# Metal-Catalyzed Cross-Coupling for the Synthesis of
β-Lactam Drugs and Related Chemical Probes

Jules Bresson, Katie Burke, Mélanie Ethève-quelquejeu, Laura Iannazzo,

Kevin Cariou

► To cite this version:

Jules Bresson, Katie Burke, Mélanie Ethève-quelquejeu, Laura Iannazzo, Kevin Cariou. Metal-Catalyzed Cross-Coupling for the Synthesis of β-Lactam Drugs and Related Chemical Probes. ChemMedChem, 2025, 20 (9), pp.e202400960. 10.1002/cmdc.202400960. hal-05287299

HAL Id: hal-05287299

https://hal.science/hal-05287299v1

Submitted on 28 Sep 2025

**HAL** is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

# Metal-Catalyzed Cross-Coupling for the Synthesis of β-Lactam Drugs and Related Chemical Probes

Jules Bresson,[a] Katie Burke,[b] Mélanie Ethève-Quelquejeu,[b, c] Laura Iannazzo,[*b] and Kevin Cariou*[a]

Antimicrobial resistance is a major public health threat, due to the emergence of new bacterial strains not responding to classical antibiotics. This review focuses on the use of transition metal cross-coupling strategies used to access new β-lactam derivatives, the most well-known and commonly used anti-biotics. This manuscript covers the seminal studies for the

synthesis of antibiotics up to the current need of accessing specific probes (by functionalizing existing drugs), crucial for the detection of resistances. These strategies also allow the linkage of a cargo to a β-lactam antibiotic for selective release for either therapeutic effect or for diagnostic purposes (in the case of probes), which will be explained in this article.

## 1. Introduction

The discovery of penicillin G by Sir Alexander Fleming in 1928 was a pivotal moment in the history of modern medicine. Fleming observed that the growth of bacterial colonies was inhibited by the presence of the mold Penicillium notatum. This initial observation laid the foundation for further research, and in 1939 H.W. Florey and E.B. Chain succeeded in isolating the active compound responsible for this antibacterial activity.[1,2] Their efforts, along with those of Fleming, were rewarded with the Nobel Prize in Physiology or Medicine in 1945.

This discovery marked the beginning of the "golden age" of antibiotic development, which lasted from the 1950s to the 1970s. During this period, penicillin was produced on an industrial scale using advanced fermentation techniques, paving the way for extensive research into new antibacterial compounds. Numerous derivatives of β-lactam antibiotics, the class to which penicillin belongs, were rapidly developed, along with other families of antibiotics such as macrolides, tetracyclines, and quinolones. Following this highly productive era, research efforts shifted to modifying existing antibiotics to improve their efficacy and broaden their spectrum of activity.

At this point, chemists played a crucial role in optimizing these drugs.

At the beginning of 20th century, antibiotics revolutionized the treatment of bacterial infections. However, the clinical introduction of each antibiotic was followed by the emergence of bacterial resistance.[3] Resistance to penicillin was reported as early as the 1940s (Figure 1). Due to selection pressures caused by the increasing use of antibiotics, the efficacy of some treatments has severely dwindled.

This phenomenon has accelerated in recent decades, driven by the overuse and misuse of antibiotics, resulting in the rise of multi-drug-resistant bacteria. A report commissioned in 2014 by the UK government predicted that antimicrobial resistance (AMR), could lead to 10 million deaths a year worldwide by 2050, surpassing cancer mortality rates.[4] An updated forecast was published in *The Lancet* in 2024.[5] β-lactams are characterized by the four-membered lactam ring which is fused to another ring, which determines their class. Penicillins display a sulfur-containing five-membered ring, cephalosporins a sulfur-containing six-membered ring (thiane ring), and carbapenems a carbonated five-membered ring (Figure 2). The rising concern of antibiotic resistance[6,7] has been the main driving force for the modification of the appended ring and for the introduction of various side chains and moieties on the β-lactam core.[8,9] One of the main mechanism of this resistance concerning β-lactam

[a] J. Bresson, Dr. K. Cariou
Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology
Chimie ParisTech, PSL University, CNRS
11 rue Pierre et Marie Curie, 75005 Paris (France)
E-mail: kevin.cariou@chimieparistech.psl.eu

[b] K. Burke, Prof. Dr. M. Ethève-Quelquejeu, Dr. L. Iannazzo
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques
Université Paris Cité, CNRS, F-75006 Paris, France
E-mail: laura.iannazzo@u-paris.fr

[c] Prof. Dr. M. Ethève-Quelquejeu
Institut Universitaire de France, Paris, 75006 France

<figure><img src="image_3.png" /></figure>

© 2025 The Authors. ChemMedChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

<figure><img src="image_4.png" /><figcaption>**Figure 1.** Chronology of the main classes of antibiotics introduction (top) and emergence of resistance (bottom).</figcaption></figure>
<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /><figcaption>Penicillins
(1940-1960)</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>Cephalosporines
(1960-1980)</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>Carbapenems
(1975-1995)</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>Monobactams
(1975-1995)</figcaption></figure>

<caption>**Figure 2.** Main classes of β-lactams antibiotics, with their ring numbering system.</caption>

antibiotics is the production by the bacteria of β-lactamases, a class of enzymes capable of hydrolyzing the antibiotic (namely the β-lactam ring itself) before it can perform its therapeutic action.

Structural modifications around the β-lactam core were initially made to fine-tune the therapeutic properties of the

molecule and improve pharmacokinetics and stability against β-lactamases.[7] The first β-lactamases identified were active against penicillins.[10] This prompted scientists to develop new classes of molecule, cephalosporins, then carbapenems. Unfortunately, new enzymes emerged that were able to hydrolyze these new generations of antibiotics, creating an "arms race" between chemists and bacteria.

This challenge calls for modifications to extend the utility of β-lactams beyond their traditional antibiotic roles, allowing more targeted approaches to both treatment and bacterial detection.

Adding an additional moiety to the β-lactam ring has long been a way to circumvent resistances, but it has now been shown to be an efficient way to modulate its mode of action. For instance, research have been focused on linking siderophores to the β-lactam antibiotics, to facilitate their uptake in the bacteria (Figure 3).[11] Using the ability of bacteria to scavenge the scarcely available iron from its environment to easily penetrate the cell, this so-called Trojan horse strategy has proven quite promising to increase the efficacy of traditional antibacterials.[12] Most of these compounds are yet to reach the clinical trial stage,[13] but the FDA approval of Cefiderocol in 2019 hopefully prefigures the release to the market of more molecules belonging to this promising family.

<figure><img src="image_10.png" /></figure>

Jules Bresson obtained his M. Sc degree in organic chemistry at Sorbonne Université in 2022. He then joined Professor Gilles Gasser's team at Chimie ParisTech – PSL to pursue his Doctorate studies under the supervision of Dr. Kevin Cariou. His work focuses on the development of novel antibiotics to fight the emergence of bacterial resistance.

<figure><img src="image_11.png" /></figure>

Laura Iannazzo graduated with an M. Sc degree in organic chemistry in 2007 in from Sorbonne University (France). She obtained her PhD in 2010 from the same university under the supervision of Dr C. Aubert for research about [2+2+2] cycloaddition. In 2011, she moved to University of Pennsylvania for a post-doctoral position with Pr G. A. Molander. She then joined the Paris Cité University to work at the interface between chemistry and biology before being recruited as CNRS researcher in 2016 in the group of Pr. M. Etheve-Quelquejeu.

