N-Heterocyclic carbene-catalyzed enantioselective synthesis of planar-chiral cyclophanes via dynamic kinetic resolution.

Planar-chiral cyclophanes have gained considerable concerns for drug discovery due to their unique conformational strain and 3D structure. However, the enantioselective synthesis of planar-chiral cyclophanes is a long-standing challenge for the synthetic community. We herein describe an N-heterocyclic carbene (NHC)-catalyzed asymmetric construction of planar-chiral cyclophanes. This transformation occurs through a dynamic kinetic resolution (DKR) process to convert racemic substrates into planar-chiral macrocycle scaffolds in good to high yields with high to excellent enantioselectivities. The ansa chain length and aromatic ring substituent size is crucial to achieve the DKR approach. Controlled experiments and DFT calculations were performed to clarify the DKR process.

N-Heterocyclic Carbene-Catalyzed Highly Enantioselective Macrolactonization to Access Planar-Chiral Macrocycles.

An N-heterocyclic carbene (NHC)-catalyzed atroposelective macrolactonization has been disclosed. This approach affords planar-chiral macrocycles in high yields with excellent enantioselectivities over a broad substrate scope. Controlled experiments suggest that the enantioselectivity might arise from the cation-n interaction between the acyl azolium and the electron-rich moiety in the substrate. This mechanism is supported by density functional theory calculations, which also suggest an important π-π interaction in stabilizing the transition state.

Palladium-Catalyzed Enantioselective C-H Olefination to Access Planar-Chiral Cyclophanes by Dynamic Kinetic Resolution.

Planar-chiral cyclophanes have received increasing attention for drug discovery and catalyst design. However, the catalytically asymmetric synthesis of planar-chiral cyclophanes has been a longstanding challenge. We describe the first Pd(II)-catalyzed enantioselective C-H olefination of prochiral cyclophanes. The low rotational barrier of less hindered benzene ring in the substrates allows the reaction to proceed through a dynamic kinetic resolution. This approach exhibits broad substrate scope, providing the planar-chiral cyclophanes in high yields (up to 99 %) with excellent enantioselectivities (up to >99 % ee). The ansa chain length scope studies reveal that the chirality of the cyclophanes arises from the bond rotation constraint of the benzene ring around the macrocycle plane, rather than the C-N axis. The C-H activation approach is also applicable to the late-stage modification of bioactive molecules and pharmaceuticals.

N-Heterocyclic Carbene-Catalyzed Enantioselective Synthesis of N-Fused Polycyclic Dihydropyrido[1,2-α]-indolones.

An NHC-catalyzed enantioselective annulation reaction of enals with an activated ketone is disclosed. The approach proceeds from a formal [3 + 2] annulation of homoenolate with activated ketone and a subsequent ring expansion of γ-lactone by the nitrogen atom of indole. This strategy features a broad substrate scope, affording the corresponding DHPIs in moderate to good yields and with excellent levels of enantioselectivities. Controlled experiments have been conducted to elucidate a plausible mechanism.

The criterion for dividing the surrounding rock EDZs of underground caverns based on the energy dissipation degree.

An energy calculation parameter named the energy dissipation degree (RUd) is introduced based on the analysis of the energy dissipation mechanism and energy evolution characteristics during conventional triaxial tests of the granite of Shuangjiangkou. The deviatoric stress‒strain curve of rock can be divided into five stages using four stress thresholds (crack closure stress σcc, crack initiation stress σci, damage stress σcd and peak stress σp), which also correspond to the four RUd thresholds (RUdc, RUdi, RUdd and RUdp) on the energy dissipation degree-strain curve. A given stress threshold increases with increasing confining pressure; however, a given RUd threshold is basically stable under different confining pressures. Then, a new criterion for dividing the excavation damaged zones (EDZs) in the rock surrounding underground caverns based on the monotonically increasing characteristics of the energy dissipation degree‒axial strain relationship curve is proposed, and it allows for the classification of the surrounding rock into five types of zones through quantitative analysis of the RUd thresholds. Based on the criterion for dividing the EDZs of the surrounding rock mass of the underground cavern, the EDZs of the surrounding rocks of the underground cavern group of the Shuangjiangkou Hydropower Station are analyzed. The distribution characteristics of the EDZs of the rock surrounding underground caverns obtained by numerical simulation calculations based on RUd are basically the same as those obtained by in situ elastic wave tests. However, the RUd-based method for classifying the EDZs of the surrounding rock has the obvious advantage of being able to probe the boundaries of the undamaged zone (UDZ) of the surrounding rock more explicitly, while the method based on wave velocity testing is not sufficiently explicit. The damage zoning of the surrounding rock based on RUd can provide support design advice for the excavation of the surrounding rock, such as the support method, the length of the free section and anchor section of the prestressing anchor, etc.

