The magic spot nucleotides (MSNs), (p)ppGpp and (p)ppApp, play central roles in bacterial stress signaling, yet their selective detection and chemical accessibility remain limited. This work presents a scalable chemo-enzymatic synthesis of natural and functionalized pentaphosphorylated MSNs based on a cyclic pyrophosphoryl phosphoramidite (cPyPA) mediated phosphorylation and RNase T2-catalyzed hydrolysis. This approach enables preparative access to defined 3 '-monophosphates (ppAp, ppGp) and the pentaphosphorylated products pppApp and pppGpp. In parallel, a metal-ligand disassembly-based fluorescence probe that operates in water was developed for the selective detection of MSNs. Coordination of the alarmone to an Fe(iii)-salen complex induces its demetallation and fluorescence activation through salicylaldehyde release, supported by theoretical and spectroscopic studies. The probe displays a two- to threefold selectivity for (p)ppGpp and (p)ppApp over other nucleotides and responds most strongly to MSNs bearing 3 '- and 5 '-pyrophosphate groups. The probe also detects enzymatically generated ppGpp from Staphylococcus aureus RelP reactions in vitro. This work combines a robust synthesis route for pentaphosphorylated MSNs with a readily accessible fluorescence sensor, thereby laying the foundation for future investigations into bacterial stress signaling.

Propadiene, together with its isomer propyne, accounts for up to 6 mol % of the crude C3 fraction obtained from steam cracking. Despite this abundance, its current industrial use as a welding gas is neither economically or environmentally optimal. Consequently, propadiene deserves greater attention as a versatile building block in chemical synthesis and catalysis. Herein, we report a multicomponent allylation and dienylation of styrene derivatives in which propadiene serves as either an allylic or dienylic precursor under palladium-catalyzed metallaphotoredox conditions. A hydrogen atom transfer (HAT) strategy was employed to generate the initial radical species, with the decatungstate anion (DT) selected as a direct HAT catalyst (d-HAT). Upon light irradiation, DT forms an electrophilic oxygen-centered radical capable of performing regioselective HAT at the most hydridic and sterically accessible C-H sites. Using this approach, 30 distinct C-H units, including alpha-heteroatom C(sp3)-H, unactivated C(sp3)-H, and formyl C(sp2)-H bonds, were selectively activated and functionalized. Moreover, the self-assembling ligand 3-DPICon, developed by our group two decades ago, proved to be the optimal choice for allylic transformations. The practicality of these protocols was demonstrated through diverse downstream derivatizations, and preliminary mechanistic studies were conducted to elucidate the reaction pathway.

Round and round – From 1,3-Enynes to Allenes and beyond. Enynes and pyrazoles are prevalent structural motifs in both natural products and pharmaceuticals. Consequently, methods for the selective functionalization of enynes, as well as the enantioselective incorporation of pyrazoles, are of significant interest. Allylation reactions are very important for target-oriented synthesis since the allyl group provides a versatile platform for all kinds of further transformation. Herein, we report the development of a rhodium-catalyzed allylic addition of pyrazoles to terminal 1,3-enynes, enabled by a rhodium/(R)-Xyl-BINAP catalytic system. The transformation proceeds through a 2-fold catalytic process involving an allene intermediate and delivers the 1,4-diamination products in high yields (up to 94%), with exclusive (Z)-diastereoselectivity and high enantiomeric ratios (up to 99:1 er), and broad functional group tolerance. The present method demonstrates the extension of our group’s established rhodium-catalyzed allylic addition of (pro)nucleophiles to allenes and alkynes towards a twofold allylic functionalization of 1,3-enynes.

We report a high-yielding total synthesis of sesquiterpenoid daphnepapytone A from (S)-glycidol. The groundwork for the synthesis is laid via reductive cleavage of a bicyclic Pauson-Khand-derived cyclopentenone ether, giving efficient access to a trisubstituted chiral cyclopentenone which is difficult to obtain by other means. To introduce the cyclobutane motif, the enone was irradiated in the presence of allene gas, yielding the unwanted exo-cyclobutane at worst and 1:1 mixtures of the endo- and exo-product at best. A serendipitous epimerization of an aldehyde in the following steps converted the unwanted exo-epimer into the endoenantiomer, which significantly improved the final yield. The final cage was connected with a second Pauson-Khand reaction, requiring only one more step to yield the natural product.

