A Carbon-to-Nitrogen Atom Swap

Welcome to this week’s Organic Synthesis Newsletter.

Monday 14^th October – Sunday 20^th October 2024 | Volume 1, Issue 30.

HIGHLIGHT OF THE WEEK
Carbon-to-Nitrogen Atom Swap Enables Direct Access to Benzimidazoles from Drug-like Indoles

A.-S. K. Paschke, Y. Brägger, B. B. Botlik, E. Staudinger, O. Green & B. Morandi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-prwm8) 🔓

The ability to selectively edit organic molecules at the atomic level has the potential to streamline lead discovery and optimization in the pharmaceutical and agrochemical industry. While numerous atom insertion and deletion reactions have recently been reported, examples of single atom swaps remain scarce due to the challenge of orchestrating the selective cleavage and formation of multiple chemical bonds around the same atom. Herein, the authors report a method for the carbon-to-nitrogen atom swap in N-alkyl indoles, allowing for the direct conversion of indoles to the corresponding benzimidazoles. The reaction is mediated by the simple combination of commercially available PIDA and ammonium carbamate as nitrogen atom source. A wide range of functional groups are tolerated, which is demonstrated by the interconversion of 15 drug-like molecules, implying its immediate applicability across a wide range of discovery programs.

NATURE CATALYSIS
The Iron-Catalysed Suzuki Coupling of Aryl Chlorides

B. J. S. Rowsell, H. M. O’Brien, G. Athavan, P. R. Daley-Dee, J. Krieger, E. Richards, K. Heaton, I. J. S. Fairlamb & R. B. Bedford*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01234-0) 🔓

The very widely exploited Suzuki biaryl coupling reaction typically requires catalysts based on palladium, but there is an increasing desire to replace this metal with a more sustainable, less expensive alternative, with catalysts based on iron being a particularly attractive target. Here, the authors show that a simple iron-based catalyst with an N-heterocyclic carbene ligand can be used to excellent effect in the Suzuki biaryl coupling of aryl chloride substrates with aryl boronic esters activated by an organolithium reagent. Mechanistic studies suggest the possible involvement of Fe(I) as the lowest oxidation state on the catalytic manifold and show that the challenging step is not activation of the aryl chloride substrate, but rather the transmetallation step.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Decarboxylative Cross-Coupling Enabled by Fe and Ni Metallaphotoredox Catalysis

R. Nsouli, S. Nayak, V. Balakrishnan, J.-Y. Lin, B. K. Chi, H. G. Ford, A. V. Tran, I. A. Guzei, J. Bacsa, N. R. Armada, F. Zenov, D. J. Weix* & L. K. G. Ackerman-Biegasiewicz*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09621) 🔓

Decarboxylative cross-coupling of carboxylic acids and aryl halides has become a key transformation in organic synthesis to form C(sp²)–C(sp³) bonds. In this report, a base metal pairing between Fe and Ni has been developed with complementary reactivity to the well-established Ir and Ni metallaphotoredox reactions. Utilizing an inexpensive FeCl₃ cocatalyst along with a pyridine carboxamidine Ni catalyst, a range of aryl iodides can be preferentially coupled to carboxylic acids over boronic esters, triflates, chlorides, and even bromides in high yields. Additionally, carboxylic acid derivatives containing heterocycles, N-protected amino acids, and protic functionality can be coupled in 23–96% yield with a range of sterically hindered, electron-rich, and electron-deficient aryl iodides.

Electroinduced Reductive and Dearomative Alkene-Aldehyde Coupling

L. J. Franov, T. L. Wilsdon, M. L. Czyz & A. Polyzos*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08691)

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

The direct coupling of alkene feedstocks with aldehydes represents an expedient approach to the generation of new and structurally diverse C(sp³)-hybridized alcohols that are primed for elaboration into privileged architectures. Despite their abundance, current disconnection strategies enabling the direct coupling of carbon–carbon π-bonds and aldehydes remain challenging because contemporary methods are often limited by substrate or functional group tolerance and compatibility in complex molecular environments. Here, the authors report a coupling between simple alkenes, heteroarenes and unactivated aliphatic aldehydes via an electrochemically induced reductive activation of C–C π-bonds. The cornerstone of this approach is the discovery of rapid alternating polarity (rAP) electrolysis to access and direct highly reactive radical anion intermediates derived from conjugated alkenes and heterocyclic compounds. The catalyst-free protocol enables direct access to new and structurally diverse C(sp³)-hybridized alcohol products. This is achieved by the controlled reduction of conjugated alkenes and the C2–C3 π-bond in heteroarenes via an unprecedented reductive dearomative functionalization for heterocyclic compounds.

