N-heterocyclic carbene (NHC)-coordinated cyclometallated palladium complexes (CYPs) have the good catalysis for the nucleophilic addition of arylboronic acids to carbonyl compounds. Previously, we have demonstrated the imidazoline-type NHC-CYPs have exceptional catalytic activity for the addition and these catalytic reactions provide a wide range of functionalized benzylic alcohols [1]. Recently, MICs (MesoIonic Cabenes) such as 1,2,3-triazole type carbene have attracted much attention as new ligands for transition metal complexes, because MICs have generally stronger δ-donor properties than imidazoline-type NHCs. Moreover, 1,2,3-triazole type MICs are easily accessible from 1,2,3-triazole, which is prepared via Cu-catalyzed azide-alkyne cycloaddition. Herein, we have synthesized novel 1-(2,6-diisopropylphenyl)-3-methyl-4-aryl-1,2,3-triazole-5-ylidene coordinated π-allylpalladium complexes. Interestingly, the Pd complexes acted as good catalysts for the 1,2-addition of arylboronates to aldehydes and the corresponding alcohol compounds were obtained in good yields with 1 mol% catalyst loading.

Reference

[1] T. Yamamoto et al., Tetrahedron., 2015, 71, 19–26

In past two decades, Transition-metal catalyzed 1,2-addition of arylboronic compounds to carbonyl compounds has been developed because is one of the powerful synthetic method that is easily access to functionalized benzylic alcohols. Although various metals such as Rh, Ni, Pd, Cu, Ru, Pt, Fe, Co are useable for the 1,2-addition to aldehydes, effective metals for the 1,2-addition to unactive ketones were until recently limited to Ni and Rh. Very recently, we have focused on the catalysis by N-heterocyclic carbene (NHC)-coordinated cyclometallated palladium complexes (CYPs) and have reported that PhS-IPent-CYP exhibits remarkable catalytic activity for the 1,2-addition to unactivated ketones in the present of an excess amount of inorganic base ^[1,2].

Herein, we will report the novel hydroxy bridged CYPs that catalyzed the 1,2-addition of arylboronates to aldehydes and ketones in the absence of additional bases to give corresponding various functionalized benzylic alcohols. Interestingly, hydroxy bridged CYPs showed the broadly similar catalytic activity as the combination of chloro bridged CYPs and bases.

References

[1] R. Akiyama, M. Sugaya, H. Shinozaki, T. Yamamoto, Synth. Commun. 2019, 49, 1193– 1201

[2] Y. Okuda, M. Nagaoka, T. Yamamoto, ChemCatChem 2020, 12, 6291–6300

Organosulfur compounds like thiosulfonates and thiocyanates are potentially important building blocks in many organic transformations and at the same time they have a wide range of biological and pharmacological application.^[1,2] In particularly, thiosulfonates contain one sulfur atom with oxidation state II (-SR₂) and another sulfur atom with oxidation state VI (R¹SO₂-), which enables them to react both with nucleophiles as well as electrophiles. Interestingly, depending on the reaction conditions they can either react as sulfenylating or as sulfonylating reactant. Literature studies reveal that despite the advantages associated with the afore-mentioned organosulfur compounds, the methods for their preparation are still limited and scattered. In general, the cross-coupling reactions of sulfonylhydrazides with thiols ^[3,4] or disulfides can lead to the formation of thiosulfonates. The strategy affords the thiosulfonates by the thiolysis reaction with sulfonyl chlorides is difficult to control due to the fast nucleophilic attack of the thiol onto the sulfenyl moiety of the thiosulfonate product, leading the formation of disulfides. Analogously, thiocyanates are important synthetic intermediates to access various valuable sulfur-containing compounds. Two main strategies are currently used to prepare these compounds: the first one consists of the reaction of various alkyl or aryl substrates that do not contain sulfur with a thiocyanating agent. The second one is based on the reaction of a substrate bearing an electrophilic or nucleophilic sulfur with a cyanating agent. Interestingly, to the best of our knowledge, no method reported so far has given the access of organothiosulfonates and organothiocyanates from a single reaction strategy. Herein, we report an efficient and chemoselective route for the synthesis of organothiosulfonates and organothiocyanates from the reaction of sulfonyl chlorides with potassium selenocyantes just by tuning the reaction temperature. It is important to mention that the obtained thiocyanates are further utilized to achieve important organic molecules such as thiopyridines, thiopyrrolines, and thioethers. In addition, the reactivities of other potassium chalcogencyanates with sulfonyl chloride have also been explored.

Scheme 1. Selective synthesis of thiosulfonates and thiocyanates 

References 

[1]      E. Salina, O. Ryabova, A. Kaprelyants, V. Makarov, Antimicrob. Agents Chemother. 2014, 58, 55–60.

[2]      J. I. Toohey, A. J. L. Cooper, Molecules 2014, 19, 12789–12813.

[3]      G. Y. Zhang, S. S. Lv, A. Shoberu, J. P. Zou, J. Org. Chem. 2017, 82, 9801–9807.

[4]      Q. Chen, Y. Huang, X. Wang, J. Wu, G. Yu, Org. Biomol. Chem. 2018, 16, 1713–1719.

The regioselective hydroxymethylation on aromatic rings provides arylmethanols which is important intermediates in various fields such as medicinal chemistry, organic electronics, and material science. Classical regioselective hydromethylation is the addition of aryllithium or magnesium reagents to formaldehyde or its equivalents. However, this route has restriction in usable functional groups due to the high reactivity of organolithium and magnesium reagents. So, we have developed the the NHC-coordinated five-membered cyclometallated palladium complex-catalyzed hydroxymethylation using arylboronic acids as aryl source. This catalytic reaction showed more functional groups tolerance than classical methods ^[1]. Herein, we will report the hydroxymethylation using N-(2-bromobenzyl)imidazole-type NHC-coordinated PEPPSI complexes and π-allyl complexes as six-membered-ring cyclometallated palladium precursors.

[1] T. Yamamoto, T. Furusawa, A. Zhumagazin, T. Yamakawa, Y. Oe, T. Ohta, Tetrahedron 2015, 71, 19–26;

The transition metal catalyzed conjugate addition reactions of organoboron compounds to enones are one of the most useful synthetic methods for the carbon-carbon bond formation. In the past two decades, palladium-catalyzed conjugate addition of organoboron compounds to enones have been developed. In general, palladacycles transformed quickly to zero-valent Pd species so are used as zero-valent Pd precursor for cross-coupling reactions [1]. but some five-membered palladacycles retain their divalent state and act as catalysts for conjugate addition reactions. When the palladacycles are used as a catalytic active species in the conjugate addition, the palladacycle structure must be maintained in the reaction system. Therefore, we though that that the palladacycle structure could be stabilize by extending the π-conjugated system of the organic group σ-bonded to Pd(II) and demonstrated the utility of 9-diphenylphosphinoanthracene based palladacycle having a trialkyl phosphite ligand [2]. The palladacycle promoted the 1,4-addition of arylboronic acids to enones under low catalyst loading but needed the addition of excess amount of inorganic base. 

Herein, we report the pyridine-2-carboxylate coordinated phosphapalladacycles that promoted the conjugate addition in the absence of additional base (Scheme 1).

Scheme 1 C^P-type palladacycle catalyzed conjugated addition reaction

[1] Soni, V.; Punji, B. Palladacycles; Catalysis and Beyond; Enantioselective Synthesis Using Chiral Palladacycles, 2019; Vol. 7, pp 297–326.

[2] Shimizu, M.; Yamamoto, T. Tetrahedron Letters, 2020, 61, 152257.

p38α/MAPK14 is intracellular signalling regulator involved in biosynthesis of inflammatory mediator cytokines (TNF-α, IL-1, IL-6, and IL-1b), which induce the production of inflammatory proteins (iNOS, NF-kB, and COX-2).In this study, drug repurposing strategies were followed to repositioning of a series of B-RAF V600E imidazol-5-yl pyridine inhibitors to inhibit p38α kinase. A group 25 reported p38α kinase inhibitors were used to build a

pharmacophore model for mapping the target compounds and proving their affinity for binding in p38α active site. Target compounds were evaluated for their potency against p38α kinase, compounds 11a and 11d were the most potent inhibitors (IC₅₀ = 47 nM and 45 nM, respectively).In addition, compound 11d effectively inhibited the production of proinflammatory cytokines TNF-α, 1L-6, and 1L-1β in LPS-induced RAW 264.7 macrophages with IC₅₀ values of 78.03 nM, 17.6 μM and 82.15 nM, respectively.

The target compounds were tested for their anti-inflammatory activity by detecting the reduction of Nitric oxide (NO) and prostaglandin (PGE2) production in LPS-stimulated RAW 264.7 macrophages. Compound 11d exhibited satisfied inhibitory activity of the production of PGE2 and NO with IC₅₀ values of 0.29 μM and 0.61 μM,respectively. Molecular dynamics simulations of the most potent inhibitor 11d were carried out to illustrate its conformational stability in the binding site of p38α kinase.

Chiral α-quaternary methanamines are common structural motifs found in a variety of natural products exhibiting wide spectrum of biological activities.^[1] Synthesis of such compounds has always been challenging because of the steric hindrance positioned at the newly formed center of chirality. The most common strategies for the construction of this class of optically active compounds is well described and mostly relies on usage of chiral transition-metal complexes, e.g. Rh(I), Pd(II), Ni(II), and Co(II).^[2] However, to the best of our knowledge, there is no literature precedent for the preparation of quaternary α-triarylsubstituted methanamines based on stereoselective organocatalytic reaction. 

In this respect, we developed a catalytic formal Betti reaction with stereoselctivity induced by chiral Brønsted phosphoric acid (CPA). This type of reaction proceeds via direct 1,2-addition of phenols to imines resulting in enantioenriched α-triarylmethanamines. Key to success of this transformation lies in the in situ generation of the reactive iminium species from 3-hydroxysubstituted isoindolinones  (Scheme 1).^[3] Various phenols added smoothly, enabling the synthesis of a variety of α-triphenylmethylamines in up to 96% isolated yield, and up to 99% ee. Functional group tolerance with respect to isoindolinone alcohols, as well as to phenols, will be presented.

Scheme 1. Stereoselective addition of phenol to 3-hydroxysubstituted isoindolinones catalyzed by chiral Brønsted Phosphoric Acid.