<figure><img src="image_12.png" /></figure>

Katie Burke graduated with a BSc (Hons) in Chemistry from Manchester Metropolitan University (UK) before moving to France to pursue a MSc in Chemistry, Biology and Medicine at the University of Strasbourg (France). She is now doing her PhD at Paris Cité University (France) working on the synthesis of narrow spectrum antibiotics, under the supervision of Dr. Laura Iannazzo and Pr. Mélanie Etheve-Quelquejeu.

<figure><img src="image_13.png" /></figure>

Kevin Cariou received his PhD in 2006 from Sorbonne Université under the supervision of Max Malacria and Louis Fensterbank. From 2007 to 2009 he worked as a postdoctoral researcher in the group of Alison Frontier at the University of Rochester (NY, USA). He was appointed as CNRS Researcher in 2009 at the Institut de Chimie des Substances Naturelles in the team led by Robert Dodd. He obtained his HDR in 2015, and moved to Chimie ParisTech, PSL University in 2020 and was appointed Director of Research in 2021. His interests lie in the development of synthetic methods to access biologically active molecules.

<figure><img src="image_14.png" /></figure>

Mélanie Etheve-Quelquejeu is Professor of Organic Chemistry at the University of Paris Cité and member of the "institute Universitaire de France" (IUF). She obtained her PhD in chemistry from the Sorbonne University in Paris in 1997. She carried out two postdoctoral research stays in the USA, the first at Stanford University and the second at the University of Santa Barbara. She leads a research team at the Laboratory of Chemistry and Biochemistry, Pharmacology and Toxicology in Paris, working on the chemical modification of RNA and on the development of small molecules with antibacterial activities.
<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /><figcaption>**Figure 3.** Structure of Cefiderocol.</figcaption></figure>

More recently, β-Lactams have also been used as probes, allowing for the precise detection of specific resistances by linking pro-fluorescent tags to the antibiotic scaffold. The hydrolysis of the β-lactam ring by an enzyme in a resistant bacteria will release the tag, allowing precise detection and imaging of resistant bacteria, depending on the enzyme responsible for the resistance.

These developments highlight the increasing importance of chemical optimization in overcoming antibiotic resistance and expanding the clinical applications of these compounds, a process that requires robust methodologies.

This review provides a comprehensive and critical overview of metal-catalyzed methods employed in the synthesis of new β-lactam antibiotics and probes, with a particular focus on cross-coupling reactions.[14-16] Organized by β-lactam classes, it starts with cephalosporins (functionalized on the C-3 position), followed by carbapenems (functionalized on the C-2 position), and within each section a chronological approach is adopted to highlight the progress made and highlight potential future directions. The amide side-chain variation will not be the focus of this review, since the synthetic methods used in this case are generally classic amide coupling conditions. A specific section dedicated to the synthesis of cargo-releasing β-lactams, used as probes or drugs, ends this review.

## 2. Cephalosporin Derivatives

The first cephalosporin, cephalosporin C, was isolated from a fungus; however, its initial activity was relatively weak. Subsequent chemical modifications led to the development of numerous synthetic analogues, significantly enhancing their potency and therapeutic properties, giving rise to several successive generations of cephalosporins.[17] The synthetic

precursor to the vast majority of synthetic cephalosporins is the 7-aminocephalosporanic acid (7-ACA, see Scheme 1).[18,19] The amine linked to the β-lactam ring on the C-7 position can easily undergo an amide coupling to add side chains (R1 moiety, Scheme 1), which is one of the main parameters that is modified when developing a new cephalosporin. However, substituents on the C-3 position can also be tuned to adjust the therapeutic properties of the drug. These modifications are usually considered more challenging and focus mainly on the displacement of the acetoxy group by sulfur or nitrogen-based nucleophiles.[20] However the direct addition of a carbon-based nucleophile is much more complex. When this type of substituent is needed, conversion of the chloro-cephalosporin derivative (accessible in 4 steps from 7-ACA) to a phosphorus ylide and a following Wittig reaction has historically been the method of choice (Scheme 1).[21,22] However, this has the disadvantage of leaving an extra carbon atom between the C-3 carbon of the ring and the R2 side chain of the introduced aldehyde, preventing direct attachment of a substituent to the thione ring.

In view of the need to create more efficiently carbon-carbon bonds directly at the C-3 position, metal-mediated cross-coupling reactions appeared as one of the most efficient methods to use.[23-27] In 1988, Farina and co-workers presented the first example of a palladium-catalyzed cross-coupling to functionalize cephalosporins with aliphatic moieties, using Stille's methodology,[28,29] in an effort to synthesize the clinical candidate Cefprozil (Scheme 2).[30] The electrophilic coupling partner used was triflate 1, easily prepared from the commercially available 3-hydroxycephem. They later investigated this reaction, determining suitable ligands, solvent effects, side-products and clarifying key mechanistic details.[31] Yields, which depend on the substrate, can reach up to 90%, with good stereospecificity. Additionally, they demonstrated that the reaction has a broad scope, tolerating alkenes, alkynes, aromatic and heteroaromatic rings with various substituents (2a–g in Scheme 2).

Farina then developed an approach based on the ring expansion of penicillins (Scheme 3). The key intermediate is the β-lactam allene 3 obtained in 4 steps from the protected sulfoxide precursor,[32] bearing a tosyl leaving group on the sulfur atom supported by the β-lactam cycle (Scheme 3).[33] Compound 3 was reacted with a vinyl organocopper reactant prepared *in situ* from the corresponding Grignard reagent, to give product 4a. The same series of compounds 4 was obtained by palladium cross-coupling[30,31] using a shorter route, avoiding the ring expansion of the penem. Tanaka and co-workers improved this reaction by further investigating the scope and

<figure><img src="image_17.png" /><figcaption>**Scheme 1.** Synthetic strategy using the Wittig reaction to functionalize the C-3 position of cephalosporins.</figcaption></figure>
<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /></figure>

Representative examples

<figure><img src="image_20.png" /></figure>

2a, 68%

<figure><img src="image_21.png" /></figure>

2b, 55%

<figure><img src="image_22.png" /></figure>

2c, 50%

<figure><img src="image_23.png" /></figure>

2d, 57%

<figure><img src="image_24.png" /></figure>

2e, 52%

<figure><img src="image_25.png" /></figure>

2f, 73%

<figure><img src="image_26.png" /></figure>

2g, 89%

<figure><img src="image_27.png" /><figcaption>**Scheme 2.** Stille coupling between a cephalosporin triflate and an organotin partner.[30,31]</figcaption></figure>

<figure><img src="image_28.png" /><figcaption>**Scheme 3.** Synthesis of C-3 functionalized cephalosporins via ring expansion.[33,34]</figcaption></figure>

optimizing the reaction conditions.[34] Their approach relied on the *in situ* formation of the organocopper reagent *via* transmetallation of an organotin with a copper salt.

