Radical Simplicity

Welcome to this week’s Organic Synthesis Newsletter.

Monday 11^th November – Sunday 17^th November 2024 | Volume 1, Issue 34

HIGHLIGHT OF THE WEEK
A General Redox-Neutral Platform for Radical Cross-Coupling

Á. Péter,^† J. Sun,^† J. He,^‡ J. Tsien,^‡ H. Zhang,^‡ B. P. Vokits, D. S. Peters, M. D. Mandler, M. D. Palkowitz, Y. Kawamata & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-40szn) 🔓

Sulfonyl hydrazides are disclosed as versatile radical precursors as exemplified with seven new C–C bond forming, redox neutral cross-couplings with: (1) unsaturated olefins, (2) alkyl halides, (3) redox active esters, (4) aryl halides, (5) alkenyl halides, (6) alkynyl halides, and (7) a trifluoromethylating reagent to forge C(sp³)-C(sp³), C(sp³)-C(sp²), and C(sp³)-C(sp) bonds. Sulfonyl hydrazides are stable and usually crystalline substances that can be accessed in a variety of ways including transiently from hydrazones to achieve a net reductive arylation of carbonyl compounds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary as these functional groups serve the dual role of radical precursor and electron donor. The operational simplicity (homogeneous, water tolerant, dump-and-stir) and practicality of the method are demonstrated as well as applications to streamlining synthesis and mild late-stage functionalization.

SCIENCE
Synchronous Recognition of Amines in Oxidative Carbonylation toward Unsymmetrical Ureas

J. Wang,^† S. Wang,^† Z. Wei,^† P. Wang, Y. Cao, Y. Huang, L. He* & A. Lei*

Science 2024, 386, 776–782 (DOI: 10.1126/science.adl0149)

Unsymmetrical ureas are commonly found in pharmaceuticals and bioactive compounds. However, devising strategies to introduce two distinct amines selectively in the construction of unsymmetrical ureas remains a challenge. In this work, the authors use a synchronous recognition strategy that takes advantage of radical and nucleophilic activation to discriminate between secondary and primary amines. Specifically, a copper catalyst preferentially oxidizes secondary amines to radical species, whereas a cobalt catalyst carbonylates primary amines to produce cobalt amides. Coupling these fragments by cooperative catalysis produces unsymmetrical ureas with high selectivity, as showcased by the modification of 41 biologically active compounds and six drugs.

NATURE
Photochemical Permutation of Thiazoles, Isothiazoles and Other Azoles

B. Roure, M. Alonso,^‡ G. Lonardi,^‡ D. B. Yildiz, C. S. Buettner, T. dos Santos, Y. Xu, M. Bossart, V. Derdau, M. Méndez, J. Llaveria, A. Ruffoni* & D. Leonori*

Nature 2024 (DOI: 10.1038/s41586-024-08342-8)

Thiazoles and isothiazoles are privileged motifs in drug and agrochemical discovery. The synthesis of these derivatives is generally approached, designed and developed on a case-by-case basis. Here, the authors report a conceptually different approach whereby photochemical irradiation can be used to alter the structure of thiazoles and isothiazoles in a selective and predictable manner. Upon photoexcitation, these derivatives populate their π,π* singlet states that undergo a series of structural rearrangements leading to an overall permutation of the cyclic system and its substituents. This approach operates under mild photochemical conditions which tolerate complex scaffolds and chemically distinct functionalities. Preliminary findings also indicate the potential for extending this method to other azole systems, including benzo[d]isothiazole, indazole, pyrazole and isoxazole.

