Enrico

Chemically modified oligonucleotides have garnered significant attention in medicinal chemistry, chemical biology, and synthetic biology due to their enhanced stability in vivo compared to naturally occurring oligonucleotides. However, current methods for synthesizing modified nucleosides, particularly at the C2′-position, are limited in terms of efficiency, modularity, and selectivity. Herein, we report a new approach for the synthesis of highly functionalized C2′-a-aryl/alkenyl nucleosides via an electrochemical nickel-catalyzed cross-coupling of 2'-bromo nucleosides with a variety of (hetero)aryl and alkenyl iodides. This method affords a diverse array of C2′- a-aryl/ alkenyl nucleosides with excellent stereoselectivities, broad substrate scope, and good functional group compatibility. We further synthesized oligonucleotides incorporating C2′-aryl-modified thymidine moieties and demonstrated that their annealed double-stranded DNAs exhibit decreased melting temperatures (Tm). Additionally, oligonucleotides with C2′-aryl modifications at the 3′ end showed enhanced resistance to 3′-exonuclease degradation and C2′-aryl modifications did not impede the cellular uptake process, highlighting the potential of these modified oligonucleotides for therapeutic applications.

Despite the established state of knowledge, synthetically useful diazotation of aliphatic amines is possible. The key of this process is the use of 1,1,1,3,3,3-hexafluoroisopropanol as a solvent. It improves the selectivity of the process and enables the transformation of the intermediates into the desired Friedel–Crafts products. In this way, after more than 150 years, also the diazotation of aliphatic amines is gaining its place in synthesis.

Abstract

While aromatic diazonium salts are important reagents in organic synthesis, ‘Diazonium ions generated from ordinary aliphatic primary amines are usually useless for preparative purposes, since they lead to a mixture of products giving not only substitution by any nucleophile present, but also elimination and rearrangements if the substrate permits.’¹ In this work, we report that this statement is no longer valid, and it is now possible to control diazotization of aliphatic amines by utilizing isopentyl nitrite in HFIP. This transformation enabled electrophilic aromatic substitution with these highly abundant and commercially available alkyl reagents, as well as transforming them into building blocks typically employed in organic synthesis. The methodology opens an avenue for reactions involving aliphatic amines, even such demanding substrates as amino acids, as a source of carbocations thus expanding the degree of chemical space.

Despite the progress made in the field of synthetic organic photocatalysis over the last decade, the use of higher wavelengths, especially those in the deep-red portion of the electromagnetic spectrum, remain comparatively rare. We have previously disclosed that a well-defined N,C,N-pincer bismuthinidene (1a) can undergo formal oxidative addition into a wide range of aryl electrophiles upon absorption of low-energy red light. In this study, we map out the photophysical dynamics of 1a and glean insights into the nature of the excited state responsible for the activation of aryl electrophiles. Transient-absorption and emission techniques reveal that, upon irradiation with red light, the complex undergoes a direct S0 → S1 metal-to-ligand charge transfer (MLCT) transition, followed by rapid intersystem crossing (ISC) to a highly reducing emissive triplet state (−2.62 V vs Fc+/0 in MeCN). The low dissipative losses incurred during ISC (~6% of the incident light energy) help rationalize the ability of the bismuthinidene to convert low-energy light into useful chemical energy. Spectroelectrochemical and computational data support a charge-separated excited-state structure with radical-anion character on the ligand and radical-cation character on bismuth. Kinetic studies and competition experiments afford insights into the mechanism of oxidative addition into aryl iodides; concerted and inner-sphere processes from the triplet excited state are ruled out, with the data strongly supporting a pathway that proceeds via outer-sphere dissociative electron transfer.

A one-pot multi-component alkene-arene and alkene-alkene aminative coupling reaction has been developed for the synthesis of secondary amines and aziridines. This was achieved through the design, synthesis and implementation of an anomeric amide reagent, capable of promoting catalyst-free alkene chloroamination transformations, installing a formal nitrene precursor that can subsequently undergo either C−H insertion or [2+1] cycloaddition.

