Pyridine → Benzene

Science

Programmed Alternating Current Optimization of Cu-Catalyzed C-H Bond Transformations

L. Zeng,^† Q. Yang,^† J. Wang,^† X. Wang, P. Wang, S. Wang, S. Lv, S. Muhammad, Y. Liu, H. Yi & A. Lei*

Science 2024, 385, 216–223 (DOI: 10.1126/science.ado0875)

Direct current (DC) electrosynthesis, which has undergone optimization over the past century, plays a pivotal role in a variety of industrial processes. Alternating current (AC) electrosynthesis, characterized by polarity reversal and periodic fluctuations, may be advantageous for multiple chemical reactions, but apparatus, principles, and application scenarios remain underdeveloped. In this work, the authors introduce a protocol for programmed AC (pAC) electrosynthesis that systematically adjusts currents, frequencies, and duty ratios. The application of representative pAC waveforms facilitates copper-catalyzed carbon-hydrogen bond cleavage in cross-coupling and difunctionalization reactions that exhibit suboptimal performance under DC and chemical oxidation conditions. Moreover, observing catalyst dynamic variation under diverse waveform applications provides mechanistic insight.

Nature Catalysis

Remote Site-Selective Arene C–H Functionalization enabled by N-Heterocyclic Carbene Organocatalysis

Q.-Z. Li,^† W.-L. Zou,^† Z.-Y. Yu, X.-X. Kou, Y.-Q. Liu, X. Zhang, Y. He & J.-L. Li*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01194-5)

Catalytic site-selective functionalization of distal C–H bonds represents a formidable challenge in organic synthesis. Particularly, the precise functionalization of distal aromatic C(sp² )–H bonds remains largely unexplored. Here, the authors present a highly para-selective acylation strategy to target ultraremote aryl C(sp² )–H bonds, eight chemical bonds away from an activated functionality, through radical N-heterocyclic carbene organocatalysis. This method is developed on the basis of a unique single-electron pathway involving the site-selective activation of aryl C–H bonds by a nitrogen-centred radical generated in situ. Importantly, this organocatalytic approach shows potential for the functionalization of drugs, amino acids and peptides, thus highlighting its importance for medicinal chemistry.

Electrocatalytic Cyclic Deracemization enabled by a Chemically Modified Electrode

C.-J. Zhu, X. Yang & J. Wang*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01189-2)

Redox chemistry, which is frequently encountered in the formation of new bonds and stereocentres, relies on the compatibility of redox potentials. Despite recent advances, achieving a general electrocatalytic cyclic deracemization process without stoichiometric redox reagents remains a formidable challenge. Here, the authors show that electrocatalytic cyclic deracemization of secondary alcohols can be accomplished through sequential iridium-catalysed enantioselective anodic dehydrogenation and rhodium-catalysed cathodic hydrogenation, utilizing metal hydride catalysis. A considerable hurdle arises as stronger hydride donors necessitate parent metal complexes to possess low reduction potentials, resulting in inherent redox potential incompatibility. Nonetheless, this incompatibility was overcome by leveraging a recyclable rhodium-catalyst-modified electrode as the cathode—an accomplishment that homogeneous rhodium catalysis could not achieve. The approach enables chemoselective stereochemical editing of bioactive compounds with remarkable functional group tolerance.

Nature Synthesis

Enantioselective Alkyl–Alkyl Coupling by Ni-Catalysed Asymmetric Cross-Hydrodimerization of Alkenes

P.-F. Yang,^† H.-T. Zhao,^† X.-Y. Chen & W. Shu*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00609-2)

