Photoexcited Uranium Selectively Splits Carbon–Fluorine Bonds

Nature Chemistry

Copper-Catalysed Asymmetric Hydroboration of Alkenes with 1,2-Benzazaborines to Access Chiral Naphthalene Isosteres

W. Su, J. Zhu, Y. Chen, X. Zhang, W. Qiu, K. Yang,* P. Yu* & Q. Song*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01505-0)

Bioisosteric replacement has emerged as a clear strategy for drug-structure optimization. Naphthalene is the core element of many chiral pharmaceuticals and drug candidates. However, as a promising isostere of naphthalene, the chiral version of 1,2-benzazaborine has rarely been explored due to the lack of efficient synthetic methods. Here, the authors describe a copper-catalysed enantioselective hydroboration of alkenes with 1,2-benzazaborines. The method provides a general platform for the atom-economic and efficient construction of diverse chiral 1,2-benzazaborine compounds (more than 60 examples) that bear a 2-carbon-stereogenic centre or allene skeleton in high yields and excellent enantioselectivities. Three 1,2-benzazaborine analogues of bioactive chiral naphthalene-containing molecules have been prepared, and a series of transformations around chiral 1,2-benzazaborines have also been developed.

Nature Synthesis

Palladium-Catalysed Methylene C(sp³)–H Lactamization and Cycloamination Enabled by Chlorinated Pyridine–Pyridone Ligands

H. S. S. Chan, Y. Lu & J.-Q. Yu*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00517-5)

Recent developments of bifunctional ligands have rapidly advanced palladium-catalysed C(sp³ )–H activation reactions directed by native carboxylic acids. However, using this approach in inter- or intramolecular C(sp³ )–H amination reactions is often hampered by N-coordination overriding the directing effect of the native carboxyl group. Here, the authors report the design and development of chlorinated pyridine–pyridone ligands, which can overcome N-coordination and enable exclusive carboxylic-acid-directed lactamization and cycloamination of N-protected ω-amino acids. The compartmentalization of directed C(sp³ )–H activation and C(sp³ )–N bond formation in this reaction is distinct from existing C(sp³ )–H amination approaches, in which both processes are directed by nitrogen. The protocols described in this report transform linear ω-amino acids into valuable cyclic β-amino acids possessing γ- and δ-lactam, pyrrolidine and tetrahydroquinoline scaffolds pertinent to drug discovery.

Journal of the American Chemical Society

Artificial Intelligence for Retrosynthetic Planning Needs Both Data and Expert Knowledge

F. Strieth-Kalthoff, S. Szymkuć, K. Molga, A. Aspuru-Guzik, F. Glorius* & B. A. Grzybowski*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c00338)

Rapid advancements in artificial intelligence (AI) have enabled breakthroughs across many scientific disciplines. In organic chemistry, the challenge of planning complex multistep chemical syntheses should conceptually be well-suited for AI. Yet, the development of AI synthesis planners trained solely on reaction-example-data has stagnated and is not on par with the performance of “hybrid” algorithms combining AI with expert knowledge. This Perspective examines possible causes of these shortcomings, extending beyond the established reasoning of insufficient quantities of reaction data. Drawing attention to the intricacies and data biases that are specific to the domain of synthetic chemistry, the authors advocate augmenting the unique capabilities of AI with the knowledge base and the reasoning strategies of domain experts.

Photouranium-Catalyzed C–F Activation Hydroxylation via Water Splitting

X. Zhao, L. Bai, J. Li & X. Jiang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.3c13908)

The C–F bond is the strongest covalent single bond (126 kcal/mol) in carbon-centered bonds, in which the highest electronegativity of fluorine (χ = 4) gives rise to the shortest bond length (1.38 Å) and the smallest van der Waals radius (r_w = 1.47 Å), resulting in enormous challenges for activation and transformation. Herein, C–F conversion was realized via photouranium-catalyzed hydroxylation of unactivated aryl fluorides using water as a hydroxyl source to deliver multifunctional phenols under ambient conditions. The activation featured cascade sequences of single electron transfer (SET)/hydrogen atom transfer (HAT)/oxygen atom transfer (OAT), highly integrated from the excited uranyl cation. The *UO₂²⁺ prompted water splitting under mild photoexcitation, caging the active oxygen in a peroxo-bridged manner for the critical OAT process and releasing hydrogen via the HAT process.

