The catalytic asymmetric conjugate additions of alkyl Grignard reagents to cyclic dienones were achieved using an (R)-Sunphos ligand L6. Chiral 2-styryl chromanone and its analogues were produced in high to excellent yields, excellent regioselectivities, and excellent enantioselectivities (82-99% ee's) with a broad substrate scope. This study expands the asymmetric 1,6-conjugate addition of Grignard reagents from linear dienones to more challenging cyclic dienones, and gram-scale reactions further demonstrate the practical applicability of this protocol.

Covering: up to 2025Protoberberine alkaloids (PBs) and tetrahydroprotoberberine alkaloids (THPBs) exhibit diverse pharmacological activities, driving significant interest in their efficient synthesis. This review systematically categorizes recent advances in the total synthesis of these alkaloids based on core-ring-closure strategies. For protoberberines, key methodologies include transition-metal-catalyzed coupling, C-H activation, Mannich/Friedel-Crafts reactions, and tandem cyclizations, enabling the rapid construction of the tetracyclic skeleton. In chiral THPB synthesis, asymmetric strategies, such as chiral auxiliaries, organocatalysis, and transition-metal-catalyzed asymmetric reactions, address the stereochemical challenges at the C14 position. Enzymatic and chemoenzymatic approaches further complement chemical synthesis by enhancing stereocontrol and sustainability. By critically analyzing the efficiency, scope, and limitations of existing strategies, this review highlights innovations in reaction design and underscores the importance of modular, catalytic, and bio-inspired methods for future alkaloid synthesis.

An asymmetric iodoaminocyclization strategy catalyzed by (DHQD)2PHAL has been developed for the synthesis of chiral 2-heteroaryl pyrrolidines, including 2-purinyl and 2-indolyl analogues. This method proceeds under mild conditions and affords the target products in high yields (up to 98%) with excellent diastereoselectivity (trans only) and enantioselectivity (up to 98% ee). The approach provides efficient access to azanucleoside-like scaffolds and demonstrates broad functional group tolerance, highlighting its potential for the synthesis of biologically active pyrrolidine derivatives.

We report an unprecedented amine transaminase-catalyzed asymmetric transamination of 4-alkylidene cyclohexanones, affording various axially chiral alkylidene cyclohexane amines in high conversions (up to 99%) and excellent stereoselectivities (mostly between 96% and 99% ee). The synthetic prospect was underscored further by efficient preparative-scale synthesis (67-83% isolated yields) and downstream product derivatization. Molecular dynamics simulations and related mutational studies were conducted to gain insights into effective catalysis, including the rationale for the superb observed enantioselectivity.

Selective and late-stage modification of the N-terminus of unprotected peptides remains challenging due to competition from lysine ε-amines. Herein, we report a chlorooxime-mediated N-terminal amidination that provides a general and lysine- tolerant platform for peptide engineering. Operating under physiological conditions, this strategy enables efficient late-stage functionalization of complex unprotected peptides and peptide therapeutics and is extended to macrocyclization and protein labeling. We further identify an unexpected amidine-induced, site-specific amide bond cleavage that reveals previously unrecognized reactivity. These findings establish chlorooxime chemistry as a versatile platform for the structural manipulation of bioactive peptides.

CuI/(S,R)-rev-Josiphos-catalyzed asymmetric 1,4-conjugate addition of alkyl Grignard reagents to 2-methyl-substituted chromone derivatives by Lewis acid activation is reported, enabling the construction of a chiral tetrasubstituted carbon center and affording a series of 2-methyl chromanone derivatives with broad substrate scope, excellent regioselectivities, and good to excellent enantioselectivities (75-97% ee). Furthermore, this methodology has been successfully applied to the total synthesis of γ-tocopherol in a 9-step longest linear sequence with an overall yield of 12%.

The structural complexity and potent biological activities of marine natural products continue to attract considerable interest from chemists and biologists due to their unique biochemical mechanisms. In this study, we investigated the protective effects of a marine-sponge derived compound MBL-1 on intestinal inflammation. In vitro assays demonstrated that MBL-1 effectively reduced the production of key pro-inflammatory mediators, including NO, ROS, and cytokines such as IL-1β and IL-18. Mechanistic studies further revealed that these anti-inflammatory effects were mediated through inhibition of the MAPK/NF-κB and NLRP3 signaling pathway. Consistently, in vivo experiments showed that MBL-1 markedly attenuated histological damage and provided strong protection against DSS-induced colitis. Collectively, these findings highlight the potential of MBL-1 as a therapeutic candidate for ulcerative colitis, exerting its anti-inflammatory effects through the systemic modulation of the MAPK/NF-κB and NLRP3 signaling cascade.

