Three Radicals Sorted Simultaneously

Nature

Asymmetric Hydrogenation of Ketimines with Minimally Different Alkyl Groups

M. Wang,^† S. Liu,^† H. Liu,^† Y. Wang, Y. Lan* & Q. Liu*

Nature 2024 (DOI: 10.1038/s41586-024-07581-z)

Asymmetric catalysis allows the synthesis of optically active compounds, often requiring the differentiation between two substituents on prochiral substrates. Despite decades of development of mainly noble metal catalysts, achieving differentiation between substituents with similar steric and electronic properties remains a significant challenge. Here, the authors introduce a class of earth-abundant manganese catalysts for the asymmetric hydrogenation of dialkyl ketimines to give a range of chiral amine products. These catalysts distinguish between pairs of minimally differentiated alkyl groups bound to the ketimine, such as methyl and ethyl, and even subtler distinctions, like ethyl and n-propyl. The degree of enantioselectivity can be adjusted by modifying the components of the chiral manganese catalyst. This reaction demonstrates a wide substrate scope and achieves a turnover number (TON) of up to 107,800.

Nature Synthesis

Rapid Automated Iterative Small-Molecule Synthesis

W. Wang,^† N. H. Angello,^† D. J. Blair, T. Tyrikos-Ergas, W. H. Krueger, K. N. S. Medine, A. J. LaPorte, J. M. Berger & M. D. Burke*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00558-w)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-qpf2x) 🔓

Automated iterative small-molecule synthesis has the potential to advance and democratize the discovery of new medicines, materials and many other classes of functional chemical matter. To date, however, this approach has been limited because each carbon–carbon bond-forming step takes about a day. Here, the authors report a next-generation small-molecule synthesizer that operates an order of magnitude faster than previous systems through improvements in both chemistry and engineering. Key advances include the discovery that rapid Suzuki–Miyaura cross-couplings under homogeneous conditions, although not tolerated by N-methyliminodiacetic acid boronates, are fully compatible with their more stable tetramethyl-N-methyliminodiacetic acid boronate counterparts, and the development of optimized cartridges for rapid catch-and-release purification.

Journal of the American Chemical Society

Triple Radical Sorting: Aryl-Alkylation of Alkenes

J. Z. Wang, E. Mao, J. A. Nguyen, W. L. Lyon & D. W. C. MacMillan*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05744)

The cross-coupling of aryl bromides with alkenes can provide access to diverse combinatorial chemical space. Two-component couplings between these partners are well-known, but three-component aryl-functionalizations of unactivated alkenes remain underdeveloped. In particular, the aryl-alkylation of unactivated alkenes would allow for rapid construction of molecular complexity and the expedient exploration of a pharmaceutically relevant and C(sp³ )-rich structural landscape. Herein, the authors report a general approach toward the aryl-alkylation of alkenes through a triple radical sorting mechanism. Over the course of the reaction, a high energy aryl radical, a primary radical, and a hindered alkyl radical are simultaneously formed. Through mediation by a nickel-based catalyst, the three radicals are sorted into productive bond-forming pathways toward the efficient aryl-alkylation of alkenes. A wide range of electronically and sterically differentiated alkenes and aryl radical precursors can be used to access complex scaffolds. This method was further applied to the synthesis of highly substituted semisaturated fused heterocycles.

Free-Radical Deoxygenative Amination of Alcohols via Copper Metallaphotoredox Catalysis

W. P. Carson II, A. V. Tsymbal, R. W. Pipal, G. A. Edwards, J. R. Martinelli, A. Cabré & D. W. C. MacMillan*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04477)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-12vxr) 🔓

Alcohols are among the most abundant chemical feedstocks, yet they remain vastly underutilized as coupling partners in transition metal catalysis. Herein, the authors describe a copper metallaphotoredox manifold for the open shell deoxygenative coupling of alcohols with N-nucleophiles to forge C(sp³ )–N bonds, a linkage of high value in pharmaceutical agents that is challenging to access via conventional cross-coupling techniques. N-heterocyclic carbene (NHC)-mediated conversion of alcohols into the corresponding alkyl radicals followed by copper-catalyzed C–N coupling renders this platform successful for a broad range of structurally unbiased alcohols and 18 classes of N-nucleophiles.