[1] S. Sakamoto, T. Miyamoto, K. Usui, H. Tanaka, S. Morimoto, J. Nat. Prod. 81, (2018), 34
[2] M. Quan, L. Wu, G. Yang, W. Zhang, Chem. Commun. 54, (2018), 10394
[3] D. Glavač, C. Zheng, I. Dokli, S.-L. You, M. Gredičak, J. Org. Chem. 82, (2017), 8752

Catalytic oxyfunctionalization reactions are of vast interest for synthetic applications due to their potential to cut short synthetic routes and streamline processes towards complex molecules.[1] Unspecific peroxygenases (UPOs) have shown high potential for selective oxyfunctionalization and stand out due to their simplicity compared to their well-known P450 counterparts since they do not rely on nicotinamide cofactors or electron transport chains.[2]  Here we report a novel unspecific peroxygenase from Hypoxylon sp. which has been structurally characterized, has a melting temperature of 77 °C and performs hydroxylations and epoxidations on various small molecules by solely using hydrogen peroxide as a cosubstrate.

To characterize the reaction potential of HpUPO, various substrates displaying a broad scope of functional groups were investigated. Notably, this biocatalyst oxidized both enantiomers of racemic phenylethanol in a semi-preperative scale reaction (2 mmol) to yield 210 mg of acetophenone (88%, GC-yield = 92%, TON = 13143) indicating a high potential for the oxidation of benzylic sec-alcohols. HpUPO was also able to efficiently produce the natural dye indigo through the oxidation of indole with conversion of up to 96 % and less than 1 % side oxidation products. This highlights HpUPO as a efficient, thermotolerant biocatalyst.

This work was supported by the Federal Ministry of Science, Research and Economy (BMWFW), the Federal Ministry of Traffic, Innovation and Technology (bmvit), the Styrian Business Promotion Agency SFG, the Standortagentur Tirol, and the Government of Lower Austrian and Business Agency Vienna through the COMET-Funding Program managed by the Austrian Research Promotion Agency FFG.

References

[1]   S. Chakrabarty, Y. Wang, J. C. Perkins, A. R. H. Narayan, Chem. Soc. Rev. 2020, 49, 8137.

[2]   M. Hobisch, D. Holtmann, P. Gomez de Santos, M. Alcalde, F. Hollmann, S. Kara, Biotechnol. Adv. 2020, 107615.

The synthesis of molecular hybrids by hybridizing two or more molecules carrying different pharmacophores, often leads to new bioactive entities and is one of the main concerns of modern chemistry. The synthesis of terpeno-heterocyclic hybrids developed intensely in the last decade fits perfectly in this field.

Terpenes used to achieve these purposes, especially those with a sesquiterpene homodrimane skeleton, are natural compounds with a wide range of pharmaceutical and biological activities. We have been reported before the synthesis of molecular terpeno-heterocyclic hybrids possessing oxadiazole, thiadiazole, 1,2,4-triazole, pyridazinone and others heterocyclic units which have shown good antifungal and antibacterial activities.

Here in we report the synthesis of new homodrimane sesquiterpenoids bearing benzothiazole fragment. The title compounds were obtained, in several steps and good overall yields, based on two isomeric bicyclohomofarnesoic and 11-homodrim-6(8)-dien-12-oic acids, derivatives of commercially available (+)-sclareolide.

The syntheses of target molecular hybrids, were performed via direct coupling reaction of corresponding acyl chlorides with 2-aminobenzothiazole, or by interaction acyl chlorides with p-toluidine, followed by treatment of resulted amides with Lawesson’s reagent. The heterocyclization reaction of resulted thioamides lead to the target benzothiazole derivatives and to an unexpected tricyclic thioamide. This is probably due to the presence of the conjugated diene fragment in the molecule of 11-homodrim-6(8)-dien-12-oic, which makes it possible to form an N-C8 bond during the thionilation of its amide.

  Introduction: A known approach is the synthetic assembly of pharmacophore fragments into new molecular systems, leading to an increase in the bioeffect of the initial substrates, but more interestingly, to the appearance of new types of activity. Previously, we synthesized derivatives (A and B) of 3-(1H-imidazol-1-yl)propan-1-amine containing imidazole [1-3] and piperidine or diazabicyclononane moieties, which are synthetic analogues of natural alkaloids. Among them, myelostimulants and plant growth stimulants were found [4,5].

The main purpose of Research is the synthetic assembly of novel molecules, containing imidazole and phosphonate fragments, as well as potential plant growth and development stimulants. In addition, a fluorine atom is introduced into the molecule as a “booster” of biological action.

Methods: Targeted aminophosphonates are synthesized by Kabachnik-Fields reactions. Plant growth action was evaluated on wheat Triticum aestivum of three Kazakh varieties. Myelostimulatory activity was carried out in rats with artificially induced myelosuppression by cytostatic - sodium cyclophosphamide.

Results and discussion: Reaction of 3-(1H-imidazol-1-yl)propan-1-amine with (o-, m- or p-) fluorobenzaldehyde and di(methyl- or ethyl-)phosphonate by refluxing in benzene for 37-61 h with simultaneous distillation of an azeotropic mixture of the obtained water with benzene leads to the target imidazole-containing aminophosphonates with 38-61% yields: 

The reaction products are crystalline compounds that are poorly soluble in water. The bioactivity of aminophosphonates was evaluated in the form of their complexes with β-cyclodexrin. 

It turned out that the synthesized substances stimulate the growth of the steam of wheat to 10% compared with the control experiment (water). One of the derivatives - dimethyl[(3-(1H-imidazol-1-yl) propylamino)(3-fluorophenyl)methyl]phosphonate, is slightly inferior in myelostimulating activity to the methyluracil used as comparison drug. 

Thus, synthesized aminophosphonates on the basis of 3-(1H-imidazol-1-yl)propan-1-amine during pre-sowing treatment of wheat seeds stimulated stem growth and only one sample slightly improved the hematopoiesis of rats with pre-artificially induced myelosuppression.

References:

1 A.E. Malmakova, A.B. Kaldybayeva, Dulatbaev A. Synthesis fluorine containing imidazole substituted aminophosphonates // Materials of the XIX International Scientific and Practical Conference named after Professor L.P. Kulev students and young scientists "Chemistry and Chemical Technology in the XXI Century" - Tomsk, 2019 .- pp. 178-179.

2 A.B. Kaldybayeva, A.E. Malmakova, V.K. Yu, K.D. Praliyev, T. Lee, G.D. Baybatyrova. Synthesis and growth-promoting activity of the diethyl[(3-(1H-imidazol-1-yl)propylamino)(2-fluorophenyl)methyl]phosphonate complex with β-cyclodextrin// Proceedings of the 10^th International Beremzhanov Congress on Chemistry and Chemical Technology – Almaty, 2019. - pp. 140-141.

3 A.E. Malmakova, V.K. Yu., V.M. Kan, P. Dauletbai, T.E. Li, A. Dulatbaev, A.B. Kaldybaeva, K.D. Praliyev. 1-(3-Aminopopopyl)imidazol as a precursor of plant growth stimulators // Chemical Journal of Kazakhstan, 2018. -  4 (64).- pp. 42-51.

The Research was supported by the Ministry of Education and Science

 of Kazakhstan, grants AP05131486 and AP05131025

 

Confocal microscope image of A549 cells treated with closo-1,2-carboranyl-coumarin, showing coumarin fluorescence (458 nm excitation, 𝜆_em = 465-565 nm).

REFERENCES:

1. Li. C, J. Am. Chem, Soc.  2020, vol142, 14789-14804.

2. G. Hong, Nat. Biomed. Eng. 2017, Vol1, 0010.

This study describes the first palladium‐catalyzed, site‐selective α‐ and γ‐arylation of α,β‐unsaturated ketones with (hetero)aryl halides. A wide range of hetero(aryl)halides coupled with α,β‐unsaturated ketones, and transformation into the arylated products proceeded with excellent to good yields. The site selectivity of the reaction is switchable by simply changing the phosphine ligand to access either α‐arylated or γ‐arylated products in good to excellent yields by using a low catalyst loading, and the method demonstrates good functional‐group compatibility.

If you are interested in my work, welcome to scan the following QR code.

Reference:
1. O.Y. Yuen, C.M. So, Angew. Chem. Int. Ed. 59 (2020) 23438–23444.

The incorporation of metal-ion complexes in existing drug structures provides new opportunities for therapeutic optimisation and expanded diagnostic capabilities. [1, 2] Through selection of the complexed metal ion and coordinated ligands, drug properties including stability and target specificity can be modified while the drug can be further enhanced with a phosphorescent capability, allowing the determination of cellular drug uptake and intracellular localisation. [3, 4] This strategy therefore has the potential to produce viable analogues of drugs that had initially showed potential in testing but were subsequently rejected due to undesirable side effects.

As an example, the drug candidate XK469 showed promising antitumour effectiveness in preclinical testing but was withdrawn from further testing due to causing myelosuppression in phase I trials. Using XK469 as a lead compound, we envisage that the incorporation of a platinum ion complex will allow the modification of derived drugs specificity and efficacy while adding theragnostic capabilities.

Herein we report the synthesis, isolation and characterisation of a range of metal-ion complexed quinoxaline peptidomimetic derivatives. Platinum ion complexes with coordinated ligands were synthesised and then conjugated to synthesised quinoxaline amines and amino acids. The conjugates were characterised through NMR and mass spectroscopy and their photophysical properties analysed through spectroscopy.

[1] Kilpin, K, Dyson, P, Chemical Science, 2013. 4: p. 1410-1419.

[2] Wang, F, Habtemariam, A, Geer, van der Erwin, Fernández, R, Melchart, M, Deeth, R, Aird, R, Guichard, S, Fabbiani, F, Lozana-Casal, P, Oswald, I, Jodrell, D, Parsons, S, Sadler, P, Proceedings of the National Academy of Sciences, 2005. 102(51): p. 18269-18274.

[3] Parker, D, Australian Journal of Chemistry, 2011. 64: p. 239-243.

[4] Bader, C, Carter, E, Safitri, A, Simpson, P, Wright, P, Stagni, S, Massi, M, Lay, P, Brooks, D, Plush, S, Molecular Biosystems, 2016. 12: p. 2064-2068.

Nowadays, ionic compounds(ICs) are of global interest since their unique physical and chemical properties as well as of their biological activity. The study and application of alternative conditions and ways of synthesizing ICs is an important part of green chemistry development. Also widely increases the research of biological activity of ICs like the stimulation of plant growth, myelostimulating activity, ecotoxicological effects etc.

The main goal of the research is to synthesis new and known ICs based on 2-benzhydryloxy-N,N-dimethylethanamine in the classical conditions and using alternative methods of activation, as well as the testing of myelostimulating activity and ecotoxicological effects.

Initial compound, 2-benzhydryloxy-N,N-dimethylethanamine was synthesized from commercially available hydrochloride by neutralization. Further syntheses of ICs were performed via alkylation of diphenhydramine with iodoalkanes. The syntheses occurred by using the classic conditions and using ultrasound and microwave activation.

