Formal Single Atom Editing of the Glycosylated Natural Product Fidaxomicin Improves Acid Stability and Retains Antibiotic Activity.

Fidaxomicin (Fdx) constitutes a glycosylated natural product with excellent antibacterial activity against various Gram-positive bacteria but is approved only for Clostridioides difficile infections. Poor water solubility and acid lability preclude its use for other infections. Herein, we describe our strategy to overcome the acid lability by introducing acid-stable S-linked glycosides. We describe the direct, diastereoselective modification of unprotected Fdx without the need to avoid air or moisture. Using our newly established approach, Fdx was converted to the single atom exchanged analogue S-Fdx, in which the acid labile O-glycosidic bond to the noviose sugar was replaced by the acid stable S-glycosidic bond. Studies of the antibacterial activity of a structurally diverse set of thioglycoside derivatives revealed high potency of acyl derivatives of S-Fdx against Clostridioides difficile (MIC range: 0.12-4 µg/mL) and excellent potency against Clostridium perfringens (MIC range: 0.06-0.5 µg/mL).

Allylic Carbocyclic Inhibitors Covalently Bind Glycoside Hydrolases.

Allylic cyclitols were investigated as covalent inhibitors of glycoside hydrolases by chemical, enzymatic, proteomic, and computational methods. This approach was inspired by the C7 cyclitol natural product streptol glucoside, which features a potential carbohydrate leaving group in the 4-position (carbohydrate numbering). To test this hypothesis, carbocyclic inhibitors with leaving groups in the 4- and 6- positions were prepared. The results of enzyme kinetics analyses demonstrated that dinitrophenyl ethers covalently inhibit α-glucosidases of the GH13 family without reactivation. The labeled enzyme was studied by proteomics, and the active site residue Asp214 was identified as modified. Additionally, computational studies, including enzyme homology modeling and density functional theory (DFT) calculations, further delineate the electronic and structural requirements for activity. This study demonstrates that previously unexplored 4- and 6-positions can be exploited for successful inhibitor design.

Total syntheses of strained polycyclic terpenes.

Terpenoids constitute a broad class of natural compounds with tremendous variability in structure and bioactivity, which resulted in a strong interest of the chemical community to this class of natural products over the last 150 years. The presence of strained small rings renders the terpenoid targets interesting for chemical synthesis, due to limited number of available methods and stability issues. In this feature article, a number of recent examples of total syntheses of terpenoids with complex carbon frameworks featuring small rings are discussed. Specific emphasis is given to the new developments in strategical and tactical approaches to construction of such systems.

Concise Total Synthesis of Peyssonnoside A.

Peyssonnoside A is a marine-derived sulfated diterpenoid glucoside with a unique 5/6/3/6 tetracyclic skeleton with a highly substituted cyclopropane ring deeply embedded into the structure. Herein, we report the first total synthesis of this natural product in a concise, efficient, scalable, and highly diastereoselective fashion. The aglucone peyssonnosol was synthesized in 21% overall yield after 15 steps, featuring a Simmons-Smith cyclopropanation and Mukaiyama hydration, fully controlled by the spatial structure of the substrates.

Ring size and nothing else matters: unusual regioselectivity of alkyne hydration by NHC gold(I) complexes.

We have investigated the role of ring sizes and substituents in NHC ligands in some (NHC)Au(i) complexes in the hydration of internal alkynes. Despite the fact that using (NHC)Au(i) complexes in the hydration of diarylacetylenes leads to Markovnikov-type products, the precise tuning of ligands allows changing the regioselectivity in arylalkylacetylene hydration to the anti-Markovnikov-type.

Cobalta-Electrocatalyzed C-H Activation in Biomass-Derived Glycerol: Powered by Renewable Wind and Solar Energy.

Aqueous glycerol was identified as a renewable reaction medium for metalla-electrocatalyzed C-H activation powered by sustainable energy sources. The renewable solvent was employed for cobalt-catalyzed C-H/N-H functionalizations under mild conditions. The cobalta-electrocatalysis manifold occurred with high levels of chemo- and positional selectivity and allowed for electrochemical C-H activations with broad substrate scope. The resource economy of this strategy was considerably substantiated by the direct use of renewable solar and wind energy.

Making endo-cyclizations favorable again: a conceptually new synthetic approach to benzotriazoles via azide group directed lithiation/cyclization of 2-azidoaryl bromides.

Although benzotriazoles are important and ubiquitous, currently there is only one conceptual approach to their synthesis: bridging the two ortho-amino groups with an electrophilic nitrogen atom. Herein, we disclose a new practical alternative - the endo-cyclization of 2-azidoaryl lithiums obtained in situ from 2-azido-aryl bromides. The scope of the reaction is illustrated using twenty-four examples with a variety of alkyl, alkoxy, perfluoroalkyl, and halogen substituents. We found that the directing effect of the azide group allows selective metal-halogen exchange in aryl azides containing several bromine atoms. Furthermore, (2-bromophenyl)diazomethane undergoes similar cyclization to give an indazole. Thus, cyclizations of aryl lithiums containing an ortho-X = Y = Z group emerge as a new general approach for the synthesis of aromatic heterocycles. DFT computations suggested that the observed endo-selectivity applies to the anionic cyclizations of other functionalities that undergo "1,1-additions" (i.e., azides, diazo compounds, and isonitriles). In contrast, cyclizations with the heteroatomic functionalities that follow the "1,2-addition" pattern (cyanates, thiocyanates, isocyanates, isothiocyanates, and nitriles) prefer the exo-cyclization path. Hence, such reactions expand the current understanding of stereoelectronic factors in anionic cyclizations.