A concise asymmetric synthesis of the anti-influenza drug (-)-oseltamivir phosphate ( 1 ) has been accomplished in 9 steps with an overall yield of 24 %, starting from ethyl propiolate. The key features in this synthesis include an efficient biphasic Pd-catalyzed regioselectively intramolecular Heck-type cyclization to provide access to the highly valued chiral six-membered carbocyclic architecture, a regioselective and diastereoselective nitroso hetero-Diels-Alder reaction to construct the bicyclic oxazine 4 as well as a Cu(OTf)2 -mediated regioselective and diastereoselective nucleophilic substitution reaction of bicyclic oxazine 4 with 3-pentanol to yield the trans -1,2-substituted diamino cyclohexyl amyl ether 16 with the correct three contiguous stereocenters. This rapid functionalization of the advanced molecular framework would offer an effective strategy for the asymmetric synthesis of other oseltamivir phosphate analogues. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

To improve the safety and selectivity of etravirine (ETR), cyclization strategy was employed by replacing the pyrimidine ring with a dihydropteridin-6(5H)-one scaffold affording a series of novel bicyclic tetrahydropteridine derivatives. Among them, compound 16a demonstrated exceptional potency against both WT HIV-1 (EC50 = 3 nM) and seven mutant strains (EC50 = 14-77 nM), comparable to ETR. Notably, 16a showed negligible cytotoxicity (CC50 = 196.46 μM) and high selectivity index (SI = 65,789), greatly surpassing ETR (CC50 > 4.6 μM, SI > 1436) and rilpivirine (RPV) (CC50 > 4.0 μM, SI > 3989). Moreover, 16a and its salt forms exhibited remarkably improved aqueous solubility in acid phosphate-buffered saline, compared to ETR and RPV. Additionally, 16a displayed minimal sensitivity to CYP enzymes, no inhibition of the hERG potassium channel, and no detectable acute toxicity at an in vivo dose of 2 g/kg. Collectively, these results highlight 16a as a highly promising on-nucleoside reverse transcriptase inhibitor candidate.

Herein, we present a photocatalytic β-C(sp2)-H alkylation of enamides with easily accessible hydrocarbons under mild conditions. The utilization of aryl thianthrenium salt as a hydrogen-atom transfer (HAT) precursor enables the smooth generation of diverse carbon-centered radicals from chemical feedstocks containing hydridic or protic C-H bonds. Noteworthy features of this protocol encompass high step efficiency, good functional group compatibility, and excellent chemo-, regio-, and stereoselectivity. Mechanistic experiments and density functional theory (DFT) calculations support the involvement of an electron donor-acceptor (EDA) complex.

Non-symmetric stapling of native peptides that crosslinking two distinct residues is a valuable tool for enriching diversity of peptide macrocycles, yet it is less achieved due to the high demand for chemo- and siteselectivity control, as well as the competitive intermolecular peptide crosslinking. Herein, we reported a noncovalent interaction activation strategy for non-symmetric stapling of tyrosine-containing peptides by employing ethenesulfonyl fluoride (ESF) as a bifunctional crosslinker. Once covalently anchored to peptide, the sulfonyl fluoride motif is activated by non-covalent interactions, which triggers an intramolecular SuFEx click reaction with tyrosine to afford peptide macrocycles. This approach efficiently crosslinks diverse residue pairs, including Cys–Tyr, His–Tyr and Pro–Tyr. Notably, the protocol is scalable and can be performed in solid-phase synthesis, providing a robust access to tyrosine-bridged peptide macrocycles with excellent diversity.

Considering the exceptional anti-HIV-1 potency of rilpivirine (RPV) against diverse mutant strains and its remarkable human ether-a-go-go related gene (hERG) potassium channel inhibition (IC50 = 0.50 μmol/L) as well as low selectivity (SI = 3989), a series of novel furo-[3,2-d]pyrimidine derivatives were rationally designed through a scaffold hopping strategy. Encouragingly, compound 10 revealed a striking reduction in hERG channel inhibition (IC50 > 30 μmol/L) and significant increase in selectivity (SI = 161580). Notably, 10 exhibited excellent antiviral activity against various HIV-1 strains (EC50 = 1.9−46.3 nmol/L). In particular, 10 displayed prominent inhibitory potency against Y188L (EC50 = 15.5 nmol/L) and F227L+V106A strain (EC50 = 8.7 nmol/L), which was superior to those of RPV (EC50 (Y188L) = 79.4 nmol/L, EC50 (F227L+V106A) = 81.6 nmol/L). Besides, no apparent cytotoxicity (CC50 = 314.8 μmol/L) and negligible suppression of CYP isoenzymes were detected. Overall, these findings illustrated that 10 was a potentially promising NNRTI for HIV-1 therapy.