Fluorspar to Fluorochemicals upon Low-Temperature Activation in Water

I. Klose,^† C. Patel,^† A. Mondal,^† A. Schwarz, G. Pupo & V. Gouverneur*

Nature 2024 (DOI: 10.1038/s41586-024-08125-1) 🔓

Hydrogen fluoride sits at the apex of the fluorochemical industry but the substantial hazards linked to its production under harsh conditions (>300 °C) and transport are typically contracted to specialists. All fluorochemicals for applications, including refrigeration, electric transportation, agrochemicals and pharmaceuticals, are prepared from fluorspar (CaF₂) through a procedure that generates highly dangerous hydrogen fluoride. Here, the authors report a mild method to obtain fluorochemicals directly from fluorspar, bypassing the necessity to manufacture hydrogen fluoride. Acid-grade fluorspar (>97% CaF₂) is treated with the fluorophilic Lewis acid boric acid (B(OH)₃) or silicon dioxide (SiO₂), in the presence of oxalic acid, a Brønsted acid that is highly effective for Ca²⁺ sequestration. This scalable process carried out in water at low temperature (<50 °C) enables access to widely used fluorochemicals, including tetrafluoroboric acid, alkali metal fluorides, tetraalkylammonium fluorides and fluoro(hetero)arenes.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Ten-Step Total Synthesis of (±)-Phaeocaulisin A Enabled by Cyclopropanol Ring-Opening Carbonylation

C. Liu, M. Zhang, L. Zeng, Y. Wan* & M. Dai*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12121) 🔓

The authors report an efficient total synthesis of (±)-phaeocaulisin A, a guaianolide sesquiterpene natural product possessing a complex tetracyclic skeleton embedded with an oxaspirolactone and a fused bicyclic lactone, four oxygen-containing stereocenters, and an 8-oxabicyclo[3.2.1]octane core. The synthesis features a novel palladium-catalyzed cyclopropanol ring-opening carbonylation to access a key γ-ketoester, a chemo- and stereoselective aldol cyclization to form the seven-membered carbocycle, and a cascade ketalization–lactonization to construct the desired tetracyclic skeleton. With these strategically important C–C and C–O bond formation transformations, a 10-step total synthesis of (±)-phaeocaulisin A was achieved. Biologically, the penultimate intermediate with an α-methylene γ-butyrolactone moiety was identified as a promising lead compound with anticancer proliferation activity against a panel of triple-negative or HER2+ breast cancer cell lines.

Concise Synthesis of Norzoanthamine Enabled by a Set of Photochemical Transformations

Y. Sun, X. Zhang, F. Jiang, M. Zhang, W. Wu & Y. Sun*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14081)

Norzoanthamine is a structurally complex polycyclic natural product that expresses a broad range of biological activities. However, efficient access to norzoanthamine and its structurally related analogs remain lacking. Here, the authors report a strategy, characterized by three key photochemical reactions, that were used to synthesize norzoanthamine in 16 steps. A photoinduced dearomative-6π-desymmetrization was developed for facile access to the ABC-tricyclic core of the alkaloid. This was supplemented by a [2+2]-photocycloaddition, a visible-light-induced decarboxylative borylation, and a retro-aldol process, constituting an effective solution to the challenging problem of establishing the C9–C22 vicinal all-carbon quaternary stereogenic centers. Finally, a one-pot cascade transformation, involving global deprotection, cyclization, and epimerization reaction, was designed for efficient and stereocontrolled assembly of the core framework of norzoanthamine.

General Alkene 1,2-syn-Cyano-Hydroxylation Procedure via Electrochemical Activation of Isoxazoline Cycloadducts

T. A. S. Wanderley, R. Buscemi, Ó. Conboy, B. Knight & G. E. M. Crisenza*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13682) 🔓

Stereoselective alkene 1,2-difunctionalization is a privileged strategy to access three-dimensional C(sp³)-rich chiral molecules from readily available “flat” carbon feedstocks. Here, the authors describe a practical, general and selective electrosynthetic strategy for olefin 1,2-syn-difunctionalization, which hinges on the design of novel reagents consisting of a nitrile oxide 1,3-dipole precursor, equipped with a sulfonyl-handle. These can selectively difunctionalize alkenes via “click” 1,3-dipolar cycloadditions and ensuing reduction of the cycloadduct triggers a radical fragmentation pathway delivering sought-after stereodefined 1,2-syn-hydroxy nitrile derivatives. The procedure tolerates a wide range of functionalities and enables the difunctionalization of electron-rich, electron-poor and unactivated olefins, providing a robust, general and selective metal-free alternative to current alkene difunctionalization strategies. Capitalizing on these features, the electrosynthetic method was employed to enable the late-stage syn-hydroxy-cyanation of natural products and bioactive compounds, and streamline the de novo synthesis of pharmaceutical agents.