For the evaluation of the ecotoxicity of the ICs towards A.fischeri the acute toxicity test was used. Studies on myelostimulatory activity were carried out on healthy animals - white laboratory rats.

The highest yields in ICs synthesis were observed by using microwave irradiation, ultrasound activation was less effective and just moderate yields were observed in classical conditions. Experimental ecotoxicity EC₅₀ values (in mg/L) were obtained for the studied ICs, the adjustable parameters a and b, and standard deviations, SD, are shown in Table 1.

According to the results shown in table 1, the measured EC₅₀ values vary between 47 and 342 mg/L, depending on the structure of the compound. The presence of an N-alkyl substituent increases the toxicity compared with the corresponding hydrochloride analogue.

Table 2 Indicators of blood hemogram

The tested compounds showed high myelostimulating activity and exceeded the comparison drug methyluracil in activity.

This work was financially supported by the Ministry of Education and Science of Kazakhstan [AP051032833/GF5, BR05236800/PTF, BR0526302/PTF, AP05131025/GF5, BR052344667/PTF].

The aim of this study was to perform a screening of natural products produced by Actinobacteria related to Nocardiopsis and Streptomyces genera under the cultivation in conditions of excess daylight, in the absence of light, and in case of aggressive UV(A) radiation. The cultivation of microorganisms was performed at a temperature of 28˚ С of 7 days. Metabolites from cultural liquid and cell biomass were extracted with ethyl acetate and a mixture of acetone:methanol, respectively. Extracts were evaporated and dissolved in methanol:DMSO mixture. Samples were initially analyzed within high-resolution LC-MS and dereplication technique using the Dictionary of Natural Products database. Data were collected and analyzed within Bruker Compass Data Analysis software.

We identified 2 compounds (members of the antibiotic family Sannamycin) known for the Streptomyces sp. when this strain was cultured in the liquid medium SG under conditions of excess daylight. The cultivation of strain in the conditions of absence of light led to the biosynthesis of 10 new natural products. The growth of Streptomyces sp. strain under the conditions of aggressive UV(A) radiation led to the appearance of 1 new amphiphilic natural product with mass 219.1730Da. Besides the number of natural products, the rate of illumination influenced the average mass of natural products produced by the studied strain Streptomyces sp. At the same time, the parameters of cultivation were less affected on the strain of Nocardiopsis sp. while UV (A) radiation led to the death of strain.

Thus, the cultivation of the Streptomyces sp. strain in the absence of light makes it possible to obtain new natural products.

The study is carried out with the main financial support of Russian Science Foundation grant 18-74-00018 with the partial financial support of Russian Foundation for Basic Research grant 18-29-05051, and Ministry of Education and Science of Russian Federation grant МК-1245.2021.1.4.

The purpose of this study was to evaluate the analgesic and anti-inflammatory activities of 4-hydroxy coumarin derivatives through different animal models and molecular docking studies with crystal structure of COXII (5IKQ). Analgesic activities were evaluated by hot-plate and writhing tests while  anti-inflammatory effects were assessed by ear edema, and paw edema tests, contents of cytokines(IL-1b, TNF-a, and PGE2) in the serum of rats in paw edema test were inspected by ELISA assays. Results. In the hot- plate test, compounds 5 and 10 could significantly extend the pain threshold when compared to the control group.  ED50 was estimated to be 8.5 mg/ kg compound 5 while fatal dose exceeds 3g/kg.  Treatment with coumarin compounds(3-11) (20 mg/kg) could significantly inhibit ear edema specially compound 3,5,10 (47.85 and 55.67%, 36.31resp.; 𝑃< 0.01). In the carrageenan-induced edema test, the inhibitory rates of compounds 5 and 10 were found 53.71% and 44.27% (𝑃< 0.01) at 1 h and 2 h after administration of compounds (20 mg/kg), respectively, and the levels of proinflammatory cytokines were significantly reduced. In addition, the ADME results showed that all compounds are carrying good pharmacokinetic qualities except compound 10. Results suggest that 4-hydroxy coumarin derivatives have analgesic and anti-inflammatory effects which may be a candidate drug for the treatment of inflammation and pain.

Recently it has been found that in the opium poppy plant Papaver somniferum the formation of (R)-reticuline from (S)-reticuline is enabled via two redox steps catalyzed by the naturally occurring fusion protein reticuline epimerase (REPI).^[1] This chimeric protein consists of one cytochrome P450 (CYP) for oxidation and a reductase enzyme catalyzing one of the bottle neck reactions in the production of morphinan alkaloids.^[2] The latter is also called 1,2-dehydroreticuline reductase (PsDRR) and catalyzes the NADPH-dependent reduction of 1,2-dehydroreticuline towards (R)-reticuline. Herein we exploit the in vitro biotransformation accessing optically pure (R)-reticuline employing overexpressed PsDRR as freeze-dried E. coli cell preparation in combination with an artificial cofactor regeneration system (Scheme 1). Since this enzyme was discovered just recently, studies about its potential in biocatalytic preparations have not been reported yet.

First, the activity of PsDRR was determined via an end point assay and 0.125 Units mL^-1 were used for the optimization studies. A time study was able to show that the reaction is completed (i.e. quantitative conversion) after 4 hours at 10 mM substrate concentration. 

Scheme 1: Asymmetric synthesis of (R)-reticuline employing the enzyme PsDRR

Different substrate loadings were investigated which revealed that the substrate concentrations of 20 and 30 mM produce the same absolute amount of optically pure (R)-reticuline. In following optimization studies parameters like the pH, temperature, different cofactor regeneration systems and different cofactor concentrations have been investigated. 

In summary it was shown that the in vitro production of (R)-reticuline lab scale (about 100-fold compared to the literature ^[2]) was achieved, nevertheless further optimization studies have still to be performed. 

This approach could serve as crucial step for the large-scale production of morphine-like compounds.

^[1] De-Eknamkul, W.; Zenk, M. H.; Phytochemistry, 1992, 3, 813 -821.

^[2] Farrow, S.C.; Hagel, J.M.; Beaudoin, G.A.; Burns, D.C.; Facchini, P.J.; Nat. Chem. Biol., 2015, 11, 728–732.

The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRAF^V600E and p38α kinases which are considered as key regulators in mitogen-activated protein kinase (MAPK) signalling pathway. The target compounds were evaluated for dual kinase inhibitory activity. The tested compounds exhibited nanomolar scale IC₅₀ values against BRAF^V600E and low to sub-micromolar IC₅₀ range against p38α. Compound 20h was identified as the most potent dual BRAF^V600E/p38α inhibitor with IC₅₀ values of 2.49 and 85 nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-α production in lipopolysaccharide-induced RAW 264.7 macrophages with IC₅₀ value of 96.3 nM. Additionally, the target compounds efficiently frustrated the proliferation of LOX-IMVI melanoma cell line. Compound 20h showed a satisfactory antiproliferative activity with IC₅₀ value of 13 µM, while, compound 18f exhibited the highest cytotoxicity potency with IC₅₀ value of 0.9 µM. The newly reported compounds represent therapeutically promising candidates for further development of BRAF^V600E/p38α inhibitors in an attempt to overcome the acquired resistance of BRAF mutant melanoma. 

The reduction of aryl diazonium salts is one of the most efficient ways to generate aryl radicals for use in a wide range of transformations, including Sandmeyer-type reactions,^a Meerwein arylations of olefins,^b and Gomberg-Bachmann-Hey arylations of heteroaromatic systems ^c and cascade reactions such as iodine abstraction from alkyl iodides.^d The aryl diazonium species can be reduced electrochemically, by UV irradiation, inner-sphere and outer-sphere single electron transfer processes (SET) from metal salts, SET from photo-excited organic catalysts, or fragmentation of adducts with weak bases (acetate, hydroxide, etc.).

This presentation details a new approach for the metal-free reduction of aryl diazonium salts with Hantzsch esters as -bond nucleophiles (scheme 1).^e This novel protocol leads to unprecedented operational simplicity: The reactions are very rapid and proceed in open air; there is no need for external irradiation or heating; and the process is compatible with many radical reactions. We illustrate these advantages by using the polar-radical crossover strategy in direct and cascade reactions by generated aryl radicals to regioselectively arylate a series of heterocyclic compounds; to synthesize ketones by arylation of silyl enol ethers; to synthesize benzothiophene and phenathrene derivatives by radical annulation reactions and effectively generate alkyl radicals in the cascade reactions from corresponding alkyl iodides to synthesize functionalized ketones, esters, sulfones and organophosphorus compounds from Michael acceptors. We demonstrated the uses of novel polar-radical-crossover cascade reaction in late stage functionalization of peptides, sugars, steroids, nucleosides and several representatives of antihistamine drugs.

References: a) T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17, 1633-1635. b) H. Meerwein, E. Büchner and K. van Emster, J. Prakt. Chem., 1939, 152, 237-266. c) M. Gomberg and W. E. Bachmann, J. Am. Chem. Soc., 1924, 46, 2339-2343. d) F. Minisci, springer, NATO ASI ser,1989, vol 260. e) E.Tatunashvili, B.Chan, C.Mcerlean, Chem.sci. Submitted manuscript

Oleanane saponins exhibited promising anti-tumor efficacies, and previously we synthesized a series of N-acyl glucosamine-bearing oleanolic saponin with great cytotoxicity against HL-60. Since the cytotoxicity was highly correlated to specific length of carbon chain modification, the effect of side chain modification and cytotoxic mechanism were further investigated.

N-acyl glucosamine-bearing saponins incorporating different triterpene cores and oleanamide saponins with various carbon chain length were synthesized, and evaluated cytotoxicity against several cancer cell lines. HL-60 cells were treated with 28-propargyloleanamides and click reaction was performed to visualize the distribution of these compounds by confocal microscopy and flow cytometry. Western blotting and quantitative proteomics were employed to elucidate the mechanism of action.

Saponins incorporating an oleanolic acid (OA) core exhibited the highest cytotoxic activity. With cell imaging, it was found that cytotoxic-active compounds located in the cytosol and inactive compounds bearing longer carbon chains were impenetrable across cell membranes. Sequential cleavage of caspase 3 and caspase 8 followed by Bid truncation revealed activation of both extrinsic and intrinsic apoptosis pathway. In quantitative proteomics, proteins expressed lower than 70% were found in ribosome, proteasome and RNA transport pathway, which were related to protein synthesis.

Our study demonstrated that the lipophilic acyl-carbon chain length can precisely regulate the cytotoxic activity of saponins, which is useful for the future development of cytotoxic agents. Using quantitative proteomics and immunolabeling, the mechanism of cytotoxicity induced by the saponin could be the result of caspase-dependent apoptosis through protein biogenesis inhibition.