A Voltage-Controlled Strategy for Modular Shono-Type Amination

S. Su, Y. Guo, B. Parnitzke, T. Poerio & J. Derosa*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12520)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-m4l1j) 🔓

Shono-type oxidation to generate functionalized heterocycles is a powerful method for late-stage diversification of relevant pharmacophores; however, development beyond oxygen-based nucleophiles remains underdeveloped. The limited scope can often be ascribed to constant current electrolysis resulting in potential drifts that oxidize a desired nucleophilic partner. Herein, the authors report a voltage-controlled strategy to selectively oxidize a broad scope of substrates, enabling modular C–N bond formation from protected amine nucleophiles. Controlled potential electrolysis (CPE) selectively generates α-functionalized C–N products in moderate to good yields using carbamate-, sulfonamide-, and benzamide-derived nucleophiles. Sulfonamide drugs, which have significant oxidation potential overlap with model substrates, are rendered competent nucleophiles under CPE. Lastly, sequential voltage-controlled C–N and C–O functionalization of a model substrate generates difunctionalized pyrrolidines further broadening the utility of this reaction.

Ni-Catalyzed Asymmetric Reductive Arylation of α-Substituted Imides

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

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09327) 🔓

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.

Green Synthesis of Morpholines via Selective Monoalkylation of Amines

K. G. Ortiz, A. T. Brusoe,* J. An, E. Chong & L. Wu

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11708)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-5vwkp-v2) 🔓

Morpholines are common heterocycles in pharmaceutical and agricultural products, yet methods to synthesize them from 1,2-amino alcohols are inefficient. Herein, the authors report a simple, high yielding, one or two-step, redox neutral protocol using inexpensive reagents (ethylene sulfate and t-BuOK) for the conversion of 1,2-amino alcohols to morpholines. Key to this methodology is the identification of general conditions that allow for the clean isolation of monoalkylation products derived from a simple S_N2 reaction between an amine and ethylene sulfate. This method can be used for the synthesis of a variety of morpholines containing substituents at various positions, including 28 examples derived from primary amines and several examples contained in known active pharmaceutical ingredients. Multiple examples have been conducted on >50 g scale and while this new methodology has many environmental and safety benefits relative to the traditional methods used to prepare morpholines from 1,2-amino alcohols, the most striking feature is the facile selective monoalkylation of a variety of primary amines.

Iriomoteolide-1a and -1b: Structure Elucidation by Integrating NMR Spectroscopic Analysis, Theoretical Calculation, and Total Synthesis

T. Obana, M. Nakajima, K. Nakazato, H. Nakagawa, K. Murata, M. Tsuda* & H. Fuwa*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11714)

The structure of iriomoteolide-1a, a marine macrolide with potent cytotoxic activity against human cancer cells, has been under scrutiny for more than a decade since the first total synthesis of the proposed structure was achieved by Horne. Here, the authors disclose the correct structure of iriomoteolide-1a. Given a huge number of possible stereoisomers, an integrated strategy was adopted towards the structural elucidation of iriomoteolide-1a: (1) NMR spectroscopic analysis/molecular mechanics-based conformational analysis for configurational reassignment of the macrolactone domain; (2) model synthesis for validating the reassigned configuration of the macrolactone domain; (3) GIAO NMR calculation/DP4+ analysis of side chain stereoisomers; and (4) total synthesis of the most likely structure. Moreover, the correct structure of iriomoteolide-1b, a natural congener, was also determined by an integration of NMR spectroscopic analysis, GIAO NMR calculation/DP4+ analysis, and total synthesis.