Saturated tertiary stereogenic carbon centres are common in small molecules and organic materials. Transition-metal-catalysed asymmetric alkyl–alkyl bond formation processes represent contemporary techniques for the straightforward and efficient construction of saturated tertiary stereogenic carbon centres. However, reaction modes for asymmetric alkyl–alkyl bond formation between sp³ -hybridized carbon atoms, C(sp³ )–C(sp³ ), are limited yet highly desirable. Here, a mode for asymmetric alkyl–alkyl bond formation enabled by Ni-catalysed asymmetric alkyl–alkyl cross-coupling between alkenes has been developed to construct tertiary stereogenic carbon centres. Ni-catalysed asymmetric cross-hydrodimerization of N-acyl enamines and unactivated alkenes enables head-to-tail regioselectivity and excellent levels of chemo- and enantioselectivity. Notably, the reaction proceeds in the presence of both reducing and oxidizing reagents, rendering alkenes as the sole precursors to forge enantioselective alkyl–alkyl bonds. The exclusive head-to-tail cross-hydrodimerization of distinct alkenes opens the way to access saturated tertiary stereogenic carbon centres from alkenes.

Nature Communications

Regioselective Fluorination of Allenes enabled by I(I)/I(III) Catalysis

Z.-X. Wang, Y. Xu & R. Gilmour*

Nat. Commun. 2024, 15, 5770 (DOI: 10.1038/s41467-024-50227-x) 🔓

The prominence and versatility of propargylic fluorides in medicinal chemistry, coupled with the potency of F/H and F/OH bioisosterism, has created a powerful impetus to develop efficient methods to facilitate their construction. Motivated by the well-established conversion of propargylic alcohols to allenes, an operationally simple, organocatalysis-based strategy to process these abundant unsaturated precursors to propargylic fluorides would be highly enabling: this would consolidate the bioisosteric relationship that connects propargylic alcohols and fluorides. Herein, the authors describe a highly regioselective fluorination of unactivated allenes based on I(I)/I(III) catalysis in the presence of an inexpensive HF source that serves a dual role as both nucleophile and Brønsted acid activator. This strategy enables a variety of secondary and tertiary propargylic fluorides to be prepared: these motifs are prevalent across the bioactive small molecule spectrum. Facile product derivatisation, concise synthesis of multi-vicinal fluorinated products together with preliminary validation of enantioselective catalysis are disclosed. The expansive potential of this platform is also demonstrated through the highly regioselective organocatalytic oxidation, chlorination and arylation of allenes.

Journal of the American Chemical Society

Regioselective Pyridine to Benzene Edit Inspired by Water-Displacement

B. R. Boswell*, Z. Zhao, R. L. Gonciarz & K. M. Pandya

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05999)

Late-stage derivatization of drug-like functional groups can accelerate drug discovery efforts by swiftly exchanging hydrogen-bond donors with acceptors, or by modulating key physicochemical properties like logP, solubility, or polar surface area. A proven derivatization strategy to improve ligand potency is to extend the ligand to displace water molecules that are mediating the interactions with a receptor. Inspired by this application, the authors developed a method to regioselectively transmute the nitrogen atom from pyridine into carbon bearing an ester, a flexible functional group handle. They applied this method to a variety of substituted pyridines, as well as late-stage transformation of FDA-approved drugs.

Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach

Z.-X. Gao,^† H. Wang,^† A.-H. Su, Q.-Y. Li, Z. Liang, Y.-Q. Zhang, X.-Y. Liu, M.-Z. Zhu, H.-X. Zhang, Y.-T. Hou, X. Li, L.-R. Sun, J. Li, Z.-J. Xu* & H.-X. Lou*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02256)

Platensilin, platensimycin, and platencin are potent inhibitors of β-ketoacyl–acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels–Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom–transfer hydrogenation and subsequent Cu-catalyzed carbenoid C–H insertion afford platensilin. Furthermore, the intramolecular Diels–Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog (47) exhibits improved antibacterial activity (MIC80 = 0.0625 μg/mL) against S. aureus compared to platensimycin.