A number of chemical reactions that allow selective protein modification under physiological conditions have been developed, including 1,4-additions, S_N2 reactions, and S_NAr reactions. While palladium- and gold-mediated arylations are attractive options to create novel types of C–X bonds with excellent selectivity and very rapid kinetics, these reactions require stoichiometric amounts of precious metals and involve the preparation of air-sensitive organometallic reagents. In contrast, we have developed operationally simple, robust coupling reactions of natural amino acids and bench-stable arylboronic acids with inexpensive nickel(II) salt.

Herein, we present selective S-arylations of cysteine and N-arylations of pyroglutamate-histidine sequences. The presence of electron withdrawing substituents, such as nitro groups, at the ortho-position of the arylboronic acid is crucial for achieving excellent conversion. Either S- or N-arylations proceed with high chemoselectivity and rapid kinetics (k_app ~1.5 M^-1s^-1), and are thus applicable for selective protein modification.

References

1. K. Hanaya, J. Ohata, Mary, K. Miller, A. E. Mangubat-Medina, M. J. Swierczynski, D. C. Yang, R. M. Rosenthial, B. V. Popp, Z. T. Ball, Chem. Commun., 2019, 55, 2841.

2. K. Hanaya, Mary, K. Miller, Z. T. Ball, Org. Lett., 2019, 21, 2445.

Dearomative functionalization is a powerful method to construct structurally complex alicyclic scaffolds from simple and abundant aromatic molecules. Although many dearomative functionalizations have been reported so far, the reaction of electron-neutral arenes such as benzenes and naphthalenes are still remained as challenging, often requiring excess amount of arenes owing to their inertness.^[1] Recently, a few reports of catalytic dearomative functionalization of benzenes as limiting reactants such as benzyl chlorides as well as phosphates, nitroarenes, and aryl malonates.^[2]

In this work, we developed two types of Pd-catalyzed dearomative C–C bond formations of aryl halides with diazo compounds; allylation using allyl borates,^[3a] and alkylation using malonates.^[3b] These reactions are thought to proceed through a palladium carbene, followed by generating a benzyl-palladium intermediate. It is noteworthy that these reactions can utilize various haloarenes ranging from benzenes to heteroarenes. Furthermore, we successfully demonstrated the synthetic values of these methods by the late-stage functionalization of pharmaceuticals as well as derivatization of products.

[1] Wertjes, W. C.; Southgate, E. H.; Sarlah, D. Chem. Soc. Rev. 2018, 47, 7996−8017.

[2] (a) Trost, B. M.; Ehmke, V.; O’Keefe, B. M.; Bringley, D. A. J. Am. Chem. Soc. 2014, 136, 8213–8216. (b) Yang, Z.-P.; Jiang, R.; Wu, Q.-F.; Huang, L.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2018, 57, 16190–16193. (c) Bao, M.; Nakamura, H.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 759–760. (d) Komatsuda, M.; Muto, K.; Yamaguchi, J. Org. Lett. 2018, 20, 4345–4357.

[3] (a) Komatsuda, M.; Kato, H.; Muto, K.; Yamaguchi, J. ACS Catal. 2019, 9, 8991–8995. (b) Kato, H.; Musha, I.; Komatsuda, M.; Muto, K.; Yamaguchi, J. to be submitted.

Herein, we describe the protecting-group-free total synthesis of two Isodon diterpenoids, (+)-ent-kauradienone and (-)-jungermannenone C through sequential applications of three radical-based reactions, including the photoinduced skeletal rearrangements of bicyclo[3.2.1]octene ring systems. Further investigations of this photochemical radical rearrangement on various terpenoids demonstrated unparalleled functional-group tolerance. Overall, the mild nature of late-stage photoinduced skeletal rearrangements might suggest some terpenoids could also be produced via such photoinduced rearrangements pathways in nature.

The tetracyclic natural product ent-norflickinflimiod C was first isolated from the orchid Flickingeria fimbriata in 2014.^[1] The pimarane nor-diterpenoid comprises a tricyclic carbon framework, a bridged γ-lactone, two secondary alcohols and seven stereocenters, six of which are adjacent. Inspired by our total synthesis of pimara-15-en-3α-8α-diol, we envisioned a transannular polyene tetracyclization of a dual nucleophilic aryl enol ether to assemble the carbon skeleton of the terpenoid.^[2] A variety of substituents R at the terminal alkene, which represent a surrogate for the hydroxy-group at C-14, were investigated with respect to their compatibility with the cyclization reaction and their regioselectivity. In the course of our studies, we discovered novel pentacyclic scaffolds that originate from unprecedented cyclization pathways.

[1] J.-L. Chen, Z.-M. Zhao, X. Xue, G.-H. Tang, L.-P. Zhu, D.-P. Yang, L. Jiang, RSC Adv. 2014, 4, 14447–14456.

[2] J. M. Feilner, K. Wurst, T. Magauer, Angew. Chem. Int. Ed. 2020, 59, 12436–12439.

Background:

SARS-COV-2 is a new generation of coronavirus, which was firstly determined in Wuhan, China, in December 2019. So far, however, there no effective treatment has been found to stop this new generation of coronavirus but discovering of the crystal structure of SARS-COV-2 main protease may facilitate searching for new therapies for SARS-COV-2 [1]. The aim was to assess the effectiveness of available FDA approved drugs which can construct a covalent bond with Cys145 inside binding site SARS-COV-2 main protease by using covalent docking screening. 

Method: We conducted the covdock module and MMGBSA module in the Schrodinger suite 2020-1, to examine the covalent bonding utilizing crystal structure of SARS-COV-2 main protease (6LU7) [2].Besides, we submitted the top three drugs to molecular dynamics simulations via Gromacs 2018.1

Results: The covalent docking showed that Saquinavir, Ritonavir, Remdesivir, delavirdine, Indinavir, Cefuroxime axetil, oseltamivir and Prevacid have the highest binding energies MMGBSA of --72.17, -72.02, -65.19, -57.65, -54.42, -54.25, -51.8, -51.14 kCal/mol, respectively. 

The 50 ns molecular dynamics simulation was conducted for saquinavir, ritonavir, and remdesivir to evaluate the stability of these drugs inside the binding pocket of SARS-CoV-2 main protease. 

Conclusion: The current study provides a powerful in silico means for rapid screening of drugs as anti-protease medications and recommend that the above-mentioned drugs can be used in the treatment of SARS-COV-2 in combined or sole therapy.

Transition-metal-catalyzed enantioselective C–H functionalization is an important strategy for creating chiral compounds. Pd^II combined with MPAAs¹ and Cp^xM^III catalysts with chiral Cp^x ligands² have been widely exploited in this context. Meanwhile, our group has investigated chiral carboxylate-assisted stereo-control using achiral Cp^xM^III catalysts,^3,4,5 in which enantioselective C–H cleavage via a carboxylate-assisted mechanism is a key step.

In this poster, we will report an achiral Cp^xRh^III-catalyzed enantioselective C(sp³)–H amidation of 2-alkylpyridine derivatives (1) with dioxazolones (2) by developing and applying a new type of chiral carboxylic acids.⁶ We designed pseudo-C₂-symmetric CCAs 4 with a binaphthyl backbone, in which the 2,2′-positions of the binaphthyl are fixed with a quaternary carbon, resulting in the reduced conformational flexibility of the chiral environment. The combination of an optimal chiral carboxylic acid and a sterically hindered rhodium catalyst (Cp*^tBuRh^III) exhibited high enantioselectivity (up to 96:4 er).

¹ Yu, J.-Q. et al. Science 2018, 359, 759.

² Cramer, N. et al. Angew. Chem. Int. Ed. 2020, https://doi.org/10.1002/anie.202008166.

³ Yoshino, T.; Matsunaga, S. et al. Angew. Chem. Int. Ed. 2018, 57, 12048.

⁴ Yoshino, T.; Matsunaga, S. et al. Angew. Chem. Int. Ed. 2019, 58, 1153.

⁵ Yoshino, T.; Matsunaga, S. et al. Angew. Chem. Int. Ed. 2019, 58, 18154.

⁶ Kato, Y.; Lin, L.; Kojima, M.; Yoshino, T.; Matsunaga, S. et al. submitted.

Rigid scaffold present in norbornanes and their oxa-derivates are excellent mimics of secondary structures, naturally occurring in polypeptides and enzymes, such as β-turns and β-hairpins. They can also be used as the inducers of well-defined hydrogen bonding pattern in peptides.¹ Hydrogen bonding is highly important in enzymes and in small molecule organocatalysis. Thioureas and guanidines are two well recognized types of such organocatalysts.^2,3 Aldol reactions with l-proline as catalyst are known to show poor diastereoselectivity in formation of anti and syn adducts what can be improved by adding guanidinium salts or thioureas as cocatalysts with good ability to form hydrogen bonds.^4,5

We report novel cocatalysts based on thiourea and guanidinium moiety, as the active site. To aid in formation of H-bonds, additional amide groups were introduced within oxa-norbornane subunit that are hydrogen bond acceptors and/or donors. Designed oxa-norbornane derivatives were tested in l-proline catalyzed aldol reactions primarily from the aspect of their diastereoselectivity and overall yield of reaction under different conditions.

¹ C. P. R. Hackenberger, I. Schiffers, J. Runsink, C. J. Bolm, J. Org. Chem. 2004, 69, 739-743.

² Z. S. Al-Taie, S. R. Anetts, J. Christensen, S. J. Coles, P. N. Horton, D. M. Evans, L. F. Jones, F. F. J. de Kleijne, S. M. Ledbetter, Y. T. H. Mehdar, P. J. Murphy, J. A. Wilson, RSC Adv. 2020, 10, 22397–22416.

³ I. Smajlagić, M. Guest, R. Durán, B. Herrera, T. Dudding, J. Org. Chem. 2020, 85, 585−593.

⁴ A. Martínez-Castañeda, B. Poladura, H. Rodríguez-Solla, C. Concelló, V. del Amo, Org. Lett. 2011, 13, 3032-3035.

⁵ N. El-Hamdouni, X. Companyó, R. Rios, A. Moyano, Chem. Eur. J. 2010, 16, 1142-1148.

