Biaryl cross-link-containing peptides make up an emerging class of ribosomally synthesized and post-translationally modified peptides (RiPPs). The C-C, C-N, and C-O cross-links in atropopeptides are installed by atropopeptide P450 synthases. In this work, we characterized three unknown atropopeptide P450 synthases (KutB, KutC, and NteB). Functional characterization of KutC and NteB provided the first in vitro analysis of atropopeptide P450 synthases and revealed that NteB generates both bridge-above and bridge-below atropisomers. Furthermore, docking models of KutB, KutC, and NteB, together with mutational analysis, suggested putative substrate recognition residues. This study provides important insights into the biosynthesis of atropopeptides.

Herein, we disclose N-sulfinyl phthalimides as a new class of bench-stable and readily accessible sulfinyl radical precursors for the direct decarboxylative sulfinylation of carboxylic acids to sulfoxides via a dual proton-coupled electron transfer (PCET) process. This method demonstrated a remarkable substrate scope and excellent chemoselectivity across a diverse array of sulfoxide compounds under mild conditions. The synthetic utility and practicability of this robust protocol were further highlighted through gram-scale reactions, product derivatization, and late-stage functionalization of natural products and drugs. Mechanistic studies implicate a sulfinyl radical in the PCET pathway of this transformation. Moreover, a proof of concept for an asymmetric protocol by a merger of acridine photocatalysis and cobalt catalysis was also reported.

Substrate- and site-selective esterification is a powerful synthetic tool to reduce the number of steps required for the synthesis of complex molecules. To address the challenges associated with achieving such selectivity, a variety of strategies have been developed. However, these methods generally require highly reactive acylating reagents. We have developed the first catalytic process for a substrate- and site-selective transesterification using nonactivated esters as acylating reagents. The precisely engineered cavity surrounding the central metal in the sodium- and magnesium-based catalysts enables efficient steric discrimination between competing reaction sites.

The first synthesis of 2'-C-ethynylgalidesivir is reported. Access to this highly congested imino-C-nucleoside required development of a LaCl3·2LiCl-enabled addition of a 9-deazaadenine-derived Grignard reagent to 2'-C-substituted cyclic nitrones. The reaction proceeds with high β selectivity and enables the synthesis of galidesivir, 2'-C-methylgalidesivir, and 2'-C-ethynylgalidesivir. The respective syntheses required 6, 11, and 11 steps from known intermediates and proceeded in 54%, 22% and 17% overall yield. NMR titration and order-of-addition studies suggested that LaCl3·2LiCl perturbs both the nitrone substrate and Grignard speciation. Antiviral evaluation of the ethynyl analogue and its phosphoramidate prodrug revealed only weak activity at high concentration.

Carbonylation reactions typically rely on toxic carbon monoxide gas, often under pressurized conditions. Herein, we report an enantioselective nickel-catalyzed carbonylative difunctionalization of activated olefins using formic acid as a safe and operationally simple CO surrogate under mild conditions. The reaction employs a chiral phosphine-based ferrocene ligand to furnish ester-functionalized oxindoles bearing stereogenic quaternary carbon centers in high yields and enantioselectivities. Isotopic-labeling and XPS studies support in situ CO generation and trapping by an alkyl-nickel intermediate.

Thioimidates exhibit an unusual conformational equilibrium among peptide backbone functional groups, often populating their trans and cis isomers in nearly equal amounts. Despite their growing use as intermediates for peptide backbone editing and macrocyclization, the structural factors governing this equilibrium have not been systematically characterized. Here, we combine NMR spectroscopy and DFT calculations to define the thermodynamics and kinetics of thioimidate isomerization in a series of model peptides. Remarkably, the near-parity trans/cis equilibrium and barrier to interconversion are largely insensitive to the steric bulk and stereochemistry of the amino acids flanking the thioimidate. In contrast, increasing the steric demand at the thioimidate S substituent produces the largest observed shift in the conformational equilibrium. This trend is consistent with the enrichment of the tentatively assigned cis isomer and suggests that the S substituent may provide a means to perturb the equilibrium. Calculations further support an isomerization mechanism involving rehybridization at nitrogen through a linear transition state rather than direct rotation about the formal C═N bond. The resulting sequence independence provides substantial flexibility in the placement of thioimidates within peptides, enabling the broad application of their dynamic conformational behavior in peptide synthesis and macrocyclization.

C-C bond cleavage and reconstruction of carboxylic acids is predominantly directed at the C-C(O) position. Herein, we have successfully developed a TfOH/HFIP cluster-promoted divergent strategy for the C-C bond cleavage of alkynoic acids and their subsequent reconstruction with arenes, affording selective access to distinct molecular architectures through tunable decarboxylation or deketonation. This platform not only facilitates mild decarboxylative functionalization but also establishes an unprecedented deketonative functionalization pathway for carboxylic acids.