Oxoammonium-Catalyzed Oxidation of N-Substituted Amines

J. Rein,^† B. Górski,^† Y. Cheng,^‡ Z. Lei,^‡ F. Buono & S. Lin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11758)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-brd62) 🔓

The authors report the development of an oxoammonium-catalyzed oxidation of N-substituted amines via a hydride transfer mechanism. Steric and electronic tuning of catalyst led to complementary sets of conditions that can oxidize a broad scope of carbamates, sulfonamides, ureas, and amides into the corresponding imides. The reaction was further demonstrated on a 100-g scale using a continuous flow setup.

Oxoammonium-Catalyzed Ether Oxidation via Hydride Abstraction: Methodology Development and Mechanistic Investigation Using Paramagnetic Relaxation Enhancement NMR

Y. Cheng, J. Rein, N. Le & S. Lin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11760)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-gzx7t) 🔓

Hydride abstraction represents a promising yet underexplored approach in the functionalization of C–H bonds. In this work, the authors report the oxidation of α-C–H bonds of ethers via oxoammonium catalysis using meta-chloroperbenzoic acid (m-CPBA) as the terminal chemical oxidant or by means of electrochemistry. Mechanistic studies revealed intricate equilibria and interconversion events between various catalytic intermediates in the presence of m-CPBA, which alone however was incompetent to drive catalytic turnover. The addition of a small amount of strong acid HNTf₂ or weakly coordinating salt NaSbF₆ turned on catalytic turnover and promoted ether oxidation with excellent efficiency. NMR experiments leveraging paramagnetic relaxation enhancement effect allowed for quantification of open-shell catalytic intermediates in real time during the reaction course, which aided the identification of catalyst resting states and elucidation of reaction mechanisms.

Enantioselective 1,4-Borylamination via Copper-Catalyzed Cascade Hydroborylation and Hydroamination of Arylidenecyclopropanes

Y.-S. Zhu, Y.-L. Guo, Y.-Y. Zhu & B. Su*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12852)

Compounds bearing both boryl and amino groups at distal positions are invaluable synthons for synthesizing pharmaceuticals, drug candidates, and natural products, but their catalytic enantioselective synthesis remains rarely explored. Here, the authors report the first enantioselective 1,4-borylamination reaction through a copper-catalyzed cascade hydroborylation and hydroamination of arylidenecyclopropanes. This reaction combines four readily available components in a highly chemo-, site-, and enantioselective fashion (>20:1 r.r. and up to 99% e.e.), yielding a diverse array of synthetically valuable enantioenriched 4-amino alkylboronates. The versatile utility of these products is highlighted by their diverse transformations and wide applications in pharmaceutical synthesis and drug discovery.

Cobalt-Hydride-Catalyzed Alkene-Carboxylate Transposition (ACT) of Allyl Carboxylates

G. Zhao,* A. Khosravi,^‡ S. Sharma,^‡ D. G. Musaev* & M.-Y. Ngai*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12583)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-glz1z) 🔓

The alkene-carboxylate transposition (ACT) of allyl carboxylates is one of the most atom-economic and synthetically reliable transformations in organic chemistry. Classic ACT transformations, including [3,3]-sigmatropic rearrangement and transition metal-catalyzed allylic rearrangement, typically yield 1,2-alkene/1,3-acyloxy shifted products through a two-electron process. However, position-altered ACT to produce distinct 1,3-alkene/1,2-acyloxy shifted products remains elusive. Here, the authors report the first cobalt-hydride-catalyzed ACT of allyl carboxylates, enabling access to these unprecedented 1,3-alkene/1,2-acyloxy shifted products via a 1,2-radical migration (RaM) strategy. This transformation demonstrates broad functional group tolerance, is suitable for late-stage modification of complex molecules, and is amenable to gram-scale synthesis.

