carrying an azido instead of an amino group in the 2-position of the imidazopyridine core.

Figure 1. Structures of ageladine A (1), photoageladine 2, tricyclic imidazolone 3, and BODIPY-inspired boron complexes 4 and 5.

Differing from the existing total syntheses for ageladine A (1), we started with a pyridine derivative instead of building up the pyridine ring. The biaryl axis of tricycle 3 was assembled in satisfactory yield only when a Pd-precatalyst was employed. As in other syntheses of the pyrrole-imidazole alkaloids, the regio- and chemoselective dibromination of the pyrrole section proved to be challenging. We solved that problem by synthesizing the BODIPY-like boron complex 4 that underwent smooth dibromination. Decomplexation to photoageladine 2 was accomplished with ZrCl₄ in MeCN/MeOH. Reduction of the azide to the amine succeeded with Na₂S and provided ageladine A (1, 7.9% over 9 steps). Encouragingly, the fluoresence of the azido compounds is much weaker than of the amino compounds. Additionally we were able to synthesize the boron complex of ageladine A 5 which shows 30 time stronger fluorescence then ageladine A (1).  

References:

[1]   T. Mineno, H. Kansui, H. Yoshimitsu, Tetrahedron Lett. 2011, 52, 3131–3132.

[2]   U. Bickmeyer, Mar. Drugs 2012, 10, 223–233.

The tremorgenic mycotoxins janthitrem A – G (B: 1) from Penicillium janthinellum cause tremors in mice and exhibit anti-insect activity.^[1,2] Their biological activity and intriguing structure makes the janthitrems interesting targets for total synthesis.

Our first approach entailed the synthesis of 5,6-disubstituted indolines, inspired by the plausible biosynthesis of the western hemisphere from a 5,6-diprenylated indole species. However, the envisioned gold-catalyzed cyclization failed for all substrates. We wondered, whether the Lewis acid promoted cyclization of an ortho-dihydropyranyl benzaldehyde by Magnus and coworkers^[3] could be applied for the first time to indoline-based systems 2. Gratifyingly, the reaction proceeded smoothly and provided tetracyclic diene 3 in good yield (48%). 

Scheme 1. Structures of janthitrem B (1), aldehyde 2 and tetracyclic diene 3.

Already, pyranocyclopentaindole 3 represents the western hemisphere of the natural product JBIR-137^[4] and hydroboration/oxidation thereof afforded the western hemisphere of janthitrem B (1). Additionally, the western hemisphere of shearinine G was prepared.

References:

[1]  a) Gallagher, R. T.; Latch, G. C.; Keogh, R. G. Appl. Environ. Microbiol. 1980, 39, 272–273. b) Lauren, D. R.; Gallagher, R. T. J. Chromatogr. A 1982, 248, 150–154. c) de Jesus, A. E.; Steyn, P. S.; van Heerden, F. R.; Vleggar, R. J. Chem. Soc. Perkin Trans. 1 1984, 697–701.

[2]  Babu, J. V.; Popay, A. J.; Miles, C. O.; Wilkins, A. L.; di Menna, M. E.; Finch, S. C. J. Agric. Food Chem. 2018, 66, 13166–13125.

[3]  Magnus, P. ; Mansley, T. E. Tetrahedron Lett. 1999, 40, 6909–6912.

[4]  Kawahara, T.; Nagai, A.; Takagi, M.; Shin-ya, K. J. Antibiot. 2012, 65, 535–538.

Anilines are ubiquitous scaffolds found in numerous natural products and biologically active substances. If their synthesis seem trivial, their selective functionalization actually remains challenging depending on the substituent to introduce and the targeted position of the aniline ring. A striking example lies on the direct ortho-arylation of anilines, which relies to date on employing rather harsh conditions using either diazonium salts or hydrazines,¹ Grignard reagents with aryllead compounds,² aryne derivatives³ or aryl sulfoxides.⁴ Moreover, most processes lack generality and robustness. To adress these limitations, we envisioned the design of an easily installable directing group,⁵ robust to be able to promote the insertion of an organometallic species into the desired ortho-C–H bond but easily cleaved after the transformation, to enable the development of a general process for the ortho-arylation of anilines.

Aminophosphines were found to be optimal and fulfil all these requirements since their N–P bond is easily cleaved under acidic conditions after successfully promoting the ortho-C–H bond activation through the formation of a 5-membered metallacycle using rhodium catalysis. The scope of this reaction was shown to be broad since variously substituted ortho-(hetero)arylated N-alkylanilines could be readily obtained in fair to high yields, thus offering an efficient and straightforward entry to ortho-(hetero)arylated anilines via C–H functionalization using a traceless directing group. The development of this reaction, its scope, limitations and application to complex substrates will be presented and discussed.

References:

¹ a) Angew. Chem. Int. Ed. 2008, 47, 9130; b) J. Org. Chem. 2012, 77, 10699. 

² J. Am. Chem. Soc. 2002, 124, 5365.

³ a) Org. Lett. 2012, 14, 5964; b) Angew. Chem. Int. Ed. 2012, 51, 1006.

⁴ Chem. Eur. J. 2020, 26, 783. 

⁵ a) Chem. Soc. Rev. 2018, 47, 660; b) Chem. Eur. J. 2021, 27, 13899.