Mixed er-NHC/phosphine Pd(ii) complexes and their catalytic activity in the Buchwald-Hartwig reaction under solvent-free conditions.

A series of novel (NHC)PdCl2-PR3 complexes were synthesized and fully characterized by 1H, 13C, 31P NMR and FT-IR spectroscopy. These complexes showed high catalytic activity toward solvent-free Buchwald-Hartwig amination. Both primary and secondary amines were efficiently utilized under the same reaction conditions. The solvent-free synthesis of valuable N-aryl carbazoles and similar N-heterocyclic systems was described.

Solvent- and transition metal-free amide synthesis from phenyl esters and aryl amines.

A general, economical, and environmentally friendly method of amide synthesis from phenyl esters and aryl amines was developed. This new method has significant advantages compared to previously reported palladium-catalyzed approaches. The reaction is performed transition metal- and solvent-free, using a cheap and environmentally benign base, NaH. This approach enabled us to obtain target amides in high yields with high atom economy.

Evidence for Indirect Action of Ionizing Radiation in 18-Crown-6 Complexes with Halogenous Salts of Strontium: Simulation of Radiation-Induced Transformations in Ionic Liquid/Crown Ether Compositions.

Ionic liquid/crown ether compositions are an attractive alternative to traditional extractants in the processes for spent nuclear fuel and liquid radioactive wastes reprocessing. These compositions are exposed to ionizing radiation, and their radiation stability, especially in the presence of metal salts, is a crucial issue. In the present study, the macrocyclic 18C6·Sr(BF4)2 and 18C6·Sr(PF6)2 complexes simulating the components of metal loaded ionic liquid/crown ether extractants were synthesized and their structures were characterized by FTIR spectroscopy and single-crystal X-ray diffraction analysis. Inclusion of Sr2+ cation into the 18C6 cavity resulted in more symmetric D3d conformations of the macrocycle. The structural transformations of the crown ether were accompanied by an elongation of polyether C-O bonds that could increase the possibility of radiolytic cleavage of the macrocycle. However, EPR study of the synthesized compounds subjected to X-ray irradiation revealed predominant formation of macrocyclic -CH2-CH-O- radicals. This result demonstrated an evidence for indirect action of ionizing radiation on individual components of the complexes and was reasonably described by a positive "hole" transfer from primary macrocyclic radical cation to fluorous anion at the primary stages of radiolysis and a subsequent interaction of fluorine atom with 18C6 macrocycle in secondary radical reactions. The observed effects may be partially responsible for enhanced sensitivity of the ionic liquid/crown ether extractants to ionizing radiation due to chemical blocking of the crown ether with radiolytic HF, radiation-chemical degradation of the 18C6, and precipitation of a low-soluble SrF2.

A general method of Suzuki-Miyaura cross-coupling of 4- and 5-halo-1,2,3-triazoles in water.

A general method of the synthesis of 1,4,5-trisubstituted-1,2,3-triazoles by Suzuki-Miyaura cross-coupling from 4- and 5-halo-1,2,3-triazoles is reported. The reaction is mediated by an expanded-ring N-heterocyclic carbene palladium complex in water. The developed reaction protocol meets the requirements of "green chemistry". Cross-coupling of 4- and 5-chlorotriazoles is reported for the first time.

Eight-membered-ring diaminocarbenes bearing naphthalene moiety in the backbone: DFT studies, synthesis of amidinium salts, generation of free carbene, metal complexes, and solvent-free copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction.

A new type of eight-membered ring N-heterocyclic carbene (NHC) bearing a rigid naphthalene moiety in the backbone is reported for the first time. Stereoelectronic properties of 4,5-dihydro-1H-naphtho[1,8-ef][1,3]diazocin-3(2H)-ylidene (NaphtDHD) and smaller ring NHCs were theoretically studied at the DFT level. Amidinium salts were prepared from corresponding amidines and dibromides. Free carbene NaphtDHD-Dipp (Dipp = 2,6-diisopropylphenyl) was generated in solution by treatment of the corresponding salt with LiHMDS. It is stable in solution at low temperatures, while decomposing rapidly at room temperature. Silver(i) and copper(i) complexes were synthesized and structurally characterized in the solid state. The copper(i) complex [(NaphtDHD-Mes)CuBr] (Mes = mesityl, 2,4,6-trimethylphenyl) exhibits high catalytic activity in alkyne-azide cycloaddition (CuAAC) reaction under solvent-free conditions.