In 1993, Kant completely removed the need for the penicillin precursors and the ring expansion concept by reacting the organocopper reagent directly with the cephalosporin triflate 1 (Scheme 4), eliminating the time-consuming preparation steps of the previous reactive β-lactam intermediates required for the ring-opening/ring-closing.[35] In 1996, Tanaka *et al.* further improved their earlier system by applying Kant's advancements, which enhanced the yield for some substrates and expanded the scope of organotin partners.[36] It's important to note that these approaches require a stoichiometric quantity of copper salt. Although these methods give

satisfactory yields, they have not been further developed and their scope remains limited, with no example of nucleophiles containing heteroatoms. Additionally, using the cephalosporin triflate precursor results in a mixture of $\Delta^2$ and $\Delta^3$ isomers 5 and 6 respectively (Scheme 4). As a result, most efforts to synthetize C-3-functionalized cephalosporins have focused on palladium-catalyzed coupling reactions.

Farina's group seminal cross-coupling work was later improved upon by other researchers. In a 1991 article, a research team from Bristol-Myers Squibb tried to replace the triflate partner with a fluorosulfonyl moiety as a cheaper alternative (compound 7 in Scheme 5).[37] They also slightly changed the reaction conditions, using a ligandless and additiveless Pd(II) system (Scheme 5). This approach generally
<figure><img src="image_29.png" /></figure>

Kant, 1993

<figure><img src="image_30.png" /></figure>

Tanaka, 1996

<figure><img src="image_31.png" /><figcaption>**Scheme 4.** C-3 functionalization based on the in-situ formation of organocopper.[35,36]</figcaption></figure>

<figure><img src="image_32.png" /><figcaption>Representative examples (R = CH₂OPh)</figcaption></figure>

<figure><img src="image_33.png" /><figcaption>**Scheme 5.** Ligandless and additiveless Pd(II) cross-coupling system.[37]</figcaption></figure>

improved the yields for the substrate used by Farina *et al.* in their 1990 study,[31] though the scope was not as broad (compounds **8a–c** in Scheme 5). Despite this, the alternative to the enol triflate achieved only moderate success and has not been widely adopted in subsequent literature.

Nevertheless, Farina's protocol was applied by several groups to access new therapeutic molecules. For example 3-hydroxypropenyl cephems (Scheme 6A), or C-3 alkyne-substituted cephalosporins 9 which displayed potent activity against both Gram-positive and Gram-negative bacteria were synthetized.[38,39] In the latter case (Barret *et al*.), some methodological developments were required as the original article only reported one example of an alkynyl-cephalosporin. They turned to a ligandless Pd(II) system as well, using the cephalosporin mesylate 10 to access alkynyls compounds **11a–d** in low to moderate yields (Scheme 6B). However, according to the authors, this is compensated by the fact that mesylate 10 is considerably more stable than the commonly used triflates. Overall, these examples are proof that there is a real need for efficient cross-coupling of cephalosporins at this position.

Although numerous studies on cephalosporin Stille-type couplings were conducted in the late 1980s and 1990s,[30,31,35,37] it wasn't until after 2000 that cephalosporin was used as the

organotin coupling partner instead of the electrophilic triflate. In 2001, Buynak's team synthesized cephalosporin stannane **12b** through a Pd-catalyzed stannylation of the vinyl-iodide cephem **12a** in order to access cephalosporin-like β-lactamase inhibitors (Scheme 7).[40] The main differences with the actual antibiotic scaffold lie in the side chain and the sulfone group replacing the thiane moiety. This intermediate was successfully coupled with 3 vinyl and aryl iodides in respectable yields (compounds **13a–c** in Scheme 7). Despite its potential as a promising synthetic transformation, no other substrates have been explored, and to date, this remains the only example of the synthesis and use of a stannylcephem in the literature, apart from a study published in 2002 by the same group.[41] They used this reaction to access cephalosporins with modified substituents at the C-3 position, with promising inhibitory activity against β-lactamases. This emphasizes the fact that this methodology is clearly underexploited, as it has not been used since.

Farina's pivotal article also explored the ability to use 3-halomethyl cephems **14a** as coupling partners (Scheme 8).[31] By applying similar conditions, with some solvent adjustments, as those used for triflates, comparable yields were achieved across the same range of substrates (compounds **15a–d** in Scheme 8). This marked the first example of a sp²–sp³ coupling on cephalosporins. Using the ability of tributyltin hydride to reduce the starting substrate, 3-methylcephem **15a** was synthesized, a compound very similar to the first-generation cephalosporin Cefalexin.

Tanaka *et al.* explored the use of Cu(I) complexes in stoichiometric amounts to achieve the same goal. The coupling proceeded successfully, albeit with a narrower scope (**16a–d**), although yields up to 84% were obtained (Scheme 9).[42] However, their most impressive achievement was their ability to couple the cephems with vinyl and aryl bromides using Cu(0), providing a great example of cross-electrophile coupling. This discovery started from a reaction pathway in the Cu(I) system forming an unwanted cephem dimer, leading the tuning of the system to use it for this new purpose. It is worth mentioning that some elimination by-products are also formed (presumably
<figure><img src="image_34.png" /></figure>

<figure><img src="image_35.png" /></figure>

<figure><img src="image_36.png" /><figcaption>**Scheme 6.** Synthesis of a 3-hydroxypropenyl cephem (A)[38] and functionalization of cephalosporin mesylate-derivative to access alkynyl compounds using Stille-type ligandless coupling (B).[39]</figcaption></figure>

<figure><img src="image_37.png" /><figcaption>**Scheme 7.** Synthesis of the cephalosporin stannane and subsequent coupling.[40]</figcaption></figure>

by some protodemetallation process). In the end it was impossible for the authors to avoid the formation of all by-products in these reactions, which probably explains why it was not exploited further.

In 2001, Tanaka and his team once again radically modified the methodology, proposing a triple-metal redox system

<figure><img src="image_38.png" /></figure>

Representative examples

<figure><img src="image_39.png" /><figcaption>**Scheme 8.** Stille coupling of 3-chloromethylcephems.[31]</figcaption></figure>

containing aluminum (introduced in stoichiometric amounts), lead and nickel (Scheme 10).[43]

The active species in the catalytic cycle is Ni(0), produced from the Ni(II) introduced in the mixture by the oxidation of Pb(0) to Pb(II). Once the lead is oxidized, it is regenerated to Pb(0) with the oxidation of aluminum from Al(0) to Al(III). They achieved moderate to good yields for the coupling of the cephalosporine triflate **1** with the vinyl and aryl bromides. The scope is rather narrow with only three examples (compounds **17a-c**). Moreover, attempts to include examples with brominated reagents containing heteroatoms in their structure were unsuccessful. In fact, when trying to reach more complex functional groups, this system suffers from unwanted reaction pathways, such as producing the reduced side-product **2a** or the cephalosporin dimer **17d**. However, this system has the advantage of being cheaper than the palladium-catalyzed couplings commonly used and offers a promising platform for the development of future methodologies.