The threat of the spread of rapidly changing viral infections caused by RNA viruses, in particular SARS-CoV-2, makes the development of new means not only for the treatment of these diseases, but also for the prevention of infection constantly urgent. In the course of our present study, a synthetic route to 5-heterocyclyl-1,2,4-triazole-3-carboxylic acids derivatives was developed and a series of new compounds were obtained. Some of the synthesized derivatives of 5-tetrahydrofuran-2-yl-, 5-tetrahydropyran-2-yl- and 5-pyrid-4-yl-1,2,4-triazole-3-carboxylic acids showed pronounced antiviral activity against coronavirus Human HCoV-OS43 and Influenza A H1N1 / California / 04/09 (from Ivanovsky Institute of Virology virus collection). Moreover, the derivatives of 5-tetrahydrofuran-2-yl- and 5-pyrid-4-yl-1,2,4-triazole-3-carboxylic acids, according to our assumption, inhibit the fusion of the SARS-CoV-2 virus with mammalian cells, which is confirmed as on experimental test-models of infection using cells or virions exhibiting spike glycoprotein (S) SARS-CoV-2, and directly using the SARS-CoV-2 virus (hCoV-19 / Russia / Moscow_PMVL-4). These data allow us to hope that further study of 5-heterocyclyl-1,2,4-triazole-3-carboxylic acid derivatives will lead to the identification of new broad-spectrum antiviral agents with a protective mechanism of action.

Various undirected, aliphatic C–H oxidation methods have been developed in the past decade. However, these methods have been rarely applied in total synthesis.¹ Here, we show our efforts to employ these transformations as late-stage functionalizations to convert simply functionalized ent-trachylobanes into higher oxidized representatives. This strategy benefits from a faster and more robust access to the unoxidized carbon core and should enable synthesis of a diverse set of natural products. We have chosen ent-trachylobanes as targets, as they comprise a broad variety of oxidation states and a unique carbon backbone with many tertiary and secondary carbon centers as well as a cyclopropane unit. As a starting point, the enantioselective total synthesis of mitrephorone B was developed. Exposure of mitrephorone B to C–H oxidation conditions has enabled direct conversion to mitrephorone A. We speculate that this oxidation might also be part of the biosynthetic pathway.²

¹M. C. White, J. Zhao, Aliphatic C–H Oxidations for Late-Stage Functionalization, J. Am. Chem. Soc. 2018, 140, 43, 13988-14009.

²L. A. Wein, K. Wurst, P. Angyal, L. Weisheit, T. Magauer, Synthesis of (−)-Mitrephorone A via a Bioinspired Late Stage C–H Oxidation of  (−)‑Mitrephorone B, J. Am. Chem. Soc. 2019, 141, 50, 19589-19593.

Transition-metal-catalyzed denitrogenative transannulation reactions of 1,2,3-benzotriazones have emerged as a powerful method in the preparation of various N-heterocycles relevant to natural products and pharmaceuticals. A variety of transannulation reactions of 1,2,3-benzotriazinones with various π-components such as alkynes, alkenes, allenes, isocyanides, and benzynes had been developed to prepare functionalized isoquinolones and isoindolinone derivatives in a highly effective manner.¹ Mechanistically, the reaction proceeds through a five membered aza-metallacycle intermediate, which is in sharp contrast to others 1,2,3-triazoles that proceed via a metallocarbene intermediate. Despite these significant contributions on annulation reactions, denitrogenative cross-coupling reactions involving 1,2,3-benzotriazones are scarcely studied and relatively unknown.

Herein, we present a new, efficient, novel and environmentally friendly approach to prepare various ortho-arylated, alkenylated and alkynylated benzamides via denitrogenative cross-coupling reaction of 1,2,3-benzotriazones with organoboronic acids and terminal alkynes.^2,3

The reaction of 1,2,3-benzotriazin-4(3H)-ones with organoboronic acids using a nickel complex as the catalyst afforded synthetically useful ortho-arylated and alkenylated benzamides in good to high yields. The reaction is compatible with both aryl and alkenyl boronic acid. Meanwhile, aliphatic terminal alkynes and tri(isopropyl)silyl acetylene furnished the corressponding ortho-alkynylated product in good yields in the presence of palladium/copper as the catalyst. Overall we believe that the present strategy is a mild and convenient way for the preparation of above said molecules, and could represent as a great advance to the chemistry of cross coupling reactions.

References:

1. Chattopadhyay B.; Gevorgyan, V. Angew. Chem. Int. Ed. Engl., 2012, 51, 862–872
2. Hari Balakrishnan, M.; Sathriyan, K.; Mannathan, S. Org. Lett. 2018, 20, 3815–3818
3. Hari Balakrishnan, M.; Mannathan, S. Org. Lett. 2020, ASAP

An efficient catalytic system for the cleavage of C–N bond of tertiary amides or C–O bond of esters has been developed. The present method utilizes Selectfluor and a catalytic amount of CuBr₂ to generate a highly electrophilic nitrogen-centered radical cation, which selectively abstracts a hydrogen atom from C–H bond at benzylic position for the subsequent bond cleavage and substitution of a fluorine atom. The resulting acyl fluorides can be used for further derivatizations with a variety of nucleophiles in a one-pot fashion. Furthermore, synthetic applications of this method for the synthesis and modification of peptides are also described.

Redox chemistry encompasses a broad diversity of reactions implemented as pivotal steps in a multitude of synthetic schemes due to easy manipulation of functional groups through transfer of electron(s). This is also well reflected by the predominant role of redox enzymes in biocatalysis. Most redox enzymes however rely on external source (reduction) or sink (oxidation) of electrons, which impacts the atom-efficiency of the reactions, since usually co-substrate/co-product and/or additional enzymes are involved. We are currently developing innovative protocols for sustainable and atom-efficient transformations, aiming at waste minimization and simplified processes, bypassing the need for stoichiometric reagents with redox enzymes.

Owing to the dual redox reactivity of aldehydes and complementary activity of alcohol dehydrogenases (ADHs) on the aldehyde functionality (oxidation/reduction), a formal intramolecular biocatalytic hydride shift [1] can be considered with dialdehyde molecules. Following our work on the disproporationation of aldehydes and the establishment of a biocatalytic Cannizzaro-type reaction using ADHs [2], we are now disclosing a broadly applicable enzymatic protocol for the synthesis of bi- and tri-cyclic lactones starting from dialdehydes (Scheme 1). An intramolecular bio-Tishchenko reaction was developed with particular attention to redox economy. High turn-over numbers for the nicotinamide cofactor (up to 1.6x10³ half-reactions) along with efficient 1,4-, 1,5- and 1,6-hydride shift on dialdehydes (1:1 ratio enzyme/cofactor) could be demonstrated, following reduction-oxidation sequence through the lactol intermediate. Noteworthy, on (1,1'-biaryl)-2,2'-dicarbaldehyde derivatives, regio- and atroposelectivity were observed with a range of wild-type and engineered ADHs and preparative scale synthesis allowed isolation of several lactone products, with no concomitant waste generation [3]. Application of these lactones in (cross-)polymerization reactions is currently being investigated.

Scheme 1. Bio-Tishchenko reaction catalyzed by alcohol dehydrogenases and product scope

Acknowledgements

Funding by the Austrian Science Fund (FWF) is gratefully acknowledged (project P30519-N36). c-LEcta and Dr. Andreas Vogel, as well as Prof. Ye Ni, are thanked for the kind gift of some of the ADHs tested in this study.

References

[1] E. Tassano, M. Hall, Chem. Soc. Rev., 2019, 48, 5596

[2] E. Tassano, K. Faber, M. Hall, Adv. Synth. Catal. 2018, 360, 2742

[3] E. Tassano, A. Swoboda, K. Merusic, I. Buljubasic, M. Aleotti, M. Hall, in preparation.

Arynes and heteroarynes are highly reactive synthetically useful reaction intermediates that enable the simultaneous creation of two bonds, including C–C, C–H, and C–X (X = heteroatom) bonds, on adjacent aromatic carbons via reactions with a range of arynophiles.¹⁾ Because unstable arynes are typically generated in situ, a judicious choice of precursors is crucial for achieving the desired transformations. Recently, phenol-based precursors, namely, 2-trimethylsilylaryltriflates, are widely used. In contrast, aniline-based precursors, represented by benzenediazonium 2-carboxylates, are considerably less common owing to their explosive character.

In this context, we herein report the development of novel aniline-based aryne precursors, namely, 2-triazenylarylboronic acids 1. 

2-Triazenylarylboronic acids 1 were readily available from 2-iodoanilines over two steps, and were obtained as solids storable at ambient temperature in air. Surprisingly, the precursors 1 generated arynes using neutral silica gel as the sole reagent, and underwent reactions with a wide range of arynophiles in high to excellent yields (Scheme 1). Notably, a heteroaryne precursor 1e was also compatible with the protocol. Furthermore, under solvent-free conditions, solid-state reactions of the precursor with various arynophiles were achieved. 

To gain insight into the reaction mechanism, we performed competition experiments between parent precursor 1a and substituted precursors 1b–d, and analysed the obtained relative rate of the reaction on the basis of the Hammett constants of the substituents. Based on the results, we proposed a dual activation mechanism, in which triazenyl and borono groups were activated as diazonio and boronate groups, respectively (Scheme 2).²⁾

1) (a) P. M. Tadross, B. M. Stoltz, Chem. Rev. 2012, 112, 3550–3577; (b) H. Takikawa, A. Nishii, T. Sakai, K. Suzuki, Chem. Soc. Rev. 2018, 47, 8030–8056.

2) Manuscript submitted.

Polycycles bearing the spirooxindole scaffold are important biofuctional molecules. Because the lengths of C-C, C-N, and C-O bonds are different, spirooxindole polycyclic scaffolds bearing oxygen-containing heterocycles should provide molecules with biological functions different from those of spirooxindole all-carbon polycyclic and N-heterocycle-containing polycyclic systems.

We recently reported the construction of spirooxindole all-carbon polycycles in which the starting material was constructed by formal (4+1) cycloaddition reaction of oxindole derivatives with 1,3-cyclohexanedione.^[1] In this presentation, the construction of spirooxindolee pyran polycycles via catalytic stereoselective annulation reactions of the same starting material will be discussed.^[2] A pyran ring in the spiro polycycles is constructed via the formation of C-C and C-O bonds through dynamic aldol-oxa-cyclization cascade reactions. During the reactions, the starting material was isomerized to the diastereomer with retention of the enantiopurity. With taking advantage of the isomerization, highly enantiomerically enriched forms of single diastereomers of spirooxindole pyran polycycles bearing six stereogenic centers were obtained. Notably, the formation of the pyran ring resulting in the formation of the polycyclic system showed stereoselectivities distinct from the formation of the cyclohexane ring leading to the all-carbon polycycles from the same starting material.

[1] Huang, J.-R.; Sohail, M.; Taniguchi, T.; Monde, K.; Tanaka, F. Angew. Chem. Int. Ed., 2017, 56, 5853.

[2] Sohail, M. Tanaka, F. Communications Chem., 2019, 2, 73, doi: 10.1038/s42004-019-0177-5.

C1q is the recognizing molecule of the classical complement pathway and as such is also involved in pathological conditions, such as systemic lupus erythematosus (SLE). Molecular events that lead to generation of autoantibodies against C1q (anti-C1q) are still unknown, although hypothesis, concerning the exact timing and mechanism exist. C1q is thought to undergo a conformational transition exposing neo-epitopes that lead to recognition of the molecule as autoantigen.