Keteniminium ions, the nitrogen analogues of ketenes pioneered by L. Ghosez, exhibit high reactivity toward olefins and π-systems.[1] Previous results from the Maulide group aiming at producing intramolecular [2+2]-cycloaddition behaviour revealed an unexpected propensity for an alternative intramolecular Claisen-type rearrangement, forming lactone 2.[2] Herein, we have conducted a cooperative density functional theory and experimental investigation of this process, seeking insight into the competition between the observed Claisen-type reaction and the historically-expected [2+2]-cycloaddition (1). Our calculations demonstrate a surprisingly small difference in free energy barrier between these two intramolecular reactions and provide a basis for experimental validation. Further theoretical and experimental investigations probe the electronics of the substrate, rationalize competing deallylation (4) and dimerization (3), and demonstrate proof-of-concept for a traceless enantioselective [2+2] variant with the help of a chiral auxiliary.[3]

[1] L. Ghosez, B. Haveaux, H. G. Viehe, Angew. Chem. Int. Ed. Engl. 1969, 8, 454–455.

[2] C. Madelaine, V. Valerio, N. Maulide, Angew. Chem. Int. Ed. 2010, 49, 1583–1586.

[3] A. J. Fernandes, M. A. Maskeri, G. Di Mauro, N. Maulide, K. N. Houk, J. Am. Chem. Soc. 2022, manuscript submitted.

Figure 1 : Overview of the collaborative work, steering the reaction pathway via fine-tuning of reaction conditions.

The rapid emergence of resistant bacterial strains is becoming a serious threat to public health, and there is a pressing need for the development of new antibacterial agents to avert the possible crisis that would lead to a so-called post-antibiotic era in which common bacterial infections might have fatal consequences. Berkeleylactone A is a novel 16-membered macrolide that was isolated from a fungal coculture from the Berkeley pit lake in 2017 and showed potent antibacterial activity, especially against MRSA.¹ Recently, our group reported the first total synthesis of berkeleylactone A, with the key step being the stereoselective sulfa-Michael addition to the unsaturated macrocycle.²

Currently, our research focuses on the development of more effective synthesis of berkeleylactone A analogues that would provide more readily available derivatives while maintaining high antibacterial activity. We identified two different approaches to the modification of the original structure, one based on modification of the S-nucleophile (red fragment) or by the modification of the macrocyclic ring (blue fragment). Modification of the macrocycle included preparation of the simplified lactone, lactam, and their corresponding adducts. As studies suggested that the biological activity of berkeleylactone A does not depend on the sulfur nucleophile attached to the macrocycle, derivatives with the nucleophile replaced by commercially available simple thiols were prepared. Another goal was to prepare Michael adducts of commercial wide-spectrum antibiotics, providing structures that would potentially serve as dual-acting antibiotic agents. Subsequently, biological activity of all prepared derivatives was evaluated.

                                           Scheme 1: Synthetic strategy                                         

1.  Stierle, A. A.; Stierle, D. B.; Decato, D.; Priestley, N. D.; Alverson, J. B.; Hoody, J.; McGrath, K.; Klepacki, D. J. Nat. Prod. 2018, 80, 1150−1160.
2. Ferko, B.; Zeman, M;, Formica, M., Veselý; S., Doháňošová, J.; Moncol, J.; Olejníková, P.; Berkeš, D.; Jakubec, P.; Dixon, D. J.; Caletková, O. J. Org. Chem. 2019, 84, 7159−7165.

The research on the synthesis of axial chiral biphenols is highly attractive as they can be frequently found in bioactive dimeric polyketides, like (-)-Gossypol, Rugulotrosin A or Mastigophorene A, and chiral auxiliaries or catalysts in asymmetric synthesis.^[1-3] Their rotational hindered and stereogenic axis is an essential factor for specific bioactivities of polyketides. In contrast to the enantioselectively easily accessible binaphthol, there is a great challenge in the atroposelective synthesis towards biphenol building blocks.^[4,5] Different methods have been established for challenging asymmetric C-C cross-coupling towards hindered tetra-ortho-substituted biphenols, which require highly stereoselective catalysts or the introduction of chiral substituents or bridges. Atroposelective transformations of racemic biaryls in a chemical or enzymatic way open a broader access to the axially chiral substrates.^[5] Here, we would like to show our investigations on an efficient, scalable synthesis route towards enantiopure biphenol building blocks and their application in a total synthesis towards bioactive natural products.

[1] Tang et al., J. Am. Chem. Soc., 2020, 8036

[2] Porco et al., Nat. Chem., 2015, 234

[3] Feringa et al., Angew. Chem. Int. Ed., 2016, 3620

[4] Tang et al., Chem. Soc. Rev., 2021, 2320

[5] Carmona et al., Chem. Soc. Rev., 2021, 2968

Silyl ethers are commonly used as protecting groups of alcohols and their steric, electronic and reactive properties are dependent on the silicon’s substituents.¹ Despite the emerging trend of protecting group-free syntheses,² the use of such tool can occasionally warrant structural diversification, such as in the case of silyl ethers.

Trisilylated diol 2, easily obtained in 3 steps from quinic acid, has been subjected to base treatment, resulting in variable mixtures of isomers. After tuning of the reaction conditions, isomer 3 was used as a synthetic intermediate in the first total synthesis of a metabolite isolated from African ants of species Crematogaster nigriceps, a family of compounds firstly described in 2003.³ Such compounds are described by a long carbon chain derived from common fatty acids and a common cyclitol backbone. This cyclitol backbone was built from isomer 3, upon a sequence of Barton–McCombie deoxygenation, selective desilylation, chemoselective mesylation of primary alcohol followed by intramolecular S_N to yield an epoxide prone for installation of the carbon chain. Epoxide opening was achieved by treatment with the corresponding Gilman reagent formed in situ and the ultimate cleavage of the secondary TBDPS-group led to the formation of the desired cyclitol 11. This work⁴ illustrated the first synthesis of the cyclitol metabolite from African ants Crematogaster nigriceps, starting from quinic acid in 10 steps and 34% overall yield.