Cu-Catalyzed Asymmetric Three-Component Radical Acylarylation of Vinylarenes with Aldehydes and Aryl Boronic Acids

Z. Li, S. Wang, S.-C. Chen, X. Zhu, Z. Lian & D. Xing*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08957)

The direct use of readily available aldehydes as acyl radical precursors has facilitated diverse three-component acylative difunctionalization reactions of alkenes, offering a powerful route to synthesize β-branched ketones. However, asymmetric three-component acylative difunctionalization of alkenes with aldehydes still remains elusive. Here, the authors report a copper-catalyzed asymmetric three-component radical acylarylation of vinylarenes with aldehydes and aryl boronic acids. This strategy enables the direct synthesis of a range of synthetically valuable chiral β,β-diaryl ketones from aldehydes and vinylarenes.

An Air-Stable, Single-Component Iridium Precatalyst for the Borylation of C–H Bonds on Large to Miniaturized Scales

K. A. D’Angelo,^† C. La,^† B. Kotecki, J. W. Wilson, C. Karmel, R. Swiatowiec, N. P. Tu,* S. Shekhar* & J. F. Hartwig*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12333)

The functionalization of C–H bonds enables the modification of complex molecules, often with the intention of forming compound libraries. The borylation of aryl C–H bonds is a widely used class of C–H bond functionalization, of which, conventional catalyst systems typically consist of an iridium source and an N,N-ligand, in conjunction with pinacolborane, to form the active iridium(III) tris(boryl) catalyst. These multicomponent catalyst systems complicate borylation reactions, in part, due to the air sensitivity of the most common iridium precursor [Ir(cod)OMe]₂. Here, the authors describe the discovery of an air-stable, single-component iridium precatalyst, [(tmphen)Ir(coe)₂Cl], that generates the same active iridium(III) tris(boryl) catalyst and reacts with higher turnovers, comparable selectivity, and similar scope to those of known catalyst systems for the borylation of aryl and heteroaryl C–H bonds.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Redox-Tunable Ring Expansion Enabled By A Single-Component Electrophilic Nitrogen Atom Synthon

P. Q. Kelly, N. R. Keramati, K. R. Kaplin, T. Lynch-Colameta, J. P. Phelan & M. Levin*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202420664)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-8rq8l) 🔓

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, the authors 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.

CHEMRXIV
Alkyl Sulfonyl Fluorides as Ambiphiles in the Stereoselective, Palladium(II)-Catalyzed Cyclopropanation of Unactivated Alkenes

Y. Cao, W. Rodphon, T. M. Alturaifi, A. V. R. D. Lisboa, Z. Ren, J. J. C. Struijs, H.-Q. Ni, T. Savchuk, P. K. Mykhailiuk, R. P. Loach, S. Yang, I. J. McAlpine, D. G. Blackmond, P. Liu*, K. B. Sharpless* & K. M. Engle*

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

The ambiphilic reactivity of alkyl sulfonyl fluorides in the stereoselective synthesis of diverse cyclopropanes from olefins under palladium(II) catalysis is presented. The sulfonyl fluoride functionality serves as both an acidifying group and an internal oxidant within the ambiphile, enabling the successive carbopalladation and oxidative addition steps in the catalytic cycle, respectively. The transformation grants access to cis-substituted cyclopropanes and exhibits broad compatibility with various alkyl sulfonyl fluorides, including those bearing –CN, –CO₂R, isoxazolyl, pyrazolyl, and aryl groups. With internal alkene substrates, 1,2-3-trisubstituted cyclopropanes that are otherwise challenging to synthesize are formed in good to moderate yield and predictable diastereoselectivity.

Merging Photoexcited Nitroarenes with Lewis Acid Catalysis for the Anaerobic Oxidation of Alkenes

J. M. Paolillo, M. R. Saleh, E. W. Junk & M. Parasram*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-3mcc5-v2) 🔓

A protocol for the oxidation of alkenes to carbonyls and acetonides via the interplay of photoexcited nitroarenes and Lewis acid catalysis is described. Terminal 1,1-disubstitued alkenes were oxidized selectively to the aldehyde products, while tri- and tetrasubstituted alkenes generated ketone products with anti-Markovnikov selectivity. Terminal mono-substituted alkenes were oxidized to acetonides when acetone was employed as a co-solvent. The mild conditions of the reaction allow for a wide range of alkenes to be oxidized.

