💡 Cut-and-Sew with Aromatic Rings

Welcome to this week’s Organic Synthesis Newsletter.

Next week’s issue on Monday 23^rd December will be our last issue of the year with the first issue of next year out on Monday 13^th January when most journals will have returned to business as usual.

Monday 9^th December – Sunday 15^th December 2024 | Volume 1, Issue 38

HIGHLIGHT OF THE WEEK
Aromatic Ring-Opening Metathesis

V. Hutskalova & C. Sparr*

Nature 2024 (DOI: 10.1038/s41586-024-08472-z)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-d6qkv) 🔓

Aromatic compounds are used across chemistry and materials science as a result of their stability, characteristic interactions, defined molecular shape and the numerous synthetic approaches for their synthesis. In contrast, the cleavage of inert aromatic carbon-carbon bonds remained largely unfeasible due to the unfavourable energetics of disrupting aromaticity on ring opening. For non-aromatic structures, alkene metathesis is established as one of the most versatile carbon-carbon bond-forming and breaking reactions. However, despite remarkable advancements, strategies to open aromatic compounds by metathesis remained elusive. Here, the authors report aromatic ring-opening metathesis (ArROM) for the cleavage of aromatic rings by employing Schrock-Hoveyda molybdenum catalysts, and show the possibility for stereoselective aromatic ring-opening metathesis with exquisite catalyst control over the configuration of atropisomers.

NATURE
Continuous Collective Analysis of Chemical Reactions

M. Hu, L. Yang, N. Twarog, J. Ochoada, Y. Li, E. I. Vrettos, A. X. Torres-Hernandez, J. B. Martinez, J. Bhatia, B. M. Young, J. Price, K. McGowan, T. H. Nguyen, Z. Shi, M. Anyanwu, M. A. Rimmer, S. Mercer, Z. Rankovic, A. A. Shelat & D. J. Blair*

Nature 2024, 636, 374–379 (DOI: 10.1038/s41586-024-08211-4)

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

The automated synthesis of small molecules from modular building blocks has the potential to transform our capacity to create medicines and materials. Although recent advances in high-throughput chemistry can speed up the development of appropriate synthetic methods, equivalent high-throughput analytical methods are needed. Here, the authors report a streamlined approach for the rapid, quantitative analysis of chemical reactions by mass spectrometry. The intrinsic fragmentation features of chemical building blocks generalize the analyses of chemical reactions, allowing sub-second readouts of reaction outcomes. Central to this advance was identifying that starting material fragmentation patterns function as universal barcodes for downstream product analysis by mass spectrometry. Combining these features with acoustic droplet ejection mass spectrometry slow chromatographic steps were eliminated and chemical reactions continuously evaluated in multiplexed formats.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Alkene Carboxy-Alkylation via CO₂^•–

Y Dang, J. Han, A. F. Chmiel, S. N. Alektiar, M. Mikhael, I. A. Guzei, C. S. Yeung* & Z. K. Wickens*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14421)

The authors introduce a new platform for alkene carboxy-alkylation designed around CO₂^•– addition to alkenes followed by radical polar crossover, which enables alkylation through carbanion attack on carbonyl electrophiles. It was discovered that CO₂^•– adds to alkenes faster than it reduces carbonyl electrophiles and that this reactivity can be exploited by accessing CO₂^•– via hydrogen atom transfer from formate. This photocatalytic system transforms vinylarenes and carbonyl compounds into a diverse array of substituted γ-lactone products. Furthermore, indoles can be engaged through dearomative carboxy-alkylation, delivering medicinally relevant C(sp³)-rich heterocyclic scaffolds.

Iterative One-Carbon Homologation of Unmodified Carboxylic Acids

E. Wheatley,^† H. Melnychenko^† & M. Silvi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13630) 🔓

The one-carbon homologation of carboxylic acids is a valuable route to construct families of homologues, which play fundamental roles in chemistry and biology. However, known procedures are based on multistep sequences, use harsh conditions or are limited in scope. Here, by exploiting the photoredox reactivity of nitroethylene, the authors disclose a practical visible-light-induced homologation of unmodified carboxylic acids. Iterations of the procedure reveal an exceptionally tunable strategy for the construction of inert carbon spacers.

👉️ For recent, complementary methodology, see: here.