Acknowledgements: Fundação para a Ciência e Tecnologia (PTDC/QUI-QOR/1131/2020 and CEE-CINST/2018) is acknowledged for financial support. 

1. Ruecker, C., Chem. Rev. 1995, 95, 1009.

2. Hui, C.; Chen, F.; Pu, F.; Xu, J. Nature Rev. Chem. 2019, 3, 85.

3. Laurent, P.; Hamdani, A.; Braekman, J.-C.; Daloze, D.; Isbell, L. A.; de Biseau, J.-C.; Pasteels, J. M. Tetrahedron Lett. 2003, 44, 1383.

4. Holmstedt, S.; Efimov, A.; Candeias, N. R. Org. Lett., 2021, 23, 3083.

β-Amino acid derivatives are key structural elements in synthetic and biological chemistry. In spite of being a hallmark method for β-amino carbonyl synthesis, the direct Mannich reaction encounters significant challenges when carboxylic acid derivatives are employed. Indeed, not only is chemoselective enolate formation a pitfall (particularly with carboxamides), but most importantly, the inability to reliably access α-tertiary amines through an enolate/ketimine coupling means that alternative approaches to β-amino carboxylic acid derivatives are needed. Herein, we report an asymmetric strategy that enables the first broad and direct coupling of carboxamides with ketimines for the synthesis of diastereo- and enantioenriched β-amino amides. This conceptually novel approach hinges on the innovative deployment of electrophilic amide activation and an enantiopure ketimine derivative. Our approach simultaneously solves the problems of chemoselectivity, reactivity and (relative and absolute) stereoselectivity. In-depth computational studies explain the observed, and unexpected, (dia)stereoselectivity and showcase the key role of intramolecular interactions, including London dispersion, for the accurate description of the reaction mechanism.

The human microbiome is the collection of the approximately 500–1,000 different microbial species that live in and on the human body. Secondary metabolites produced by these commensal communities represent the undeciphered language by which its members interact and elicit responses. Mutanobactin D is a non-ribosomal, cyclic peptide isolated from the human colonizer Streptococcus mutans. The molecule shows activity reducing biofilm formation of the pathogenic fungus Candida albicans, another member of the human microbiota. 

We report the first total synthesis of this intriguing natural product alongside configurational assignment of all previously unassigned stereocenters. The synthesis relies on enantioselective, zinc-mediated 1,3-dipolar cycloaddition followed by reduction of the resulting isoxazoline moiety, providing the key lipidated γ-amino acid found in mutanobactin D. Application of the recently developed infrared sequence alignment (IRSA) algorithm in combination with quantum chemical calculations proved key to assign the α-substituted β-keto amide, which constitutes the natural product's most elusive structural motif. Of note, this assignment was not possible by means of other characterization methods like NMR spectroscopy or X-ray diffraction. To the best of our knowledge, this study features the largest and stereochemically most complex molecule where IR spectroscopy in combination with computational methods have been implemented successfully to distinguish between diastereoisomers. Moreover, our results showcase how total synthesis is central to drive biological studies that shed light on the complex network of interspecies communications within the realm of human colonizers.

AC1-004 is a potent inhibitor of the hypoxia-inducible factor alpha (HIF-1α) pathway which is essential for the growth, angiogenesis and metastasis of tumors. We now modelled a series of gold(I) complexes on AC1-004 by retaining its 5-carboalkoxybenzimidazole as an NHC ligand while replacing its 2-aryloxymethyl residue with diversely modified thiolato gold(I) fragments. The intention was to augment the HIF-1α inhibition by further conducive effects, such as an inhibition of the tumoral thioredoxin reductase (TrxR), an increase in reactive oxygen species (ROS), as well as cytotoxic and antiangiogenic effects. We report the synthesis and biological effects of nine new N,N’-dialkylbenzimidazol-2-ylidene gold(I) complexes. They were obtained in average yields of 65% for the thiophenolato and 45% for the novel p-(2-adamantyl)thiophenolato complexes. The structure of one complex was validated via single-crystal X-ray diffraction. Structure activity relationships (SAR) were derived by variation of the N-substituents (Me, Et, iPr, Pen, Bn) and of the thiolato ligand. Their cytotoxicity against various human cancer cell lines of different entities reached IC₅₀ values in the single digit micromolar range. The complexes were assayed also for the induction of tumor cell apoptosis (activation of caspase-3/7), TrxR inhibition, antiangiogenic effects in Zebra fish and HIF-1α inhibition. Some promising candidates for further tests were identified.

Host-guest chemistry employing two roof-shaped host compounds was investigated as an alternative isomer separation strategy for the C₈H₁₀ aromatic fraction of crude oil, that is, the xylenes (o-Xy, m-Xy, p-Xy) and ethylbenzene (EB). Most current separation methods involve fractional distillations which are extremely energy-intensive and costly, and oftentimes the subsequent product streams still contain some of the undesired isomers. The challenge to separate these isomers is because of their very similar physical properties, including boiling points. Therefore, diacid host compound H1, formed by means of a Diels-Alder reaction between anthracene and fumaric acid, served as the first host compound in this work. This diacid was then esterified with methanol to afford the diester H2, the second host compound to be investigated. H1 demonstrated virtually complete selectivity for p-Xy owing to the resulting o-Xy/p-Xy and m-Xy/p-Xy complexes containing 96.6 % and 93.6 %, respectively, of the p-Xy guest when H1 was recrystallized from these equimolar binary mixtures. H2, unfortunately, displayed only a moderate selectivity towards the same guest when presented with the various guest mixtures. For example, recrystallization of H2 from a mixture of all four guest compounds showed the resultant mixed complex to contain 29.3% p-Xy, 28.2% m-Xy and 26.1 % o-Xy. Finally, the complexes of H1 and H2 with p-Xy were subjected to SCXRD analyses which revealed very few host···guest interactions. The thermal data also correlated with observations from the competition experiments.