### 3. Carbapenem Derivatives

The first antibiotic from the carbapenem class, thienamycin, was isolated in 1978 from *Streptomyces cattleya*.[44,45] These antibiotics exhibit greater activity against bacteria than their counterparts and resist a wider range of β-lactamase enzymes. They are usually used reserved for hospitals to treat severe, multidrug-resistant infections and cannot be prescribed by general practitioners.[46] Consequently, they are generally used as a last resort when other antibiotics have failed to treat the disease.[47,48] Due to these interesting properties, chemists have sought to expand this class of antibiotics for many years, mostly by changing the side chain attached to the sulfur atom on the
<figure><img src="image_40.png" /></figure>

<figure><img src="image_41.png" /></figure>

<figure><img src="image_42.png" /><figcaption>Unwanted reaction pathways and side-products</figcaption></figure>

<figure><img src="image_43.png" /><figcaption>**Scheme 9.** Functionalization of 3-halomethyl cephems using a sp³–sp³ coupling.[42]</figcaption></figure>

<figure><img src="image_44.png" /><figcaption>**Figure 4.** Structures of the FDA approved carbapenems and their precursor, thienamycin.[49]</figcaption></figure>

C-2 carbon. These molecules are accessed through complex total synthesis, and four of them have been approved by the FDA (Figure 4).[49]

The need for novel carbapenem antibiotics calls for the development of a robust methodology, allowing to easily modify a carbon-based side chain. Conversely, the rise of resistances has called for the need to understand them better.[5] In particular, carbapenem-based chemical probes (used to detect such resistances) have recently witnessed a growing interest, which led to the need of new synthetic routes.[50–52] In both cases, metal-mediated cross-coupling appears to be the ideal tool to address these needs. The first example of such reactions applied to a carbapenem comes from Rano *et al.* in 1990.[53] In an article inspired by Farina’s work[30] on cephalosporins, they successfully managed to access simple 2-arylcarbapenems (examples 19a–19c) through a Stille coupling (Scheme 11A). The highly labile enol triflate 18 tends to decompose easily, necessitating the *in situ* protection of the C-8 hydroxyl as a silyl ether. This resulting metastable intermediate

proved to be the most practical for the cross-coupling reaction. Overall, this is a three-step one-pot procedure. Moreover, the reaction called for the use of phosphine, which had a key influence on both the yield and the rate of the reaction. The authors rationalized that phosphines bearing electron-donating groups helped optimize these two metrics, and tris(2,4,6-trimethoxyphenyl)phosphine proved to be the most effective. Other authors, however, were able to efficiently expand the scope of this reaction. Thus α-alkoxyalkenyl carbapenems were successfully synthesized[54] (19b, by Casson *et al.*), as well as 2-hydroxymethyl carbapenems[55] (19c, by Yasuda *et al.*), which can be used as a useful handle for post-functionalization. A clinical candidate, ME1036 (Scheme 11B), was accessed using this reaction after incorporation of an aminothiazole motif (19e).[56] This compound was tested on S. pneumoniae strains: it is highly active, with a MIC₉₀ of 0.03 µg/mL, compared to 0.5 µg/mL for Meropenem.[57] It is also active against Methicillin-Resistant Staphylococcus Aureus (MRSA), with MICs well below 1 µg/mL.[58,59] A 2004 study by Kurazono *et al.* tested its activity against 16 strains from multiple species, and ME1036 is active against almost all of them.[60] Fluorogenic probe CB-1, which allows the detection of carbapenemase-producing bacteria, was also synthesized thanks to this cross-coupling methodology (see below, Scheme 17, section 4 of this review).[52]

The research team of Mark Jensen at Merck improved upon this reaction by changing the organotin partner to a stannatrane (a caged poly heterocyclic structure).[61] A heteroalkyl side chain was incorporated thanks to this sp²–sp³ coupling, which proceeded with an excellent yield (Scheme 12). Drug candidate L-786,392 was synthesized using this method, displaying a MIC as low as 0.5 µg/mL on MRSA strains.[62]

Moreover, the stannatrane was entirely recovered leaving only trace amounts of tin in the coupling product, a key factor to consider when synthesizing drug candidates.

However, pharmaceutical companies are still reluctant to use Stille couplings, due to the high toxicity of tin. Suzuki-coupling with organoboron reagents is usually preferred as a
<figure><img src="image_45.png" /></figure>

<figure><img src="image_46.png" /><figcaption>**Scheme 10.** Cephalosporin coupling using a triple-redox system.[43]</figcaption></figure>

<figure><img src="image_47.png" /><figcaption>**Scheme 11.** Stille coupling of a carbapenem triflate with arylstannanes (A),[53-55] and access to ME1036 (B).[56]</figcaption></figure>

safer and greener alternative. The first example of such a
coupling was provided in 1993 by Yasuda and co-workers.[63]
Similarly to the work of Rano,[53] aryl substituents were
introduced at the C-2 position of the carbapenem in a three-
step one-pot sequence (including protection of the C-8
hydroxyl group), usually with higher yield when compared to

their Stille counterparts (see for example 73% for **19a**,
Scheme 11A, vs 93% for **20a**, Scheme 13A).

A styrene moiety was also successfully coupled (20f), being
the only example in the scope where the aromatic ring was not
directly attached to the C-2 position of the carbapenem. A
variant of these conditions was successfully used to access the
<figure><img src="image_48.png" /></figure>

<figure><img src="image_49.png" /><figcaption>Scheme 12. Stille coupling using a stannatrane as the nucleophile to access drug candidate L-786,392.[61]</figcaption></figure>

<figure><img src="image_50.png" /><figcaption>Scheme 13. Suzuki coupling of a carbapenem triflate with arylboronic acids (A),[63] and structure of drug candidate L-742,728 (B).[64]</figcaption></figure>

drug candidate, L-742,728 (Scheme 13B).[64] This antibiotic was tested against a strain of carbapenemase-producing *E. Coli*.[65] It displayed a MIC of 32 µg/mL, that was lowered to 2 µg/mL in presence of a carbapenemase thioester inhibitor.

Despite these obvious advantages, the scope of this reaction remains narrow. The work of Narukawa *et al.* in 1996[66] aimed to tackle this problem by providing examples of a sp²–sp³ Suzuki coupling (more precisely a β-alkyl Suzuki, Scheme 14).[67] Various carbamate-bearing alkyl chains were introduced in the presence of PdCl₂(dppf) as the catalyst and NaOH as the base, in good yields. The authors then slightly expanded the scope in a later publication.[68] Although this article was published almost 30 years ago, this work has not been expanded upon since.

It is worth noting that all the C-1 methylated carbapenem examples provided so far share a common electrophilic partner: a carbapenem triflate (18) which is usually synthesized from either the commercially available monobactam 22, after several steps including cyclisation step or from the slightly more advanced monobactam diazomalonate 23 (Figure 5). Surprisingly, very few teams have tried to test carbapenem cross-coupling conditions with anything other than this molecule. This could be explained by the fact that the only other commercially available carbapenem currently on the market is the β-methyl vinyl phosphate 24 which is not compatible with metal cross-coupling reactions due to its lack of reactivity.

<figure><img src="image_51.png" /><figcaption>Scheme 14. sp²–sp³ Suzuki coupling of carbapenem triflates.[66,68]</figcaption></figure>

The exception is Huffman *et al.* in 1998, whose initial intentions were to optimize the reaction with the previously described commercial β-methyl vinyl phosphate 24.[69] Unfortunately, it failed at the initial screening with even simpler
<figure><img src="image_52.png" /></figure>

<figure><img src="image_53.png" /></figure>

22

<figure><img src="image_54.png" /></figure>

23

<figure><img src="image_55.png" /></figure>

24

<caption>**Figure 5.** Different carbapenem precursors currently available commercially</caption>

substrates. The carbapenem tosylate **25** proved to be the only successful example in the literature to date at varying the carbapenem electrophile partner (Scheme 15).