Palladium-Catalyzed Addition of Aryl Halides to N-Sulfinylamines for the Synthesis of Sulfinamides

M.-K. Wei, D. F. Moseley, R. M. Bär, Y. Sempere & M. C. Willis*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06726) 🔓

Sulfinamides are versatile, synthetically useful intermediates, and final motifs. Traditional methods to synthesize sulfinamides generally require substrates with preinstalled sulfur centers. However, these precursors have limited commercial availability, and the associated synthetic routes often require harsh reaction conditions and highly reactive reagents, thus severely limiting their application. Herein, the authors report the synthesis of sulfinamides from aryl and alkenyl (pseudo)halides and N-sulfinylamines, enabled by palladium catalysis. The reactions use mild conditions and are achieved without the use of highly reactive preformed organometallic reagents, resulting in transformations of broad generality and high functional group tolerance. In particular, substrates featuring protic and electrophilic functional groups can be used successfully. The modification of complex aryl cores and natural product derivatives demonstrates the utility of this method.

Cooperative Phosphine-Photoredox Catalysis Enables N–H Activation of Azoles for Intermolecular Olefin Hydroamination

K. Sedillo, F. Fan, R. R. Knowles* & A. G. Doyle*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05881)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-cpspw) 🔓

Catalytic intermolecular olefin hydroamination is an enabling synthetic strategy that offers direct and atom-economical access to a variety of nitrogen-containing compounds from abundant feedstocks. However, despite numerous advances in catalyst design and reaction development, hydroamination of N–H azoles with unactivated olefins remains an unsolved problem in synthesis. The authors report a dual phosphine and photoredox catalytic protocol for the hydroamination of numerous structurally diverse and medicinally relevant N–H azoles with unactivated olefins. Hydroamination proceeds with high anti-Markovnikov regioselectivity and N-site selectivity. The mild conditions and high functional group tolerance of the reaction permit the rapid construction of molecular complexity and late-stage functionalization of bioactive compounds. N–H bond activation is proposed to proceed via polar addition of the N–H azole to a phosphine radical cation, followed by P–N α-scission from a phosphoranyl radical intermediate.

Enantioconvergent Hydroboration of E/Z-Mixed Trisubstituted Alkenes

Y. Bao, C. Zheng, K. Xiong, C. Hu, P. Lu*, Y. Wang & Z. Lu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06585)

The lack of mode for chirality recognition makes it particularly challenging to carry out asymmetric transformations on E/Z-mixed minimally functionalized trisubstituted alkenes. Here, the authors report a catalytic enantioconvergent hydroboration of minimally functionalized trisubstituted E/Z-mixed alkenes to construct chiral organoboronic esters with excellent enantioselectivity using chiral radical cobalt catalyst. This C(sp³ )-H borylation protocol showed good functional group tolerance and products could be converted to valuable compounds via C–B derivatizations. The mechanistic studies, which included control experiments, nonlinear effect experiments, deuterated labeling experiments, and X-ray diffraction, demonstrated that the favorable compatibility between the thermodynamically unfavorable isomerization and hydroboration was the key factor in achieving convergent transformation.

Site-Selective Carbonylative Cyclization with Two Allylic C–H Bonds Enabled by Radical Differentiation

Y. Ding, J. Wu, T. Zhang, H. Liu & H. Huang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05360)

Controlling the site-selectivity of C–H functionalization is of significant importance and a formidable undertaking in synthetic organic chemistry, motivating the continuing development of efficient and sustainable technologies for activating C–H bonds. However, methods that control the site-selectivity for double C–H functionalization are rare. The authors herein report a conceptually new method to achieve highly site-selective C–H functionalization by implementing a radical single-out strategy. Leveraging the steric hindrance-sensitive CO-insertion as the radical differentiation process, a site-selective and stereoselective carbonylative formal [2+2] cycloaddition of imines and alkenes by sequential double allylic C–H bond activation was established without special and complicated HAT-reagents. This reaction was compatible with a wide range of alkenes and imines with diverse skeletons to deliver allylic β-lactams that are of synthetic and medicinal interest.