Building blocks based on benzene-1,3,5-tricarboxamide (BTA) have been widely investigated, due to their simple synthesis and countless possibilities of modification. Very well-studied and extremely important group of BTAs is amino ester decorated molecules.[1] The amino acid moiety as a structural motif has major impact on the supramolecular structure, due to encoded H-bonding pattern, which generally leads to helical structures. [2]

Herein we present the non-covalent assembly of four benzene-1,3,5-tricarboxamide (BTA) derivatives formed from glycine or L-valine esters (-Me, -iPr), in the solid state and in chloroform solution by means of several analytical methods (NMR, FT-IR, CD, single crystal and powder XRD, TGA). Two types of self-assembled structures were characterized: dimeric capsule formed by -NH···O=C- (ester) and columnar assembly wit -NH···O=C- (amide) bond (Figure 1).

Figure 1. Representation of influence amino acid side chain and ester group on the self-assembly in solution and solid state.

In-depth solid state study revealed the crucial role of C-terminus protecting group structure to supramolecular aggregation in solid state, which has not been thoroughly investigated yet. The isopropyl ester group prevents the molecule from assembly into columnar structure, instead dimeric assembly is observed. On the other hand, it has no effect in chloroform solutions, where amino acid chain determines the self-assembly. Our study points out the essential influence of substituent in both – alpha atom of the amino ester and the ester group.

We thank National Science Centre (SONATA BIS 2018/30/E/ST5/00032) for financial support.

[1] A. Desmarchelier, B. G. Alvarenga, X. Caumes, L. Dubreucq, C. Troufflard, M. Tessier, N. Vanthuyne, J. Ide, T. Maistriaux, D. Beljonne, P. Brocorens, R. Lazzaroni, M. Raynal, L. Bouteiller, Soft Matter 2016, 12, 7824-7838; 

[2] P. J. Stals, M. M. Smulders, R. Martin-Rapun, A. R. Palmans, E. W. Meijer, Chem. Eur. J 2009, 15, 2071-2080;

Computer-assisted synthesis planning represents a growing area of research and with the rapid advancements of computing hardware and machine learning algorithms, new generation CASP tools hold the promise of bringing an innovative step change in synthesis planning and help chemists plan the strategy for making target molecules. 

Waller and Segler et al. (Nature 2018, 555, 604–610) in collaboration with Reaxys (R) have developed a deep learning computer algorithm that produces blueprints for the sequences of reactions needed to create small organic molecules, such as drug-like compounds. This has led to an artificial-intelligence tool trained on > 15 million unique single-step organic reactions from Reaxys, which generates a retrosynthesis tree back to commercially available starting materials for a given target molecule. This approach has the potential to transform the way synthetic chemists work in the future.  

Here, we present a case study involving drug-like compounds and natural products, examining the synthetic strategies that Reaxys Predictive Retrosynthesis applies towards these molecules. We will consider the routes proposed by Reaxys in comparison with previously used synthesis strategies within our research group.  

By processing a large variety of different structures, including terpenoids, peptides, heterocyclic and drug-like compounds we concluded that the Reaxys Retrosynthesis feature is user friendly, intuitive, and easy to use. It provided robust predictions for drug like molecules, however, chemists do need to review the predicted routes and make small adjustments as required. Fast development of a synthesis route, easily accessible literature precedences and suggested reaction conditions combine to successfully save the chemist’s time. We concluded that Reaxys Predictive Retrosynthesis can be part of a chemist’s workflow for designing synthesis routes and can augment and support their work. We will further discuss the current capabilities, future development, and limitations of the software on selected examples.

Due to the increasing problem of antibiotic resistance, new antibiotic compounds with novel modes of action, including such from natural sources, are desperately needed. The promising kibdelomycin was isolated in 2011 from Kibdelosporangium sp. and later turned out to be structurally identical to amycolamicin, isolated from Amycolatopsis sp. MK575-fF5. Its unique horseshoe-like mode of binding and so inhibiting the bacterial topoisomerase IV and gyrase B rules out any cross-resistance with other known classes of antibiotics. Its structure features the highly functionalized sugar amykitanose linked via an N-glycosidic bond to a 3-acyltetramic acid. The latter is itself linked via a nonpolar decalin spacer to the 2-deoxy-sugar amycolose, which carries a pyrrole fragment. Our synthetic approach builts up the amykitanose fragment from L-rhamnose by inversion of the stereocenter at position 4, followed by selective acetylation and methylation. The amycolose moiety is synthesized starting from D-mannose which gets desoxygenated at positions 2 and 6, with subsequent diastereoselective introduction of a C₂-synthon, which itself is converted to an amide. The synthesis of the decalin fragment starts with the Pd-catalyzed cross coupling of iodinated butyric acid ethyl ester and sorbic acid thioester, followed by CBS reduction of the internal ketone. After α-hydroxylation of the ester and its reduction to the aldehyde, the Evans auxiliary is added via HWE-olefination. The following intramolecular Diels-Alder (IMDA) reaction affords the bicyclic structure which is subsequently methylenated and linked β-selectively to the amycolose. The convergent total synthesis is finished by the introduction of the tetramic acid and N-glycosylation with amykitanose.