All these methodological advancements suffer from the same pitfalls as the cephalosporin cross-couplings mentioned earlier in this review. The core of these methodologies relies widely on Farina's groundbreaking work on the cephalosporin Stille couplings.[30] Although Suzuki couplings, a less toxic alternative, have been developed, their scope remains quite

<figure><img src="image_56.png" /><figcaption>**Scheme 15.** Use of a carbapenem tosylate as the electrophile in a Suzuki coupling.[69]</figcaption></figure>

narrow and suffers from the lack of recent improvements. Merck, a key player in developing these coupling reactions, went as far as to publish a review expressing their satisfaction with this approach, which they deemed reliable and efficient.[27] Yet, this contrasts with the lack of research on this particular topic in the past 20 years.

### 4. β-Lactam Conjugates for Cargo Release

One of the main bacterial resistance mechanisms against β-lactams involves β-lactamases, enzymes that hydrolyze the β-lactam core, rendering the antibiotic inactive (Scheme 16A). However, this hydrolysis can be turned into an advantage by using it to trigger a cascade reaction that releases a desired molecule (Scheme 16B).

The earliest applications of this concept were surprisingly not linked to the treatment of bacterial infections, but to treat cancer. Doxorubicin and phenylenediamine mustard (two anticancer drugs) were linked to a cephalosporin scaffold. Separately, a β-lactamase was covalently bound to a tumor-targeting antibody, allowing the selective release of the drug only in the vicinity of the tumor (where it encountered the β-lactamase).[70–72]

Concerning antimicrobial purposes, the released molecule ("cargo") can be a fluorescent probe, used for diagnostic, allowing efficient detection of an infection by a β-lactamase-expressing (thus resistant) bacterium. Various dyes have been linked to the antibiotics, the most common ones being derivatives of coumarins or Tokyo Green (such as CC1 in Figure 6).[20,73] Moreover, this mechanism can be used to release a therapeutic payload as the cargo. Such drugs can be of

<figure><img src="image_57.png" /><figcaption>**Scheme 16.** Mechanism of action of serine β-lactamases (A), and release of cargo (B).</figcaption></figure>
<figure><img src="image_58.png" /></figure>

<figure><img src="image_59.png" /><figcaption>**Figure 6.** Several examples of cephalosporin-prodrug conjugates.[73,75–78]</figcaption></figure>

various natures. A few groups focused on the development of β-lactam-nitric oxide (NO) donor conjugates, which is an effective way of killing resistant bacteria.[74–76] Nitric oxide affects various cellular pathways non-selectively, thus killing whichever cell it is released in. NO release triggered by β-lactamase allows it to only accumulate in bacterial cells, leaving human cells unharmed and preventing the buildup of future resistance. Examples of such conjugates based on cephalosporins are presented in Figure 6.

Cephalosporins have also been combined with other types of drugs presenting anti-bacterial activity. Other classical antibiotics have been repurposed for new applications, notably to treat mycobacterial infections by linking them to classical cephems. The cephalosporine-pyrithione conjugate (Figure 6) was found to have activity against *Mycobacterium tuberculosis* (Mtb) (despite the reputation of β-lactams as being ineffective antimicrobials against mycobacteria).[77] The drug killed non-replicating Mtb, a feat that could not be achieved with previous penicillins and carbapenems. Another cephalosporine conjugated with fluoroquinolone can selectively kill β-lactamase-producing bacteria, the fluoroquinolone warhead being unaffected by this resistance mechanism.[78] All of the aforementioned conjugates (Figure 6) were the subject of a review published in 2022, and clearly all these very recent reports highlight the need for reliable synthetic functionalization methods to broaden the range of conjugates that should be accessible for developing better diagnostic and therapeutic tools.[20]

Quite strikingly, none of the cephem-based examples above have been synthetized using cross-coupling methods. This is in stark contrast with carbapenem conjugates, for which gentle metal-catalyzed cross couplings have permitted the synthesis of complex molecules used as probes to study bacterial resistance.

In 2017, Xie and coworkers reported a carbapenem-based fluorogenic probe for the detection of carbapanemases in carbapenemase-producing organisms (CPOs).[52] They devel-

oped a multi-step synthesis to access carbapenem CB-1 starting from the commercially available compound 27 (Scheme 17). The first key step of the synthesis employed a Stille coupling reaction in the presence of tributyl-vinyl stannane, affording compound 28 in 91% yield. A second metal-catalyzed Heck cross coupling reaction was then used to introduce the BODIPY core (although not efficiently with a yield of only 24%), with a catalytic system composed of Pd(OAc)₂, P(o-Tol)₃ and Et₃N in DMF at 80 °C for 16 h. Additional deprotection steps were applied to access the carbapenem-based fluorogenic probe CB-1. Fluorescence turn-on experiments were then conducted to detect β-lactamase activity. The carbapenem-BODIPY probe CB-1 did not show any fluorescence upon excitation at 503 nm, however hydrolysis by carbapenemases triggered a degradation process of the compound, leading to a strong green fluorescence of the BODIPY core.

Recent examples, independently reported by the groups of Xie[79,80] and Yang[81] described the use of fluorogenic probes for the detection of metallo- and serine-carbapenemases activities. A self-immolative linker containing a vinyl group was designed to release good leaving groups such as umbelliferone or resorufin (Scheme 18).

CPC-2 was prepared by a cross-metathesis reaction in the presence of vinyl carbapenem 28, 7-allyloxycoumarin 30 and the 2nd generation Hoveyda-Grubbs catalyst (with a modest yield of 35%), followed by the deprotection of the alcohol and carboxylic acid functions (Scheme 18A). The activation of the fluorogenic reagent CPC-2 by enzymatic activation with both metallo- and serine-carbapenamases, led to the release of a fluorescent umbelliferone moiety that was used to visualize β-lactamase activities.[80] While this study represent a valuable proof of concept, the rather modest yields for both the metathesis and deprotection steps, underline the need for more diverse and robust methods to access this type of probes.
<figure><img src="image_60.png" /></figure>

<figure><img src="image_61.png" /><figcaption>**Scheme 17.** Synthesis of carbapenem-based fluorogenic probe **CB-1**.[52]</figcaption></figure>

<figure><img src="image_62.png" /><figcaption>**Scheme 18.** Synthesis of carbapenem-based fluorogenic probe **CPC-2** (A)[80] and **CARBA-H** (B).[81]</figcaption></figure>

A similar strategy was developed in 2021 by Yang and coworkers. The author described the synthesis of the off-on fluorogenic probe **CARBA-H** starting from the triflate analogue **18d** and pinacol boronic ester **31** under Suzuki-Miyaura cross-coupling conditions (Scheme 18B). The probe was then used to develop a protocol for the detection of carbapenemase activities from clinical isolates. The resorufin was selected to demonstrate a strong turn-on fluorescence upon uncaging. The C1 substitution on the carbapenem scaffold, with or without 1β-methyl group, turned out to be a stereochemical determinant for β-lactamase selectivity.[81]