Selective Ni(I)/Ni(III) Process for Consecutive Geminal C(sp³)–C(sp²) Bond Formation

X. Li, Y. Gan, Y.-Y. Wang & B. Ye*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12581)

Ni-catalyzed multicomponent cross-couplings have emerged as a powerful strategy for constructing complex molecular architectures from an array of organic halides. Despite its potential, selectively forming multiple chemical bonds in a single operation, particularly in the realm of cross-electrophile coupling catalysis, remains a significant challenge. In this study, the authors have developed a consecutive open-shell reductive Ni catalysis, enabling the formation of two geminal C(sp³)–C(sp²) bonds from two stereoelectronically similar C(sp²)–I reactants in conjunction with a methylene electrophile. Using zirconaaziridine and elemental Mg⁰ as reductants, this protocol exhibits broad applicability across a wide range of (hetero)aromatic, alkenyl, and glycal halides, allowing for the rapid assembly of medicinally relevant scaffolds with excellent functional group tolerance.

Sequential Photocatalysis for Homologative Diversification of α-Amino Acids to β-Amino Acids via Phosphonium Ylide Linchpin Strategy

H. Qiu, A. Matsumoto* & K. Maruoka*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14860)

β-Amino acids serve as crucial building blocks for a broad range of biologically active molecules and peptides. While numerous methods have been developed for the synthesis of β-amino acids, most of them require multistep preparation of specific reagents and substrates. In this regard, a homologative transformation of abundant and readily available α-amino acids would be an attractive approach for β-amino acid synthesis. Herein, the authors disclose the development of a sequential process to provide diverse β-amino acids from α-amino acid derivatives and commercially available phosphonium ylides via visible light photoredox catalysis. In this two-step protocol, phosphonium ylides function as a bifunctional linchpin: they act as a carbon nucleophile to forge a C–C bond in the first step and as a carbon-centered radical source for diverse modifications of the β-amino acid scaffold in the second step.

Tunable Thiazolium Carbenes for Enantioselective Radical Three-Component Dicarbofunctionalizations

S. Jana & N. Cramer*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11947) 🔓

Asymmetric N-heterocyclic carbene (NHC) organocatalysis is a cornerstone of synthetic organic chemistry. The emerging concept of single-electron NHC catalysis broadened the scope of C–C bond-forming reactions, facilitating the synthesis of a variety of attractive racemic compounds. However, the development of chiral NHC catalysts for asymmetric radical-mediated reactions has been challenging. In this report, the authors introduce a family of highly tunable chiral thiazolium carbenes with three distinct positions for broad electronic and steric modulation. The catalytic efficacy of these chiral carbenes is demonstrated in an enantioselective SET-type three-component acyl-difluoroalkylation of olefins. This method provides straightforward access to a diverse set of β-difluoroalkylated α-chiral ketones (65 examples, up to 87% yield, up to >99:1 e.r.). The utility of this methodology is further outlined by enantio- and diastereoselective late-stage modifications of pharmaceutically relevant compounds.

Ruthenium-Catalyzed Carbocycle-Selective Hydrogenation of Fused Heteroarenes

C. Luo, C. Wu, X. Wang, Z. Han,* Z. Wang* & K. Ding*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05365)

The homogeneous catalytic hydrogenation of benzo-fused heteroarenes generally provides partially hydrogenated products wherein the heteroaryl ring is preferentially reduced, such as quinoline hydrogenation, leading to 1,2,3,4-tetrahydroquinoline. Herein, the authors report a carbocycle-selective hydrogenation of fused N-heteroarenes using the Ru complex of a chiral spiroketal-based diphosphine (SKP) as the catalyst, affording the corresponding 5,6,7,8-tetrahydro- products in high chemoselectivities. This catalytic system is also effective for the asymmetric carbocycle hydrogenation of fused heteroarenes bearing boryl or amino groups.

Harnessing Oxetane and Azetidine Sulfonyl Fluorides for Opportunities in Drug Discovery

O. L. Symes, H. Ishikura, C. S. Begg, J. J. Rojas, H. A. Speller, A. M. Cherk, M. Fang, D. Leung, R. A. Croft, J. I. Higham, K. Huang, A. Barnard, P. Haycock, A. J. P. White, C. Choi & J. A. Bull*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c14164) 🔓

Four-membered heterocycles such as oxetanes and azetidines represent attractive design options in medicinal chemistry due to their small, polar nature and potential to impact the physiochemical properties of drug molecules. However, the challenging preparation of these derivatives has limited their combination with other medicinally relevant groups. Here, the authors report the development and use of oxetane sulfonyl fluorides (OSFs) and azetidine sulfonyl fluorides (ASFs), which behave as precursors to carbocations in an unusual defluorosulfonylation reaction pathway (deFS). The small-ring sulfonyl fluorides are activated under mild thermal conditions (60 °C), and the generated reactive intermediates couple with a broad range of nucleophiles. The synthetic utility of novel OSF and ASF reagents was demonstrated through the synthesis of 11 drug analogs and the application of these reagents as linker motifs was shown through the incorporation of pendant groups suitable for common conjugation reactions. Productive deFS reactions with E3 ligase recruiters such as pomalidomide and related derivatives provide new degrader motifs and potential PROTAC linkers.