Carbon dioxide (CO₂) impacts many aspects of life, such as biology (molecular respiration), food science (fermentation, carbonated drinks) or climatology (climate change, carbon cycle). As a result, numerous sensing technologies have been established to detect or monitor this molecule. However, despite the large potential of sensing CO₂ at the molecular level in the presence of other reactive species, this still remains an unmet challenge.

In this work, we introduced a unique class of fluorescent sensors that are selective for CO₂ and that addresses several existing challenges, such as selectivity and sensitivity, through an activity-based approach. Our sensor design is based on a fluorophore with a reactive iminophosphorane trigger attached, that selectively reacts with CO₂. The formed isocyanate then reacts intramolecularly with a strategically placed pendant amine to form a cyclic urea. This causes a change in electronic properties of the fluorophore, which leads to a "turn-on" signal that can only be triggered by a reaction with CO₂, even in the presence of other reactive carbon species such as CO, formaldehyde, or acyl chlorides. We further evaluated the utility of our sensors by modulating and fine-tuning them to give varying degrees of reactivity and distinct spectral properties. With this, we could apply them in a broad range of multidisciplinary applications, including atmospheric sensing, chemical reaction monitoring, an enzymatic inhibition assay, and live-cell imaging.

Intracellular accumulation of neurofibrillary tangles (NFTs) is a hallmark of Alzheimer´s disease (AD). The main component of NFTs is tau,¹ a microtubule-binding protein that upon hyperphosphorylation aggregates into paired helical filaments during disease development. O-GlcNAcylation is a reversible post-translational modification that involves the addition of a single sugar residue (O-linked N-acetylglucosamine) onto serine (Ser) or threonine (Thr) residues of numerous intracellular proteins. Despite of the fact that this process was discovered in the 80s,² the research in this area has only developed rapidly after the finding that human tau is O-GlcNAc modified representing a potential link with neurodegeneration. O-GlcNAcase (OGA) is the enzyme which catalyses the hydrolysis of the O-GlcNAc moiety from Ser/Thr residues. It has been shown that increasing O-GlcNAcylation of tau in the brain using the O-GlcNAcase inhibitor Thiamet G could decrease tau pathology in transgenic mice.³ On the basis of these findings OGA inhibition has emerged as a promising therapeutic strategy to treat tau pathology in Alzheimer´s disease and related tauopathies. Although Thiamet G provided the initial preclinical proof of concept this compound is a carbohydrate substrate mimetic and as such has poor CNS drug properties. Given these limitations we initiated a drug discovery program to identify structurally distinct CNS-like O-GlcNAcase inhibitor scaffolds. Following different hit finding strategies for the identification of novel OGA inhibitors (virtual screen, HTS and FBDD approaches) a series of piperidine-based inhibitors was identified (I).  The exploration around this series is presented in this poster.

(1) Lee, V. M.-Y.; Goedert, M.; Trojanowski, J. Q. Annu. Rev. Neurosci. 2001, 24, 1121-1159

(2) Torres, C.R.; Hart, G.W. J. Biol Chem. 1984, 259 (5), 3308-3317

(3) Yuzwa, S.A.; Shan, X.; Macauley, M.S.; Clark, T.; Skorobogatko, Y. Vosseller, K, et al. Nat Chem Biol. 2012, 8, 393-399

Spirocyclic molecules have become increasingly sought-after in drug discovery due to their intrinsic rigidity, three-dimensionality and structural novelty.¹ This study has focused on the development of innovative methods for the strain-release-driven synthesis of azetidine-containing spirocycles by exploiting the inherent ring strain of the azabicyclo[1.1.0] butane (ABB) fragment. Our general strategy hinges on the coupling of the versatile carbenoid, ABB-Li (1), to ambiphilic species (2) to generate compounds predisposed to ring-closure, with the challenging spirocyclisation step driven by the opening of the highly strained aza-bicycle (Scheme 1).

Our group has demonstrated that this strain-release-driven spirocyclisation can proceed via semi-pinacol rearrangement, epoxidation and nucleophilic addition/desilylation reactions, generating a range of azetidine-containing spirocycles in a highly modular fashion (4a-d; Scheme 2).² Recently, we have extended this strategy to a novel acid-mediated Friedel-Crafts spirocyclisation reaction for the synthesis of a library of azetidine spiro-tetralins 7 (Scheme 3).³ Mechanistic investigations identified the existence of an unexpected azabicyclo[2.1.1]hexane-containing dearomatised intermediate (6). This species, formed exclusively as a single diastereomer, can be subsequently converted to Friedel-Crafts product 7 upon electrophilic activation of the tertiary amine, or trapped as the Diels-Alder adduct (8) in one-pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain-release-driven spirocyclisation strategy to be utilised in the synthesis of medicinally relevant scaffolds.

References:

[1]           Y.-J. Zheng, C. M. Tice, Expert Opin. Drug Discov. 2016, 11, 831–834.

[2]           a) C. H. U. Gregson, A. Noble, V. K. Aggarwal, Angew. Chem. Int. Ed. 2021, 60, 7360–7365.  b) J. L. Tyler, A. Noble, V. K. Aggarwal, Angew. Chem. Int. Ed. 2021, 60, 11824–11829.

[3]           J. L. Tyler, A. Noble, V. K. Aggarwal, Angew. Chem. Int. Ed. 2022, 61, e202114235.