Photogeneration of α-Bimetalloid Radicals via Selective Activation of Multifunctional C1 Units

L. McGhie, A. Marotta, P. O. Loftus, P. H. Seeberger, I. Funes-Ardoiz* & J. J. Molloy*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02261) 🔓

Light-driven strategies that enable the chemoselective activation of a specific bond in multifunctional systems are comparatively underexplored in comparison to transition-metal-based technologies, yet desirable when considering the controlled exploration of chemical space. With the current drive to discover next-generation therapeutics, reaction design that enables the strategic incorporation of an sp³ carbon center, containing multiple synthetic handles for the subsequent exploration of chemical space would be highly enabling. Here, the authors describe the photoactivation of ambiphilic C1 units to generate α-bimetalloid radicals using only a Lewis base and light source to directly activate the C–I bond. Interception of these transient radicals with various SOMOphiles enables the rapid synthesis of organic scaffolds containing synthetic handles (B, Si, and Ge) for subsequent orthogonal activation. In-depth theoretical and mechanistic studies reveal the prominent role of 2,6-lutidine in forming a photoactive charge transfer complex and in stabilizing in situ generated iodine radicals, as well as the influential role of the boron p-orbital in the activation/weakening of the C–I bond.

Ruthenium/η⁵-Phenoxo-Catalyzed Amination of Phenols with Amines

K. Chen, Y. Ma, Y. Lin, J.-Y. Li & H. Shi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02089)

Ruthenium(II) complexes are known to form η⁶ -arene complexes with benzene-containing compounds through π-coordination, a property extensively utilized to initiate reactions not typically observed with free arenes. A prime example is nucleophilic aromatic substitution, where ruthenium-complexed aryl halides undergo nucleophilic attack. However, this activation relies on the electron-withdrawing effect of the Ru(II) species, as well as is hindered by the resistance of η⁶ -arenes to arene exchange. In this study, the authors extended the ruthenium activation strategy to umpolung substitution reactions of phenols. The amination proceeds through a direct condensation between phenols and amines, with a key intermediate identified as [bis(η⁵ -phenoxo)Ru], which is in situ generated from a commercially available ruthenium catalyst. In comparison with the well-studied cyclopentadienyl (Cp) type ligands, the authors demonstrated that an η⁵ -phenoxo motif, as a superior alternative to Cp, contributes to the amination of phenols in two crucial ways: its less electron-donating nature enhances the withdrawing effect of the ruthenium unit, facilitating substitution on the phenol complex; its distinctive behavior in arene exchange allows for conducting the amination with a catalytic amount of metal.

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π+2σ] Cycloaddition Reactions

J. L. Tyler,^† F. Schäfer,^† H. Shao, C. Stein, A. Wong, C. G. Daniliuc, K. N. Houk* & F. Glorius*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04403) 🔓

Previously highlighted as a ChemRxiv preprint on Monday 1^st April.

As the chemistry that surrounds the field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous to develop alternative reactivity modes that harness their unique properties to access new regions of chemical space. Herein, the authors report the use of photoredox catalysis to promote the single-electron oxidation of bicyclo[1.1.0]butanes. The synthetic utility of the resulting radical cations is highlighted by their ability to undergo highly regio- and diastereoselective [2π+2σ] cycloaddition reactions. The most notable feature of this transformation is the breadth of alkene classes that can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies.

Desymmetric Hydrogenation of meso-Dicarboxylic Acids

L. Yang, T. Yang, Y. Qian, X. Zhang* & J. Wen*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02538)

Efficient transformation of platform chemicals into key intermediates has been increasingly important for the pharmaceutical industry. The development of the catalytic reduction of abundant carboxylic acids with molecular hydrogen has been of both practical and theoretical value. The authors report the homogeneous hydrogenation of dicarboxylic acids with the strategy of desymmetrization. Using a rhodium/bisphosphine catalyst, one carboxyl group of meso-diacids was selectively reduced to yield chiral lactones with satisfactory enantioselectivity. This method provides a straightforward approach to produce chiral lactone intermediates for the manufacture of biotin, telaprevir, and other antivirus drugs.

