Mapping Electrophile Chemoselectivity in DalPhos/Nickel N-Arylation Catalysis: The Unusual Influence of Remote Sterics.

We disclose herein our evaluation of competitive (hetero)aryl-X (X: Br > Cl > OTf) reactivity preferences in bisphosphine/Ni-catalyzed C-N cross-coupling catalysis, using furfurylamine as a prototypical nucleophile, and employing DalPhos and DPPF as representative ancillary ligands with established efficacy. Beyond this general (pseudo)halide ranking, other intriguing structure-reactivity trends were noted experimentally, including the unexpected observation that bulky alkyl (e.g., R = tBu) substitution in para-R-aryl-X electrophiles strongly discourages (pseudo)halide reactivity relative to smaller substituents (e.g., nBu, Et, Me), despite being both remote from, and having a similar electronic influence on, the reacting C-X bond; such effects on nickel oxidative addition have not been documented previously and were not observed in our comparator reactions presented herein involving palladium. Density functional theory modeling of such PhPAd-DalPhos/Ni-catalyzed C-N cross-couplings revealed the origins of competitive turnover of C-Br over C-Cl, and possible ways in which bulky para-alkyl substitution might discourage net electrophile uptake/turnover, leading to inversion of halide selectivity.

Stable and Versatile Pd Precursors for the Preparation of Robust Pd Catalysts under Continuous-Flow.

The chemical and engineering communities require the development of versatile precursors that can be used to synthesize robust catalysts to achieve global sustainability. To meet this demand, we developed a new Pd precursor for incorporating fine Pd metal into supports in a highly efficient manner. An atmospherically stable Pd precursor (Pd-80) was prepared by the thermally promoted aerobic oxidation of tetrakis(triphenylphosphine)palladium. The physical properties of Pd-80 were investigated using NMR spectroscopy, SEM, XPS, solvent-relaxation NMR spectroscopy, and dynamic light scattering (DLS) experiments. We also prepared a cordierite-supported Pd catalyst (Pd/cordierite) by stirring Pd-80 and cordierite powder in chloroform at room temperature. Pd/cordierite selectively catalyzes the hydrogenation of various reducible functional groups, including alkynes, azides, nitro groups, olefins, CO2Bn, N-Cbz, O-Bn, aromatic ketones, and styrene oxide, in continuous-flow hydrogenation reactions. The Pd/cordierite-catalyzed continuous-flow hydrogenation of nitrobenzene derivatives afforded the corresponding anilines, with catalyst activity maintained for over 250 h of continuous operation and a turnover number (TON) of 61,090 recorded.

Ursolic acid-based 24-nor- and A-seco-24-oxy-triterpenoids.

Using methyl 2-cyano-3,4-seco-12(13),4(23)-diene-ursolate as a starting scaffold a series of 3-oxo-24-nor-ursolate and A-seco-ursanes holding hydroxy-, furoyloxy-, p-tosyloxy- as well as aldehyde fragments at C24 that possess cytotoxic activity has been synthesised. The structures of the new ursanes were confirmed by detailed spectral data analysis. The chemoselectivity of methyl 2-cyano-3,4-seco-12(13),4(23)-diene-ursolate oxidation involving the double bond in the A cycle was observed.

Modular and Diverse Synthesis of Acrylamides by Palladium-Catalyzed Hydroaminocarbonylation of Acetylene.

The development of all kinds of covalent drugs had a major impact on the improvement of the human health system. Covalent binding to target proteins is achieved by so-called electrophilic warheads, which are incorporated in the respective drug molecule. In the last decade, specifically acrylamides emerged as attractive warheads in covalent drug design. Herein, a straightforward palladium-catalyzed hydroaminocarbonylation of acetylene has been developed, allowing a modular and diverse synthesis of bio-active acrylamides. This general protocol features high atom efficiency, wide functional group compatibility, high chemoselectivity and proceeds additive free under mild reaction conditions. The synthetic utility of this protocol is showcased in the synthesis of ibrutinib, osimertinib, and other bio-active compound derivatives.

Chemoselectivity Switch between Enantioselective [2,3]-Wittig Rearrangement and Conia-Ene-Type Reactions of Propargyloxyoxindoles.