A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

G. L. Barnes,^† N. L. Magann,^† D. Perrotta, F. M. Hörmann, S. Fernandez, P. Vydyam, J.-Y. Choi, J. Prudhomme, A. Neal, K. G. Le Roch, C. B. Mamoun & C. D. Vanderwal*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11897) 🔓

On the basis of a streamlined route to the pyrroloiminoquinone (PIQ) core, the authors made 16 natural products spread across four classes of biosynthetically related alkaloid natural products, and multiple structural analogs, all in ≤8 steps longest linear sequence (LLS). The strategy features a Larock indole synthesis as the key operation in a five-step synthesis of a key methoxy-PIQ intermediate. Critically, this compound was readily diverged via selective methylation of either (or both) of the imine-like or pyrrole nitrogens, which then permitted further divergence by either O-demethylation to o-quinone natural products or displacement of the methoxy group with a range of amine nucleophiles. Based on a single, early report of their potential utility against the malaria parasite, these compounds were assayed against several strains of Plasmodium falciparum, as well as two species of the related protozoan parasite Babesia. In combination with evaluations of their human cytotoxicity, several compounds were identified with potent (low-nM IC50) antimalarial and antibabesial activities that are much less toxic toward mammalian cells and are therefore promising lead compounds for antiprotozoal drug discovery.

Highly Enantioselective Decarboxylative Difluoromethylation

X. Zhao,^† C. Wang,^† L. Yin^† & W. Liu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11257)

Organofluorine molecules that contain difluoromethyl groups (CF₂H) at stereogenic centers have gained importance in pharmaceuticals due to the unique ability of CF₂H groups to act as lipophilic hydrogen bond donors. Despite their potential, the enantioselective installation of CF₂H groups into readily available starting materials remains a challenging and underdeveloped area. In this study, the authors report a nickel-catalyzed decarboxylative difluoromethylation reaction that converts alkyl carboxylic acids into difluoromethylated products with exceptional enantioselectivity. This Ni-catalyzed protocol exhibits broad functional group tolerance and is applicable for synthesizing fluorinated bioisosteres of biologically relevant molecules.

Asymmetric Amination of Unstrained C(sp³)–C(sp³) Bonds

Y. Liu, Y.-W. Chen, Y.-X. Yang, J. F. Hartwig* & Z.-T. He*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11802)

The asymmetric functionalization of unstrained C(sp³)–C(sp³) bonds could be a powerful strategy to stereoselectively reconstruct the backbone of an organic compound, but such reactions are rare. Although allylic substitutions have been used frequently to construct C–C bonds by the cleavage of more reactive C–X bonds (X is usually an O atom of an ester) by transition metals, the reverse process that involves the replacement of a C–C bond with a C–heteroatom bond is rare and generally considered thermodynamically unfavorable. Here, the authors show that an unstrained, inert, allylic C–C σ bond can be converted to a C–N bond stereoselectively via a designed solubility-control strategy, which makes the thermodynamically unfavorable process possible. The C–C bond amination occurs with a range of amine nucleophiles and cleaves multiple classes of alkyl C–C bonds in good yields with high enantioselectivity. A novel resolution strategy is also reported that transforms racemic allylic amines to the corresponding optically active allylic amine by the sequential conversion of a C–N bond to a C–C bond and back to a C–N bond.

Catalyst-Controlled Chemoselective γ-C(sp³)–H Lactonization of Carboxylic Acid: Methyl versus Methylene

J.-L. Yan,^† L. Hu,^† Y. Lu & J.-Q. Yu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12907)

Despite recent advances in ligand-enabled C(sp³)–H functionalization of native substrates, controlling chemoselectivity in the presence of methyl and methylene C(sp³)–H bonds remains a significant challenge. Herein, the authors report the first example of the Pd(II)-catalyzed chemoselective lactonization of γ-methyl and methylene C(sp³)–H bonds of carboxylic acids. Exclusive chemoselectivity of methyl or methylene γ-lactonization was achieved by using two different classes of Quinoline-Pyridone ligands. The bidentate ligand coordinating with Pd(II) via five-membered chelation favors γ-methyl C–H lactonization, whereas the ligand forming six-membered chelation affords γ-methylene C–H lactonization exclusively. This method provides simple and versatile access to γ-lactones, including spiro- and fused ring systems.

Si-Linked Glycomimetics through a Stereoselective Silicon Transfer and Anion Addition

S. V. Shelar, T. Davis, N. Ryan, K. Fisch & M. A. Walczak*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10978)

The authors report a synthesis of silicon-linked glycomimetics, demonstrating unique structural properties and metabolic stability due to the inertness of the C–Si bond. The method focuses on the stereoselective transfer of silicon and anion addition, revealing that chirality at the silicon atom can be controlled through kinetic resolution. This approach allows for the selective generation of 1,2-cis and 1,2-trans-isomers via the manipulation of C2-protected silicon ethers and nucleophilic opening of glycal epoxides. High selectivity at the anomeric carbon was achieved and the scope was expanded to include various saccharides and substituted silanes. Additionally, the chiral silanes produced hold promise for medicinal chemistry applications, addressing significant gaps in the synthesis and utility of glycomimetics.