We addressed the issue of C1q autoantigenicity by studying structural features of C1q when recognized by human anti-C1q from sera of SLE patients. We screened the naive phage library Griffin.1 for anti-idiotype single-chain variable fragment (scFv) antibodies, that mimicked the globular head regions of native C1q (ghC1q) and thus were tools to localize C1q autoepitopes. We selected the inhibitory monoclonal scFvA1 which is further used in in-silico modelling to characterise new binding sites in ghC1q.

The generated 3D model and the loop similarity model of scFvA1 sequence show that the three CDRs of scFv V_H have analogs in the apex of ghC1q chains, which exhibit marked differences in their surface patterns, with respect to both charged and hydrophobic residues. Hence we elucidated CDR similarity to the apical region of gC1q thus mapping indirectly for the first time a globular autoepitope of C1q. The similar regions are situated in all of the three globular fragments suggesting that the globular autoepitope may consist of number of linear stretches, thus being a conformational one. This is consistent with the fact that anti-C1q were extracted from SLE sera, positive only for the intact C1q. The mimicry of scFvA1 to parts of all C1q chains reveals their involvement in the interaction with SLE autoantibodies, hypothesizing enlargement of the spectrum of the C1q targets.

Acknowledgement. The experimental work was financed by Grant DH01/9,2016 of the Bulgarian NSF.

The introduction of gem-diborylalkenes ^[1] as radical-labile substrates are explored for the first time. This method provides an efficient and general method for the photochemistry reaction of gem-diborylalkenes to a rabidly access of 1,1-bisborylalkanes.^[2] This method is based on a novel photoredox decarboxylative radical addition^[3] to gem-diborylalkenes which undergoes through the unprecedented formation of α-gemdiboryl carbon-centred radicl. Remarkably, the reaction offers a highly modular and regioselective approach to synthesize γ-amino gem-diborylalkanesMoreover, this methodology can serve as an end point late-stage diversification and as a site for subsequent functionalization of simple organic molecules, natural compounds, and bioactive molecules.

1. J. Royes; A. B. Cuenca; E. Fernández Eur. J. Org. Chem. 2018, 2728.
2. R. Nallagonda; K. Padala; A. Masarwa Org. Biomol. Chem. 2018, 16, 1050.
3. A. Noble; R. S. Mega; D. Pflӓsterer; E. L. Myers; V. K. Aggrawal Angew. Chem. Int. Ed. 2018, 57, 2155.

[1] W.-B. Zhang, X. Yu, C.-L. Wang, H.-J. Sun, I.-F. Hsieh, Y. Li, X.-H. Dong, K. Yue, R. Van Horn, S. Z. D. Cheng, Macromolecules 2014, 47, 1221.

[2] X. Yu, K. Yue, I.-F. Hsieh, Y. Li, X.-H. Dong, C. Liu, Y. Xin, H.-F. Wang, A.-C. Shi, G. R. Newkome, R.-M. Ho, E.-Q. Chen, W.-B. Zhang, S. Z. D. Cheng, Proc. Natl. Acad. Sci. 2013, 110, 10078.

[3] F. Djojo, E. Ravanelli, O. Vostrowsky, A. Hirsch, Eur. J. Org. Chem. 2000, 1051.

[4] C. P. Ioannou, G. I. Ioannou, E. E. Moushi, K. Velonia, N. Chronakis, Eur. J. Org. Chem., 2015, 4598.

poly-Boronate species are polynucleophilic organometallic equivalents, which are known as valuable reagents in modern organic synthesis, providing an efficient access to a wide array of C–B bonds transformations including the construction of C–C and C–heteroatom bonds. ^[1][2][3] Here we describe the use of unsymmetrical-gem-diborylalkenes as dienophile-reactive groups for Diels-Alder reaction. These reactions provide a general method for the regio- and stereoselective conversion of gem-diborylalkenes to rapidly access poly-borylatedcyclohexenes. The utility of the poly-borylatedcyclohexenes building blocks was demonstrated by ring-opening metathesis polymerization (ROMP), providing a highly modular approach to the first preparation of the gem-diboron-based polymers. 

1. R. Nallagonda; K. Padala; A. Masarwa Org. Biomol. Chem. 2018, 16, 1050-1064.
2. J. Royes; A. B. Cuenca; E. Fernández Eur. J. Org. Chem. 2018, 2728. 
3. N. Eghbarieh,^#  N. Hanania, ^#   A. Zamir,  M. Nassir, T. Stein, A. Masarwa,  J. Am. Chem. Soc. 2021, 143, 6211−6220 (^# equal contribution)

         Weinreb amide has rapidly become popular in organic synthesis since it is useful for selective synthesis of ketone by addition of Grignard or alkyllithium reagents. Although many ketone syntheses from the Weinreb amide have been reported, the addition of nucleophile to α, β-chlorinated Weinreb amide with α-proton has not been reported. This is because nucleophilic addition to α, β-chlorinated Weinreb amide resulted in undesired unsaturated carbonyl compound such as compound 2 by the abstraction of acidic α-proton. To overcome this situation, some parameters have been optimized to obtain α, β-dichloroketone from the Weinreb amide.

            As a model substrate, amide anti-1 was employed for the optimization of the reaction conditions with lithium acetylide prepared from 1-hexyne. (eq 1) After extensive investigations of solvent, temperature and quench conditions, 4 M HCl in dioxane as a quenching reagent (commercially available) was the most effective for the selective formation of the desired ketone anti-3. In contrast, when saturated NH₄Cl was used, undesired unsaturated ketone 2 was formed as a single product. Other anti-dichlorinated ketones were also selectively prepared in high yields by the addition of R¹-Li or R¹-MgX (R¹ = vinyl, methyl, n-pentyl, and so on) under the optimized conditions. 

           Diastereomer syn-1 also reacted with various R¹-Li, affording the target ketone syn-3, selectively. (eq 2) However, if R¹-MgX was used in the addition reaction, higher amount of elimination product 2 and other compounds were generated although high selectivity of syn-3 was observed if MeMgBr was used as a nucleophile.

Scalarane sesterterpenoids are secondary metabolites which demonstrate relevant biological properties, such as antifeedant, antimicrobial, antifungal, antitubercular, antitumor and anti-inflammatory activities [1]. Many efforts for the synthesis of this framework have been undertaken [2,3]. The current work is dedicated to a potential solution for the problem of efficient synthesis of C(12) oxygenated scalaranes.

The retrosynthetic approach is based on the homologation of the known tricyclic aldehyde 1, available from commercial sclareol [3]. Interaction of 1 with diketene led to the acetoacetic ester 2, which represented the substrate for a Michael intramolecular addition, triggered efficiently on treatment with cesium carbonate. A successive intramolecular aldol condensation of the resulting aldo-ketone 3 provided the required tetracyclic skeleton 4. Hydrogenation of the Δ¹⁵⁽¹⁶⁾ double bond resulted in the saturated pentacyclic nor-18-epi-scalarane 5, having the required trans-junction between C-D cycles. The transformation of 5 into the natural analogues is currently under investigation.

References

1.    Evidente, A.; Kornienko, A.; Lefranc, F.; Cimmino, A.; Dasari, R.; Evidente, M.; Mathieu, V.; Kiss, R. Curr. Med. Chem., 2015, 22(30), 3502-3522. 

2.    Ungur, N.; Kulcitki, V. Phytochem. Rev., 2004, 3(3), 401-415.

3.    Fan, W.Y.; Wang, Z.L.; Zhang, Z.G.; Li, H.C. and Deng, W.P. Tetrahedron, 2011, 67(31), 5596-5603.

Acknowledgments

The financial support from National Agency for Research and Development (ANCD) of the Republic of Moldova, project “New products with preventive and therapeutic potential basing on natural products of vegetal origin and modern methods of organic synthesis” (code 20.80009.8007.03) is acknowledged.

Zinc methyl pheophorbides a/a’, which possess oxo and methoxycarbonyl groups at the C13¹- and C13²-positions, respectively, on the exo-five membered ring fusing the cyclic tetrapyrrole of their chlorin π-skeletons, were prepared via chemical modifications of chlorophyll a produced in phototrophs. The 13¹-hydroxylated and unsubstituted analogues were synthesized by reduction of the ketone moiety. The 13¹- and 13²-stereochemistry of these semi-synthetic compounds was confirmed by ¹H NMR and circular dichroism spectroscopies. A methoxycarbonyl group at the chiral C13²-position in the ketone was stereo-inverted under basic conditions, whereas those in the corresponding alcoholic and dihydro-forms were not. The in vitro BciC enzymatic reaction of the (13²R)-ketone Zn-1a was found to stereoselectively hydrolyze the C13²-methoxycarbonyl group, followed by spontaneous decarboxylation of Zn-2a to Zn-3a. Similarly, the (13²R)-COOCH₃ group in the (13¹S)-alcohol Zn-1b was hydrolyzed to Zn-2b, whereas the group in the (13¹R)-epimer was not. After the enzymatic reaction of C13¹-dihydro-compound Zn-1c to Zn-2c, its (13²S)-decarboxylated and hydroxylated product Zn-3c was observed. 

Phenoxyamine ligands with varied substitutions were synthesized and they were reacted with titanium alkoxides [Ti(OiPr)₄ and Ti(OtBu)₄] which resulted in 2:1 ligand to metal complexes (except for adamntyl which resulted in 1:1 complex). The titanium complexes were characterized, using ¹H NMR, ¹⁹F NMR, Elemental Analysis, and Single crystal XRD. Furthermore, the synthesized compounds were used as catalysts for bulk polymerization of rac-lactide. The activity and microstructure of polylactic acid is varied with the complexes bearing different substituents. The detailed study of each complex shows the highest activity for fluorine substitutent while isopropyl substituent shows the highest heterotacticity. These polymers were further characterized by ¹³C NMR. A tendency toward formation of heterotactic-biased poly(rac-LA) was observed in the bulk polymerizations.

Figure/Table

Conventional synthesis of janusene (5,5a,6,11,11a,12-hexahydro-5,12:6,11-di-o-benzenonaphthacene) consists of several reaction steps starting from anthracene. In this account, one-pot synthesis of janusene N-methyl-5a,11a-dicarboximide employing 2,3-dibromo-N-methylmaleimide as acetylene equivalent is reported. Molecular structure of janusene has been determined by X-ray crystallography.