The chromatin remodeler CHD1, a regulator of gene activity and potential drug target in prostate cancer (PCa), contains a tandem chromodomain (tCD) binding histone H3 trimethylated at lysine 4 (H3K4me3). We developed the first submicromolar inhibitors (2n and 2s) that target the H3K4me3 binding site of the CHD1 tCD with K d values of 0.15 μM and 0.14 μM, respectively. Co-crystal structures of these quinoline-based compounds revealed aromatic cage interactions and extended ligand contacts in other parts of the H3K4me3 peptide pocket as the main determinants of high-affinity ligand binding. 2n and 2s engage endogenous CHD1 in cell lysates or the exogenous CHD1 tCD in cells. Furthermore, we provide evidence for selectivity against a panel of methyl-lysine readers and epigenetic enzymes as well as impairment of PCa cell viability. Due to their high potency and defined binding mode, our ligands offer new directions for further optimization.

A palladium-catalyzed domino sequence has been unlocked through the advent of a hitherto unreported class of ortho-X-allenyl tethered aryl isocyanides, highly reactive scaffolds that enable streamlined access to fused polycyclic heterocycles, including 2-substituted benzoxazoles, benzothiazoles, and benzimidazoles. The transformation forges two C-X and four C-C bonds in a single sequence and proceeds with broad functional-group tolerance, delivering the products in moderate to good yields. Mechanistic studies support a domino sequence involving allene isomerization, isocyanide insertion, migratory cycloisomerization, and a final [4 + 2] cycloaddition reaction, as validated by control experiments. This work unveils an unprecedented reactivity mode of functionalized isocyanides and provides a concise strategy for assembling densely fused heterocyclic frameworks.

A regio- and enantioselective rhodium/copper-catalyzed coupling of readily available terminal alkynes and allenes is reported. This method enables direct, atom-economic access to chiral 1,4-enynes, a versatile class of compounds widely employed in the synthesis of natural products and pharmaceuticals. The transformation proceeds in high yields with excellent enantioselectivities and displays broad functional-group tolerance. The synthetic utility of the resulting products is further demonstrated through a range of downstream functionalizations that exploit the orthogonal reactivity of the alkyne and alkene moieties.

An intermolecular rhodium-catalyzed regioselective addition of N-hydroxyl imides to internal alkynes leads to branched O-allyl compounds, which can be readily transformed to allylic alcohols and O-allyl hydroxylamines after deprotection. Isotopic labeling experiments suggest a plausible reaction mechanism.

6-(Diphenylphosphino)pyridin-2(1H)-one (6-DPPon) is a unique ligand that can self-assemble in transition metal complexes. This self-assembly is achieved through hydrogen bonding interactions that mimic a bidentate coordination sphere. This enables high selectivity in catalytic transformations while ensuring sufficient flexibility for high catalytic activity. As a consequence, there is considerable interest in preparing derivatives of 6-DPPon and optimizing their synthesis. Herein, we present a comprehensive overview of the preparation methods for self-assembling pyridone-based phosphorus ligands. Nineteen pyridone ligands were prepared using electrophilic and nucleophilic routes, including eleven P-chiral ligands.