👉️ For recent, complementary methodology, see: here.

ACS CATALYSIS
Nickel-Catalyzed Asymmetric Synthesis of β- or β,γ-Substituted GABA Derivatives Enabled by Photoactive Ternary Electron Donor–Acceptor Complex

Y. Xie, Z.-M. Lai, A. S. C. Chan, J. Guo* & G. Lu*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c06549)

Enantiopure γ-amino butyric acids (GABA) and derivatives have important applications in medicinal chemistry, especially for the treatment of central nervous system diseases. Here, the authors have developed a highly enantioselective catalytic strategy for forging β- or β,γ-substituted GABA derivatives by exploiting an unexplored ternary electron donor–acceptor (EDA) complex driven by visible light and a chiral Ni catalyst. With this cooperative catalytic system, a range of structurally diverse β- or β,γ-substituted GABA derivatives have been achieved in high yields with good enantio- and diastereoselectivities (up to 88% yield, >99% e.e., >19:1 d.r.). The synthetic value of this method was demonstrated by enabling easy access to pharmaceuticals or related bioactive molecules such as pregabalin, baclofen, rolipram and phenibut.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Photoredox-Catalyzed Decarboxylation of Oxetane-2-Carboxylic Acids Initiated by Oxidation of DIPEA

E. C. McFee, K. A. Rykaczewski & C. S. Schindler*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202405125)

Oxetanes are valuable motifs in medicinal chemistry with demonstrated potential to serve as bioisosteres for an array of functional groups. Through the visible-light-mediated photoredox hydrodecarboxylation of 2-aryl oxetane 2-carboxylic acids this work enables access to the products of a [2+2]-photocycloaddition between alkenes and aryl aldehydes without the challenges associated with a traditional UV-light-mediated Paternò-Büchi reaction.

CHEMRXIV
Flow Electroreductive Nickel-Catalyzed Cyclopropanation of Alkenes using gem-Dichloroalkanes

M. Regnier, C. Vega,^‡ D. I. Ioannou,^‡ Z. Zhang & T. Noël*

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

Cyclopropanes are valuable motifs in organic synthesis, widely featured in pharmaceuticals and functional materials. Herein, the authors report an efficient electrochemical methodology for the cyclopropanation of alkenes, leveraging a nickel-catalyzed process in continuous-flow. The developed protocol demonstrates broad substrate scope, enables the synthesis of methylated, deuterated, and chloro-substituted cyclopropanes, and can accommodate both electron-rich and electron-poor alkenes with high functional group tolerance. The reaction operates under ambient conditions, tolerates air and moisture, and achieves scalability to multigram quantities through continuous-flow technology.

Chemoenzymatic Diazo Synthesis enabled by Enzymatic Halide Recycling with Vanadium-Dependent Haloperoxidases

M. Sharma,^† Y. Li,^† L. Layug, K. M. Davis & K. F. Biegasiewicz*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-f0w08) 🔓

Diazo compounds are privileged carbene precursors in synthetic organic chemistry. Despite their versatility in both chemo- and biocatalytic synthesis, their preparation typically requires the use of reagents that are expensive, toxic, and unsustainable. Herein, the authors describe a chemoenzymatic strategy for the preparation of stabilized diazo compounds enabled by enzymatic halide recycling by vanadium-dependent haloperoxidase (VHPO) enzymes. The process involves the conversion of a carbonyl-containing compound to an intermediate hydrazone that is subjected directly to a VHPO-catalyzed nitrogen-nitrogen (N-N) bond oxidation to the corresponding diazo compound. The protocol was applied to a broad range of benzoylformate and isatin derivatives, and was interfaced with lipase-mediated transacylation to produce a collection of diazo derivatives starting from a single benzoylformate starting material.

Organocatalytic Aerobic Oxidative Monodealkylation of tert-Amines to sec-Amines

Y. Sasano,* H. Shimabayashi, S. Akutsu, R. Sasaki & Y. Iwabuchi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-9dfqc) 🔓

The monodealkylation of tertiary amines is a direct method to produce secondary amines; however, existing catalytic methods are mainly limited to N-demethylation and encounter challenges related to substrate scope and efficiency. Here, the authors present an efficient, organocatalytic, and aerobic oxidative monodealkylation of tertiary amines. The synergistic catalytic combination of a hydroxylamine and NO_x promotes selective N-monodealkylation, yielding secondary amines in high yields under mild conditions with atmospheric oxygen pressure. This method enables the removal of various alkyl groups, including non-methyl groups, and demonstrates excellent functional group tolerance and broad applicability to various substrates, including natural products, such as amino acids and alkaloids.