Despite the existence of three competing reactions for propargyloxyoxindoles, we report a chemoselectivity switch between enantioselective propargyl [2,3]-Wittig rearrangement and Conia-ene-type reactions, with suppression of the [1,2]-Wittig-type rearrangement. Using C1-symmetric imidazolidine-pyrroloimidazolone pyridine as the ligand and Ni(acac)2 as the Lewis acid, diverse 3-hydroxy 3-substituted oxindoles containing allenyl groups were obtained in up to 98 % yield and 99 % ee via asymmetric propargyl [2,3]-Wittig rearrangement. In the presence of AgOTf-Duanphos, chiral spiro dihydrofuran oxindoles were given in up to 98 % yield and 91 % ee through a Conia-ene-type reaction.

Regioselective Deacetylation in Nucleosides and Derivatives.

Nucleoside analogues are a promising class of natural compounds in the pharmaceutical industry, and many antiviral, antibacterial and anticancer drugs have been created through structural modification of nucleosides scaffold. Acyl protecting groups, especially the acetyl group, play an important role in the protection of hydroxy groups in nucleoside synthesis and modification; consequently, numerous methodologies have been put forth for the acetylation of free nucleosides. However, for nucleosides that contain different O- and N-based functionalities, selective deprotection of the acetyl group(s) in nucleosides has been studied little, despite its practical significance in simplifying the preparation of partially or differentially substituted nucleoside intermediates. In this mini-review, recent approaches for regioselective deacetylation in acetylated nucleosides and their analogues are summarized and evaluated. Different regioselectivities (primary ester, secondary ester, full de-O-acetylation, and de-N-acetylation) are summarized and discussed in each section.

C-S-Selective Stille-Coupling Enables Stereodefined Alkene Synthesis.

A palladium-catalyzed highly C‒S-selective Stille cross-coupling between aryl thianthrenium salts and tri- or tetrasubstituted alkenyl stannanes is described. Herein, critical challenges including site- and chemoselectivity control are well addressed through C‒H thianthrenation and C‒S alkenylation, thereby providing an expedient access to stereodefined tri- and tetrasubstituted alkenes in a stereoretentive fashion. Indeed, the palladium-catalyzed Stille-alkenylation of poly(pseudo)halogenated arenes displays privileged capability to differentiate C‒S over C‒I, C‒Br, C‒Cl bonds, as well as oxygen-based triflates (C‒OTf), tosylates (C‒OTs), carbamates and sulfamates under mild reaction conditions. Sequential and multiple cross-couplings via selective C‒X functionalization should be widely applicable for increasing functional molecular complexity. Modular installation of stereospecific alkene motifs into pharmaceuticals illustrated the synthetic application of the present protocol in drug discovery.

Allenamides as a Powerful Tool to Incorporate Diversity: Thia-Michael Lipidation of Semisynthetic Peptides and Access to ß-Keto Amides.

Lipopeptides are an important class of biomolecules for drug development. Compared with conventional acylation, a chemoselective lipidation strategy offers a more efficient strategy for late-stage structural derivatisation of a peptide scaffold. It provides access to chemically diverse compounds possessing intriguing and non-native moieties. Utilising an allenamide, we report the first semisynthesis of antimicrobial lipopeptides leveraging a highly efficient thia-Michael addition of chemically diverse lipophilic thiols. Using chemoenzymatically prepared polymyxin B nonapeptide (PMBN) as a model scaffold, an optimised allenamide-mediated thia-Michael addition effected rapid and near quantitative lipidation, affording vinyl sulfide-linked lipopeptide derivatives. Harnessing the utility of this new methodology, 22 lipophilic thiols of unprecedented chemical diversity were introduced to the PMBN framework. These included alkyl thiols, substituted aromatic thiols, heterocyclic thiols and those bearing additional functional groups (e.g., amines), ultimately yielding analogues with potent Gram-negative antimicrobial activity and substantially attenuated nephrotoxicity. Furthermore, we report facile routes to transform the allenamide into a ß-keto amide on unprotected peptides, offering a powerful "jack-of-all-trades" synthetic intermediate to enable further peptide modification.

Proton-triggered chemoselective halogenation of aliphatic C-H bonds with nonheme FeIV-oxo complexes.