Catalytic transformations of feedstock chemicals into value‐added products are a long‐standing challenge. A side product of the steam‐cracking process – propadiene – which is formed in 2.5 x 10 5 t/y ‐ regardless of its potentially rich chemistry ‐ is usually wasted by burning it. To make more economical and sustainable use of valuable carbon atoms from feeds stocks, herein we report a palladium metallaphotoredox dual catalyzed multi‐component allylation and dienylation of styrene derivatives with propadiene as either an allylation or a dienylation reagent. The chemoselectivity for both directions are higher than 20:1 and pronounced functional group tolerance has been elucidated in both cases. Gram scale synthesis and orthogonal reactivities towards thermo allylation demonstrate the practicability of our protocols. Moreover, DFT calculation suggested an outer‐sphere reductive elimination at a Pd I complex to be the most energetically favored route for both directions.

alpha,beta-Unsaturated aldehydes are important structural motifs in organic synthesis and have wide applications in the synthesis of olfactory compounds, agrochemicals, and drugs. While the traditional synthesis of alpha,beta-unsaturated aldehydes requires harsh reaction conditions involving multistep processes, we have developed a unique one-step synthesis utilizing an ene-yne coupling reaction, an efficient process to build the linear carbon chain in an atom-economic way. The traditional reductive ene-yne coupling reaction requires (super)stoichiometric metal, Grignard reagent, borane, or silane as a reductant. The present method describes an alternative route using Hantzsch ester as an organic reductant under Co-Ir dual catalysis. Importantly, the specific choice of the alkene, i.e., vinylene carbonate, was key to obtaining the alpha,beta-unsaturated aldehydes following a reaction sequence of reductive ene-yne coupling, beta-oxygen elimination, decarboxylation, and enol-enal tautomerization. The developed reaction conditions tolerate a wide range of functional groups and display broad substrate scope.

Lysine methyltransferase 9 (KMT9), an obligate heterodimer (KMT9α/KMT9β), belongs to the few described Rossmann-fold histone lysine methyltransferases and monomethylates histone H4 at lysine 12 (H4K12me1). KMT9 depletion or inhibition impairs the proliferation of tumors, including prostate, lung, colon, and bladder cancer cells, underscoring its therapeutic potential. Here, we show the development of branched cofactor analogues with a methionine side chain as highly potent KMT9 inhibitors. Through structure-guided design, a basic nitrogen and 4-chlorophenoxy-2-fluorobenzene in the substrate branch contribute most to the high potency and selectivity. Due to the zwitterionic methionine side chain, the inhibitors did not show cellular activity. Importantly, an ethyl ester prodrug 8 exhibits cellular target engagement and effectively blocks the proliferation of colon cancer cell lines, further validating pharmacological inhibition of KMT9 as a promising strategy for cancer therapy.

A rhodium catalyst modified with a self-assembling pyridone-based phosphine ligand enables a chemoselective hydroformylation of protected propargylic alcohols to furnish either 4-siloxy enals or protected 4-hydroxy aldehydes depending on the reaction conditions.

Inorganic polyphosphate (polyP), a linear biopolymer composed only of orthophosphate units, has emerged as a molecule of critical biological importance across species. While commercially available polyPs are polydisperse mixtures - irrespective of their origin (chemical, biochemical) - recent strategies have focused on the bottom-up synthesis of monodisperse polyPs that have distinct advantages in mechanistic studies. However, until now, syntheses have been limited to defined chains of up to eight phosphate units due to challenges in deprotection-associated degradation and purification. Here, we disclose a new strategy based on two terminal coumarin photocages to synthesize the longest monodisperse polyP chain available to date: polyP10. The photoremovable protecting groups facilitate purification and enable efficient deprotection with light. By tuning the photocage, we achieve control over uncaging wavelengths, integrate targeting modifications and incorporate 18O-labels. This is the first example of a photouncaging strategy in which an 18O-labeled photocage is specifically designed to release an 18O-labeled metabolite for downstream applications. During the uncaging, we observe an unprecedented aromatic substitution reaction from a cleaved coumarin photocage cation onto the second photocage that is still attached to the polyP chain. This suggests a pi-stacking facilitated loop-like arrangement of caged polyP in water that is supported by DFT calculations.