Abstract

Despite the prominence of C−N bond forming cross-coupling reactions as a strategy to assemble molecular fragments, aminative coupling approaches, in which two fragments are assembled directly at the heteroatom, represents a rarely exploited retrosynthetic strategy. Herein, we report the design, synthesis, and implementation of an anomeric amide reagent capable of promoting highly regioselective aminative alkene-arene and alkene-alkene coupling reactions. This transformation follows a sequence of catalyst-free chloroamination, N-deprotection, and formal nitrene functionalization, all in one-pot. Due to the simplicity of both the protocol and the building blocks required, high-throughput experimentation (HTE) was employed, in combination with a full-scale scope, to rapidly and efficiently explore a wide range of chemical space and determine the limits of reactivity. In addition, alternative reactivity modes from the functionalized intermediates delivered by this protocol demonstrate the divergent nature of this aminative coupling strategy.

A concise and convergent synthesis of the isosteroidal alkaloids veratramine and 20-epi-veratramine has been accom-plished. A Horner-Wadsworth-Emmons olefination joins two chiral building blocks of approximately equal complexity and a transition-metal catalyzed intramolecular Diels-Alder cycloaddition-aromatization cascade constructs the tetrasubstituted arene. Other key steps include a highly diastereoselective crotylation of an N-sulfonyl iminium ion and an Eschenmoser fragmentation. The chiral building blocks developed for this synthesis could be used to access a range of additional isoster-oidal alkaloids using our diversifiable strategy. Our work shows that 20-epi-veratramine is not identical with a natural product proposed to have that structure. The single crystal X-ray structures of veratramine and 20-epi-veratramine are reported.

Nature Synthesis, Published online: 27 November 2024; doi:10.1038/s44160-024-00701-7

Electrochemical fragmentation for alkene difunctionalization

Nature Chemistry, Published online: 21 November 2024; doi:10.1038/s41557-024-01674-y

Aza-heterocycles with rings of more than 6 members are underrepresented in medicinal chemistry owing to challenges with their synthesis. Now, the conversion of 5- and 6-membered saturated cyclic amines into 7- and 8-membered aza-heterocycles can be achieved via a ring expansion cascade reaction.

The combination of a site-selective thianthrenation with a Catellani reaction provides access to 3,5-dimethylated arenes. The developed reaction is complementary to the previously discovered reductive ipso-alkylation of aryl thianthrenium salts and extends the possibilities for late-stage methylation of arenes with a single aryl thianthrenium salt.

Abstract

Here we report the reaction of aryl thianthrenium salts that allows selective functionalization of the meta position of arenes. The combination of a site-selective thianthrenation with a Catellani reaction provides access to 3,5-dimethylated arenes. The developed reaction is complementary to the previously discovered reductive ipso-alkylation of aryl thianthrenium salts and extends the possibilities for late-stage methylation of arenes with a single aryl thianthrenium salt.

Nature, Published online: 20 November 2024; doi:10.1038/s41586-024-08195-1

A transition-metal-free platform enables the formation of challenging C(sp3)–C(sp3) bonds in organic compounds via single-electron transfer, facilitating the coupling of functionalized fragments and expanding possibilities for efficient organic synthesis and reaction design.

Short text: The first synthesis of hexa-arylborazines with ortho-substituted aryl groups expands their three-dimensional structure. By selecting the appropriate ortho-substituent, the ArLi adds to the BN-core in a controlled manner, guiding the stereochemical outcome of the three-substitution reaction. This stereoselective approach enables the synthesis of multichromophoric borazine derivatives, demonstrating how the stereochemical arrangement influences their redox behavior.

Abstract

Borazine and its derivatives can be considered critical doping units for engineering hybrid C(sp²)-based molecules with tailored optoelectronic properties. Herein, we report the first synthesis of hexa-arylborazines that, bearing ortho-substituted aryl moieties, extend three-dimensionally. Using a one-pot protocol, we first form an electrophilic chloroborazole and then react it with an aryl lithium (ArLi). By selecting the appropriate ortho-substituent, we can guide the ArLi to add to the BN-core in a specific way, ultimately controlling the stereochemical outcome of the three-substitution reaction. Rationalization of the stereochemical model through computational analysis allowed us to show that when aryl lithium nucleophiles bearing rigid long-range ortho-substituents are used, i.e., stiff substituents. The ortho-substituent shields its side of the electrophilic B₃N₃ core, biasing the incoming ArLi to add anti at each addition step, forming the final tri-aryl borazine exclusively as cc-isomer. Leveraging this stereoselective approach, prototypical multichromophoric borazine derivatives were prepared, and we showcased how the stereochemical arrangement of these chromophores distinctly influences their redox behavior. This methodology paves the way for previously inaccessible borazines to serve as privileged precursors to transcend the conventional bidimensionality associated with graphenoid systems and pioneer the construction of new forms of three-dimensional C(sp²)-based architectures.