ORGANIC LETTERS
Stereoretentive Decarboxylative Amidation of α,β-Unsaturated Carboxylic Acids to Access Enamides

J. Kweon, M. Lee, D. Kim & S. Chang*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c04234)

Enamides have emerged as robust alternatives for enamines, exhibiting versatile reactivity for further synthetic modifications, including nucleophilic addition, cycloaddition, and asymmetric hydrogenation. In this study, the authors report a mild and convenient stereoretentive decarboxylative amidation of α,β-unsaturated carboxylic acids with easily procurable 1,4,2-dioxazol-5-ones, providing a practical synthetic route to enamides.

Halodealkenylation: Ozonolysis and Catalytic Fe^II with Vitamin C Convert C(sp³)–C(sp²) Bonds to C(sp³)–Halide Bonds

B. W. Dehnert, Y. Yin & O. Kwon*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c04084)

The authors report a halodealkenylation in which the C(sp³)–C(sp²) bonds of alkenes are cleaved and C(sp³)–halide bonds are formed via a radical intermediate. These transformations occur through Criegee ozonolysis and Fe^II-catalyzed reductive coupling assisted by vitamin C as a stoichiometric reductant. The strategy was applied to the formal synthesis of (R,R,R)-γ-tocopherol.

JOURNAL OF ORGANIC CHEMISTRY
One-Step Regioselective Synthesis of N-1-Substituted Dihydrouracils: A Motif of Growing Popularity in the Targeted Protein Degradation Field

I. D. G. Nixon,^† J. M. Bateman,^† I. N. Michaelides, G. Fairley, M. J. Pemberton, E. L. Braybrooke, K. Sutton & P. J. Lindsay-Scott*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c02136)

The increasing popularity of the dihydrouracil motif in cereblon (CRBN) recruiting proteolysis-targeting chimeras (PROTACs) has necessitated the development of facile, cost-effective, and high-yielding methods for its introduction into molecules. To this end, the authors disclose an N-1 selective Pd-catalyzed cross-coupling of dihydrouracil with aryl electrophiles to provide access to medicinally relevant scaffolds in a single step. This approach exhibits excellent functional group tolerance and broad applicability to an abundance of (hetero)aryl halides and phenol derivatives and utilizes readily available catalyst/ligand systems.

CHEMRXIV LATEST VERSIONS

• Merging Photoexcited Nitroarenes with Lewis Acid Catalysis for the Anti-Markovnikov Oxidation of Alkenes, J. M. Paolillo, M. R. Saleh, E. W. Junk & M. Parasram,* ChemRxiv, DOI: 10.26434/chemrxiv-2024-3mcc5-v3 (Previously highlighted as V2 in Radical Simplicity and V1 in Cracking Cyclopropane).

• Accessing Azetidines through Magnesium-Mediated Nitrogen Atom Transfer from Iminoiodinane to Donor-Acceptor Cyclopropanes, A. H. Bansode, L. Yin, N. Deng, M. Afrasi, Y. Zhu & M. Parasram,* ChemRxiv, DOI: 10.26434/chemrxiv-2024-sgwcn-v2 (Previously highlighted as V1 in Programmable Polysubstitution).

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
A Long Shot

💉 A long shot. Science have announced that their 2024 Breakthrough of the Year is Gilead Sciences’ lenacapavir, a twice-yearly injectable HIV-1 capsid inhibitor that—in a blinded study of over 5000 women in South Africa and Uganda earlier this year—provided 100% protection in what was described as the “first Phase 3 HIV prevention trial ever to show zero infections”. Unlike other HIV drugs, lenacapavir binds to the capsid proteins that form a protective cone around the virus’ genetic material, preventing it from entering into the cell’s nucleus; however, even if that step fails, the drug capably interferes with the production of new capsid subunits. It’s hard to improve upon already impressive statistics but Gilead Sciences have recently unveiled plans for a 12-month formulation of lenacapavir and are eyeing clinical trials as early as next year in what would be the “closest thing to a vaccine the HIV field has produced in four decades of research”. It is hoped that lenacapavir may help bring cases of HIV down from over 1 million a year towards the United Nations Programme on HIV/AIDS (UNAIDS) goal of under 200,000 by 2030.

💡 Gilead Sciences’ synthesis of lenacapavir, alongside a follow-up manuscript detailing the synthesis of the complex pyrazole starting material, was recently disclosed in Organic Process Research & Development.