ORGANIC PROCESS RESEARCH & DEVELOPMENT
Advancing Base-Metal Catalysis: Developing Nickel Catalysis for the Direct Telescope of Miyaura Borylation and Suzuki–Miyaura Cross-Coupling Reactions

H. A. Esteves, M. J. Goldfogel,* A. Shemet, C. Peng, B. Hritzko, E. M. Simmons & S. R. Wisniewski

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00327)

The development of an efficient and general telescoped nickel-catalyzed Suzuki–Miyaura coupling (SMC) process from a nickel-catalyzed borylation reaction to form Csp²–Csp² bonds without isolation of the intermediate aryl boronate has been a long-standing interest for process chemists. Most scalable borylation/SMC sequences currently use palladium catalysts in subsequent catalytic steps, yet the ability to utilize nickel has the potential to greatly improve efficiency and decrease cost while also improving sustainability. This work introduces nickel-catalyzed SMC methodology that operates under homogeneous biphasic conditions to minimize inhibition from reaction byproducts of borylation and benefits from the addition of methanol as a cosolvent. These findings enabled the development of a one-pot, two-reaction method, which is demonstrated with a variety of complex heterocyclic coupling partners as both the nucleophilic aryl boronic acid and the electrophilic aryl halide, including an array of bioactive molecules that are representative of pharmaceutical synthetic targets. A comparison of this nickel-catalyzed telescoped process to the analogous palladium-catalyzed telescoped process is included to guide future use cases. A decagram scale telescoped process utilizing pharmaceutically relevant aryl halides demonstrates its scalability.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Fe-Catalyzed α-C(sp³)–H Amination of N-Heterocycles

A. Geraci & O. Baudoin*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202417414) 🔓

The authors report a site-selective intermolecular C(sp³)–H amination of N-heterocycles catalyzed by inexpensive FeCl₂, which allows for the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C–H amination occurs selectively at the α-position to the nitrogen atom, even when weaker C–H bonds are present, and furnishes Troc-protected aminals or amidines. The method employs the N-heterocycle as the limiting reagent and is applicable to the late-stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α-aminated products and the application to a concise total synthesis of the reported structure for senobtusin.

Photochemical Deracemization of N-Carboxyanhydrides en route to Chiral α-Amino Acid Derivatives

M. Iglhaut, P. Freund & T. Bach*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202418873) 🔓

Readily accessible, racemic N-carboxyanhydrides (NCAs) of α-amino acids underwent a deracemization reaction upon irradiation at λ = 366 nm in the presence of a chiral benzophenone catalyst. The enantioenriched NCAs (up to 98% e.e.) serve as activated α-amino acid surrogates and, due to their instability, they were directly converted into consecutive products. N-Protected α-amino acid esters were obtained after reaction with MeOH and N-benzoylation (14 examples, 70%-quant., 82–96% e.e.). Other consecutive reactions included amide (10 examples, 65%-quant., 90–98% e.e.) and peptide (3 examples, 75–89%, 88–94% d.e.) bond formation.

CHEMRXIV
Organophotocatalytic Reduction of Benzenes to Cyclohexenes

K. Devi,^† A. Shehzad^† & M. P. Wiesenfeldt*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-pzf57) 🔓

The reduction of abundant benzene rings to scarce C(sp³)-rich motifs is invaluable for drug design as C(sp³) content is known to correlate with clinical success. Cyclohexenes are attractive targets as they can be rapidly elaborated into large product libraries and are stable against rearomatization. However, partial reduction reactions of benzenes to cyclohexenes are rare and have a very narrow scope. Herein, the authors report a broadly applicable method that converts electron-poor benzenes to cyclohexenes and tolerates Lewis-basic functional groups like triazoles and thioethers, as well as reducible groups like cyanides, alkynes, and sulfones. The reaction utilizes an organic donor that induces mild arene reduction by pre-association to a photo-excitable electron-donor-acceptor (EDA) complex and mild isomerization of redox-inert 1,4-cyclohexadienes to reducible 1,3-cyclohexadienes without a strong base in its oxidized thioquinone methide form.