In 2020, Shabat and coworkers reported the first carbapenemase-sensitive chemiluminescent probe (CPCL) to monitor CPO activity (Scheme 19).[60] Their approach was based on a Suzuki-Miyaura cross-coupling step using $Pd_2(dba)_3$ and aqueous potassium carbonate in a $CH_2Cl_2/DMF$ mixture to introduce a 4-hydroxymethylphenyl linker between the carbapenem moiety **18c** and the dioxetane luminophore **32**. After further deprotection steps, the enol ether **34** was oxidized with singlet

oxygen under yellow light to access the **CPCL** probe. They hypothesized that the hydrolysis by the β-lactamases could trigger the decomposition of the carbapenem core leading, after chemical excitation of the oxetane intermediate, to the emission of a green photon. This phenomenon was used to measure the chemiluminescence and correlated with the carbapenemase activity.[82]

Recently, the group of Liu designed a modularly chromogenic carbapenem substrate (CCS) by modification of the C2 position of the carbapenem scaffold with a vinyl benzene derivative bearing an electronegativity-tunable substituent.[83] The reaction proceeds through a Stille type coupling to introduce the vinyl fragment, followed by Heck-coupling. They observed that the introduction of positively charged substituent [such as $-N+(CH_3)_3$] in CCS lead to a red shift of the absorption band. Additionally, such substitution favor the molecular interactions for the carbapenemases by improving the sensitivity of the chromogenic probe.
<figure><img src="image_63.png" /></figure>

<figure><img src="image_64.png" /><figcaption>Scheme 19. Synthesis of carbapenem-sensitive chemiluminescent probe CPCL.[82]</figcaption></figure>

## 5. Summary and Outlook

With bacterial infections possibly becoming a leading cause of death by 2050, developing new antibiotics should be a key priority. To facilitate the discovery of new drugs, robust synthetic methodologies are mandatory. Metal-catalyzed cross-couplings naturally spring to mind, as they are one of the most widely used tools in the pharmaceutical industry.[23-27] This review has highlighted the various developments in this area, covering both the functionalization of cephalosporins and carbapenems. Despite the wide variety of cross-couplings in other areas of the literature, the examples shown belong to a rather narrow chemical space. Almost all of them use palladium as their catalyst in nearly identical conditions, since these articles' core all rely on the same seminal work.[30] While Suzuki-Miyaura couplings have been developed to functionalize carbapenems, Stille couplings are still the method of choice for cephalosporins. Yet, their toxicity usually prevents them from being the go-to synthetic method in the pharmaceutical industry. As such it is particularly noteworthy that no new methodology aiming to functionalize the C-3 position of cephalosporins thanks to cross-couplings has been developed since 2001. This clearly must be associated with the general lack of interest of the industry for antibiotics in general, and β-lactams during the last two decades. Therefore, an update of the methodologies is long overdue and overall, there is still room for improvement. Emerging technologies, such as photo-chemical and electrochemical methods, present exciting opportunities to rethink classical synthetic paradigms. These approaches, which have already begun to transform various areas of organic chemistry, could potentially unlock new reactivity or enhance the efficiency and sustainability of cross-coupling reactions involving β-lactam structures.

This becomes particularly urgent in a context where the development of new rationally designed antibiotics and innovative probes is crucial to counter the rise of bacterial resistance. One could hope that considering antimicrobial resistance is poised to become one of the major public health concerns, scientists will

seize the opportunity, and companies will take a renewed interest in furthering the research on this very timely topic.

## Acknowledgements

We thank Narrow Spectrum Antibiotics to Fight the Emergence of Bacterial Resistance project (NASPEC, 20-PAMR-0007) founded by Agence Nationale de la Recherche for financial support and PhD fellowship for JB and KB. KC and LI thank the CNRS, KC and JB thank Chimie ParisTech-PSL University, KB, MEQ and LI thank Université Paris-Cité and MEQ thanks Institut Universitaire de France for their financial support. We thank Reviewer 1 for their extremely valuable comments and suggestions. The graphical abstract was drawn using images from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 4.0 Unported License (CC BY) (https://smart.servier.com/citation-sharing/) (https://creativecommons.org/licenses/by/4.0/).

## Conflict of Interests

The authors declare no conflict of interest.

**Keywords:** antibiotics • carbapenems • cephalosporins • chemical probes • metal catalyzed cross-coupling • β-lactamase

[1] E. P. Abraham, E. Chain, *Nature* **1942**, *149*, 328-328.

[2] E. P. Abraham, W. Baker, E. Chain, H. W. Florey, E. R. Holiday, R. Robinson, *Nature* **1942**, *149*, 356-356.

[3] A. E. Clatworthy, E. Pierson, D. T. Hung, *Nat. Chem. Biol.* **2007**, *3*, 541-548.

[4] J. O'Neill, *Tackling Drug-Resistant Infections Globally: Final Report and Recommendations 2016*.

[5] M. Naghavi, et al., *The Lancet* **2024**, *404*, 1199-1226.

[6] R. J. Fair, Y. Tor, *Perspect. Med. Chem. 2014*, **6**, PMC.S14459.

[7] M. F. Chellat, L. Raguž, R. Riedl, *Angew. Chem. Int. Ed.* **2016**, *55*, 6600-6626.

[8] S. B. Singh, J. F. Barrett, *Biochem. Pharmacol.* **2006**, *71*, 1006-1015.

[9] K. Lewis, R. E. Lee, H. Brötz-Oesterhelt, S. Hiller, M. V. Rodnina, T. Schneider, M. Weingarth, I. Wohlgemuth, *Nature* **2024**, *632*, 39-49.
<figure><img src="image_65.png" /></figure>

[10] C. L. Tooke, P. Hinchliffe, E. C. Bragginton, C. K. Colenso, V. H. A. Hirvonen, Y. Takebayashi, J. Spencer, *J. Mol. Biol.* **2019**, *431*, 3472–3500.

[11] H. Kong, W. Cheng, H. Wei, Y. Yuan, Z. Yang, X. Zhang, *Eur. J. Med. Chem.* **2019**, *182*, 111615.

[12] U. Möllmann, L. Heinisch, A. Bauernfeind, T. Köhler, D. Ankel-Fuchs, *BioMetals* **2009**, *22*, 615–624.

[13] M. C. Almeida, P. M. da Costa, E. Sousa, D. I. S. P. Resende, *J. Med. Chem.* **2023**, *66*, 32–70.

[14] C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus, *Angew. Chem. Int. Ed.* **2012**, *51*, 5062–5085.

[15] A. de Meijere, F. Diederich, *Metal-Catalyzed Cross-Coupling Reactions*, John Wiley & Sons, Ltd, **2004**.

[16] L.-C. Campeau, N. Hazari, *Organometallics* **2019**, *38*, 3–35.

[17] W. A. Craig, D. R. Andes, in *Mand. Douglas Bennetts Princ. Pract. Infect. Dis. Eighth Ed.* (Eds.: J. E. Bennett, R. Dolin, M. J. Blaser), W. B. Saunders, Philadelphia, **2015**, pp. 278–292.e4.

[18] A. L. Demain, in *Antibiot. Contain. Beta-Lact. Struct.* (Eds.: A. L. Demain, N. A. Solomon), Springer, Berlin, Heidelberg, **1983**, pp. 189–228.