Bacterial degradation of ubiquitous and persistent steroids such as steroid hormones is important for their removal from the environment. Initial studies of steroid degradation in anaerobic bacteria suggested that ring-cleaving hydrolases are involved in oxygen-independent sterane skeleton degradation. However, the enzymes involved in ring A cleavage of the common intermediate androsta-1,4-diene-3,17-dione have remained unknown. Here, we enriched a ring A hydrolase from cholesterol/nitrate grown Sterolibacterium denitrificans and from Escherichia coli after heterologous expression of its gene. This enzyme specifically cleaves the cyclic 1,3-diketone of the central degradation intermediate, androsta-1,3,17-trione to 1,17-dioxo-2,3-seco-androstan-3-oate (DSAO), a hallmark reaction of anaerobic steroid degradation. The highly conserved ring A hydrolase was identified in all known and many previously unknown steroid-degrading proteobacteria. Using enriched enzymes, we enzymatically produced DSAO from the chemically synthesised androsta-1-en-3,17-dione precursor, allowing the identification of subsequent metabolites involved in ring A degradation. The results obtained suggest the involvement of an additional hydrolase, an aldolase, and a β-oxidation-like cascade for complete ring A degradation to form the three-ring 5,10-seco-1,2,3,4-tetranorandrosta-5,17-dione. The results identified a key enzyme of anaerobic steroid degradation that may serve as a functional marker for monitoring steroid contaminant degradation at anoxic environmental sites.

Homoallylic amines can be found in pharmaceutically interesting molecules and are versatile building blocks for total synthesis. Herein, we present a three-component coupling reaction of an aldehyde, an aniline and an allylic carbonate or allene to yield branched homoallylic amines in good yields and diastereoselectivity. Our straightforward protocol proceeds via the addition of an allyl nickel species to an in situ formed imine and represents the first photocatalytic realization of the classic approach of allyl metal addition to imines. Next to some follow-up transformations, a detailed reaction mechanism backed by experimental observations is presented.

The rise of drug resistances in malaria necessitates the exploration of novel therapeutic strategies. Targeting epigenetic pathways could open new, promising treatment avenues. In this study, the focus is on the essential Bromodomain protein 1 (PfBDP1) of the malaria pathogen Plasmodium falciparum. Utilizing the pan-selective bromodomain inhibitor MPM6, a potent initial hit is identified and it is subsequently developed into a nanomolar binder. Through a combination of virtual docking, isothermal titration calorimetry, and X-ray crystallography, the molecular interactions of the new inhibitors with the bromodomain (BRD) of the protein (PfBDP1-BRD) are elucidated. The findings include the first co-crystallized inhibitors with the structures of PfBRD1-BRD as well as the bromodomain of the close homologous protein of Plasmodium vivax (PvBDP1-BRD). The structures provide new insights into their binding mechanisms. Further validation using conditional knockdown of PfBDP1 in P. falciparum demonstrates parasite sensitivity to the inhibitor, underscoring its potential in a targeted therapeutic approach against malaria.

In this study, an enantioselective Rh-catalyzed cycloisomerization of 1,5-bis(allenes) to furnish 1,2-cis-ethynyl- and vinyl-substituted five-membered (hetero)cycles in high yields and with excellent diastereo- and enantioselectivity is presented. The possibility of further functionalization to access different chiral cyclic and bicyclic skeletons is provided by the two orthogonal functional groups (alkyne and alkene). We also demonstrate the scalability of the reaction through a gram-scale synthesis and illustrate the synthetic utility of the resulting 1,2-cis-ethynyl- and vinyl-substituted cyclic product via several transformations. The proposed reaction mechanism is supported by both density functional theory (DFT) calculations and control experiments.

While the vinyl cyclopropane (VCP) scaffold exhibits unique reactivity in chemical transformations, its synthesis presents certain challenges. Herein, we report the visible-light photoredox-catalyzed radical-polar crossover cyclization (RPCC) of terminal and internal allenes with carboxylic acids, realizing the construction of functionalized vinyl cyclopropanes (VCPs) with highly chemo-, and regioselectivities under mild conditions. Moreover, this photoredox protocol exhibits good functional group tolerance, a broad substrate scope, facile scalability and easy rearrangement to give various cyclopentene units.