Generation of Connections Between Protein Sequence Space and Chemical Space to Enable a Predictive Model for Biocatalysis

A. E. Paton, D. A. Boiko, J. C. Perkins, N. I. Cemalovic, T. Reschützegger, G. Gomes* & A. R. H. Narayan*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-w4dtr) 🔓

The application of biocatalysis in synthesis has the potential to offer dramatically streamlined routes toward target molecules as well as more sustainable processes. Despite these advantages, biocatalytic synthetic strategies can be high risk to implement, often calling for extensive screening of enzymes and protein engineering. Strategies for predicting which enzyme is most likely to be compatible with a given small molecule have been hindered by the lack of well-studied biocatalytic reactions. The under exploration of connections between chemical and protein sequence spaces constrains navigation between these two landscapes. Herein, this longstanding challenge is overcome in a two-phase effort relying on high throughput experimentation to populate connections between substrate chemical space and biocatalyst sequence space, and the subsequent development of machine learning models that enable the navigation between these two landscapes. Using a curated library of α-ketoglutarate-dependent non-heme iron (NHI) enzymes, the BioCatSet1 dataset was generated to capture the reactivity of each biocatalyst with >100 substrates. In addition to the discovery of novel chemistry, BioCatSet1 was leveraged to develop a predictive workflow that provides a ranked list of enzymes that have the greatest compatibility with a given substrate. To make this tool accessible to the community, the authors built CATNIP, an open access web interface to their predictive workflows.

Synthesis and Functionalization of Sulfoximine-Bicyclo[1.1.0]butanes: Functionalizable, Tuneable and Cysteine-Selective Chiral Warheads

Z. Zhong, B. J. W. Hocking, C. P. Brown, T.-K. Ma, A. J. P. White, David J. Mann, Alan Armstrong & J. A. Bull*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-4pknv) 🔓

Electrophilic covalent warheads with appropriate reactivity and selectivity are crucial to the investigation of protein function and the discovery of therapeutics. Here, the authors report the synthesis of sulfoximine bicyclo[1.1.0]butanes (BCBs) as novel thiol reactive chiral warheads, achieved in one-pot from methylsulfoximines. Unusually the warhead can then be derivatized, keeping the BCB intact, over 3 vectors: i) sulfoximine N-modification instills a broad range of strain-release reactivity; ii) sp²-cross-coupling reactions on aryl-BCB-sulfoximines allows direct diversification, and iii) functionalization of the BCB motif itself is achieved by metalation and trapping with electrophiles. The BCB sulfoximines are shown to react selectively with cysteine including in a protein model (CDK2) under biocompatible conditions. Preliminary data indicate suitability for chemoproteomic applications, and enantioselective cysteine-labelling. The reactivity of sulfoximine BCBs with electron withdrawing groups on nitrogen is comparable to acrylamides with low to moderate reactivity.

JOURNAL OF ORGANIC CHEMISTRY
Impact of C–H Cross-Coupling Reactions in the One-Step Retrosynthesis of Drug Molecules

B. Mahjour, K. M. Flynn, S. S. Stahl* & T. Cernak*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c01567)

Pharmaceutical synthesis requires a diversity of chemical reactions. The discovery of new reactions enable novel retrosynthetic disconnections, potentially expediting access to complex molecules. This Synopsis demonstrates the use of enumerative combinatorics to find impactful underdeveloped reactions for drug synthesis. By mapping pharmaceutical target molecules onto available building blocks using just one retrosynthetic disconnection even if the requisite reaction is not yet known, the authors highlight the importance of site-selective C–H cross-coupling methods. This cheminformatics-driven retrosynthetic analysis identifies novel reaction methods of value to the synthesis toolbox.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
A Molecular “Dimmer Switch”

🔦 A molecular “dimmer switch”. Scientists at Novo Nordisk, in collaboration with Carbometrics and the University of Bristol, have developed a “smart” insulin that is capable of dynamically responding to changes in blood glucose levels. The modified insulin, which was equipped with a molecular “dimmer switch” to allow for precise control over blood glucose levels, was found to effectively lower these levels in pigs and rats as good as normal human insulin without causing them to drop too much, avoiding potentially deadly hypoglycaemia.