Organic & Biomolecular Chemistry最新文献

While thioamides are widely utilized as nucleophilic or ambiphilic synthons to construct heterocycles, strategies harnessing their inherent electrophilic reactivity to form carbon-heteroatom bonds through desulfurization with intact amino groups reserved for downstream cyclization are scarcely documented. Herein, we report a metal-free I₂-DMSO-mediated tandem cyclization protocol that exploits the underexplored electrophilic nature of thioamides for facile one-pot assembly of trifunctionalized pyrido[1,2-b]indazoles. Moreover, further derivatization of these products furnishes 1-imino-3-phenyl-1H,3H-furo[3',4':4,5]pyrimido[1,2-b]indazol-11-amine, an unprecedented fused polycyclic scaffold.

N-Methyl-2-pyrrolidone hydroperoxide (NMP-HP) is an underrated oxidant for organic synthesis. We present its application to the synthesis of oxiranes via tandem epoxidation/ring cleavage of 3,4-diarylfuran-2,5-diones. The reaction occurs in NMP in the presence of potassium carbonate and air. This process effectively competes with the formation of potassium diarylmaleates and most likely begins with the previously unreported epoxidation of a disubstituted furan-2,5-dione.

Manganese, the 12^th most abundant element in Earth's crust, offers unprecedented opportunities to produce valuable products from simple hydrocarbon scaffolds via C-H bond transformations. Owing to its rich redox chemistry, low toxicity, and natural abundance, manganese has emerged as a versatile tool for derivatizing sp³ C-H bonds, particularly unactivated ones. Its outstanding tunability and ability to generate high-valent, redox-active intermediates have enabled direct modification and activation of a remote sp³ C-H bond. Decades of studies show that manganese has been used to convert unactivated sp³ C-H bonds into vital C-Z bonds. These protocols demonstrate that manganese, combined with selective oxidants and additives, provides powerful synthetic utility for the functionalization of distant, unactivated sp³ C-H bonds into desired C-Z bonds. This review offers a thorough summary of current developments and limitations in manganese-catalyzed functionalization of unactivated sp³ C-H bonds, reported in the past seven years (2020-2026).

Cephanolide B (5) is a benzenoid cephalotane-type 14,17-dinorditerpenoid, isolated from Cephalotaxus sinensis, featuring a densely functionalized 6/6/5/6/6 pentacyclic framework with a bridged δ-lactone moiety. Herein, we report a concise and efficient total synthesis of (±)-cephanolide B (5) as well as the formal syntheses of (±)-cephanolide C (6) and (±)-cephinoid H (3). This synthesis features the stereoselective construction of the complex pentacyclic framework through key α-alkylation, Stork-Danheiser-type transposition and Pd-catalyzed cascade carbonylative Heck cyclization reactions.

The allyl group is a ubiquitous structural motif found in numerous natural products and bioactive molecules. It can also serve as a highly reactive and versatile building block for the preparation of pharmaceuticals and functional materials in organic chemistry. Currently, the introduction of allyl groups mainly relies on chemical methods that require transition metals, especially precious ones. Although biocatalytic allylation using allylated S-adenosyl-L-methionine (SAM) as the allyl donor provides a promising, sustainable route to allylated compounds, the current access to allylated SAM is still not sufficiently efficient for further preparative-scale applications. In this study, we successfully engineered an Arabidopsis thaliana halide methyltransferase mutant named AtHMT A144G for the efficient synthesis of allylated SAM. Experimental results showed that the A144G variant (∼2.6 × 10^-5 s^-1 μM^-1) exhibited an ∼44-fold higher catalytic efficiency (k_cat/K_M) relative to the previously reported V140T mutant (∼5.9 × 10^-7 s^-1 μM^-1, newly measured in our study). In addition, the mutation did not alter the stereoselectivity of the enzyme, which still exclusively afforded the reactive (S)-diastereoisomer. To fully exploit the superior catalytic performance of A144G, we systematically optimized the reaction conditions, including the buffer system (KPi buffer), pH (7.5), and temperature (30 °C). With the optimal reaction conditions in hand, the feasibility of using AtHMT A144G as a catalyst to efficiently supply allylated SAM was validated in a cascade reaction with C/N/O-methyltransferases (e.g., NovO, COMT, and NMT) for allyl transfer. Furthermore, the desired allylated products were successfully obtained, confirming the practicality of A144G as an allyl donor platform for diverse downstream allyl transfer reactions.