A Type of Chiral C₂-Symmetric Arylthiol Catalyst for Highly Enantioselective Anti-Markovnikov Hydroamination

L. Tang, C. Shen, S. Hao & K. Dong*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04596) 🔓

The development of chiral hydrogen donor catalysts is fundamental in the expansion and innovation of asymmetric organocatalyzed reactions via an enantioselective hydrogen atom transfer (HAT) process. Herein, an unprecedented type of chiral C₂-symmetric arylthiol catalysts derived from readily available enantiomeric lactate ester was developed. With these catalysts, an asymmetric anti-Markovnikov alkene hydroamination–cyclization reaction was established, affording a variety of pharmaceutically interesting 3-substituted piperidines with moderate to high enantioselectivity.

Angewandte Chemie International Edition

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp²)–C(sp³) Couplings via Nickel Catalysis

F. Lukas,^† M. T. Findlay,^† M. Fillols, J. Templ, E. Savino, B. Martin, S. Allmendinger, M. Furegati & T. Noel*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202405902)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-b7kv6) 🔓

The development of robust and reliable methods for the construction of C(sp² )–C(sp³ ) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, the authors show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.

Umpolung-Enabled Divergent Dearomative Carbonylations

M.-Y. Wang, W.-L. Zeng, L. Chen, Y.-F. Yuan & W. Li

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202403917)

Although dearomative functionalizations enable the direct conversion of flat aromatics into precious three-dimensional architectures, the case for simple arenes remains largely underdeveloped due to the high aromatic stabilization energy. The authors report a dearomative sequential addition of two nucleophiles to arene π-bonds via umpolung of chromium-arene complexes. This mode enables divergent dearomative carbonylations of benzene derivatives by tolerating various nucleophiles in combination with alcohols or amines under CO-gas-free conditions, thus providing modular access to functionalized esters or amides. The tunable synthesis of 1,3- or 1,4-cyclohexadienes as well as the construction of all-carbon quaternary centers further highlight the versatility of this dearomatization. Diverse late-stage modifications and derivatizations towards synthetically challenging and bioactive molecules reveal the synthetic utility.

A Merger of Relay Catalysis with Dynamic Kinetic Resolution Enables Enantioselective β-C(sp³)-H Arylation of Alcohols

B. Lainer,^† S. Li,^† F. Mammadova^† & P. Dydio*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202408418)

The conceptual merger of relay catalysis with dynamic kinetic resolution strategy is reported to enable regio- and enantioselective C(sp³ )−H bond arylation of aliphatic alcohols, forming enantioenriched β-aryl alcohols typically with >90:10 enantiomeric ratios (up to 98:2 e.r.) and 36-74% yields. The starting materials bearing neighbouring stereogenic centres can be converted to either diastereomer of the β-aryl alcohol products, with >85:15 diastereomeric ratios determined by the catalysts. The reactions occur under mild conditions, ensuring broad compatibility, and involve readily available aryl bromides, an inorganic base, and commercial Ru- and Pd-complexes.

ChemRxiv

Unraveling C4 Selectivity in the Light-Driven C–H Fluoroalkylation of Pyridines and Quinolines

L. Kim,^† W. Lee^† & S. Hong*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-cfncv) 🔓

Given the prevalence of pyridine motifs in FDA-approved drugs, selective fluoroalkylation of pyridines and quinolines is essential for preparing diverse bioisosteres. However, conventional Minisci reactions often face challenges in achieving precise regioselectivity due to competing reaction sites of pyridine and the limited availability of fluoroalkyl radical sources. Herein, the authors present a light-driven, C4-selective fluoroalkylation of azines utilizing N-aminopyridinium salts and readily available sulfinates. The approach employs electron donor-acceptor complexes, achieving highly C4-selective fluoroalkylation under mild conditions without an external photocatalyst. This practical method not only enables the installation of CF₂H groups but also allows for the incorporation of CF₂-alkyl groups with diverse functional entities, surpassing the limitations of previous methods. The versatility of the radical pathway is further demonstrated through straightforward three-component reactions involving alkenes and [1.1.1]propellane.

Modular, Scalable Total Synthesis of Lapparbin

J. Zhang,^† L. Yu,^† H. Ogawa, Y. Nagata & H. Nakamura*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-0wjsp) 🔓

This work reports the development of a novel synthetic approach for the highly strained atrop-Tyr C-6-to-Trp N-1' linkage, which can be executed on a decagram scale using a modular strategy involving Pd-catalyzed C-H biarylation followed by Larock macrocyclization. Moreover, the first total synthesis of lapparbin was achieved by applying this synthetic strategy. Furthermore, the modular synthesis utilizing C-H biarylation and Larock macrocyclization, discovered in the total synthesis of lapparbin, was demonstrated to be applicable to various arbitrary biaryl linkages, including non-natural types.