Figure 1. Janusene imide and its X-ray structure

Cyclic sulfamidates are important and versatile synthetic intermediates, which are broadly used for the synthesis of various functionalized amines, functionalized lactams and functionalized piperazines/thiomorpholines. We have developed a novel gold(I)-catalyzed intramolecular dehydrative amination of allylic alcohol with sulfamate ester to furnish cyclic sulfamidates under mild conditions. The reactions proceed smoothly at room temperature in the presence of a catalyst combination of (IPr)AuCl (5 mol%) and AgBF₄ (5 mol%). The improved reactivity of the (IPr)AuCl combined with AgBF4 derives from the counterion and the intrinsic activity of the gold(I) catalyst rather than from the silver(I) catalyst This method allows a facile access to cyclic sulfamidates in good to excellent yields with high selectivity. This method is also well applicable to the synthesis of various cyclic sulfamidates.

Figure 1: Diagram of coumarin amphiphiles associating with bacterial membrane lipids.

By 2050 antimicrobial resistance is predicted to become the direct cause of 10 million deaths annually.¹ Antibacterial agents that permeabilise or destabilise bacterial membranes induce minimal formation of resistance and display potent broad-spectrum activity.² Natural membrane-active antibacterial agents such as antimicrobial peptides (AMPs) achieve membrane targeting by adopting an amphiphilic conformation, with potent agents containing cationic heads, to facilitate phospholipid association, and hydrophobic lipid-like tails, to facilitate membrane disruption.^3-5 Incorporating these amphiphilic features onto low molecular weight scaffolds provides new classes of antibacterial agents which are more readily synthesised and exhibit improved metabolic stability compared to larger macromolecular structures.⁶ This work explores the chemistry behind functionalisation of a coumarin framework to generate membrane-active antibacterial compounds.

References

1. J. O'Neill, Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations, 2014.
2. J. Hoque, M. M. Konai, S. Gonuguntla, G. B. Manjunath, S. Samaddar, V. Yarlagadda and J. Haldar, Journal of Medicinal Chemistry, 2015, 58, 5486-5500.
3. M. Zasloff, Nature, 2002, 415, 389-395.
4. W. Hamley, Chemical Communications, 2015, 51, 8574-8583.
5. J. G. Hurdle, A. J. O'Neill, I. Chopra and R. E. Lee, Nature Reviews Microbiology, 2011, 9, 62-75.
6. C. Ghosh and J. Haldar, ChemMedChem, 2015, 10, 1606-1624.

The 7-amino coumarin scaffold is a commonly used chromophore owing to its favourable photophysical properties such as high fluorescent quantum yields and large Stokes shifts. Many groups install an amino group in the 7-position masked as an amide, carbamate or sulfonamide. The installation of these groups is typically achieved using classical methods and often requires for time consuming chromatographic purification steps. Buchwald-Hartwig Pd-cross coupling reactions offer an alternative route to access C-N functionalised aromatic substrates and have been shown to be advantageous when compared to traditional methods in other fluorophore systems. However, the success of Pd-cross coupling reactions is heavily reliant on the substrate/catalyst combination which means each system needs to be thoroughly investigated before derivatives can be efficiently produced.

This presentation describes the conversion of a readily accessible and shelf-stable 7-nonaflate umbelliferone starting material to a range of amide, carbamate and sulfonamide derivatives using Buchwald-Hartwig chemistry. Advantages of this procedure include good functional group tolerance, operationally simple product isolation (no chromatographic step required), low catalytic loadings (1 mol%) and amenability to gram scales. The photophysical properties of all compounds soluble in H₂O (with 1% DMSO) were evaluated with a Boc-protected 7-amino-4-methylcoumarin analogue found to be a very impressive fluorophore (ɸ_F = 0.94). Furthermore, an acrylamide derivative was converted to a novel fluorescent p(HEMA) hydrogel which was resistant to leaching in ultrapure H₂O.

We previously reported that amphiphilic iridium(III) complex-peptide hybrids (IPHs), which possess cationic peptide sequence such as KKKGG (K: lysine, G: glycine) at the 5’-position and 4’-position of tpy and ppy ligands, respectively, induce cell death of cancer cells (T-lymphocyte leukemia Jurkat cells), and the cell death is detected by their green or yellow phosphorescence (EC₅₀ = 2.4-7.4 mM).  Moreover, we reported new IPHs having the same peptide sequence through an electron-donating hydroxyacetyl (glycolic acid) side chain at the 4’-position of ppy ligands that exhibit more potent anticancer activity and a green emission for more detailed mechanistic studies.  The positive relationship between the number of the KKKGG peptide parts and their anticancer activity was confirmed.  It has also been found that these IPHs induce paraptosis-like cell death, which is one of the programmed cell death.  The results of more detailed mechanic study suggest that IPHs induce through the increase in mitochondrial Ca²⁺ concentrations by the direct Ca²⁺ from endoplasmic reticulum (ER) and the decrease in mitochondrial membrane potential.  In this paper, these results will be discussed.

The 4-[(E)-3-phenylprop-2-enyl]phenols are rather important structures found in natural products and biologically significant compounds. Obtusastyrene and obtustyrene are two such phenol based natural products isolated from Dalbergia retusa. Herein, we present a [Pd]-catalyzed highly regioselective para-allylation of phenols. Simple allylic alcohols have been utilized as allylating coupling partners with phenols. Notably, the strategy enabled the formation of 4-[(E)-3-phenylprop-2-enyl]phenols under open-air and mild reaction conditions. In addition, demonstrated the direct synthesis of obtusastyrene and obtustyrene.

Abstract:

PTP1B dephosphorylate (removal of Phosphate group) the insulin receptor (IR), Insulin Receptor Substrate (IRS), Janus Kinase-2(JAK2) & STAT3 which is present in the downstream of insulin and leptin receptor respectively. PTP1B inhibitors are used for the treatment of diabetes and obesity as a singly drug therapy due to simultaneously acting in both insulin and leptin signalling pathway. In present study effort has been made to design and synthesized the novel PTP1B Inhibitors as antidiabetic agents. Pharmacophore mapping and Molecular docking study has been formed by using Glide modules of Schrodinger computational software to identifying binding affinity of novel compounds at active site of the protein.

Synthesis Scheme of Novel PTP1B Inhibitors

Lignans are naturally existing plant phenols that show an enormous class of pharmacologically active compounds. For example, enterolactone shows anti-cancer, anti-oxidant, anti-inflammatory and anti-angiogenic properties¹. We have already reported an intramolecular Tishchenko type reaction using an iridium aminoalkoxide complex under mild conditions². As a continuous study, we will report the synthetic study of enterolactones using asymmetric Tishchenko-type reaction of meso-dialdehyde using a chiral iridium diamine complex. The reaction is a redox neutral reaction and one of the borrowing hydrogen methodology³. The reaction afforded the key intermediate lactone in 78% yields with 91% ee. The lactone was transformed the corresponding diiodide for the coupling reaction for the lignan derivatives. The detail of the synthetic process will be discussed under the symposium.⁴

References

1. Adlercreutz, H., Crit. Rev. Clin. Lab. Sci. 2007, 44, 483-525.

2. Suzuki, T.; Yamada, T.; Matsuo, T.; Watanabe, K.; Katoh, T. Synlett 2005, 1450-1452.

3. Suzuki, T. Chem. Rev. 2011, 111, 1825-1845.

4. Ismiyarto; Kishi, N.; Adachi, Y.; Jiang, R.; Doi, T.; Zhou, D.-Y.; Asano, K.; Obora, Y.; Suzuki, T.; Sasai, H.; Suzuki, T., RSC Adv. 2021, 11, 11606-11609

Based on the chiral backbone of trans-1,2-cyclohexane diamine a variety of bifunctional ammonium salt catalysts with hydrogen-bonding donor moieties can be synthesized to facilitate asymmetric reactions like the enantioselective α-fluorination of β-ketoesters [1].

Chiral quaternary urea- and thiourea-containing ammonium salt catalysts have already been introduced and proved their applicabilitiy in various different asymmetric transformation reactions [2,3]. In addition, we recently researched on the synthesis of chiral quaternary ammonium salt catalysts based on a guanidine hydrogen-bond donor group. In on-going investigations focusing on the optimization and on the applications of catalysts of this sort, we have introduced several promising synthesis routes starting from trans-1,2-cyclohexane diamine.

This presentation gives an overview on the designed quaternary ammonium salt hydrogen bond catalysts, their synthesis, as well as on their applications.

[1] J. Novacek, M. Waser, Eur. J. Org. Chem. 2013, 637-648. [2] J. Novacek, M. Waser, Eur. J. Org. Chem. 2014, 802-809. [3] (a) M. Tiffner, J. Novacek, A. Busillo, K. Gratzer, A. Massa, M. Waser, RSC Adv. 2015, 5, 78941-78949. (b) A. Di Mola, M. Tiffner, F. Scorzelli, L. Palombi, R. Filosa, P. De Caprariis, M. Waser, A. Massa, Beilstein J. Org. Chem. 2015, 11, 2591-2599. (c) J. Novacek, J. A. Izzo, M. J. Vetticatt, M. Waser, Chem. Eur. J. 2016, 22, 17339-17344.

Asymmetric inverse-electron-demand Diels-alder (IEDDA) reaction has been recognized as one of the most powerful atom-economical tools for the construction of six-member carbocycles and heterocycles, and for the application to the asymmetric synthesis of natural products and biologically active molecules.¹ Asymmetric IEDDA reaction has been extensively studied using metal catalysis and organocatalysis.^1b Among them organocatalysts have an advantage over metal catalysts in terms of eco-friendly and cost-effective nature. Recently, we have reported the first organocatalytic approach for the asymmetric synthesis of 3,4-disubstituted cyclohexadiene carbaldehydes through an inverse-electron-demand Diels–Alder (IEDDA) reaction starting from ,,,-unsaturated aldehydes and arylacetaldehydes with excellent diastereo- and enantioselectivities.² We have successfully applied this methodology for the formal total synthesis of cyclobakuchiols A and C. Using this asymmetric organocatalytic IEDDA reaction as a key step, we have recently achieved a first total synthesis of more potent cannabinoid, 9-11-hydroxyhexahydrocannabinol.³

References

1. (a) Oliveira, B. L.; Guo, Z.; Bernardes, G. J. L. Chem. Soc. Rev. 2017, 46, 4895–4950. (b)
Jiang, X.; Wang, R. Chem. Rev. 2013, 113, 5515–5546.