A Lewis Acid-Promoted Michael Addition and Ring-Expansion Cascade for the Construction of Nitrogen-Containing Medium-Sized Rings.

A Lewis acid-promoted annulation of azadienes and cyclobutamines was developed. This reaction proceeded through Michael addition and ring-expansion cascade, affording the corresponding nitrogen-containing medium-sized rings with a broad scope in moderate to high yields. The catalytic asymmetric version of this reaction has also been explored using a chiral base.

A Review on Generation and Reactivity of the N-Heterocyclic Carbene-Bound Alkynyl Acyl Azolium Intermediates.

N-heterocyclic carbene (NHC) has been widely used as an organocatalyst for both umpolung and non-umpolung chemistry. Previous works mainly focus on species including Breslow intermediate, azolium enolate intermediate, homoenolate intermediate, alkenyl acyl azolium intermediate, etc. Notably, the NHC-bound alkynyl acyl azolium has emerged as an effective intermediate to access functionalized cyclic molecular skeleton until very recently. In this review, we summarized the generation and reactivity of the NHC-bound alkynyl acyl azolium intermediates, which covers the efforts and advances in the synthesis of achiral and axially chiral cyclic scaffolds via the NHC-bound alkynyl acyl azolium intermediates. In particular, the mechanism related to this intermediate is discussed in detail.

A marine microbiome antifungal targets urgent-threat drug-resistant fungi.

New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug-resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.

A general strategy for diversifying complex natural products to polycyclic scaffolds with medium-sized rings.

The interrogation of complex biological pathways demands diverse small molecule tool compounds, which can often lead to important therapeutics for the treatment of human diseases. Since natural products are the most valuable source for the discovery of therapeutics, the derivatization of natural products has been extensively investigated to generate molecules for biological screenings. However, most previous approaches only modified a limited number of functional groups, which resulted in a limited number of skeleta. Here we show a general strategy for the preparation of a library of complex small molecules by combining state-of-the-art chemistry - the site-selective oxidation of C-H bonds - with reactions that expand rigid, small rings in polycyclic steroids to medium-sized rings. This library occupies a unique chemical space compared to selected diverse reference compounds. The diversification strategy developed herein for steroids can also be expanded to other types of natural products.

Intermolecular Regio- and Stereoselective Hetero-[5+2] Cycloaddition of Oxidopyrylium Ylides and Cyclic Imines.

We have developed the first intermolecular hetero-[5+2] cycloaddition reaction between oxidopyrylium ylides and cyclic imines with excellent control of regio- and stereoselectivity. Surprisingly, divergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide. This new reaction provides quick access to highly substituted nitrogen-containing seven-membered rings-azepanes. Notably, a broad range of oxidopyrylium ylides and cyclic imines participate in this novel hetero-[5+2] cycloaddition reaction and the cycloadducts can be readily transformed into the core skeletons of bioactive natural products. DFT calculations revealed that the cycloaddition proceeds through a stepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition.

Enantioselective [3+3] atroposelective annulation catalyzed by N-heterocyclic carbenes.

Axially chiral molecules are among the most valuable substrates in organic synthesis. They are typically used as chiral ligands or catalysts in asymmetric reactions. Recent progress for the construction of these chiral molecules is mainly focused on the transition-metal-catalyzed transformations. Here, we report the enantioselective NHC-catalyzed (NHC: N-heterocyclic carbenes) atroposelective annulation of cyclic 1,3-diones with ynals. In the presence of NHC precatalyst, base, Lewis acid and oxidant, a catalytic C-C bond formation occurs, providing axially chiral α-pyrone-aryls in moderate to good yields and with high enantioselectivities. Control experiments indicated that alkynyl acyl azoliums, acting as active intermediates, are employed to atroposelectively assemble chiral biaryls and such a methodology may be creatively applied to other useful NHC-catalyzed asymmetric transformations.

Enantioselective Intermolecular Enamide-Aldehyde Cross-Coupling Catalyzed by Chiral N-Heterocyclic Carbenes.