The allylic phosphonates are unique reagents for the preparation of dienes and polyenes. Hitherto, there is still no method for the stereodivergent synthesis of allylic phosphonates. In this article, a transition-metal-free method has been developed under mild conditions for the stereodivergent synthesis of allylic phosphonates from readily available dialkyl phosphites, vinyltriphenylphosphonium chloride, and aldehydes. An array of cis- and trans-allylic phosphonates is produced on demand with good to excellent stereoselectivities and yields.

The design of suitable polymorphic thermally activated delayed fluorescence (TADF) emitters is crucial for advancing multifunctional organic luminescent materials. Herein, a unique multifunctional molecule, the benzoimido-benzamide derivative DMAC-PYZ, was synthesized through a green photo-oxidation reaction. This compound exhibited polymorphism (DG and DY), TADF, mechanochromic luminescence (MCL), and aggregation-induced emission (AIE) properties. The DG and DY crystals displayed green and yellow fluorescence, respectively, with delayed fluorescence lifetimes of 65.76 mu s (DG) and 0.29 mu s (DY). Furthermore, it demonstrated an aggregation-dependent TADF characteristic and MCL behavior in response to mechanical stimuli. Crystal structure and density functional theory (DFT) analysis revealed that the aggregation-dependent TADF originated from variations in the D-A molecular twist angle across different aggregation states. Upon thermal stimulation at 60 degrees C, amorphous powders of DG and DY reversibly revert to their original crystalline packing structures and emission. These characteristics stemmed from the high stability of crystalline enantiomers. This rare reversible polymorph-toamorphous phase transition has been successfully applied to information security and encryption. This study presented a novel MCL-active TADF material capable of reversible polymorph-to-amorphous phase transition, elucidating the conformation-property relationship in aggregated states.

A general and efficient strategy was developed for the cross-coupling of enamides with sulfoxonium ylides under sustainable and environmentally benign conditions, enabling the modular assembly of unsymmetric 1,4-diketones.

Gas-forming gas–liquid systems are common in pharmaceutical, chemical, and energy processes. Microchannel reactors offer an effective platform for intensifying such multiphase systems. In this study, bubble growth dynamics in viscous Newtonian (glycerol) and non-Newtonian (xanthan gum) fluids within a rectangular microchannel were investigated experimentally and theoretically. Carbon dioxide bubbles were generated via the reaction of sulfuric acid with sodium bicarbonate. A high-speed camera was used to observe bubble evolution. Results showed that increasing concentrations of either glycerol or xanthan gum reduced bubble growth rates, whereas total flow rate had a negligible effect. A theoretical model was developed to describe bubble growth with chemical reactions in both fluid types, and its predictions agreed remarkably well with experimental data. The insights obtained can be helpful for the design and optimization of gas–liquid microchannel reactors for relevant applications.

delta-Trifluoromethyl-delta-hydroxyketones are challenging to construct from simple starting materials. A highly efficient, concise hydroxyalkylation has been successfully achieved, in which the cyclopropanols and alpha-(trifluoromethyl)alkenes can be utilized for construction of valuable delta-trifluoromethyl-delta-hydroxyketone scaffolds in an economic and green manner. The reaction proceeded efficiently under mild, additive-free reaction conditions using ambient air as a benign oxidant, aligning with green chemistry principles such as atom economy, step economy and waste minimization. This transformation without competitive beta-fluoride elimination, exhibits a broad substrate scope, excellent functional group compatibility, and scalability, demonstrating significant potential for practical applications. The recyclability of the catalytic system further underscores the sustainability of this transformation.

N-Glycosides widely exist in nature and have very important biological activities. Although the traditional ionic N-glycosylation strategy has many advances, the challenges remain, including water sensitivity, stoichiometric/excess promoters, precious metal catalysts, and unsatisfactory efficiency. Herein, we describe a copper-catalyzed radical N-glycosylation method using ortho-(1-acyloxyimino)ethylphenyl thioglycoside donors. This N-glycosylation protocol features photocatalyst-free, oxidant-free, mild and practical conditions, high stereoselectivity, broad substrate scope, and earth-abundant metal copper catalysis, and is applicable to the late-stage modification and synthesis of marketed drugs and natural products.

Transition metal-catalyzed cycloisomerization of 1,6-enynes is a highly effective approach to generating five-membered rings. Among the various catalytic systems developed, the use of chiral ligands in Rh-catalyzed cycloisomerization induced exceptional reactivity and enantioselectivity. In this study, we describe a novel approach to obtained kinds of five-membered rings via Rh-catalyzed cycloisomerization of N-aryl 1,6-enynes, employing a novel spirosilane diphosphine ligand with a significantly enhanced enantioselectivity. Mechanistic experiments and DFT calculations have provided insights into the reaction mechanism.