Nitrogen Insertion, Nitrogen Deletion.

Welcome to this week’s Organic Synthesis Newsletter.

Monday 27^th January – Sunday 2^nd February 2025 | Volume 2, Issue 4

HIGHLIGHT OF THE WEEK
Enantioselective Synthesis of 2-Substituted Bicyclo[1.1.1]pentanes via Sequential Asymmetric Imine Addition of Bicyclo[1.1.0]butanes and Skeletal Editing

J.-T. Che,^† W.-Y. Ding,^†* H.-B. Zhang, Y.-B. Wang, S.-H. Xiang & B. Tan*

Nat. Chem. 2025 (DOI: 10.1038/s41557-024-01710-x)

1,3-Difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely used as bioisosteres for para-substituted phenyl rings, whereas 2-substituted BCPs (substituted at the bridge position) function as alternatives to ortho- or meta-substituted arene rings. However, the efficient and enantioselective construction of these scaffolds remains challenging. Here, the authors present an approach for synthesizing enantioenriched 2-substituted BCPs by a nitrogen-atom insertion-and-deletion strategy involving the chiral Brønsted acid-catalysed enantioselective cycloaddition of bicyclo[1.1.0]butanes with imines and nitrogen deletion of resulting aza-bicyclo[2.1.1]hexanes (aza-BCHs).

NATURE COMMUNICATIONS
A Reagent to Access Methyl Sulfones

Y. Poplavskyi, V. Ripenko, S. Bova, A. Biitseva, Y. V. Dmitriv, A. A. Tolmachev, I. V. Sadkova, I. Pishel, O. Grygorov, V. Q. H. Phan, H. V. R. Dias* & P. K. Mykhailiuk*

Nat. Commun. 2025, 16, 1132 (DOI: 10.1038/s41467-024-55027-x) 🔓

A chemical reagent to access methyl sulfones has been developed. Its reaction with various bis-nucleophiles leads to the rapid formation of previously unknown heteroaromatic methyl sulfones. Analogous strategy can also be used to construct alkyl-, CHF₂-, CF₃- and even bicyclo[1.1.1]pentane-containing derivatives.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
N-Protonated Acridinium Catalyst Enables Anti-Markovnikov Hydration of Unconjugated Tri- and Disubstituted Olefins

B. A. van der Worp & T. Ritter*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c18185) 🔓

The authors present the first general method for direct, catalytic anti-Markovnikov hydration of unconjugated tri- and disubstituted olefins. The key advancement is made possible by an oxidative (E*_red = 2.15 V) N-H acridinium catalyst, which allowed for the functionalization of alkenes that were previously unreactive in such transformations due to their high oxidation potential. The developed protocol can also be extended to hydroetherifications.

Enantioselective Total Syntheses of Vallesamidine and Schizozygane Alkaloids

G. V. Ramakrishna, Z. Latif & F. Romiti*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16900)

A general streamlined strategy for the enantioselective total syntheses of the schizozygane family of natural products and related alkaloid vallesamidine is described. Specifically, a catalytic enantioconvergent cross-coupling sets the quaternary stereocenter of a key intermediate, a late-stage catalytic oxidative lactamization of an alkyne is instrumental in the first-generation synthesis of the schizozygane alkaloids, and in the second-generation approach, a novel application of the van Leusen reaction for the generation of lactams is pivotal to accessing the schizozygane alkaloids from a common intermediate.

Enantioselective Synthesis of Tetrahydro-1H-1,3-methanocarbazoles by Formal (3+3)-Cycloaddition Using Bicyclo[1.1.0]butanes

S. Dutta, C. G. Daniliuc, C. Mück-Lichtenfeld & A. Studer*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14276)

Asymmetric synthesis presents many challenges with the selective formation of chiral bridged polyheterocycles being a notable example. Cycloadditions using bicyclo[1.1.0]butanes (BCB) offer a promising solution, yet—despite significant advances—asymmetric control has remained limited thus far. Here, the authors describe an organocatalytic, enantioselective formal (3+3)-cycloaddition of BCBs with 1H-indol-3-yl((hetero)aryl)methanol derivatives. This approach enables the rapid and efficient synthesis of chiral tetrahydro-1H-1,3-methanocarbazole derivatives from readily available starting materials in excellent stereochemical control (up to 98:2 e.r.).