The Lycopodium alkaloid huperzine A is one of the most potent known acetylcholine esterase inhibitors.¹ The potential application of this compound from scarce natural resources in the treatment of neurogenerative diseases has driven several synthetic studies toward efficient preparations of huperzine-type alkaloids – with limited applicability so far.² The enzymatic steps in the biosynthesis of huperzine-type alkaloids from L-lysine are not completely understood yet, prohibiting a scalable biomanufacturing process. Recently however, a set of enzymes responsible for late-stage modification of Lycopodium alkaloids was discovered.³ These non-heme iron(II)-dioxygenases use α-ketoglutarate to activate oxygen for highly specific C–H functionalization of metabolites and natural products. In this study we present experimental and computational results in support of an unprecedented biocatalytic retro-aza-Prins mechanism for the transformation of N-desmethyl-β-obscurine into casuarinine H – an immediate biosynthetic precursor of huperzine A. The transformation presumably entails oxidative activation of a piperidine-moiety (i.e. C–H-abstraction from C11) by an iron(II)-oxo species followed by rearrangement to a formiminium ion species. C9 is finally excised from the scaffold as formaldehyde (detected by headspace GC-MS). The substrate for this heterocycle-cleaving enzyme Pt2OGD-1 was prepared from synthetically accessible N-desmethyl-α-obscurine⁴ by another non-heme iron enzyme (Pt2OGD-3). Together, these new insights provide the basis for further investigations toward a potential chemoenzymatic preparation of members of this pharmacologically relevant compound class.

[1] Kozikowski, A. P.; Tuckmantel, W. Acc. Chem. Res. 1999, 32, 641–650.

[2] Siengalewicz, P.; Mulzer, J.; Rinner, U. The Alkaloids: Chemistry and Biology; Knölker, H.-J., Ed.; Academic Press: 2013; Vol. 72, pp 1–151.

[3] Nett, R. S.; Dho, Y.; Low, Y.-Y.; Sattely, E. S. PNAS 2021, 118, e2102949118.

[4] Haley, H. M. S.; Payer, S. E.; Papidocha, S. M.; Clemens, S.; Nyenhuis, J.; Sarpong, R. J. Am. Chem. Soc. 2021, 143, 4732-4740, and references therein.

Late-stage functionalization is a convenient strategy in organic synthesis with applications in relevant fields of science and technology, including drug discovery. [1]

In this report, [2] we disclose a metal-free cross-coupling strategy which allows practical connection of complex molecular fragments bearing carboxylic acids and aldehydes, ubiquitous functional groups in chemistry.

The process merges two cornerstones of organic synthesis—namely, the Wittig reaction [3] and photoredox catalysis [4]—in a catalytic cycle that couples a radical addition with the redox generation of a phosphonium ylide. The procedure is highly functional group tolerant and can be used for the late-stage functionalization of native-form natural products and bioactive molecules without the need of exogeneous functional groups and no (or very limited) use of protecting groups. The chemistry connects the fragments forging a new alkene functional group with a programmable E–Z stereochemistry.

Figure 1: Merging photoredox catalysis with the Wittig reaction for a conjunctive olefination.

References:

[1] Börgel, J., Ritter, T., Late-Stage Functionalization. Chem., 6, 1877-1887 (2020).

[2] Filippini, D., Silvi, M. Visible light-driven conjunctive olefination. Nat. Chem. 14, 66–70 (2022).

[3] Wittig, G. Nobel Lecture: from Diyls to My Idyll https://www.nobelprize.org/uploads/2018/06/wittig-lecture.pdf (1979)

[4] Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

The natural products unciaphenol and sealutomicins B – D (Figure 1) are anthraquinone-bearing secondary metabolites whose biosyntheses are proposed to proceed via a Bergmann cyclisation of enediyne precursors.^1,2 Unciaphenol inhibits in vitro HIV-1 replication without concomitant cytotoxicity to host T-cells; similar effects are observed against recombinant viruses resistant to current marketed anti-retroviral therapies. Sealutomicins B – D all display antibacterial activity against Gram-positive bacteria however as yet there have been no reports concerning their potential antiviral activities. As such, these four natural products are synthetic targets of potential therapeutic and medicinal use.

Our group has developed a route to common core A from which we anticipate unciaphenol and sealutomicins B - D may be obtained via differential manipulation of this key intermediate. Core A is prepared in 98% ee from commercially available 2-bromobenzaldehyde and 5-methoxyisatin in a 10-step sequence featuring an enantioselective dihydroquinoline synthesis using a proline-derived catalyst and an organolithium cyclisation to form a key arene-ketone bond. Current work is focused on the conversion of the aldehyde handle of A to the α,β-unsaturated ester motifs of sealutomicins B – D, with a route to the (E)-β-methyl enoate side chain of sealutomicin C now established. We envisage that the anthraquinone moiety of all four natural products may be installed via a Hauser-Kraus annulation as used by Nicolaou et al in the total synthesis of the uncialamycin, whilst a directed C-H oxidation is expected to furnish the phenol group of unciaphenol.³ This presentation will discuss both the synthesis of core A and subsequent efforts towards the target natural products.

(1) Org. Lett., 2015, 5304 – 5307

(2) J. Antibiotics, 2021, 291 – 299

(3) J. Am. Chem. Soc., 2016, 8235 – 8246

INTRODUCTION

An enriched-triterpenes fraction from Eucalyptus tereticornis leaves (OBE 100) intraperitoneally administrated has a synergistic effect on the reversal of metabolic abnormalities, established in a diet-induced obesity mouse model (DIO). This standardized fraction of triterpenes consists mainly of ursolic acid (UA), oleanolic acid (OA) and an ursolic acid lactone (UAL) 1,2. 