Halogenation of aliphatic C-H bonds is a chemical transformation performed in nature by mononuclear nonheme iron dependent halogenases. The mechanism involves the formation of an iron(IV)-oxo-chloride species that abstracts the hydrogen atom from the reactive C-H bond to form a carbon-centered radical that selectively reacts with the bound chloride ligand, a process commonly referred to as halide rebound. The factors that determine the halide rebound, as opposed to the reaction with the incipient hydroxide ligand, are not clearly understood and examples of well-defined iron(IV)-oxo-halide compounds competent in C-H halogenation are scarce. In this work we have studied the reactivity of three well-defined iron(IV)-oxo complexes containing variants of the tetradentate 1-(2-pyridylmethyl)-1,4,7-triazacyclononane ligand (Pytacn). Interestingly, these compounds exhibit a change in their chemoselectivity towards the functionalization of C-H bonds under certain conditions: their reaction towards C-H bonds in the presence of a halide anionleads to exclusive oxygenation, while the addition of a superacid results in halogenation. Almost quantitative halogenation of ethylbenzene is observed when using the two systems with more sterically congested ligands and even the chlorination of strong C-H bonds such as those of cyclohexane is performed when a methyl group is present in the sixth position of the pyridine ring of the ligand. Mechanistic studies suggest that both reactions, oxygenation and halogenation, proceed through a common rate determining hydrogen atom transfer step and the presence of the acid dictates the fate of the resulting alkyl radical towards preferential halogenation over oxygenation.

Asymmetric and Chemoselective Iridium Catalyzed Hydrogenation of Conjugated Unsaturated Oxime Ethers.

Research on the chemoselective metal-catalyzed hydrogenation of conjugated π-systems has mostly been focussed on enones. Herein, we communicate the understudied asymmetric hydrogenation of enimines catalyzed by N,P-iridium complexes and chemoselective toward the alkene. A number of enoxime ethers underwent hydrogenation smoothly to yield the desired products in high yield and stereopurity (up to 99 % yield, up to 99 % ee). No hydrogenation of the C=N π-bond was observed under the applied reaction conditions (20 bar H2, rt, DCM). It was demonstrated that the chiral oxime ether could be hydrolyzed into the ketone with complete preservation of the installed stereogenity at the α-carbon. At last, a binding mode of the substrate to the active iridium catalyst and the consequence for the stereoselective outcome was proposed.

Product Distribution of Steady-State and Pulsed Electrochemical Regeneration of 1,4-NADH and Integration with Enzymatic Reaction.

The direct electrochemical reduction of nicotinamide adenine dinucleotide (NAD+) results in various products, complicating the regeneration of the crucial 1,4-NADH cofactor for enzymatic reactions. Previous research primarily focused on steady-state polarization to examine potential impacts on product selectivity. However, this study explores the influence of dynamic conditions on the selectivity of NAD+ reduction products by comparing two dynamic profiles with steady-state conditions. Our findings reveal that the main products, including 1,4-NADH, several dimers, and ADP-ribose, remained consistent across all conditions. A minor by-product, 1,6-NADH, was also identified. The product distribution varied depending on the experimental conditions (steady state vs. dynamic) and the concentration of NAD+, with higher concentrations and overpotentials promoting dimerization. The optimal yield of 1,4-NADH was achieved under steady-state conditions with low overpotential and NAD+ concentrations. While dynamic conditions enhanced the 1,4-NADH yield at shorter reaction times, they also resulted in a significant amount of unidentified products. Furthermore, this study assessed the potential of using pulsed electrochemical regeneration of 1,4-NADH with enoate reductase (XenB) for cyclohexenone reduction.

Diastereoselective Three-Component 1,3-Dipolar Cycloaddition to Access Functionalized ß-Tetrahydrocarboline- and Tetrahydroisoquinoline-Fused Spirooxindoles.

A chemselective catalyst-free three-component 1,3-dipolar cycloaddition has been described. The unique polycyclic THPI and THIQs were creatively employed as dipolarophiles, which led to the formation of functionalized ß-tetrahydrocarboline- and tetrahydroisoquinoline-fused spirooxindoles in 60-94% of yields with excellent diastereoselectivities (10: 1->99: 1 dr). This reaction not only realizes a concise THPI- or THIQs-based 1,3-dipolar cycloaddition, but also provides a practical strategy for the construction of two distinctive spirooxindole skeletons.

Molecular Basis for Chemoselectivity Control in Oxidations of Internal Aryl-Alkenes Catalyzed by Laboratory Evolved P450s.