The unprecedented N-heterocyclic carbene (NHC)-catalyzed intermolecular cross-coupling of enamides and aldehydes is described. Upon exposure of enamides to aldehydes in the presence of a NHC catalyst, catalytic C-C bond formation occurs, providing highly enantioselective N-protected amines, bearing a quaternary carbon center, in good yields and with high enantioselectivities.

N-Heterocyclic Carbene Catalyzed Dynamic Kinetic Resolution of Pyranones.

The dynamic kinetic resolution of 6-hydroxypyranones with enals or alkynals through an asymmetric redox esterification is catalyzed by a chiral N-heterocyclic carbene. The resulting esters are obtained in good to high yields and with high levels of enantio- and diastereocontrol. The reaction products are further derivatized to obtain functionalized sugar derivatives and natural products.

Fe-catalyzed direct dithioacetalization of aldehydes with 2-chloro-1,3-dithiane.

Present methods to synthesize 1,3-dithiane molecules require either harsh reaction conditions or highly specialized reagents. We have developed a catalytic dithioacetalization process that directly gains access to the corresponding 1,3-dithianes using aldehydes and 2-chloro-1,3-dithiane in a highly efficient manner. This methodology is beneficial due to mildness of the reaction conditions, and the dithioacetaliation process results in good to excellent yields by using 15 mol % of an iron catalyst.

Bioinspired total synthesis of gymnothelignan N.

Bioinspired total synthesis of gymnothelignan N was accomplished in 13 steps and 6.7% overall yield. The synthesis features a syn Evans aldol reaction, an intramolecular hydrogenative dehydration reaction, and a phenol oxidative dearomatization/Friedel-Crafts reaction, which provides a new plausible biosynthetic pathway for the gymnothelignans and other symbiotic members. Meanwhile, another tetrahydrofuran-type lignan beilschmin A was also synthesized.

Gold-catalyzed 1,2-acyloxy migration/intramolecular [3+2] 1,3-dipolar cycloaddtion cascade reaction: an efficient strategy for syntheses of medium-sized-ring ethers and amines.

A highly efficient strategy for the formation of medium-sized-ring ethers and amines based on a gold-catalyzed cascade reaction, involving enynyl ester isomerization and intramolecular [3+2] cyclization, has been developed. Various multisubstituted medium-sized-ring unsaturated ethers and amines were obtained through this transformation. This method represents one of the relatively few transition metal catalyzed intramolecular cycloaddition reactions for medium-sized ring synthesis.

Diels-Alder/oxidative aromatization approach towards the all-carbon DEF tricyclic skeleton of daphenylline.

Daphenylline is a recently isolated Daphniphyllum alkaloid with an unprecedented novel hexacyclic scaffold. In this study, the synthesis of the fused all-carbon DEF tricyclic skeleton of daphenylline has been accomplished. Key steps of the reported sequence involve Evans asymmetric allylation, aldol condensation, Diels-Alder reaction, and oxidative aromatization reactions. The developed strategy might lead to the total synthesis of daphenylline.

Concise enantioselective synthesis of cephalosporolide†B, (4R)-4-OMe-cephalosporolide†C, and (4S)-4-OMe-cephalosporolide†C.

Ring around the rosie: The effective enantioselective synthesis of the antimalarial nonenolide title compounds was achieved in a convergent strategy. Oxy-Michael addition reaction was used to introduce the chiral methoxy group at C-4, and ring-closing metathesis (RCM) reaction (53 % yield) facilitated the key construction of the 10-membered ring.

Asymmetric total synthesis of fusarentin 6-methyl ether and its biomimetic transformation into fusarentin 6,7-dimethyl ether, 7-O-demethylmonocerin, and (+)-monocerin.

A concise asymmetric total synthesis of a fusarentin ether (1) with sequential biomimetic transformation to its analogues fusarentin 6,7-dimethyl ether (2), 7-O-demethylmonocerin (3), and (+)-monocerin (4) has been accomplished. The cis-fused furobenzopyranones of 7-O-demethylmonocerin (3) and (+)-monocerin (4) were efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of fusarentin 6-methyl ether (1) using hypervalent iodine reagent.

PtCl2-catalyzed tandem enyne cyclization/1,2 ester migration reaction controlled by substituent effects of all-carbon 1,6-enynyl esters.

On the move: A novel PtCl2-catalyzed tandem 1,6-enyne cyclization/1,2-acyloxy migration reaction was developed, which was shown to be controlled by substitution effects. Using this method, a series of substituted enol esters containing the cyclopentenyl motif were prepared in moderate to high yields.