METHODS

This work developed an oral nanoformulation to deliver OBE100 in a DIO mouse model. OBE100 was encapsulated in a polymeric nanocarrier (PNs) self-assembled from the poly lactic-co-glycolic acid polymer using the solvent evaporation method. The PNs size, Z potential (ZP), polydispersity index (PDI), encapsulation efficiency (EE), loading capacity (LC), and release kinetics were determined. Metabolic biomarkers in a DIO mouse model and release kinetics in an in vitrohuman gastrointestinal model (H-GIM) were evaluated. 

RESULTS

The nanoformulation has PN of 165 nm, -35,1 ZP, 0,18 PDI, 98% EE, and 3,5% LC. The release kinetics showed 80% of OBE100 released in the first 6 hours and up to 85% after 72 hours. 

We demonstrated that nanoformulation based on OBE100 (three triterpenes mix) effectively ameliorated hyperglycemia, insulin resistance and glucose intolerance in the DIO mouse model. Additionally, it reduces body weight, insulin, triacylglycerols, LDL and HDL blood levels in treated animals. 

The H-GIM showed a 63% UAL release in the stomach reactor and 82% in the ascending colon reactor. UA + OA showed a 39% and 85% release in the stomach reactor and ascending colon reactors, respectively.

CONCLUSIONS

We developed an oral polymeric nanocarrier to encapsulate a natural product that showed the potential to decrease the effects of pre-diabetes and obesity in mice and open the way toward developing new strategies of therapeutic agents using natural products combined with nanobiotechnology to control T2DM and obesity.

 INTRODUCTION

Obesity is a complex condition with adipocyte hypertrophy as an essential source for developing adipose tissue inflammation that plays a central role in the pathogenesis of many obesity-associated complications. Ursolic acid (UA), Oleanolic acid (OA) and Ursolic acid lactone (UAL) are the main molecules (78%) in an Eucalyptus tereticornis (Eu) extract (OBE100). This enriched-triterpene fraction mixed with unknown minor metabolites has a synergistic effect providing superior anti-inflammatory and hypolipidemic effects than reconstituted triterpenoid mixtures1.  

 METHODS

A crude methanolic extract (OBE100) from leaves of Eu was partitioned with ethyl acetate, concentrated and purified by Sephadex LH-20. UA and OA were purchased from Sigma-Aldrich, and UAL was purified by Sephadex column and preparative chromatography from OBE100. Murine macrophage J774A.1, activated with lipopolysaccharide (LPS) and INF-γ and 3T3-L1 adipocyte cell lines were used to evaluate the effect of OBE100, a mix of triterpenes with the concentration present in OBE100 (M1) and UA, OA and UAL on cell viability, oxidative burst, mitochondrial membrane potential, ADP/ATP ratio and AMPK phosphorylation levels. 

 RESULTS

The treatment of macrophages and adipocytes with OBE100 was less toxic than those treated with triterpene M1 or UA. Only OBE100 extract reduced the oxidative burst in activated J774A.1 macrophages and significantly increased the mitochondrial membrane potential and ADP/ATP ratio in both cell lines. OBE100 treatment also increased AMPK phosphorylation levels in both cell lines. 

 CONCLUSIONS

Natural extract OBE100 contains minor molecules that modify mitochondrial membrane potential and ADP/ATP ratio without affecting cell viability. The combination of triterpenes with other minor molecules present in the vegetal extract has a synergistic effect that improves them, reducing the toxicity of the triterpenes and the production of reactive oxygen species, increasing AMPK phosphorylation levels. These cellular changes help to understand OBE100 anti-inflammatory and hypolipidemic effects.

Nucleophilic substitution reactions of alkyl halides and related electrophiles are imperative transformations in academic labs worldwide, as well as the broader pharmaceutical industry.^[1] Herein we report a novel redox-neutral protocol for the iodination and bromination of a variety of primary, secondary, aliphatic and benzylic alcohols, by exploiting the chemical behaviour of a H-phosphonate promoter. Alcohols are desirable precursors due to their ready availability and their environmentally benign nature.^[2] Lithium halide salts are an attractive alternative for toxic molecular halogens and reactive halogenating agents. Their use enables an enhanced safety profile for this transformation, as well as significantly improving the halide incorporation and thus atom economy, relative to the current state-of-the-art.^[3,4]

As H-phosphonates are accessible through hypophosphorous acid,^[5] this protocol has the additional benefit of using a phosphorus source that is not derived from PCl₃. Reducing use of halogens at the source by making use of organophosphorus compounds that aren’t derived from PCl₃ decreases energy consumption and minimizes the generation of halogenated waste.^[6] This operationally simple protocol is also amenable for use in p-cymene as a biorenewable solvent, culminating in a lower net environmental impact for the process. Reactivity studies of the various proposed intermediates have been conducted which has revealed the likely mechanistic pathway of the reaction. The chemistry developed within this project enables a more sustainable synthesis of a versatile range of alkyl iodides and alkyl bromides from the corresponding parent alcohols in yields up to 97%, making this protocol a valuable addition to the synthetic chemist’s toolbox.

References:

1) Org. Biomol. Chem. 2006, 4, 2337.

2) Chem, 2016, 1, 32.

3) Org. Lett. 2018, 20, 3061.

4) Org. Lett. 2018, 20, 2980.

5) Eur. J. Org. Chem. 2013, 35, 7973.

6) Phosphorus, Sulfur Silicon Relat. Elem. 2013, 188, 66.