Cp*Rh(III)-Catalyzed Enantioselective C(sp³)–H Amidation of Azine-Linked Cyclobutanes

X. Xu, H. Shi, P. Biallas, A. J. M. Farley, C. Genicot, K. Yamazaki* & D. J. Dixon*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-8rlk4) 🔓

The highly enantioselective desymmetrizing C(sp³ )–H amidation of azine-linked cyclobutanes with dioxazolones, to afford enantioenriched cis-configured amido-cyclobutane scaffolds is described. The reaction is catalyzed by an electron-deficient Cp*Rh(III) complex in combination with a newly designed axially chiral carboxylic acid (CCA) that was found to be key in obtaining high levels of enantiocontrol. Computational studies using DFT uncovered the reaction pathway and revealed the presence of multiple non-covalent interactions including inter- and intramolecular n–π* interactions and CH−π interactions which contributed to the high enantioselectivity. The methodology was found to be broad in scope with respect to the dioxazolone and could be further extended to larger cycloalkyl derivatives as well as bis-amidated cyclobutane derivatives.

A Light-Activated Hypervalent Iodine Agent Enables Diverse Aliphatic C–H Functionalization

Z. Lu, J. Putziger & S. Lin*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-btxdb) 🔓

The functionalization of aliphatic C–H bonds is a crucial step in the synthesis and transformation of complex molecules relevant to medicinal, agricultural, and materials chemistry. As such, there is significant interest in the development of general synthetic platforms that will enable efficient diversification of aliphatic C–H bonds. Here, the authors report a new hypervalent iodine reagent that releases a potent hydrogen atom abstractor for C–H activation under mild photochemical conditions. Using this reagent, they demonstrate the selective (N-phenyltetrazole)thiolation of aliphatic C–H bonds for a broad scope of substrates. The synthetic utility of the thiolated products is showcased through various derivatizations. Simply by altering the radical trapping agent, the method can be used to directly transform C–H bonds into diverse functionalities, including C–S, C–Cl, C–Br, C–I, C–O, C–N, and C–C bonds.

Chemical Science

Copper/Ruthenium Relay Catalysis Enables 1,6-Double Chiral Inductions with Stereodivergence

H.-R. Yang, X. Cheng, X. Chang, Z.-F. Wang, X.-Q. Dong* & C.-J. Wang*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC01804D) 🔓

The dual catalysis strategy is an efficient and powerful tool to fulfill the stereodivergent synthesis of stereoisomeric products from the same set of starting materials. Great attention has been given to the construction of chiral compounds with two contiguous stereocenters. However, the synthesis of two remote noncontiguous stereocenters is more challenging and is less developed, despite the high demand for synthetic tactics. The authors developed an unprecedented example of the stereodivergent preparation of synthetically useful and biologically important chiral ζ-hydroxy amino ester derivatives containing remote 1,6-noncontiguous stereocenters and a unique β,γ-unsaturation moiety. This cascade dehydrogenation/1,6-Michael addition/hydrogenation protocol between readily-available ketoimine esters and racemic branched dienyl carbinols was rationally realized with bimetallic copper/ruthenium relay catalysis. All four stereoisomers of chiral ζ-hydroxy amino ester derivatives were easily achieved by the orthogonal permutations of a chiral copper catalyst and chiral ruthenium catalyst.

Organic Letters

β-Hydroxy Esters as Malonic Semialdehyde Proelectrophiles in Enantioselective Butadiene-Mediated Crotylation: Total Synthesis of Octalactins A and B

J. Wu & M. J. Krische*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01644)

Tractable and commercially available esters (and amides) of β-hydroxypropionic acid serve as malonic semialdehyde proelectrophiles in enantioselective ruthenium-catalyzed hydrogen autotransfer crotylations mediated by butadiene. Through iterative asymmetric butadiene-mediated crotylations of ethyl 3-hydroxypropanoate, total syntheses of the polyketide natural products octalactin A and B were achieved in fewer steps than previously possible.

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