💡 2024 Wrapped

Welcome to a special “2024 Wrapped” edition of the Organic Synthesis Newsletter.

We’ve crunched the numbers to find out the Top 10 Most Popular Papers highlighted in the newsletter within the last 6 months. As the newsletter only started just under 9 months ago, we can’t go back to the start of the year but we can still highlight some facts and trends from the last 6 months:

• Skeletal editing dominated (of course).

• Cross-coupling approaches for C(sp³)–C(sp³) bond formation followed.

• A solution to the 100-year-old problem of anti-Bredt olefins was discovered.

Monday 3^rd June – Wednesday 18^th December 2024 | 2024 Wrapped

#1
Photocatalytic Furan-to-Pyrrole Conversion

D. Kim,^† J. You,^† D. H. Lee, H. Hong, D. Kim & Y. Park*

Science 2024, 386, 99–105 (DOI: 10.1126/science.adq6245)

The identity of a heteroatom within an aromatic ring influences the chemical properties of that heterocyclic compound. Systematically evaluating the effect of a single atom, however, poses synthetic challenges, primarily as a result of thermodynamic mismatches in atomic exchange processes. The authors present a photocatalytic strategy that swaps an oxygen atom of furan with a nitrogen group, directly converting the furan into a pyrrole analog in a single intermolecular reaction. High compatibility was observed with various furan derivatives and nitrogen nucleophiles commonly used in drug discovery, and the late-stage functionalization furnished otherwise difficult-to-access pyrroles from naturally occurring furans of high molecular complexity.

#2
Ph₃PCN₂: A Stable Reagent for Carbon-Atom Transfer

T. Koike, J.-K. Yu & M. M. Hansmann*

Science 2024, 385, 305–311 (DOI: 10.1126/science.ado4564)

Precise modification of a chemical site in a molecule at the single-atom level is one of the most elegant yet difficult transformations in chemistry. A reagent specifically designed for chemoselective introduction of monoatomic carbon is a particularly formidable challenge. Here, the authors report a straightforward, azide-free synthesis of a crystalline and isolable diazophosphorus ylide, Ph₃PCN₂, a stable compound with a carbon atom bonded to two chemically labile groups, triphenylphosphine (PPh₃) and dinitrogen (N₂). Without any additives, the diazophosphorus ylide serves as a highly selective transfer reagent for fragments, including Ph₃PC, to deliver phosphorus ylide–terminated heterocumulenes and CN₂ to produce multisubstituted pyrazoles. Ultimately, even exclusive carbon-atom transfer is possible. In reactions with aldehydes and acyclic and cyclic ketones (R₂C=O), the carbon-atom substitution forms a vinylidene (R₂C=C:) en route to alkynes or butatrienes.

#3
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.

#4
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.

#5
A Solution to the anti-Bredt Olefin Synthesis Problem

L. McDermott,^† Z. G. Walters,^† S. A. French,^‡ A. M. Clark,^‡ J. Ding,^‡ A. V. Kelleghan, K. N. Houk & N. K. Garg*

Science 2024, 386, eadq3519 (DOI: 10.1126/science.adq3519)

The π-bonds in unsaturated organic molecules are typically associated with having well-defined geometries that are conserved across diverse structural contexts. Nonetheless, these geometries can be distorted, leading to heightened reactivity of the π-bond. Although π-bond–containing compounds with bent geometries are well utilized in synthetic chemistry, the corresponding leveraging of π-bond–containing compounds that display twisting or pyramidalization remains underdeveloped. Perhaps the most notorious class of geometrically distorted molecules that contain π-bonds are anti-Bredt olefins (ABOs). ABOs have been known since 1924, and conventional wisdom maintains that ABOs are difficult or impossible to access. Here, the authors provide a solution to this long-standing problem.

#6
Regioselective Pyridine to Benzene Edit Inspired by Water-Displacement

B. R. Boswell*, Z. Zhao, R. L. Gonciarz & K. M. Pandya

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05999)

Late-stage derivatization of drug-like functional groups can accelerate drug discovery efforts by swiftly exchanging hydrogen-bond donors with acceptors, or by modulating key physicochemical properties like logP, solubility, or polar surface area. A proven derivatization strategy to improve ligand potency is to extend the ligand to displace water molecules that are mediating the interactions with a receptor. Inspired by this application, the authors developed a method to regioselectively transmute the nitrogen atom from pyridine into carbon bearing an ester, a flexible functional group handle. They applied this method to a variety of substituted pyridines, as well as late-stage transformation of FDA-approved drugs.

#7
Coupling of Unactivated Alkyl Electrophiles using Frustrated Ion Pairs

S. Roediger, E. Le Saux, P. Boehm & B. Morandi*

Nature, 2024, 636, 108–114 (DOI: 10.1038/s41586-024-08195-1) 🔓

Cross-electrophile coupling reactions have evolved into a major strategy for rapidly assembling important organic molecules. Two readily accessible electrophiles are coupled to form new C–C bonds, providing a key advantage over traditional cross-coupling strategies that require the preformation of reactive organometallic species. Yet, the formation of C(sp³)–C(sp³) bonds that form the core of nearly all organic compounds remains highly challenging with current approaches, calling for the design of innovative new strategies. Here, the authors report a distinct, transition-metal-free platform to form such bonds without the need for activating or stabilizing groups on the coupling partners. The reaction is enabled by an unusual single-electron transfer in a frustrated ion pair, and it can couple fragments containing functional groups that would be challenging in related transition-metal-catalysed processes.

#8
A General Strategy for the Synthesis of Taxane Diterpenes

L. Pan,*^† F. Schneider,^† M. Ottenbruch, R. Wiechert, T. List, P. Schoch, B. Mertes & T. Gaich*

Nature 2024, 632, 543–549 (DOI: 10.1038/s41586-024-07675-8)

Previously: Research Square (DOI: 10.21203/rs.3.rs-4019390/v1) 🔓

The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties. As such, taxane diterpenes are one of the most well known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anti-cancer therapeutic for more than 25 years. In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here, the authors report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the first total syntheses of taxinine K, canataxapropellane and dipropellane C from a single advanced intermediate.

#9
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.

#10
The Sugar Cube: Network Control and Emergence in Stereoediting Reactions

H. M. Carder,^† G. Occhialini,^† G. Bistoni, C. Riplinger, E. E. Kwan* & A. E. Wendlandt*

Science 2024, 385, 456–463 (DOI: 10.1126/science.adp2447)

Stereochemical editing strategies have recently enabled the transformation of readily accessible substrates into rare and valuable products. Typically, site selectivity is achieved by minimizing kinetic complexity by using protecting groups to suppress reactivity at undesired sites (substrate control) or by using catalysts with tailored shapes to drive reactivity at the desired site (catalyst control). The authors propose “network control,” a contrasting paradigm that exploits hidden interactions between rate constants to greatly amplify modest intrinsic biases and enable precise multisite editing. When network control is applied to the photochemical isomerization of hexoses, six of the eight possible diastereomers can be selectively obtained. The amplification effect can be viewed as a mesoscale phenomenon between the limiting regimes of kinetic control in simple chemical systems and metabolic regulation in complex biological systems.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
The Best Science Images of 2024

🔭 Best of 2024. Nature have just released their selection of the best science images of 2024, featuring the Perseid meteor shower over Stonehenge and an incredible partial solar eclipse photographed behind the Washington Monument in Washington DC.