A general method to form tertiary alkoxyl radicals from the corresponding hydroperoxides under mild and cost-effective conditions is presented. Upon treatment with oxalyl chloride, tertiary hydroperoxides are converted in situ to peroxyoxalates that decompose under thermal conditions liberating the desired alkoxyl radicals. This approach has been shown to be suitable to take full advantage of the well-established reactivity of alkoxyl radicals such as intramolecular hydrogen atom transfer (remote functionalization), fragmentation and cyclization.[1–3]

References:

[1] P. D. Bartlett, E. P. Benzing, R. E. Pincock, J. Am. Chem. Soc. 1960, 82, 1762–1768

[2] J. Boukouvalas, J. M. Tanko, Encyclopedia of Reagents for Organic Synthesis 2007

[3] L. Gnägi, S. V. Martz, D. Meyer, R. M. Schärer, P. Renaud, Chemistry – A European Journal 2019, 25, 11646–11649

b-Hydroxy a-amino acids are compounds of high interest in medicinal chemistry, mainly due to their prevalence in natural products, including antibiotics and enzyme inhibitors, and their presence as structural components of many biologically active compounds. In this context, the asymmetric aldol reaction of glycine Schiff bases constitutes a very effective protocol for the production of b-hydroxy a-amino acids because concomitant to the assembly of the 1,2-aminoalcohol functionality during the carbon-carbon bond forming step, up to two vicinal stereogenic centers are created in a single synthetic operation.

Although some catalytic direct aldol reactions of Schiff bases of glycine esters have been reported by phase-transfer / metal catalysis, as far as we know, the only report providing the syn isomers was described by Trost in 2014 using a zinc-ProPhenol catalyst. The protocol affords the corresponding syn-aldols with good results for a-branched aldehydes, but provides less satisfactory results for linear alkyl aldehydes.

Here we present the highly enantio- and syn-selective synthesis of b-hydroxy a-amino acids from glycine imine derivatives under Bronsted base (BB) catalysis.1 The key of this approach is the use of benzophenone-derived imine of glycine o-nitroanilide, as a pronucleophile, where the o-nitroanilide framework provides an efficient hydrogen-bonding platform that accounts for nucleophile reactivity and reaction diastereoselectivity. 

References

(1) Silvia Vera; Ana Vázquez; Ricardo Rodriguez; Sandra del Pozo; Iñaki Urruzuno; Abel de Cózar; Antonia Mielgo; Claudio Palomo,  J. Org. Chem. 2021, 86, 7757–7772. 

Acknoledgements: we thank the Spanish government-MCIU(PID 2019-109633GB-C21) and Basque Government (IT1236-19) for financial support. A FPU grant to Ricardo Rodriguez is also Acknowledgements

Aldehydes, and particularly, highly substituted aldehydes, are interesting building blocks for the synthesis of more complex molecules. Therefore, protocols to directly access a-functionalized aldehydes in an efficient, enantioselective and simple way are highly demanding. However, the direct enantioselective a-functionalization of aldehydes is challenging because side reactions like self-addition, or Cannizzaro and Tischenko disproportionations often take place. In this context, aminocatalysis has proven to be a powerful tool in the enantioselective a-functionalization of linear aldehydes, and at present a wide range of efficient protocols for introducing different functionalities at the alpha position are available. Despite this progress, the a-functionalization of a-branched aldehydes using this strategy has shown to be more problematic due to steric hindrance, the lower enamine reactivity and E/Z enamine selectivity problems.

Here, the results of our preliminary investigations on Ca-H activation of a-branched aldehydes by Brønsted base (BB) catalysis are presented.  a-Branched a-aminoaldehydes as well as a-branched aryl acetaldehydes are efficiently activated by amino acid containing squaramide-derived bifunctional BBs to afford, in their reaction with nitroolefins,1 the corresponding adducts in very good yield and high stereoselectivity, with concomitant creation of quaternary stereocenters. 

1) a) García-Urricelqui, A.; de Cózar, A.; Mielgo, A.; Palomo, C. Chem. Eur. J. 2021, 27, 2483–2492. (b) García-Urricelqui, A.; de Cózar, A.; Campano, T. E.; Mielgo, A; Palomo, C.  Eur. J. Org. Chem. 2021, 3604–3612.

ACKNOWLEDGEMENTS: We thank the Spanich Government (PID2019-109633GB-C21) and Basque Government (IT1236-19) for financial support

Malaria, an infectious disease caused by five species of Plasmodium parasites, affected 241 million people and claimed 627 000 lives in 2020. The lack of an effective vaccine and the increasing resistance of Plasmodium to approved antimalarial drugs demands the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Harmisinins represent hybrids that combine two moieties with different mechanisms of antiplasmodial activity in one molecule, i.e., artemisinin scaffold, known to destroy the parasite through formation of free radicals, and a ß-carboline ring capable of binding to P. falciparum heat shock protein 90. The synthesis of the targeted compounds was achieved by the coupling reaction between artesunate and ß-carboline amines, using HATU/DIEA, at rt for 5 hours. The required amines were synthesized from harmine, harmole or analogues ß-carboline, bearing phenol at the position 6,  by a two-step reaction. In the first step harmine was alkylated at the position N-9, harmole at the position O-7 and ß-carboline at the position O-6 with 2-(Boc-amino)ethyl bromide in the presence of caesium carbonate in DMF, followed by the removal of Boc protecting group in acidic medium (HCl in MeOH). The structures of the newly prepared hybrid compounds were confirmed by IR, ¹H and ¹³C NMR spectroscopy and mass spectrometry.

Scheme. Synthesis of harmisinins.

This work was fully supported by the Croatian Science Foundation under the project number UIP-2017-05-5160. The work of Marina Marinovic was supported by the Young researcher’s career development project – training of doctoral students of the Croatian Science Foundation founded by the European Union from the European Social Fund.