💡 Reducing Benzenes with Light

Welcome to this week’s Organic Synthesis Newsletter.

Monday 2^nd December – Sunday 8^th December 2024 | Volume 1, Issue 37

HIGHLIGHT OF THE WEEK
Organophotocatalytic Reduction of Benzenes to Cyclohexenes

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

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14669)

Previously: ChemRxiv (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 such as triazoles and thioethers as well as reducible groups such as cyanides, alkynes, and sulfones.

NATURE COMMUNICATIONS
Palladium-Catalyzed Remote Internal C(sp³)−H Bond Chlorination of Alkenes

Y.-X. Wang, Z. Wang & X.-H. Yang*

Nat. Commun. 2024, 15, 10629 (DOI: 10.1038/s41467-024-54896-6) 🔓

C(sp³)–Cl bonds are present in numerous biologically active molecules and can also be used as a site for diversification by substitution or cross-coupling reactions. Herein, the authors report a remote internal site-selective C(sp³)–H bond chlorination of alkenes through sequential alkene isomerization and hydrochlorination, enabling the synthesis of both benzylic and tertiary chlorides with excellent site-selectivity. The regioconvergent synthesis of a single alkyl chloride from unrefined mixtures of isomeric alkenes—which can be extracted directly from petrochemical sources—was also demonstrated.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Total Synthesis of Euphorbialoid A

J. Taguchi, S. Fukaya, H. Fujino & M. Inoue*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14520)

Euphorbialoid A belongs to the rare diterpenoid family of premyrsinanes and exhibits potent anti-inflammatory effects. The 5/7/6/3-membered carbocycle (ABCD-ring) contains 11 contiguous stereocenters and 7 oxygen-containing functional groups. Moreover, four of the six hydroxy groups are concentrated in the southern sector and flanked by four structurally different acyl groups. As a reflection of its formidable complexity, synthesis of euphorbialoid A or any other premyrsinane diterpenoids has not yet been reported. Here, the authors devised a novel strategy comprising two stages and achieved the first total synthesis of euphorbialoid A (35 steps; longest linear sequence).

Copper(I)-Catalyzed Enantioselective α-Alkylation of 2-Acylimidazoles

Z.-C. Liu,^† H.-M. Zhang,^† Y. Li, Z.-Q. Wang & L. Yin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12154)

Catalytic asymmetric α-alkylation of simple carboxylic acid derivatives is challenging due to the difficulties in achieving high catalytic efficiency and controlling enantioselectivity. Herein, by using a copper(I)-(R)-DTBM-SEGPHOS complex as a catalyst and 2-acylimidazoles as pronucleophiles, a general method for the catalytic asymmetric α-alkylation of simple carboxylic acid derivatives is accomplished. Various alkyl electrophiles, including allyl bromides, benzyl bromides, propargyl bromide, and unactivated alkyl sulfonates, serve as efficient alkylation reagents. Finally, the synthetic utility of the method is demonstrated by the asymmetric formal synthesis of AZD2716, a potent secreted phospholipase A₂ inhibitor.

Catalytic Intermolecular Asymmetric [2π+2σ] Cycloadditions of Bicyclo[1.1.0]butanes: Practical Synthesis of Enantioenriched Highly Substituted Bicyclo[2.1.1]hexanes

Y.-J. Li,^† Z.-L. Wu,^† Q.-S. Gu,^† T. Fan,^† M.-H. Duan, L. Wu, Y.-T. Wang, J.-P. Wu, F.-L. Fu, F. Sang, A.-T. Peng, Y. Jiang,* X.-Y. Liu* & J.-S. Lin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10968)

Three-dimensional (3D) bridged motifs have recently garnered significant interest in medicinal chemistry with bicyclo[2.1.1]hexanes (BCHs) emerging as potential 3D benzene bioisosteres; however, the synthesis of chiral, highly substituted BCHs is underexplored. Here, the authors disclose the Lewis acid-catalyzed asymmetric intermolecular [2π+2σ] cycloaddition of bicyclo[1.1.0]butanes with coumarins, 2-pyrone, or chromenes to access diverse enantioenriched tetrasubstituted BCHs bearing vicinal tertiary-quaternary stereocenters. The resulting BCHs hold significant potential as benzene bioisosteres in the synthesis of chiral BCHex-Sonidegib and BCHex-BMS-202, mimicking the anticancer drug Sonidegib and the PD-1/PD-L1 inhibitor BMS-202, respectively.