P450 enzymes naturally perform selective hydroxylations and epoxidations of unfunctionalized hydrocarbon substrates, among other reactions. The adaptation of P450 enzymes to a particular oxidative reaction involving alkenes is of great interest for the design of new synthetically useful biocatalysts. However, the mechanism that these enzymes utilize to precisely modulate the chemoselectivity and distinguishing between competing alkene double bond epoxidations and allylic C-H hydroxylations is sometimes not clear, which hampers the rational design of specific biocatalysts. In a previous work, a P450 from Labrenzia aggregata (P450LA1) was engineered in the laboratory using directed evolution to catalyze the direct oxidation of trans-ß-methylstyrene to phenylacetone. The final variant, KS, was able to overcome the intrinsic preference for alkene epoxidation to directly generate a ketone product via the formation of a highly reactive carbocation intermediate. Here, additional library screening along this evolutionary lineage permitted to serendipitously detect a mutation that overcomes epoxidation and carbonyl formation by exhibiting a large selectivity of 94 % towards allylic C-H hydroxylation. A multiscalar computational methodology was applied to reveal the molecular basis towards this hydroxylation preference. Enzyme modelling suggests that introduction of a bulky substitution dramatically changes the accessible conformations of the substrate in the active site, thus modifying the enzymatic selectivity towards terminal hydroxylation and avoiding the competing epoxidation pathway, which is sterically hindered.

Understanding the behavior of phenylurazole-tyrosine-click electrochemical reaction using hybrid electroanalytical techniques.

In this work, the electrochemical behavior of 4-phenylurazole (Ph-Ur) was studied and the latter was used as a molecular anchor for the electrochemical bioconjugation of tyrosine (Y). Cyclic voltammetry (CV) and controlled potential coulometry (CPC) allowed the in-situ generation of the PTAD (4-phenyl-3 H-1,2,4-triazole-3,5(4 H)-dione) species from phenylurazole on demand for tyrosine electrolabeling. The chemoselectivity of the reaction was studied with another amino acid (lysine, Lys) and no changes in Lys were observed. To evaluate the performance of tyrosine electrolabeling, coulometric analyses at controlled potentials were performed on solutions of phenylurazole and the phenylurazole-tyrosine mixture in different proportions (2:1, 1:1, and 1:2). The electrolysis of the phenylurazole-tyrosine mixture in the ratio (1:2) produced a charge of 2.07 C, very close to the theoretical value (1.93 C), with high reaction kinetics, a result obtained here for the first time. The products obtained were identified and characterized by liquid chromatography coupled to high-resolution electrospray ionization mass spectrometry (LC-HRMS and LC- HRMS2). Two products were formed from the click reactions, one of which was the majority. Another part of this work was to study the electrochemical degradation of the molecular anchor 4-phenylazole (Ph-Ur). Four stable degradation products of phenylurazole were identified (C7H9N2O, C6H8N, C6H8NO, C14H13N4O2) based on chromatographic profiles and mass spectrometry results. The charge generated during the electrolysis of phenylurazole (two-electron process) (2.85 C) is inconsistent with the theoretical or calculated charge (1.93 C), indicating that secondary/parasitic reactions occurred during the electrolysis of the latter. In conclusion, the electrochemically promoted click phenylurazole-tyrosine reactions give rise to click products with high reaction kinetics and yields in the (1:2) phenylurazole-tyrosine ratios, and the presence of side reactions is likely to affect the yield of the click phenylurazole-tyrosine reaction.

Systematic Studies of Functional Group Tolerance and Chemoselectivity in Carbene-Mediated Intramolecular Cyclopropanation and Intermolecular C-H Functionalization.

Generating reliable data on functional group compatibility and chemoselectivity is essential for evaluating the practicality of chemical reactions and predicting retrosynthetic routes. In this context, we performed systematic studies using a functional group evaluation kit including 26 kinds of additives to assess the functional group tolerance of carbene-mediated reactions. Our findings revealed that some intermolecular heteroatom-hydrogen insertion reactions proceed faster than intramolecular cyclopropanation reactions. Lewis basic functionalities inhibited rhodium-catalyzed C-H functionalization of indoles. While performing these studies, we observed an unexpected C-H functionalization of a 1-naphthol variant used as an additive.

Mechanistic Studies on Rhodium-Catalyzed Chemoselective Cycloaddition of Ene-Vinylidenecyclopropanes: Water-Assisted Proton Transfer.