Herein, we report a potassium persulfate (K₂S₂O₈) promoted methodology for the selective N-methoxymethylation of benzamides. Utilizing methanol as both the solvent and a sustainable C1 source, the developed protocol exhibits broad functional group tolerance with good to excellent yields. The deuterium-labelling experiment and reported literature suggest a radical-mediated pathway, offering a green, operationally simple approach for the synthesis of N-methoxymethylated benzamides.

We report a visible-light photoredox-catalyzed acylative oximation of electron-deficient alkenes using tert-butyl nitrite and α-oxocarboxylic acids, providing direct access to β-keto oxime derivatives under mild conditions. The protocol combines tert-butyl nitrite as an NO donorwith acyl radicals generated through photoredox-mediated decarboxylation of α-oxocarboxylic acids. Vinyl sulfones and several other activated alkenes undergo the transforamtion to afford the corresponding products in moderate yields. Preliminary mechanistic studies support the involvement of acyl radical intermediates. The transformation can also be implemented under continuous photoflow conditions, demonstrating the operational adaptability of the protocol.

Modern oligonucleotide based therapeutics rely on chemical modification to achieve the desired potency, stability and safety for therapeutic applications. In this study, we investigated the biophysical characteristics and potency of the 3',4'-cyclopropyl (Cp) uridine monomer and its 5'-vinyl phosphonate (VP) and ethyl phosphonate (EP) analogues. We incorporated these modifications into 9-mer strands, antisense oligonucleotides (ASOs), and small interfering RNAs (siRNAs) to identify position-dependent trends. Incorporation of these specific chemical modifications into 9-mer oligonucleotides resulted in a narrow range of thermal effects, from marginal stabilization to mild destabilization per modification. These modifications, when incorporated into ASOs, resulted in significant destabilizing effects, particularly when placed in the wings of the gapmer and as the number of modifications increased. However, these modifications caused relatively less destabilization in siRNAs compared to ASOs. Parallel in vitro assessments revealed that Cp modifications slightly improved the potency of ASO constructs but yielded no increase for siRNA molecules. In vitro snake venom phosphodiesterase (SVPD) assays demonstrated that Cp-modified ASOs exhibit significantly enhanced nuclease resistance over the unmodified parent sequence, sometimes providing near-complete protection. This differential effect on stability and potency across the different oligonucleotide lengths and modalities warrants further investigation to fully delineate the mechanism of action of these modifications and to further optimize their application in therapeutic oligonucleotide design. Here, based on these results, we propose Cp monomers as a novel class of molecules for oligonucleotide therapeutic applications.

Gymnothelignan L is a representative dibenzocyclooctene-type member of a large class of novel gymnothelignan natural products. We have previously achieved its first total synthesis by developing a bioinspired Friedel-Crafts cyclization approach. Herein, we report a second-generation synthesis to serve as an alternative synthetic route to gymnothelignan L through intramolecular dehydration and Friedel-Crafts cyclization from a linear gymnothelignan precursor with a C9 alcohol and a C6 aldehyde.

A one-pot, air-promoted base-catalyzed rearrangement of triterpenic indoles forming spiro- and quinolone-containing compounds, and, most notably, an unexpected C1(2)-epoxy-indolenine derivative, has been discovered. The structure of the obtained molecules was established using NMR spectroscopy, including two-dimensional correlation experiments, which also proved the β-orientation of the epoxy unit. Also, a significant influence of the presence of atmospheric oxygen on the regioselectivity of base-mediated alkylation of indolo-triterpenes was demonstrated, resulting in N-alkylation (under inert conditions) and a preference for C2-substituted indolenine formation (C-alkylation). For compounds containing spirooxindole and quinolone fragments, X-ray structural analysis data have been obtained. This protocol is attractive for synthesizing potential biologically active indole derivatives because it is simple and does not require transition metals and strong oxidants.