Total Synthesis of Keramaphidin B and Ingenamine by Base-Catalyzed Diels–Alder Reaction Using Dynamic Regioselective Crystallization

Y. Kurihara, M. Yagi, T. Noguchi, H. Yasufuku, A. Okita, S. Yoshimura, T. Oishi, N. Chida, T. Okamura & T. Sato*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02338)

The control of the selectivity is a central issue in the total synthesis of complex natural products. In this paper, the authors report the total synthesis of (±)-keramaphidin B and (±)-ingenamine. The key reaction is a DMAP-catalyzed Diels–Alder reaction in which the regioselectivity is completely controlled by dynamic crystallization. The synthesis successfully demonstrates that dynamic crystallization can be an alternative when the selectivity is not controlled by either kinetic or thermodynamic approaches in solution.

Editing Tetrasubstituted Carbon: Dual C–O Bond Functionalization of Tertiary Alcohols Enabled by Palladium-Based Dyotropic Rearrangement

T. Delcaillau, B. Yang, Q. Wang & J. Zhu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02924)

Many elegant asymmetric syntheses of enantioenriched tertiary alcohols have been developed, and both the transition metal-catalyzed and the radical-based peripheral functionalization of tertiary alcohols have attracted intensive research interest in recent years. However, directly editing tetrasubstituted carbons remains challenging. Herein, the authors report a Pd-catalyzed migratory fluoroarylation reaction that converts tertiary alcohols to α-fluorinated tertiary alkyl ethers in good to excellent yields. An unprecedented 1,2-aryl/Pd^IV dyotropic rearrangement along the C–O bond, integrated in a Pd^II -catalyzed domino process, is key to the dual functionalization of both the hydroxyl group and the tetrasubstituted carbon.

Angewandte Chemie International Edition

Photoinduced C(sp³)-H Bicyclopentylation Enabled by an Electron Donor–Acceptor Complex-Mediated Chemoselective Three-Component Radical Relay

X. Dang, Z. Li, J. Shang, C. Zhang, C. Wang & Z. Xu*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202400494)

The photoredox electron donor–acceptor (EDA) complex-mediated radical coupling reaction has gained prominence in the field of organic synthesis, finding widespread application in two-component coupling reactions. However, EDA complex-promoted multi-component reactions are not well developed with only a limited number of examples have been reported. Herein, the authors report a photoinduced and EDA complex-promoted highly chemoselective three-component radical arylalkylation of [1.1.1]propellane, which allows the direct functionalization of C(sp³ )–H with bicyclo[1.1.1]pentanes (BCP)-aryl groups under mild conditions.

Controllable Skeletal and Peripheral Editing of Pyrroles with Vinylcarbenes

Y. Yang,^‡ Q. Song,^‡ P. Sivaguru, Z. Liu,* D. Shi, T. Tian, G. de Ruiter & X. Bi*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202401359)

The skeletal editing of azaarenes through insertion, deletion, or swapping of single atoms has recently gained considerable momentum in chemical synthesis. Here, the authors describe a practical skeletal editing strategy using vinylcarbenes generated in situ from trifluoromethyl vinyl N-triftosylhydrazones, leading to the first dearomative skeletal editing of pyrroles through carbon-atom insertion. Furthermore, depending on the used catalyst and substrate, three types of peripheral editing reactions of pyrroles are also disclosed: α- or γ-selective C–H insertion, and [3+2] cycloaddition. These controllable molecular editing reactions provide a powerful platform for accessing medicinally relevant CF₃-containing N-heterocyclic frameworks.

Mechanistic Approach Toward the C4-Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen

H. Choi,^‡ W. S. Ham,^‡ P. van Bonn, J. Zhang, D. Kim & S. Chang*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202401388)

The development of site-selective functionalization of N-heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4-aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, the authors report a reaction manifold for the C4-selective amination of pyridines by employing nucleophilic substitution of hydrogen (S_NH). Through 4-pyridyl pyridinium salt intermediates, 4-aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with maximization of polarizability in the proton elimination stage.