Low-Temperature Borylation of C(sp³)–O Bonds of Alkyl Ethers by Gold–Metal Oxide Cooperative Catalysis

H. Nishio, H. Miura* & T. Shishido*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13003)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-h6mw9) 🔓

Since ether moieties are found not only in petrochemical products but also in natural organic molecules, the development of methods for manipulating C–O bonds of ethers is important for expanding the range of compound libraries synthesized from biomass resources, which should contribute to the goal of carbon neutrality. Here, the authors report that gold nanoparticles supported on Lewis acidic metal oxides, namely α-Fe₂O₃, showed excellent catalytic activity for the reaction of dialkyl ethers and diborons, which enables the conversion of unactivated C(sp³)–O bonds to C(sp³)–B bonds at around room temperature. Various acyclic and cyclic ethers as well as a series of diborons participated in the heterogeneous gold-catalyzed borylation of unactivated C(sp³)–O bonds, to give a series of alkylboronic esters in high yields.

Intermolecular Asymmetric Arylative Dearomatization of 1-Naphthols

M. Kadarauch, T. A. Moss & R. J. Phipps*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14754) 🔓

Arylative dearomatization forms quaternary stereocenters in cyclic systems with the concomitant introduction of an aromatic ring. Pd-catalyzed arylative dearomatization, which uses conditions analogous to cross-coupling, has emerged as a powerful method in an intramolecular context. But translating this from intramolecular cyclizations to an intermolecular process has proven extremely challenging. The authors describe a strategy that utilizes attractive interactions between the ligand and substrate to overcome this challenge and promote intermolecular, highly enantioselective arylative dearomatization of naphthols using a broad range of aryl bromide electrophiles.

Biocatalytic Generation of Trifluoromethyl Radicals by Nonheme Iron Enzymes for Enantioselective Alkene Difunctionalization

J. G. Zhang,^† A. J. Huls,^† P. M. Palacios, Y. Guo* & X. Huang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14310)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-17g6k-v3) 🔓

The trifluoromethyl (−CF₃) group represents a highly prevalent functionality in pharmaceuticals. Over the past few decades, significant advances have been made in the development of synthetic methods for trifluoromethylation. In contrast, there are currently no metalloenzymes known to catalyze the formation of C(sp³)–CF₃ bonds. In this work, the authors demonstrate that a nonheme iron enzyme, hydroxymandelate synthase from Amycolatopsis orientalis (AoHMS), is capable of generating CF₃ radicals from hypervalent iodine(III) reagents and directing them for enantioselective alkene trifluoromethyl azidation. A high-throughput screening (HTS) platform based on Staudinger ligation was established, enabling the rapid evaluation of AoHMS variants for this abiological transformation. The final optimized variant accepts a range of alkene substrates, producing the trifluoromethyl azidation products in up to 73% yield and 96:4 enantiomeric ratio (e.r.). The biocatalytic platform can be further extended to alkene pentafluoroethyl azidation and diazidation by altering the iodine(III) reagent.

Copper-Catalyzed Regio-, Diastereo-, and Enantioselective Allylic Alkylation with 1,1-Diborylalkanes

M. Kim, G. Kim, D. Kim & S. H. Cho*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14150)

The authors report a copper-catalyzed regio-, diastereo-, and enantioselective allylic alkylation of allyl bromides using 1,1-diborylalkanes as prochiral nucleophiles. The methodology employs copper(I) bromide as a catalyst, an (R)-BINOL-derived phosphoramidite as a ligand, and lithium benzoate as a crucial additive. The reaction affords enantioenriched homoallylic boronic esters possessing vicinal stereocenters in good yields and high diastereo- and enantioselectivity. The developed method demonstrates a broad substrate scope with respect to a wide range of 1,1-diborylalkanes and allyl bromides.