ACS Central Science

Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine

C. Jordan, T. Hayashi, A. Löbbert, J. Fan, C. S. Teschers, K. Siebold, M. Aufiero, F. Pape, E. Campbell, A. Axer, K. Bussmann, K. Bergander, J. Köhnke*, A. D. Gossert* & R. Gilmour*

ACS Cent. Sci. 2024, ASAP (DOI: 10.1021/acscentsci.4c00622) 🔓

Carbohydrates regulate an inimitable spectrum of biological functions, yet successfully leveraging this therapeutic avenue continues to be frustrated by low affinities with glycan-specific proteins. A conspicuous exception is the interaction of monosialotetrahexosylganglioside (GM1) with the carbohydrate-recognition domain of cholera toxin from Vibrio cholerae: this is one of the strongest protein–carbohydrate interactions known. To establish the importance of a long-discussed key hydrogen bond between C2 of the terminal galactose of GM1 and the B subunit pentamer of cholera toxin (CTB₅), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps. This process of molecular editing (O^δ- H → F^δ- ) strategically deletes the hydrogen bond donor while retaining the localized partial charge of the substituent. Comparison of the binding affinity of F-GM1/CTB₅ with native GM1, the GM1 carbohydrate epitope, and meta-mononitrophenyl-α-galactoside (MNPG) revealed a trend that fully supports the importance of this key interaction. These NMR data suggest that F-GM1 binds in a closely similar conformation as native GM1. Crystallographic analyses of the complex also confirm that the OH → F bioisosteric exchange at C2 of the terminal galactose induces a ring conformation that eliminates key hydrogen bonds: these interactions are compensated for by inter- and intramolecular fluorine-specific interactions.

Angewandte Chemie International Edition

Overcoming Challenges in O-Nitration: Selective Alcohol Nitration Deploying N,6-Dinitrosaccharin and Lewis Acid Catalysis

A. J. Fernandes, V. Valsamidou & D. Katayev*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202411073) 🔓

Nitrate esters hold pivotal roles in pharmaceuticals, energetic materials, and atmospheric processes, motivating the development of efficient synthesis routes. Here, the authors present a novel catalytic method for the synthesis of nitrates via the direct O-nitration of alcohols, addressing limitations of current traditional methods. Leveraging bench-stable and recoverable N,6-dinitrosaccharin reagent, the catalytic strategy employs magnesium triflate to achieve mild and selective O-nitration of alcohols, offering broad substrate scope and unprecedented large functional group tolerance (e.g. alkenes, alkynes, carbonyls). DFT mechanistic studies reveal a dual role of the magnesium catalyst in the activation of both the nitrating reagent and the alcohol substrate. They also unveil a barrierless proton transfer upon formation of a widely-accepted—yet elusive in solution—nitrooxonium ion intermediate.

Total Synthesis of (±)-Baphicacanthcusine A Enabled by Sequential Ring Contractions

P. P. Sinclair & R. Sarpong*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409139) 🔓

The authors report the first total synthesis of the poly-pseudoindoxyl natural product baphicacanthcusine A. The synthesis leverages the oxidative rearrangement of indoles to pseudoindoxyls to install vicinal pseudoindoxyl heterocycles in a diastereoselective manner. Key steps include an acid-mediated cyclization/indole transposition, two diastereoselective oxidative ring contractions, and a site-selective C­–H oxygenation. The synthesis of the oxidation precursors was guided by recognition of an element of hidden symmetry.