Collective Asymmetric Synthesis of the Strychnos Alkaloids via Thiophene S,S-Dioxide Cycloaddition Cascades

K. H. Park,^† J. Park,^† N. Frank, H. Zhang, F. Duarte,* & E. A. Anderson*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-tk00d) 🔓

The Strychnos alkaloids have long been regarded as landmark targets for chemical synthesis due to their captivating architectures and notorious biological properties. The family has fascinated chemists for almost 100 years, since the decades-long debate over the structure of the “flagship” member strychnine, and its first total synthesis by Woodward. In spite of this rich history, the design of approaches that can access multiple family members, in an asymmetric, concise, and atom-economical fashion, remains a significant challenge. Here, the authors show that thiophene S,S-dioxides (TDOs) offer a modular and concise entry to the Strychnos natural products. The rapid assembly of a tryptamine-tethered TDO enables the synthesis of akuammicine in just three steps from tryptamine, with minimal waste generation. Exceptional levels of stereocontrol were demonstrated in unprecedented asymmetric cycloadditions of chiral thiophene S,S-dioxides; these afford tricyclic indolines that are of interest for medicinal chemistry applications, and also enable highly concise, stereoselective and scalable syntheses of the Strychnos alkaloids by either intra- or intermolecular asymmetric cycloadditions.

ORGANIC LETTERS
Rapid and General Amination of Aryl Boronic Acids and Esters Using O-(Diphenylphosphinyl)hydroxylamine (DPPH)

M. G. Kung, P. Onnuch & R. Y. Liu*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c03625)

O-(Diphenylphosphinyl)hydroxylamine (DPPH) is a general reagent for the conversion of (hetero)aryl boronic acids and esters to primary anilines. The transformation proceeds rapidly at ambient temperature and exhibits a broad substrate scope and exceptional functional-group tolerance. In terms of rate, the reaction is relatively insensitive to the electronic properties of the substrate, in contrast to similar reactions using electrophilic amination reagents such as hydroxylamine-O-sulfonic acid. Consequently, this protocol is particularly useful for accessing electron-deficient (hetero)aryl anilines, which had been challenging to prepare using prior methods.

THE JOURNAL OF ORGANIC CHEMISTRY
Expedited Aminoglutarimide C–N Cross-Coupling Enabled by High-Throughput Experimentation

J. W. Gu, M. S. Oderinde, H. Li, F. Roberts, J. M. Ganley* & M. D. Palkowitz*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c02536)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-1skr0) 🔓

A simple protocol for the Buchwald–Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse cereblon binding motifs is disclosed. The development of this C–N cross-coupling method was enabled by high-throughput combinatory screening of solvents, bases, temperatures, and ligands. Scope studies revealed generality across various heteroaryl and aryl halides with the reaction proceeding under mild conditions. In comparison, this method demonstrated strategic superiority over previously reported approaches, as evidenced by a significant decrease in step count from known syntheses in the patent literature.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Artemisinin Resistance Detected in Children with Severe Malaria

🦟 Artemisinin resistance in children with severe malaria raises concerns. In 2022, over 600,000 people died from malaria with 95% of those deaths occurring in the WHO African Region where children under 5 accounted for 80% of that figure. First-line treatments for uncomplicated malaria involve the use of artemisinin-based combination therapies (ACTs) but more complicated, severe cases, require the intravenous use of the semi-synthetic artemisinin derivative, artesunate, followed by ACTs. While partial resistance to artemisinin (characterised by a delay in the clearance of malaria parasites following ACTs) has been observed in uncomplicated malaria, only now has a new study of 100 children with severe malaria in Uganda found that 10% showed this resistance. While the study was too small to determine whether or not artemisinin partial resistance leads to worse clinical outcomes, the worry is that slower acting therapies may lead to increased mortality, especially for those who are most vulnerable.