Rhodium-Catalyzed Homogeneous Asymmetric Hydrogenation of Naphthol Derivatives

S.-X. Zhang, L. Long, Z. Li, Y.-M. He, S. Li, H. Chen,* W. Hao & Q.-H. Fan*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15673)

The authors report the homogeneous asymmetric hydrogenation of naphthol derivatives catalyzed by tethered rhodium–diamine catalysts to afford 1,2,3,4-tetrahydronaphthols in high yields with excellent regio-, chemo-, and enantioselectivities (up to 98% yield and >99% e.e.). This protocol provides a straightforward route to the synthesis of key intermediates for several chiral drugs. In particular, Nadolol, a drug for the treatment of hypertension, angina pectoris and congestive heart failure was synthesized enantioselectively for the first time.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Photochemical Conversion of Indazoles into Benzimidazoles

T. dos Santos,^† C. S. Buettner,^† D. B. Yildiz, M. Mamone, A. Ruffoni & D. Leonori*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202423804)

The authors introduce a photochemical strategy for the direct permutation of 1H- and 2H-indazoles into benzimidazoles. This transformation exploits the distinct photochemical properties of these heteroaromatics and proceeds under mild conditions. The approach demonstrates broad substrate scope, high yields and compatibility with a variety of functional groups.

Flow Electroreductive Nickel-Catalyzed Cyclopropanation of Alkenes Using gem-Dichloroalkanes

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

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202500203) 🔓

The authors report an electrochemical cyclopropanation of alkenes leveraging nickel-catalysis in continuous-flow. The protocol demonstrates broad substrate scope, accommodating both electron-rich and electron-poor alkenes with high functional group tolerance. Beyond dichloromethane as a feedstock methylene source, the methodology enables the synthesis of methylated, deuterated, and chloro-substituted cyclopropanes. Notably, the reaction operates under ambient conditions, tolerates air and moisture, and achieves scalability through continuous-flow technology.

Shifting Lithium Amide Reactivity to the Radical Domain: Regioselective Radical C-H Functionalization of 3-Iodooxetane for the Synthesis of 1,5-Dioxaspiro[2.3]hexanes

P. Natho,^† M. Colella,^† A. Vicenti, G. Romanazzi, F. Ullah, N. S. Sheikh, A. J. P. White, F. Pasca & R. Luisi*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202424346) 🔓

The authors report the synthesis of strained spirocyclic 1,5-dioxaspiro[2.3]hexanes via a lithium-amide induced single-electron transfer to benzophenones, which generates an N-centered radical and a ketyl radical anion. This pair works synergistically to selectively abstract the β-hydrogen from 3-iodooxetane initiating an exergonic radical-radical coupling reaction between the oxetane core and benzophenone derivatives, ultimately yielding 1,5-dioxaspiro[2.3]hexanes.

CHEMRXIV
Ligand Design Enables the Palladium-Catalyzed Intermolecular Carbochlorocarbonylation of Alkynes and Cyclopentenone Formation

E. H. Denton,^† H. L. Schmitt,^† O. Stepanović,^† P. Müller, A. F. Müller, D. Svoboda & B. Morandi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-vpptw) 🔓

The authors demonstrate that ligand design enables the direct addition of acid chlorides across alkynes in a single step with complete atom economy to afford α,β-unsaturated acid chloride products. This carbochlorocarbonylation reaction, which proceeds through formal cleavage and reassembly of C–COCl bonds, was developed and explored for a range of acid chlorides and alkynes. During the course of this work, the formation of synthetically useful cyclopentenones, through a formal C–H functionalization step, was serendipitously observed at elevated temperatures.

Deconjugative Photoisomerization of Cyclic Enones

L. Blank,^† J. Kim,^† C. G. Daniliuc, A. Götzinger, M.-A. Müller, J. Schütz, B. Wüstenberg & R. Gilmour*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-wf19q) 🔓

The deconjugative isomerization of α,β-unsaturated carbonyl compounds enables regioisomeric products to be forged with simultaneous Umpolung of alkene reactivity. Although highly enabling, the endergonic nature of the process coupled with governing regioselectivity outcomes, renders it challenging. Here, the authors report an operationally simple photochemical isomerization of cyclic enones using near-UV (372 nm) irradiation with catalytic amounts of Brønsted acid (HCl). This platform enables exocyclic deconjugative isomerization of an array of enones including α-isophorone (a key intermediate in a variety of industrial processes), terpenoids and steroids.

Total Synthesis of (+)-Hazuntiphylline, (–)-Anhydrohazuntiphyllidine, and (–)-Hazuntiphyllidine

R.-C. Raclea, M. Mewald, K. L. White & M. Movassaghi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-75jk6) 🔓

The first total synthesis of the bisindole alkaloids (+)-hazuntiphylline, (–)-anhydrohazuntiphyllidine, and (–)-hazuntiphyllidine is described. An efficient synthetic strategy based on a plausible biosynthetic hypothesis was designed for the rapid assembly of these complex alkaloids via successive methylenation of an oxidized variant of the natural product (–)-mehranine.