Iron-Catalyzed C-7 Selective NH₂ Amination of Indoles

Z.-L. Wang, J.-K. Cheng & F. Wang*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202412103)

7-Aminoindoles are important synthetic intermediates to a broad range of bioactive molecules. Transition metal-catalyzed directed C–H amination is among the most straightforward route for their synthesis, whereas methods that could directly incorporate an NH₂ group in a highly selective manner remains elusive. Moreover, there is still high demand for the development of earth-abundant metal catalysis for such attractive reactivity. The authors present here the first C-7 selective NH₂ amination of indoles through a directed homolytic aromatic substitution (HAS) with iron-aminyl radical. The reaction exhibits broad substrate scope, tolerates variety of functional groups, and is readily scalable with catalyst loading down to 0.1 mol% and turnover number (TON) up to 4500.

Photoinduced Electron Donor Acceptor Complex-Enabled α-C(sp³)-H Alkenylation of Amines

J. Lu, K. Yuan, J. Zheng, H. Zhang, S. Chen, J. Ma, X. Liu, B. Tu, G. Zhang* & R. Guo*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409310)

Allylic amines are prevalent and vital structural components present in many bioactive compounds and natural products. Additionally, they serve as valuable intermediates and building blocks, with wide-ranging applications in organic synthesis. However, direct α-C(sp³ )-H alkenylation of feedstock amines, particularly for the preparation of α-alkenylated cyclic amines, has posed a longstanding challenge. Herein, the authors present a general, mild, operationally simple, and transition-metal-free α-alkenylation of various readily available amines with alkenylborate esters in excellent E/Z ratios and diastereoselectivities. This method features good compatibility with water and oxygen, broad substrate scope, and excellent functional group tolerance, thereby enabling the late-stage modification of various complex molecules.

ChemRxiv

Ni-Catalyzed Asymmetric Reductive Arylation of ⍺-Substituted Imides

L.-M. Chen, C. Shin, T. J. DeLano, G. Gheibi & S. E. Reisman*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2023-97hjq-v2) 🔓

α-Aryl imides are common structural motifs in bioactive molecules and proteolysis-targeting chimeras designed for targeted protein degradation. An asymmetric Ni-catalyzed reductive cross-coupling of imide electrophiles and (hetero)aryl halides has been developed to synthesize enantioenriched α-arylglutarimides from simple starting materials. Judicious selection of electrophile pairs allows for coupling of both electron-rich and electron-deficient (hetero)aryl halides in good yields and enantioselectivities.

Organic Letters

Sandmeyer Chlorosulfonylation of (Hetero)Aromatic Amines Using DABSO as an SO₂ Surrogate

L. Pincekova, A. Merot, G. Schäfer* & M. C. Willis*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01908) 🔓

Sulfonyl chlorides not only play a crucial role in protecting group chemistry but also are important starting materials in the synthesis of sulfonamides, which are in-demand motifs in drug discovery chemistry. Despite their importance, the number of different synthetic approaches to sulfonyl chlorides is limited, and most of them rely on traditional oxidative chlorination chemistry from thiol precursors. In this report, the authors disclose a novel Sandmeyer-type sulfonyl chloride synthesis from feedstock anilines and DABSO, used as a stable SO₂ surrogate, in the presence of HCl and a Cu catalyst. The method works on a wide range of anilines and allows for the isolation of the sulfonyl chloride after aqueous workup or its direct conversion into the sulfonamide by simple addition of an amine after the completion of the Sandmeyer reaction. The scalability of this method was demonstrated on a 20 g scale, and the corresponding heterocyclic sulfonyl chloride was isolated in 80% yield and excellent purity.

Journal of Organic Chemistry

3-Substituted 6-Azabicyclo[3.1.1]heptanes: Nonclassical Piperidine Isosteres for Drug Discovery

A. V. Chernykh, B. V. Vashchenko, S. V. Shishkina, D. M. Volochnyuk & O. O. Grygorenko*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c00326)

Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with cis-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, N-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)₄-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave N-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of cis- and trans-diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure cis- and trans-N-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that cis-isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine chair conformer, whereas trans-isomers can be considered as unusual “boat” piperidines.

That’s all for this issue! Have a great week and we’ll see you next Monday.