Phosphonium salts are valuable intermediates in organic synthesis, but their preparation often requires harsh conditions and specific carbon precursors. Herein, we report a photoinduced decarboxylative phosphoniumation of redox-active esters (RAEs) for the direct synthesis of alkyl and benzyl phosphonium salts. A photoresponsive ternary charge-transfer complex (CTC) formed from NaI, tertiary phosphines, and RAEs enables the reaction under transition-metal- and external-photocatalyst-free conditions. The method tolerates diverse benzyl and aliphatic RAEs and tertiary phosphines, including commercial phosphine ligand frameworks, and enables the late-stage phosphoniumation of complex carboxylic-acid-derived substrates.

Conjugated polyene represents a ubiquitous structural motif found in natural products and pharmaceutical agents. In this study, we demonstrate that γ-substituted allenoates can act as nucleophilic C4 synthon equivalents of dienes under phosphine catalysis, enabling their efficient addition with nitroalkenes to afford β-nitro 1,3-diene derivatives in moderate to good yields. This transformation features a remarkably broad substrate scope and good functional group compatibility, and it can be applied to the late-stage functionalization of complex natural product derivatives. The utility of the resulting β-nitro conjugated dienes is further demonstrated through subsequent transformations, affording a diverse library of conjugated triene compounds. A plausible reaction mechanism along with representative applications are also discussed.

Selective α-C(sp3) sulfonylation of ethers and nitrogen heterocycles provides atom- and step-economical access to aliphatic sulfones, which are prevalent building blocks in pharmaceuticals and fine chemicals. Organic electrosynthesis and iron catalysis represent sustainable synthetic platforms for radical C-S bond formation, yet their combination for aliphatic α-C(sp3) sulfonylation remains underexplored. Herein, an undivided-cell iron-catalyzed electrochemical α-sulfonylation of ethers and N-protected pyrrolidines with sulfonyl chlorides is reported. The method benefits from traceless electrical redox equivalents, a cheap earth-abundant catalyst, and broad functional group compatibility. Gram-scale reactions and product derivatizations demonstrate its synthetic practicability. This electro-driven protocol leverages an anodic Fe(III)/Fe(II) redox shuttle to generate ethers and pyrrolidine derivatives as substrate-derived radical cation intermediates, with sulfonyl radicals originating from direct cathodic reduction of sulfonyl chlorides.

A one-pot stereodivergent strategy for synthesizing E- and Z-vinylated oxindoles has been developed using a Pd-based tandem catalysis and Pd/Ir relay catalysis. The Pd(0)-catalyzed tandem sequence features a cyclization/C(sp3)-H activation/intermolecular Heck coupling to afford the E-isomer in high yields with excellent stereoselectivities. Integration of this transformation with an Ir-based energy-transfer process in a relay-catalytic mode enables access to the geometrically challenging Z-isomer. The broad substrate scope, late-stage functionalization of bioactive molecules, and synthetic derivatization highlight the method's utility.

Cyclopropylated nucleoside derivatives as adenosine receptor ligands were designed and synthesized using an olefin geometry-independent intramolecular SN2' enolate alkylation as a key step. Notably, (Z)-olefin, which has been reported to favor conventional SN2 reactivity over SN2', afforded efficient SN2' cyclopropanation with a markedly improved regioselectivity when calcium bases were employed. Our computational analysis suggests that the calcium cation complex, involving a bulkier cationic species with weaker Lewis acidity, enhances selectivity toward the SN2' pathway. In the regiodivergent TSs leading to SN2 and SN2' reactions, where two activated substrate molecules coordinate to Ca2+, we found that the SN2' pathway was favored energetically.

Fluoindeneacids A and B (5 and 6, respectively), featuring an unprecedented indene core linked to a 2,3-dihydroxybenzoyl moiety, were isolated from the FlsO1-catalyzed reaction of prejadomycin (1). Their structures were established by spectroscopic analysis and ECD calculations. Biochemical and isotopic labeling studies indicate their formation via an enzyme-triggered, nonenzymatic skeletal rearrangement of putative precursor 10. Both compounds exhibited potent in vitro antioxidant activity and cytoprotection against H2O2-induced damage.

A photocatalyst-free synthesis of isobenzofuran-1(3H)-ones from 2-formylbenzamides via photoinduced intramolecular 1,5-hydrogen atom transfer is reported. Irradiation at 365 nm in ethyl acetate afforded 15 products in 66%-99% yields. The products enable formal amide-aldehyde 1,2-transposition, while selected derivatives exhibited DPPH radical-scavenging and intracellular antioxidant activities.

The development of modular and efficient routes to functionalized bicyclo[2.1.1]hexanes (BCHs) is of considerable importance in synthetic and medicinal chemistry. Herein, we disclose a photocatalytic [2π + 2σ] cycloaddition between bicyclo[1.1.0]butanes (BCBs) and N-vinylamides that enables the direct and regioselective construction of 2-aminobicyclo[2.1.1]hexanes (2-aminoBCHs). Biological evaluation revealed that some of the BCH derivatives exhibit potent activity against A549 (lung cancer) and MDA-MB-231 (triple negative breast cancer) cell lines, outperforming their aromatic bioisosteres.