A novel hypervalent iodine reagent that allows electrophilic nitrenoid transfer is reported. α-amination of indanone β-ketoesters allows divergent ring expansions to either isoquinolones (thermal conditions) or isoquinolines (photochemical conditions). Mechanistic studies for each pathway are presented alongside a comparison to other nitrene precursors.

Abstract

Controllable installation of a single nitrogen atom is central to many major goals in skeletal editing, with progress often gated by the availability of an appropriate N-atom source. Here we introduce a novel reagent, termed DNIBX, based on dibenzoazabicycloheptadiene (dbabh), which allows the electrophilic installation of dbabh to organic substrates. When indanone β-ketoesters are aminated by DNIBX, the resulting products undergo divergent ring expansions depending on the mode of activation, producing heterocycles in differing oxidation states under thermal and photochemical conditions. The mechanism of each transformation is discussed, and the different reactivity modes of the indanone-dbabh adducts are compared to other nitrogenous precursors.

We report a new strategy for the C−H difunctionalization of purely aliphatic alkane substrates. The reaction proceeds with complete regio- and diastereoselectivity and enables access to a wide range of previously inaccessible acyl 9-decalinols. Additionally, the application of this method translated well to simple monocyclic alkane substrates.

Abstract

C−H functionalization of purely aliphatic substrates is a challenging endeavor, as the absence of directing groups generally thwarts attempts at regiocontrol. This is particularly true for difunctionalization reactions, where the control of relative stereochemistry poses an additional obstacle. The Baddeley reaction of decalins, despite suffering from strong limitations with regard to yield and generality, stands as one of only few known transformations capable of regio- and stereocontrol in aliphatic C−H functionalization. Herein, we report a regio- and diastereoselective method for the double functionalization of decalins enabling access to a novel, unreported regioisomer in synthetically useful yields. This method was also successfully applied to a range of other alkane substrates, enabling a straightforward synthesis of keto alcohols from the simplest alkane building blocks.

Electrochemical, fully stereoselective P(V)-radical hydrophosphorylation of olefins and carbonyl compounds using a P(V) reagent is disclosed. By strategically selecting the anode material, radical reactivity is accessible for alkene hy-drophosphorylation whereas a polar pathway operates for ketone hydrophosphorylation. The mechanistic intricacies of these chemoselective transformations was explored in-depth

Owing to their structural complexity, target-oriented syntheses of natural products usually require the design of individualized routes that are tailor-made for the specific targets. As such, route re-design is needed when targets of different skeletal connectivities are considered. Here, we report a versatile synthetic strategy that runs counter to this conventional wisdom and allows access to a range of terpenoids with distinct skeletal frameworks from the sesquiterpene lactone sclareolide as the starting material. By viewing a biocatalytically-installed alcohol as an exploitable motif rather than a structural endpoint, a number of abiotic skeletal rearrangements were designed, resulting in significant structural divergence from the original drimane ring system of sclareolide. Using this approach, the syntheses of four terpenoid natural products, namely merosterolic acid B, cochlioquinone B, (+)-daucene and dolasta-1(15),8-diene, were achieved.

Despite extensive efforts to develop γ-lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C−H insertion, or radical C−H abstraction strategies, γ-lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein we report copper-catalyzed γ-C(sp3)−H lactamization and iminolactonization of tosyl-protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ-Lactams or γ-iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro-, fused-, and bridged-lactams and iminolactones, as well as isoindolinones are accessible by this method. Further derivatization of the γ-lactam products enables the synthesis of a range of biologically important motifs, including γ-amino acids, δ-amino alcohols, and pyrrolidines.