Asymmetric Migratory Tsuji–Wacker Oxidation Enables the Enantioselective Synthesis of Hetero- and Isosteric Diarylmethanes

E. Frank,^† S. Park,^† E. Harrer, J. L. Flügel, M. Fischer, P. Nuernberger, J. Rehbein* & A. Breder*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09405) 🔓

Diarylmethanes play a pivotal role in the design of highly potent, chiral, non-racemic drugs whose bioactivity is typically affected by the substitution pattern of their arene units. In this context, certain arenes can cause particular synthetic challenges, since isosteric residues at the central methane carbon atom are typically indistinguishable for a chiral catalyst. Here, the authors report a generalized enantioselective synthesis of chiral diarylmethanes by means of an asymmetric migratory Tsuji–Wacker oxidation of simple stilbenes. The protocol relies on the well-adjusted interplay of aerobic photoredox and selenium-π-acid catalysis to allow for the installation of a broad variety of arenes, including isosteric ones, into the methane core. The multicatalytic platform offers the target structures with high levels of enantioselectivity in up to 97% e.e., which has also been successfully exploited in expedited syntheses of antihistaminic (R)- and (S)-neobenodine.

ACS CATALYSIS
Pd-Catalyzed Difluoroalkylation of Alkenes Using Chlorodifluoroalkanes

J. Wang,^† Q. Zhou,^† L. Zhou & Z. Zhang*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c06842)

The gem-difluoromethylene unit (−CF₂−) is capable of inducing unique molecular geometries and physicochemical properties, making it highly desirable in the development of pharmaceuticals. Despite their significance, efficient and versatile methods for incorporating −CF₂– groups into organic molecules remain lacking. Here, the authors describe a palladium-catalyzed difluoroalkylation of alkenes via a formal Mizoroki–Heck reaction, providing a straightforward route to synthesize a diverse array of RCF₂-alkenes from readily available alkenes and chlorodifluoroalkanes. This method facilitates the incorporation of gem-difluoromethylene groups into complex molecules under mild conditions and demonstrates remarkable functional group tolerance, enabling late-stage functionalization.

Pd and Fe Cocatalyzed Synthesis of Remotely Borylated Aza-Heterocycles

S. Bhatt,^† A. M. Nicely,^† C. U. Powell, M. E. Huff, S. B. Thibodeaux, Y.-N. Wang, S. Vasylevskyi & K. L. Hull*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c05702)

The authors report the intramolecular 1,n-aminoboration for the simultaneous synthesis of aza-heterocycles with distal carbon–boron bonds. Pd-catalyzed remote 1,n-aminoboration occurs with 1,2-disubstituted alkenes; upon aminopalladation of the olefin, chain walking generates the terminal Pd-alkyl intermediate, which selectively undergoes Fe-catalyzed borylation. Terminal bishomoallylic amines, amides, carbamates, and ureas afford the borylated pyrrolidines and lactams through 1,2-aminoboration. Forty-one examples of 1,n-borylated heterocycles are presented with yields up to 92%. Derivatization of the products is explored: cross-coupling, amination, and oxidation to access unnatural amino alcohols and acids.

Dual Nickel/Photoredox-Catalyzed Aryl Etherification Enabled by an Oxidative Near-Infrared-to-Blue Triplet–Triplet Annihilation Upconversion System Leveraging Spin-Forbidden Excitation

L. R. Beck, K. A. Xie, B. C. Lainhart, T. C. Sherwood, E. R. Welin, C. L. Joe & T. Rovis*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c06084)

The authors describe a near-infrared-to-blue triplet–triplet annihilation upconversion system that produces a highly oxidizing excited state. The spin-forbidden excitation of the osmium sensitizer and thermally assisted triplet energy transfer to the anthracene annihilator enable an anti-Stokes shift of 1.25 V. This system is then applied to the dual nickel/photoredox-catalyzed cross-coupling of aryl halides and alcohols. Finally, upconversion is implicated as the promoter for reductive elimination of a nickel(II) aryl alkoxide complex.

Artificial Intelligence-Driven Development of Nickel-Catalyzed Enantioselective Cross-Coupling Reactions

Y. Gao,^† K. Hu,^† J. Rao, Q. Zhu & K. Liao*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c04277)

The authors present a workflow for the development of a series of nickel-catalyzed asymmetric cross-coupling reactions, leveraging artificial intelligence (AI) and high-throughput experimentation (HTE) technology. A predictive model for nickel-catalyzed enantioselective coupling reactions was developed, elucidating the general rules governing enantioselectivity. Through the application of data science tools and HTE technology, a data set was curated to construct an AI-based model. This model was subsequently utilized to facilitate the discovery of efficient nickel hydride-catalyzed enantioselective and regioselective cross-coupling reactions. Employing AI-assisted virtual ligand screening and HTE-enabled condition optimization, optimal ligands for eight coupling reactions were successfully identified. Consequently, a series of chiral sp³ C–C bonds were synthesized with high yield and enantioselectivity.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
“Angular” Spirocyclic Azetidines: Synthesis, Characterization, and Evaluation in Drug Discovery