[19] B. Alcaide, C. Aragoncillo, P. Almendros, in *Compr. Heterocycl. Chem. III* (Eds.: A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor), Elsevier, Oxford, **2008**, pp. 111–171.

[20] M. S. Cole, P. V. Hegde, C. C. Aldrich, *ACS Infect. Dis.* **2022**, DOI 10.1021/acsinfecdis.2c00315.

[21] T. Naito, H. Hoshi, S. Aburaki, Y. Abe, J. Okumura, K. Tomatsu, H. Kawaguchi, *J. Antibiot.* **1987**, *40*, 991–1005.

[22] H. Kamachi, Y. Narita, T. Okita, Y. Abe, S. limura, K. Tomatsu, T. Yamasaki, J. Okumura, T. Naito, T. Oki, H. Kawaguchi, *J. Antibiot.* **1988**, *41*, 1602–1616.

[23] E. Negishi, *Angew. Chem. Int. Ed.* **2011**, *50*, 6738–6764.

[24] A. Suzuki, *Angew. Chem. Int. Ed.* **2011**, *50*, 6722–6737.

[25] J. Magano, J. R. Dunetz, *Chem. Rev.* **2011**, *111*, 2177–2250.

[26] A. O. King, N. Yasuda, in *Organomet. Process Chem.*, Springer, Berlin, Heidelberg, **2004**, pp. 205–245.

[27] N. Yasuda, *J. Organomet. Chem.* **2002**, *653*, 279–287.

[28] W. J. Scott, J. K. Stille, *J. Am. Chem. Soc.* **1986**, *108*, 3033–3040.

[29] C. Cordovilla, C. Bartolomé, J. M. Martínez-Ilarduya, P. Espinet, *ACS Catal.* **2015**, *5*, 3040–3053.

[30] V. Farina, S. R. Baker, C. Sapino, *Tetrahedron Lett.* **1988**, *29*, 6043–6046.

[31] V. Farina, S. R. Baker, D. A. Benigni, S. I. Hauck, C. Sapino, *J. Org. Chem.* **1990**, *55*, 5833–5847.

[32] V. Farina, J. Kant, *Tetrahedron Lett.* **1992**, *33*, 3559–3562.

[33] J. Kant, V. Farina, *Tetrahedron Lett.* **1992**, *33*, 3563–3566.

[34] H. Tanaka, Y. Kameyama, S. Sumida, S. Torii, *Tetrahedron Lett.* **1992**, *33*, 7029–7030.

[35] J. Kant, *J. Org. Chem.* **1993**, *58*, 2296–2301.

[36] H. Tanaka, S. Sumida, S. Torii, *Tetrahedron Lett.* **1996**, *37*, 5967–5970.

[37] G. P. Roth, C. Sapino, *Tetrahedron Lett.* **1991**, *32*, 4073–4076.

[38] Y. S. Lee, J. Y. Lee, J.-H. Jeong, H. Park, *Arch. Pharmacal Res.* **1997**, *20*, 288–290.

[39] D. Barrett, T. Terasawa, S. Okuda, K. Kawabata, N. Yasuda, T. Kamimura, K. Sakane, T. Takaya, *J. Antibiot.* **1997**, *50*, 100–102.

[40] J. D. Buynak, L. Vogeti, H. Chen, *Org. Lett.* **2001**, *3*, 2953–2956.

[41] J. D. Buynak, L. Vogeti, V. R. Doppalapudi, G. M. Solomon, H. Chen, *Bioorg. Med. Chem. Lett.* **2002**, *12*, 1663–1666.

[42] H. Tanaka, S. Sumida, S. Torii, *J. Org. Chem.* **1997**, *62*, 3782–3786.

[43] H. Tanaka, J. Zhao, H. Kumase, *J. Org. Chem.* **2001**, *66*, 570–577.

[44] J. S. Kahan, F. M. Kahan, R. Goegelman, S. A. Currie, M. Jackson, E. O. Stapley, T. W. Miller, A. K. Miller, D. Hendlin, S. Mochales, S. Hernandez, H. B. Woodruff, J. Birnbaum, *J. Antibiot.* **1979**, *32*, 1–12.

[45] Y. Doi, H. F. Chambers, in *Mand. Douglas Bennetts Princ. Pract. Infect. Dis. Eighth Ed.* (Eds.: J. E. Bennett, R. Dolin, M. J. Blaser), W. B. Saunders, Philadelphia, **2015**, pp. 293–297.e2.

[46] M. McKenna, *Nature* **2013**, *499*, 394–396.

[47] E. Temkin, A. Adler, A. Lerner, Y. Carmeli, *Ann. N. Y. Acad. Sci.* **2014**, *1323*, 22–42.

[48] L. K. Logan, R. A. Weinstein, *J. Infect. Dis.* **2017**, *215*, S28–S36.

[49] N. Kardos, *SunText Rev. Biotechnol.* **2020**, *01*, 103.

[50] W. A. Velema, *Chem. Commun.* **2023**, *59*, 6148–6158.

[51] J. Kim, Y. Kim, A. Z. Abdelazem, H. J. Kim, H. Choo, H. S. Kim, J. O. Kim, Y.-J. Park, S.-J. Min, *Bioorganic Chem.* **2020**, *94*, 103405.

[52] W. Mao, L. Xia, H. Xie, *Angew. Chem. Int. Ed.* **2017**, *56*, 4468–4472.

[53] T. A. Rano, M. L. Greenlee, F. P. DiNinno, *Tetrahedron Lett.* **1990**, *31*, 2853–2856.

[54] S. Casson, P. Kocieński, *J. Chem. Soc. Perkin Trans. 1* **1994**, *0*, 1187–1191.

[55] N. Yasuda, C. Yang, K. M. Wells, M. S. Jensen, D. L. Hughes, *Tetrahedron Lett.* **1999**, *40*, 427–430.

[56] Z.-J. Han, Y.-B. Li, L.-X. Yang, A. Song, H. Chen, Y.-M. Li, *Lett. Org. Chem.* **2015**, *12*, 745–752.

[57] Y. Hirai, S. Takahata, K. Yamada, T. Ida, K. Maebashi, *J. Antibiot.* **2011**, *64*, 741–746.

[58] K. Yanagihara, Y. Ohnishi, Y. Morinaga, S. Nakamura, S. Kurihara, M. Seki, K. Izumikawa, H. Kakeya, Y. Yamamoto, Y. Yamada, S. Kohno, S. Kamihira, *Int. J. Antimicrob. Agents* **2008**, *32*, 401–404.

[59] H. S. Sader, T. R. Fritsche, R. N. Jones, *Antimicrob. Agents Chemother.* **2008**, *52*, 1153–1155.

[60] M. Kurazono, T. Ida, K. Yamada, Y. Hirai, T. Maruyama, E. Shitara, M. Yonezawa, *Antimicrob. Agents Chemother.* **2004**, *48*, 2831–2837.

[61] M. S. Jensen, C. Yang, Y. Hsiao, N. Rivera, K. M. Wells, J. Y. L. Chung, N. Yasuda, D. L. Hughes, P. J. Reider, *Org. Lett.* **2000**, *2*, 1081–1084.