The addition of chiral sulfinimines to keteniminium ions generated through electrophilic amide activation enables a [3,3]-sigmatropic sulfonium rearrangement to yield enantioenriched β-ketoamides in a single step. The transformation proceeds with high enantio- and chemoselectivity as well as functional group tolerance, and—in contrast to imide-based chiral auxiliary approaches—directly delivers stereochemically stable amide products.

Abstract

The synthesis of enantioenriched α-substituted 1,3-dicarbonyls remains a contemporary challenge in synthesis due to their tendency to undergo racemization via keto-enol tautomerization. Herein, we report a method to access enantioenriched β-ketoamides by a chiral sulfinimine-mediated [3,3]-sigmatropic sulfonium rearrangement. The transformation displays good chirality transfer, as well as excellent chemoselectivity and functional group tolerance. Diastereoselective reduction of the ketone moiety, also achievable in one-pot fashion, affords enantioenriched β-hydroxyamides.

“A turning point in my career was when I realized that I was running a marathon, not a 100-meter dash… When I was a kid I wanted to be an inventor – and I think I did not end up too far from that...” Find out more about Gabriele Laudadio in his Introducing… Profile.

Nature Synthesis, Published online: 25 October 2024; doi:10.1038/s44160-024-00684-5

Electrochemical etherification and amination

Synthetic organic electrochemistry is a highly useful redox method, enabling diverse transformations. This study explores pyrolytic carbon electrodes in powerful rAP processes and C−C as well as C−N bond-forming reactions. Pyrolytic carbon offers a cost-effective alternative to traditional amorphous carbon materials (glassy carbon, GC, or reticulated vitreous carbon, RVC), which are often expensive or unsuitable for large-scale flow reactions.

Abstract

Synthetic organic electrochemistry is recognized as one of the most sustainable forms of redox chemistry that can enable a wide variety of useful transformations. In this study, readily prepared pyrolytic carbon electrodes are explored in several powerful rAP transformations as well as C−C and C−N bond forming reactions. Pyrolytic carbon provides an alternative to classic amorphous carbon-based materials that are either expensive or ill-suited to large-scale flow reactions.

To bridge the gap between the customizability of in-house machined reactors and the reproducibility of commercially available reactors, we have developed a suite of 3D-printed components that are compatible with the ElectraSyn. These components serve to increase the applicability, range of reactions and contexts that can be used with it. They can be downloaded and inexpensively recreated.

Abstract

Electrosynthetic reactions are performed in either custom-made reactors that are developed and machined in-house or commercially available systems that offer good reproducibility but come at a high cost. To bridge this divide between customizability and reproducibility, we have developed the Open-ESyn, which is a suite of 3D-printed components compatible with the popular ElectraSyn. This collection of parts increases the electrosynthesis that can be performed with the ElectraSyn, expanding, for example, the scale, temperature and the type of electrodes that can be used. The standardized reactor environment can be inexpensively recreated, thereby maintaining the reproducibility of the ElectraSyn ecosystem.

The synthesis of polysubstituted (hetero)aromatic compounds is essential in various fields, including pharmaceuticals, where such compounds are fundamental to many approved drugs. In this study, we present a novel electrochemical method for sin-gle-carbon insertion targeting various (hetero)aromatic compounds, with a particular focus on pyridines. In this process, the electrochemical oxidation of pyrrole derivatives produces a radical cation intermediate, which then undergoes nucleophilic attack by diazo compounds to yield polysubstituted pyridine derivatives. Notably, the insertion position is influenced by the electronic properties of N-protecting groups, allowing for unprecedented para-selective insertion through the introduction of electron-withdrawing groups. This approach is applicable to various substrates such as indole, imidazole, indene, and cyclo-pentadiene, resulting in the desired carbon-inserted products. Insights from in-situ spectroscopy and theoretical calculations suggest the involvement of distonic radical cation intermediates, facilitating carbon-atom migration on the aromatic ring and enabling insertion at different positions. This study expands the chemical toolkit for synthesizing polysubstituted (het-ero)aromatic compounds and introduces a new concept for single-carbon insertion chemistry.