Expediting Hit-to-Lead Progression in Drug Discovery Through Reaction Prediction and Multi-Objective Molecular Optimization

D. F. Nippa,^† K. Atz,^† Y. Stenzhorn, A. T. Müller, A. Tosstorff, J. Benz, H. Binch, M. Bürkler, A. Haider, D. Heer, R. Hochstrasser, C. Kramer, M. Reutlinger, P. Schneider, T. Shema, A. Topp, A. Walter, M. B. Wittwer, J. Wolfard, B. Kuhn, M. van der Stelt, R. E. Martin,* U. Grether* & G. Schneider*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-0lxhw-v2) 🔓

This study demonstrates an integrated medicinal chemistry workflow that effectively diversifies hit and lead structures, enabling an efficient acceleration of the critical hit-to-lead optimization phase. Employing high-throughput experimentation (HTE), a comprehensive data set was generated encompassing 13,490 novel Minisci-type C-H alkylation reactions. This data set served as the foundation for training deep graph neural networks to accurately predict reaction outcomes. Scaffold-based enumeration of potential Minisci reaction products, starting from moderate inhibitors of monoacylglycerol lipase (MAGL), yielded a virtual library containing 26,375 molecules. This virtual chemical library was evaluated using reaction prediction, physicochemical property assessment, and structure-based scoring, identifying 212 potential MAGL inhibitor candidates. Of these, 14 ligands were synthesized and exhibited subnanomolar activity, representing a potency improvement of up to 4500 times over the original hit compound.

ADVANCED SYNTHESIS & CATALYSIS
Metal-Free, Selective ortho-Deuteration of N-Heterocyclic Oxides

A. Montoli, A. Dimasi, A. Citarella, P. Ronchi, D. Passarella & V. Fasano*

Adv. Synth. Catal. 2025, Accepted (DOI: 10.1002/adsc.202401585)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-1g8tf) 🔓

Direct hydrogen isotope exchange has largely been restricted to the use of reactive organolithium reagents or metal-catalysed deuteration methods. In this work, the authors present a metal-free, selective ortho-deuteration of N-heterocycles starting from their corresponding N-oxides and proceeding at room temperature in just 5 minutes. This method achieves high deuterium incorporation across a broad range of N-heterocycles, including bioactive compounds.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
An End to America’s Opioid Epidemic?

💊 An End to America’s Opioid Epidemic? Each year, over 80 million patients in the U.S. alone are prescribed medication to treat acute pain with approximately half of those prescribed an opioid analgesic. More worryingly, 10% of those 40 million will continue to use opioids for a prolonged period and 85,000 will develop an opioid use disorder within a year of prescription—further contributing to America’s ongoing opioid epidemic that claims nearly 100,000 lives annually.

This is where Suzetrigine (JOURNAVX™) comes in. Developed by Vertex Pharmaceuticals, Suzetrigine is a first-in-class, non-opioid and non-addictive analgesic that selectively targets Na_V1.8, a voltage-gated sodium channel expressed in pain-sensing neurons. Its approval last week for the treatment of moderate-to-severe acute pain marks the culmination of nearly 25 years of work in the pain space since their acquisition of Aurora Biosciences in 2001 and 10 years since their first Na_V1.8-targeting compound, VX-150, advanced to clinical trials (but was ultimately superseded by Suzetrigine).

Selectively targeting Na_V1.8 is no mean feat, there are nine mammalian Na_V subtypes (Na_V1.1–Na_V1.9) and when the project started 2 decades ago, Na_V1.7 was the target of interest, as Bryan Moyer, senior VP for discovery at Latigo Biotherapeutics said “If you weren’t working on Na_V1.7, it was like, Why not? You’re not in neuroscience at that point”. However, despite years of development, Na_V1.7-targeting compounds have so far failed to achieve success in the clinic.

Suzetrigine is the first new painkiller approved for use in more than 20 years that works through a new mechanism and its success will likely invigorate other companies to invest in the targeting of voltage-gated sodium channels for safe and precise pain management.

☄️ An Early Christmas Present. Don’t bother making any plans for 2032 just yet, NASA has calculated that recently detected asteroid 2024 YR₄ has a 1% chance of colliding with Earth on the 22^nd December that year. At between 130–330 feet long, the asteroid is currently rated as a 3 on the Torino Scale (out of a possible 10) with the latter typically being reserved for Hollywood movies. However, there’s no reason to panic as NASA’s DART mission has already shown that we can alter the trajectory of asteroids but failing that, Armageddon has given us a play-by-play breakdown of a more direct approach… Still, maybe it’s best to use up any annual leave before the holidays that year.