[62] R. W. Ratcliffe, R. R. Wilkening, K. J. Wildonger, S. T. Waddell, G. M. Santorelli, D. L. Parker, J. D. Morgan, T. A. Blizzard, M. L. Hammond, J. V. Heck, J. Huber, J. Kohler, K. L. Dorso, E. St. Rose, J. G. Sundelof, W. J. May, G. G. Hammond, *Bioorg. Med. Chem. Lett.* **1999**, *9*, 679–684.

[63] N. Yasuda, L. Xavier, D. L. Rieger, Y. Li, A. E. DeCamp, U.-H. Dolling, *Tetrahedron Lett.* **1993**, *34*, 3211–3214.

[64] N. Yasuda, M. A. Huffman, G.-J. Ho, L. C. Xavier, C. Yang, K. M. Emerson, F.-R. Tsay, Y. Li, M. H. Kress, D. L. Rieger, S. Karady, P. Sohar, N. L. Abramson, A. E. DeCamp, D. J. Mathre, A. W. Douglas, U.-H. Dolling, E. J. J. Grabowski, P. J. Reider, *J. Org. Chem.* **1998**, *63*, 5438–5446.

[65] G. G. Hammond, J. L. Huber, M. L. Greenlee, J. B. Laub, K. Young, L. L. Silver, J. M. Balkovec, K. D. Pryor, J. K. Wu, B. Leiting, D. L. Pompliano, J. H. Toney, *FEMS Microbiol. Lett.* **1999**, *179*, 289–296.

[66] Y. Narukawa, K. Nishi, H. Onoue, *Tetrahedron Lett.* **1996**, *37*, 2589–2592.

[67] S. R. Chemler, D. Trauner, S. J. Danishefsky, *Angew. Chem. Int. Ed.* **2001**, *40*, 4544–4568.

[68] Y. Narukawa, K. Nishi, H. Onoue, *Tetrahedron* **1997**, *53*, 539–556.

[69] M. A. Huffman, N. Yasuda, *Synlett* **1999**, *1999*, 471–473.

[70] T. A. Shepherd, L. N. Jungheim, D. L. Meyer, J. J. Starling, *Bioorg. Med. Chem. Lett.* **1991**, *1*, 21–26.

[71] D. E. Kerr, G. J. Schreiber, V. M. Vrudhula, H. P. Svensson, I. Hellström, K. E. Hellström, P. D. Senter, *Cancer Res.* **1995**, *55*, 3558–3563.

[72] H. P. Svensson, V. M. Vrudhula, J. E. Emswiler, J. F. MacMaster, W. L. Cosand, P. D. Senter, P. M. Wallace, *Cancer Res.* **1995**, *55*, 2357–2365.

[73] W. Gao, B. Xing, R. Y. Tsien, J. Rao, *J. Am. Chem. Soc.* **2003**, *125*, 11146–11147.

[74] X. Tang, T. Cai, P. G. Wang, *Bioorg. Med. Chem. Lett.* **2003**, *13*, 1687–1690.

[75] N. Barraud, B. G. Kardak, N. R. Yepuri, R. P. Howlin, J. S. Webb, S. N. Faust, S. Kjelleberg, S. A. Rice, M. J. Kelso, *Angew. Chem. Int. Ed.* **2012**, *51*, 9057–9060.

[76] S. A. Collins, M. J. Kelso, A. Rineh, N. R. Yepuri, J. Coles, C. L. Jackson, G. D. Halladay, W. T. Walker, J. S. Webb, L. Hall-Stoodley, G. J. Connett, M. Feelisch, S. N. Faust, J. S. A. Lucas, R. N. Allan, *Antimicrob. Agents Chemother.* **2017**, *61*, 10.1128/aac.02086-16.

[77] L. Lopez Quezada, K. Li, S. L. McDonald, Q. Nguyen, A. J. Perkowski, C. W. Pharr, B. Gold, J. Roberts, K. McAulay, K. Saito, S. Somersan Karakaya, P. E. Javidnia, E. Porras de Francisco, M. M. Amieva, S. P. Diaz, A. Mendoza Losana, M. Zimmerman, H.-P. H. Liang, J. Zhang, V. Dartois, S. Sans, S. Lagrange, L. Goullieux, C. Roubert, C. Nathan, J. Aubé, *ACS Infect. Dis.* **2019**, *5*, 1433–1445.

[78] L. E. Evans, A. Krishna, Y. Ma, T. E. Webb, D. C. Marshall, C. L. Tooke, J. Spencer, T. B. Clarke, A. Armstrong, A. M. Edwards, *J. Med. Chem.* **2019**, *62*, 4411–4425.

[79] X. Qian, S. Zhang, S. Xue, W. Mao, M. Xu, W. Xu, H. Xie, *Bioorg. Med. Chem. Lett.* **2019**, *29*, 322–325.

[80] J. Wang, W. Xu, S. Xue, T. Yu, H. Xie, *Org. Biomol. Chem.* **2020**, *18*, 4029–4033.

[81] C.-W. Ma, K. K.-H. Ng, B. H.-C. Yam, P.-L. Ho, R. Y.-T. Kao, D. Yang, *J. Am. Chem. Soc.* **2021**, *143*, 6886–6894.

[82] S. Das, J. Ihssen, L. Wick, U. Spitz, D. Shabat, *Chem. Eur. J.* **2020**, *26*, 3647–3652.

[83] W. Li, J. Wang, C. Li, Z. Zong, J. Zhao, H. Gao, D. Liu, *JACS Au* **2023**, *3*, 227–238.
This review focus on the use of transi-
tion metal cross-coupling strategies
for the synthesis of beta-lactam deriv-
atives. This manuscript encompasses
the seminal studies for the synthesis
of antibiotics up to the current need
of accessing specific probes that are
crucial for the detection of resistan-
ces.

<figure><img src="image_66.png" /></figure>

J. Bresson, K. Burke, Prof. Dr. M. Ethève-Quelquejeu, Dr. L. Iannazzo*, Dr. K. Cariou*

1 – 15

Metal-Catalyzed Cross-Coupling for
the Synthesis of β-Lactam Drugs
and Related Chemical Probes

@chimieparistechpsl.bsky.social @cariouk.bsky.social @upcite.bsky.social @EtheveMelanie @J_Bresson_

Share your work on X! ChemMedChem promotes selected articles on X (formerly known as Twitter). Each article post contains the title, name of the corresponding author, a link to the article, selected handles and hashtags, and the ToC picture. If you, your team, or your institution have an X account, please include its handle @username below. We recommend sharing and interacting with these posts through your personal and/or institutional accounts to help increase awareness of your work! Please follow us @Chem_Europe.

ORCID (Open Researcher and Contributor ID)

Please check that the ORCID identifiers listed below are correct. We encourage all authors to provide an ORCID identifier for each coauthor. ORCID is a registry that provides researchers with a unique digital identifier. Some funding agencies recommend or even require the inclusion of ORCID IDs in all published articles, and authors should consult their funding agency guidelines for details. Registration is easy and free; for further information, see http://orcid.org/.

Jules Bresson

Katie Burke

Prof. Dr. Mélanie Ethève-Quelquejeu http://orcid.org/0000-0002-4105-3243

Dr. Laura Iannazzo http://orcid.org/0000-0002-2181-4885

Dr. Kevin Cariou http://orcid.org/0000-0002-5854-9632