Roger Marti

The synthetic alkyl-lysophospholipid (ALP) Edelfosine has garnered attention due to its potent in vivo activity, oral administration route, and synergistic effects with other therapies. Its development as a preclinical candidate, however, is constrained by challenges associated with the economical, large-scale preparation of the enantiopure compound. Herein, we describe the development of a novel synthetic route that provides enantiopure (S)-Edelfosine in a scalable manner, amenable to industrial implementation. Through several iterations, we achieve synthetic improvements via a more convergent assembly of the substituted glycerol portion of the title compounds. By exploiting a chiral benzylglycidyl ether as the key synthon, we demonstrate the successful four-step, formal, and total syntheses of (S)- and (R)-Edelfosine respectively─the shortest demonstrably scalable routes of their kind. Finally, we establish phenyl trimethylammonium iodide as a suitable green alternative to carcinogenic iodomethane in this context. Our streamlined chiral pool approach thus furnishes a significant improvement in the synthetic accessibility of optically pure Edelfosine and paves the way for the parallel development of both medicinally relevant ALP enantiomers.

Respiratory syncytial virus infection (RSV) is a major global health concern, particularly in infants and elderly populations. In this work, we have screened and identified 3 double-stapled peptides derived from a minimal domain of the RSV F heptad repeat, namely 3/4i, 3/4m, and 4/4g, which are potent inhibitors of RSV fusion and remain active against viral escape mutants resistant to small-molecule fusion inhibitors. Our structural activity relationship (SAR) analysis demonstrates that combining a limited set of staples is sufficient to achieve high antiviral potency. X-ray crystallography revealed that the enhanced potency of 3/4i and 3/4m primarily arises from strong hydrophobic interactions between the N-terminal staple and the trimeric HR1 coiled coil of RSV F. In vivo pharmacokinetic, imaging, and feasibility studies in RSV-infected Balb/c mice further support intranasal administration as a promising route for delivering these stapled peptides to the lung, highlighting their potential as therapeutics against RSV.

The use of green solvents is a key element in making chemical processes more sustainable. In this work, three biobased solvents, diformyl xylose (DFX), dipropyl xylose (DPX), and n ‐butyl tetrahydrofurfuryl ether (Solvinol), were tested as cosolvents in the Suzuki–Miyaura reaction using micellar catalysis in water (TPGS‐750‐M system). 2% DPX gave > 99% conversion and 86% yield, while 2% DFX reached 86% conversion and 82% yield. Solvinol required 15% loading to give similar results. DFX was easily removed in the aqueous phase upon work‐up, while DPX and Solvinol were more difficult to remove due to their poor water solubility and high boiling points. These results demonstrate the potential of biomass‐derived solvents as green alternatives to classical organic solvents. The overall environmental efficiency of the various processes was assessed via our internal methodology. Their efficiency at low loadings supports their use in more sustainable and environmentally friendly processes.

Continuous processes (often referred to as flow chemistry) offers multiple advantages over batch processes and are of particular interest for industrial applications as they provide a more direct path towards process intensification, increased safety and efficiency. However, some chemical processes are still challenging to run in a continuous fashion, such as reactions producing fouling, using stoichiometric amounts of solids, or requiring long residence times. For those kinds of reactions, batch approaches are usually preferred even though some processes would still benefit from the advantages inherent to flow. We herein report our testing and development of a scalable continuous flow reactor equipped with active mixing that was designed to handle those challenging continuous processes, such as the continuous formation of a Grignard reagent from a magnesium powder slurry.

Single-atom heterogeneous catalysts (SACs) are potential, recoverable alternatives to soluble organometallic complexes for cross-coupling reactions in fine-chemical synthesis. When developing SACs for these applications, it is often expected that the need for ligands, which are essential for organometallic catalysts, can be bypassed. Contrary to that, ligands remain almost always required for palladium atoms stabilized on commonly used functionalized carbon and carbon nitride supports, as the catalysts otherwise show limited activity. Despite this, ligand optimization has received little attention, and their role in activating SACs is poorly understood. Here, we explore the impact of structurally diverse phosphine ligands on the performance of nitrogen-doped carbon supported single-atoms (Pd₁@NC) in the Sonogashira-Hagihara (SH) cross-coupling reaction, using X-ray absorption spectroscopy and density functional theory simulations to rationalize the observed trends. Compared to the ligand-free SAC, SH activity is enhanced in almost all ligand-assisted systems, with reactivity varying by up to 8 orders of magnitude depending on the ligand choice. Distinct trends emerge based on the free ligand volume and ligand class. Unlike molecular systems, the electronic effects of phosphine ligands are less significant in SACs due to the modulating influence of the support. Instead, the performance of SAC-ligand systems is governed by a balance between the ligand deformation energy during coordination with metal centers, and their resulting accessibility to cross-coupling reagents. These findings offer key insights into optimizing Pd-SACs by leveraging phosphine ligands to activate metal centers and tailor the 3D environment.