A. A. Kirichok, H. Tkachuk, K. Levchenko, D. Granat, T. Yegorova, D. Lesyk, A. Anisiforova, Y. Holota, V. Zomchak, I. Bodenchuk, V. Kosach, P. Borysko, R. A. Korzh, G. Al-Maali, V. Kubyshkin, H. S. Rzepa & P. K. Mykhailiuk*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202418850)

The previously neglected “angular” spirocyclic azetidines have been synthesized, characterized, and validated in drug discovery. The authors have shown that these compounds could act as bioisosteres for common saturated six-membered heterocycles. Their incorporation into the structure of the anticancer drug Sonidegib (instead of morpholine), and Danofloxacine (instead of piperazine) provided novel patent-free analogs with similar physicochemical properties and high activity.

CHEMRXIV
trans-Spanning Ligands Promote Pd-Catalyzed α-Hydroalkenylation and -Hydroalkynylation of Activated Olefins

W.-J. He, E. W. Morgan,^‡ S. Shanker,^‡ A. M. Vasquez, G. A. Connolly, J. A. Gurak, Jr. & K. M. Engle*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-nsr7l) 🔓

The palladium-catalyzed “regioreversed” α-hydroalkenylation and -hydroalkynylation of conjugated alkenes is reported. The unconventional selectivity of this reaction is achieved through the utilization of trans-spanning bidentate phosphine ligands that stabilize the proposed trans-Pd(II)L_n(R)(H) (R = alkenyl or alkynyl) intermediate. The α-hydrofunctionalization methods tolerate a variety of electron-deficient alkenes including α,β-unsaturated amides, esters and vinyl pyridines. A range of different alkenyl/alkynyl bromides are demonstrated to be effective coupling partners in the reaction. The phosphine-ligated palladium catalyst operates under mild weakly basic or neutral conditions and is resistant to air and moisture, giving rise to practical methodology for construction of β,γ-unsaturated carbonyl compounds.

CHEMICAL SCIENCE
Tungsten-Catalyzed Stereodivergent Isomerization of Terminal Olefins

T. C. Jankins,^† C. Z. Rubel,^† H. C. Ho, R. Martin-Montero & K. M. Engle*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC07093C) 🔓

Catalytic alkene isomerization is a powerful synthetic strategy for preparing valuable internal alkenes from simple feedstocks. The utility of olefin isomerization hinges on the ability to control both positional and stereoisomerism to access a single product among numerous potential isomers. Here, the authors describe a tungsten-catalyzed, positionally selective alkene isomerization reaction in which tuning the ligand environment grants access to either the E- or Z-stereoisomer. The reactions employ simple, commercially available precatalysts and ligands.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Fire and Ice

🔥🧊 Fire and ice. Antarctica is home to over 100 volcanoes, most of which are buried beneath its vast ice sheet but some rise up beyond the ice for thousands of metres. One such example, Mount Erebus, is the Earth’s southernmost active volcano. Measuring in at 3800 metres, it towers over McMurdo Station—Antarctica’s biggest research base. Now, researchers have started to install seismic sensors along the rim of Erebus to better understand its activity and the threat it may pose, no easy feat when facing wind chills down to −59 °C. Using Erebus as a model, the team hope to gain a better understanding of volcanism in the region. This may also help provide clues as to whether or not ice loss caused by climate change may reawaken less-active volcanoes, such as Mount Waesche, some 1500 kilometres away from Erebus and whose past history has indicated that previous eruptions may have been caused by ice loss. This could put into motion a dangerous feedback loop where as the ice melts, the weight on the volcanoes is relieved, allowing gases trapped in the magma to release, encouraging eruptions and driving further ice loss—a dynamic that has played out before in Iceland, meaning that our fate may be in the hands of one of the most remote places on Earth.

💡 Mount Erebus was discovered and named in 1841 by the explorer Sir James Clark Ross for his ship, HMS Erebus, which itself was named after Erebus, the personification of darkness and one of the earliest beings in Greek mythology. He was the son of Chaos, the formless void from which everything came into existence, and the father of Aether (brightness) and Hemera (day).