ChemRxiv

A General Nitrene Transfer to Sulfides Enabled by Visible-Light-Mediated Triplet Energy Transfer to Sulfonyl Azides

N. Arichi,* T. Amano,^‡ S. Wu,^‡ S. Inuki & H. Ohno*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-85rxf-v2) 🔓

Sulfilimines and their derivatives have garnered considerable interest in both synthetic and medicinal chemistry. Photochemical nitrene transfer to sulfides is known as a conventional synthetic approach to sulfilimines. However, the existing methods have a limited substrate scope stemming from the incompatibility of singlet nitrene intermediates with nucleophilic functional groups. Herein, the authors report a general nitrene transfer for the synthesis of N-sulfonyl sulfilimines enabled by visible-light-mediated energy transfer to sulfonyl azides, uncovering the neglected reactivity of triplet nitrenes with sulfides.

Organic Process Research & Development

Total Synthesis with Gram-Scale Radical Process: An Inspiration for Pharmaceutical Industry

S. Fu & B. Liu*

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00041)

Radical reactions have emerged as indispensable tools in the synthesis of complex molecules. In this perspective, the authors discuss selected total syntheses that make use of radical processes in a scale of at least one gram as the essential transformation, to showcase their potential applicability in the industry related to pharmaceuticals and fine chemicals. The discussion is divided into three main sections: metal-catalyzed hydrogen atom transfer (HAT) cyclization, nonmetal-mediated radical cyclization, and metal-catalyzed reductive cross-coupling reactions.

Organic Letters

General Approach to Amides through Decarboxylative Radical Cross-Coupling of Carboxylic Acids and Isocyanides

Q. Yan, Q.-J. Yuan, A. Shatskiy, G. R. Alvey, E. V. Stepanova, J.-Q. Liu*, M. D. Kärkäs* & X.-S. Wang*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00872) 🔓

The authors report a silver-catalyzed protocol for decarboxylative cross-coupling between carboxylic acids and isocyanides, leading to linear amide products through a free-radical mechanism. The disclosed approach provides a general entry to a variety of decorated amides, accommodating a diverse array of radical precursors, including aryl, heteroaryl, alkynyl, alkenyl, and alkyl carboxylic acids. Notably, the protocol proved to be efficient for decarboxylative late-stage functionalization of several elaborate pharmaceuticals, demonstrating its potential applications.

Late-Stage C–H Nitration of Unactivated Arenes by Fe(NO₃)₃·9H₂O in Hexafluoroisopropanol

Y. Zheng, Q.-Q. Hu, Q. Huang & Y. Xie*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01006)

Operationally simple and generally applicable arene nitration with cheap and easily accessible chemicals has been a long-sought transformation in the synthetic organic community. The authors have realised this goal with non-toxic and inexpensive Fe(NO₃)₃·9H2O as the nitro-source and easily recyclable solvent hexafluoroisopropanol as the promotor via a network of hydrogen-bonding interactions. As a result of the relative mildness and high reliability of this protocol, late-stage nitration of various highly functionalized natural products and commercially available drugs was realised.

Chromium-Catalyzed Alkene Isomerization with Switchable Selectivity

J. Zhong, X. Wang, M. Luo* & X. Zeng*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00737)

The authors report a single additive-responsive chromium-catalyzed system for selectively producing either of two different internal alkene isomers. The chromium catalyst, in the presence of HBpin/LiOt-Bu, enables the isomerization of alkenes over multiple carbon atoms to give the most thermodynamically stable isomers. The same catalyst allows for the selective isomerization of terminal alkenes over one carbon atom without an additive, exhibiting efficient and controllable alkene transposition selectivity.

Journal of Organic Chemistry

Total Synthesis of (±)-Oxacyclododecindione

K. Seipp, V. Grölz, H. Glass, E. Quraishi, N. Vierengel & T. Opatz*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c00333)

Racemic total synthesis of the natural product oxacyclododecindione, isolated in 2008 as the first member of the oxacyclododecindione family, is reported. Studies toward this molecule commenced with a biomimetic late-stage C–H oxidation starting from 14-deoxyoxacyclododecindione as a known precursor. This provided insights into the reactivity of the macrolactone class but did not permit the synthesis of the target natural product. Based on these results, a synthetic strategy through intramolecular Friedel–Crafts acylation combined with Barton decarboxylation to introduce the tertiary alcohol, a major challenge in previous synthetic efforts, was envisioned. This resulted in an 11-step racemic total synthesis of (±)-oxacyclododecindione, renowned for its potent anti-inflammatory and antifibrotic activities.

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