Rhodium-catalyzed cycloaddition reactions are a powerful tool for the construction of polycyclic compounds. Combined experimental and DFT studies were used to investigate the temperature-controlled chemoselectivity of cationic rhodium-catalyzed intramolecular cycloaddition reactions of ene-vinylidenecyclopropanes. After a series of mechanistic studies, it was found that trace amounts of water in the reaction system play an important role in generating the product with endo double bond located on a five-membered ring and revealed that trace amounts of water in the reaction system, including the rhodium catalyst, substrate and solvent, were sufficient to promote the formation of the product with endo double bond located on a five-membered ring, and additional water could not further accelerate the reaction. DFT calculation results show that the addition of water indeed significantly lowers the energy barrier of the proton transfer step, making the formation of the product with endo double bond located on a five-membered ring more likely to occur and confirming the rationality of water-assisted proton transfer occurring in the selective access to the product with endo double bond located on a five-membered ring.

Bioinspired Synthesis of Allysine for Late-Stage Functionalization of Peptides.

Inspired by the enzyme lysyl oxidase, which selectively converts the side chain of lysine into allysine, an aldehyde-containing post-translational modification, we report herein the first chemical method for the synthesis of allysine by selective oxidation of dimethyl lysine. This approach is highly chemoselective for dimethyl lysine on proteins. We highlight the utility of this biomimetic approach for generating aldehydes in a variety of pharmaceutically active linear and cyclic peptides at a late stage for their diversification with various affinity and fluorescent tags. Notably, we utilized this approach for generating small-molecule aldehydes from the corresponding tertiary amines. We further demonstrated the potential of this approach in generating cellular models for studying allysine-associated diseases.

Electrochemical Nickel-Catalyzed Hydrogenation.

Olefin hydrogenation is one of the most important transformations in organic synthesis. Electrochemical transition metal-catalyzed hydrogenation is an attractive approach to replace the dangerous hydrogen gas with electrons and protons. However, this reaction poses major challenges due to rapid hydrogen evolution reaction (HER) of metal-hydride species that outcompetes alkene hydrogenation step, and facile deposition of the metal catalyst at the electrode that stalls reaction. Here we report an economical and efficient strategy to achieve high selectivity for hydrogenation reactivity over the well-established HER. Using an inexpensive and bench-stable nickel salt as the catalyst, this mild reaction features outstanding substrate generality and functional group compatibility, and distinct chemoselectivity. In addition, hydrodebromination of alkyl and aryl bromides could be realized using the same reaction system with a different ligand, and high chemoselectivity between hydrogenation and hydrodebromination could be achieved through ligand selection. The practicability of our method has been demonstrated by the success of large-scale synthesis using catalytic amount of electrolyte and a minimal amount of solvent. Cyclic voltammetry and kinetic studies were performed, which support a NiII/0 catalytic cycle and the pre-coordination of the substrate to the nickel center.

Regio- and Chemoselective Palladium-Catalyzed Additive-Free Direct C─H Functionalization of Heterocycles with Chloroaryl Triflates Using Pyrazole-Alkyl Phosphine Ligands.

A series of new pyrazole-alkyl phosphine ligands with varying cycloalkyl ring sizes that enable additive-free regio- and chemoselective C─H arylation of heterocycles are reported. Excellent α/ß selectivity of various heterocycles such as benzo[b]thiophene, thiophene, furan, benzofuran, and thiazole can be achieved using these ligands, along with excellent chemoselectivity of C─Cl over C─OTf of chloroaryl triflates. Mechanistic studies supported by both experimental findings and density functional theory calculations indicate that the pyrazole phosphine ligands with optimal ring sizes allow the reaction to proceed with a lower energy barrier via a concerted metalation-deprotonation pathway.

Scope and Limitations of Using Microemulsions for the Covalent Patterning of Graphene.

Patterning of graphene (functionalizing some areas while leaving others intact) is challenging, as all the C atoms in the basal plane are identical, but it is also desirable for a variety of applications, like opening a bandgap in the electronic structure of graphene. Several methods have been reported to pattern graphene, but most of them are very technologically intensive. Recently, we reported the use of microemulsions as templates to pattern graphene at the µm scale. This method is very simple and in principle tunable, as emulsions of different droplet size and composition can be prepared easily. Here, we explore in detail the scope of this methodology by applying it to all the combinations of four different emulsions and three different organic reagents, and characterizing the resulting substrates exhaustively through Raman, SEM and AFM. We find that the method is general, works better when the reactive species are outside the micelles, and requires reactive species that involve short reaction times.