2. Maurya, V.; Appayee, C. Org. Lett. 2018, 20, 4111–4115.

3. Maurya, V.; Appayee, C. J. Org. Chem. 2019, Article ASAP.
https://doi.org/10.1021/acs.joc.9b02962

Due to their invaluable functions in biological systems, carbohydrates have long been within the keen sight of synthetic chemists. To this end, selective modification of the hydroxyl groups of sugars has been an invincible challenge due to their proximate relative reactivity. Customarily, the preparation of carbohydrate building blocks commences with the functionalization of the anomeric carbon, followed by the protection-deprotection manipulation of the remaining protecting groups. Meanwhile, these tedious sequences of events during the synthesis of carbohydrate scaffolds are considered among the bottlenecks of chemical glycosylation. As one of possible mitigation strategy, we herein report our discovery on the TMSOTf-catalyzed selective acetylation of the non-anomeric groups of several per-O-TMS sugar substrates leaving their anomeric O-TMS moiety intact. The resulting 1-O-TMS-equipped glycosyl building blocks can be directly used in ensuing reactions without farther manipulation of the protecting group at the anomeric center unlike typical synthetic routines. Therefore, the easy and step-economic attainment of such synthetically versatile building blocks can expedite chemical glycosylation reactions by abating the loss of time and energy due to employment of lengthy protocols.

Introduction: The chromone scaffold is presented in numerous biological active compounds and natural products, the development of novel synthetic methods which allow for the rapid synthesize these analogues would be highly desirable. The efficient C−C bond formation of the Friedel-Crafts reaction (via electrophilic aromatic substitution) is a green and atom economical approach. Our method which employs Friedel-Crafts, chelation assisted C–H activation, and one-pot sequential reactions to allow facile synthesis of chromone derivatives of interest in life sciences.

Methods: In this study, we use the Friedel-Crafts reaction with arylallyl alcohol and 3-allylchromone as starting materials and arenes for the creation of 1,3-diarylpropene. When used as an intermediate, the native double bond of 1,3-diarylpropenes can be employed to direct the production of the 3-substituted chromone derivatives through metal-catalyzed C–H activation reactions (i.e., olefination and arylation). We also employed intramolecular cyclization reactions involving 1,3-dicarbonyls to produce tricyclic and tetracyclic compounds.

Results and Discussion: We developed the efficient method for the synthesis of 3-substituted chromone derivatives via the sequential Friedel-Crafts/chelation-assisted C‒H bond activation reactions. The method produced the desired chromone products when the reaction was performed when Pd was used as a catalyst. We were also able to generate arylation and olefination products in good yields using a variety of substrates based on this method.

Epoxy-guaiane sesquiterpenes are a class of natural products found in some species of Phyllanthus. One member of this family, (-)-englerin A, has attracted extensive attention from chemists, biologists and physicians due to its potent inhibitory activity toward renal cancer cell lines as well as its complex structure. Until now, about 20 research groups have reported total synthesis or formal synthesis of englerin A. We developed a two-stage approach, which combined microbial production of the guaiene scaffold with chemical transformations to provide (-)-englerin A in six steps. Other members of this family, including (-)-oxyphyllol, (+)-orientatol E and (+)-orientalol F, were obtained via the same approach.

The biosynthetic pathways of epoxy-guaiane sesquiterpene natural products have not been elucidated. We realized that STC5, a fungus sesquiterpene synthase which could convert farnesyl pyrophosphate (FPP) into the guaiene scaffold could be harnessed to synthesize these natural products. By engineering the mevalonate pathway and overexpression of FPP synthase and STC5, the key intermediate guaian-6,10(14)-diene was obtained in E. coli. The four epoxy-guaiane sesquiterpenes were then synthesized in 2-6 steps from the intermediate.

Heterologous production of terpenoids or their precursors has been reported by several groups. However, the applications of this strategy to produce medicinal plant terpenoids are limited thus far owing to a few reasons. Our approach demonstrated the power of combining microbial production and organic synthesis, and could facilitate syntheses of (-)-englerin A analogues for evaluation of their therapeutic potentials in drug discovery.

References

1. Wu, Z.; Zhao, S.; Fash, D. M.; Li, Z.; Chain, W. J.; Beutler, J. A., Englerins: A Comprehensive Review. J. Nat. Prod. 2017, 80, 771-781.

2. Mou, S-B.; Xiao, W.; Wang, H-Q.; Wang, S-J.; Xiang, Z., Efficient Syntheses of Epoxy-guaiane Sesquiterpenes (-)-Englerin A, (-)-oxyphyllol, (+)-orientatol E and (+)-orientalol F: A Synthetic Biology Approach. Org. Lett. 2020, 22, 1976-1979.

3. Siemon, T.; Wang, Z.; Bian, G.; Seitz, T.; Ye, Z.; Lu, Y.; Cheng, S.; Ding, Y.; Huang, Y.; Deng, Z.; Liu, T.; Christmann, M. Semisynthesis of plant-derived englerin A enabled by microbe engineering of guaia-6,10(14)-diene as building block. J. Am. Chem. Soc. 2020, 142, 2760-2765.

Cycloaddition reactions of highly electrophilic alkenes are attractive in view of their wide applicability for construction of various skeletons. We have studied intramolecular cycloaddition reactions of styrene-derived ethenetricarboxylate amides.¹ Reaction of ethenetricarboxylic acid 1,1-diester and cinnamylamines with EDCI/HOBt/Et₃N led to pyrrolidine products via intramolecular [2+2] and [4+2] cycloadditions in sequential processes depending on the substituents on benzene ring. It is of interest to extend the reactions to intermolecular and intramolecular reactions in various ring formations and examine the effects of subsituents. In this work, inter- and intramolecular cycloaddition reactions of ethenetricarboxylates with styrenes and α-halostyrenes (X = F, Cl, Br, I) have been investigated.

The reactions of ethenetricarboxylates 1 with styrenes 2 or α-bromostyrenes 4 in the presence of SnCl₄ or SnBr₄ gave highly substituted cyclobutanes 3 or 5, stereoselectively. (E)- and (Z)-4-aryl-3-butenylamides 6 were prepared as isolable products. While the reaction of (Z)-4-aryl-3-butenylamide with 1-1.5 equiv. of Lewis acids such as SnCl₄ gave cis-fused cyclobutanes 7 as major products, (E)-4-aryl-3-butenylamide with catalytic amounts of Lewis acids gave trans-fused cyclobutanes. Formation of seven-membered ring-fused cyclobutane has also been attempted. The reaction of (E)-5-phenyl-4-pentenylamide with 1 equivalent of AlCl₃ gave a trans-fused 3-azabicyclo[5.2.0]nonane derivative 7 as a major product via [2+2] cycloaddition. Reaction of (E)-3-phenyl-3-bromo-2-propene-1-amide with Et₃N in benzene at 80 °C gave a cis-fused tricyclic compound 8 via [4+2] cycloaddition/H-transfer. Reaction of the amide with SnBr₄ at room temperature gave cyclobutane-fused pyrrolidine 7 as a major product.

In order to obtain some insights for the mechanism and the selectivities, DFT calculations have been carried out.

 ¹ (a) Yamazaki, S.; Sugiura, H.; Ohashi, S.; Ishizuka, K.; Saimu, R.; Mikata, Y.; Ogawa, A. J. Org. Chem. 2016, 81, 10863. (b) Sugiura, H.; Yamazaki, S.; Go, K.; Ogawa, A. Eur. J. Org. Chem. 2019, 204.

A Cu^II complex of C₂-chiral bisamidine-type sp²N bidentate ligand, (S,S)-Naph-diPIM-dioxo-iPr (L_S), catalyzes the enantioselective Friedel-Crafts (FC) reaction of indole (1) with ethyl trifluoropyruvate (2) to give quantitatively the FC adduct 3 with a 98:2 S/R enantiomer ratio (er). The reaction shows no nonlinear effect (NLE) under the standard conditions of [1] = [2] = 100 mM; [Cu(OTf)₂] = [L_S + L_R] = 0.10 mM (Cu^II:L_S:L_R = 1:x:(1–x) (x ≤ 1)); CPME; and 0 °C irrespective of the catalyst aging temperature. A five-fold increase in the catalyst concentration (0.50 mM) changes the situation, leading to a strong (+)-NLE with phase separation of a white solid. The NLE is expressed by the Noyori-type mechanism: Aggregate of heterochiral dimer CuL_SCuL_R is separated from the reaction system (K_hetero > 1 > K_homo). Furthermore, a strong (+)-NLE is observed via a purple solid liberation even with [Cu^II] = 0.10 mM after the catalyst aging at 100 °C in the presence of an excess amount of chiral ligand (Cu^II:L_S:L_R = 1:1:x (x ≤ 1)). A mechanistic study has revealed i) that the sterically disfavored homochiral 1:2 complex CuL_SL_S is more stabilized by an intramolecular n-π* interaction than the sterically favored heterochiral 1:2 complex CuL_SL_R and ii) that the (+)-NLE originates from the phase separation of heterochirally interacted (CuL_SL_SCuL_RL_R)_n but neither from (CuL_SL_R)_n (Kagan mechanism) nor (CuL_SCuL_R)_n (Noyori mechanism). The mechanism switch as well as the unprecedented new mechanism evokes attention toward interpretation of NLE-generating reactions by Noyori and Kagan mechanisms.

References

1.  T.P. Le, S. Tanaka, M. Yoshimura, M. Kitamura. Bull. Chem. Soc. Jpn. 93 (2020) 1319–1333. 
2.  T.P. Le, K. Higashita, S. Tanaka, M. Yoshimura, M. Kitamura. Org. Lett. 20 (2018) 7149–7153.

Five bidentate Pyridinyl Schiff bases and their Silver(I) complexes are reported in this study. The Silver(I) salts used are; AgNO₃, AgClO₄, AgCF₃SO₃. The pyridinyl Schiff base ligands, L_1-5 were synthesized by refluxing an equimolar amount of 2-pyridine carboxaldehyde with 2-aminophenol, 2-aminothiophenol, 2-fluoroaniline, p-toluidine, and 2-thiophenemethylamine, respectively. Two equivalent of the obtained ligands were reacted with one equivalent of silver(I) salts in anhydrous ethanol under constant stirring at room temperature forming complexes of general formula [AgL₂]⁺X^-. Elucidation of the complexes’ structure was done using ¹H-NMR, ¹³C-NMR, Electrospray ionization mass spectrometry, Elemental analysis, Infrared spectroscopy, and some by Single-crystal X-ray diffraction analysis. The ligands coordinated via the azomethine nitrogen and pyridine nitrogen to the silver(I) ion in a distorted tetrahedral geometry having the counter anion outside the coordination sphere. The compounds were investigated for biological activities and binding affinities with calf thymus DNA (CT-DNA) and protein (bovine serum albumin). An excellent in vitro antimicrobial and antioxidant activities were recorded for the complexes and high binding affinity with CT-DNA and protein. The complexes showed fair cytotoxicity against HELA (cervical cancer cell), MDA-MB231 (breast cancer cell) and SHSY5Y (neuronal cancer cell), especially towards HELA and complex [Ag(L5)₂]ClO₄  with thiophene moiety had better selectivity.