The large-scale production of platform chemicals from biomass requires efficient, cost-effective, and sustainable methods. Here, we present three one-pot synthesis routes for producing diformylxylose (DFX), a sugar-based solvent and platform chemical, using d-xylose or corncobs as feedstocks. With yields of approximately 80%, these routes were seamlessly scaled from lab to kilogram-scale in a 15 L batch reactor. Techno-economic assessment demonstrates the competitiveness of the proposed methods against fossil- and biobased analogues. Life-cycle analysis shows the potential of these processes to reduce environmental and societal impacts from cradle to gate. At the "end of life", DFX is demonstrated to be inherently biodegradable. Overall, we present a compelling case study of scaling a novel platform chemical guided by techno-economic and environmental concerns leading to balanced cost-competitiveness and life-cycle sustainability.

The use of sustainable oxidants is of great interest to the chemical industry, considering the importance of oxidation reactions for the manufacturing of chemicals and society's growing awareness of its environmental impact. Molecular oxygen (O₂), with an almost optimal atom efficiency in oxidation reactions, presents one of the most attractive alternatives to common reagents that are not only toxic in most cases but produce stoichiometric amounts of waste that must be treated. However, fire and explosion safety concerns, especially when used in combination with organic solvents, restrict its easy use. Here, we use state-of-the-art 3D printing and experimental feedback to develop a miniature continuous stirred-tank reactor (mini-CSTR) that enables efficient use of O₂ as an oxidant in organic chemistry. Outstanding heat dissipation properties, achieved through integrated jacket cooling and a high surface-to-volume ratio, allow for a safe operation of the exothermic oxidation of 2-ethylhexanal, surpassing previously reported product selectivity. Moving well beyond the proof-of-concept stage, we characterize and illustrate the reactor's potential in the gas-liquid-solid triphasic synthesis of an endoperoxide precursor of antileishmanial agents. The custom-designed magnetic overhead stirring unit provides improved stirring efficiency, facilitating the handling of suspensions and, in combination with the borosilicate gas dispersion plate, leading to an optimized gas-liquid interface. These results underscore the immense potential that lies within the use of mini-CSTR in sustainable chemistry.

A sol-gel process for the synthesis of a multi-component oxide material from the system SiO2-ZrO2-Al2O3underwent optimization and up-scaling. Initially, on a laboratory scale, components including precursors, catalysts, and additives were methodically evaluated to ensure a safe and efficient transition to larger volumes. Subsequently, the equipment for the whole setup of the sol-gel process was strategically selected. Leveraging insights from these optimizations, the process was successfully scaled-up to pilot-scale operation, conducting hydrolysis, condensation reactions, gelation, aging, and drying within a single, integrated conical dryer system for an 80 L batch. A visual test and FTIR spectroscopy were applied for process control and monitoring.

Sustainably producing plastics with performance properties across a variety of materials chemistries is a major challenge—especially considering that most performance materials use aromatic precursors that are still difficult to source sustainably. Here we demonstrate catalyst-free, melt polymerization of dimethyl glyoxylate xylose, a stabilized carbohydrate that can be synthesized from agricultural waste with 97% atom efficiency, into amorphous polyamides with performances comparable to fossil-based semi-aromatic alternatives. Despite the presence of a carbohydrate core, these materials retain their thermomechanical properties through multiple rounds of high-shear mechanical recycling and could be chemically recycled. Techno-economic and life-cycle analyses suggest selling prices close to those of nylon 66 with a reduction of global warming potential of up to 75%. This work illustrates the versatility of a carbohydrate moiety to impart performance that can compete with that of semi-aromatic polymers across two important materials chemistries.