Biocatalytic site-selective desaturation: a tool for late-stage functionalization of complex molecules

Join us for the Thieme Cheminar dedicated to Professor Erick Carreira Thursday, August 14, 2025 3:00 PM (CET) This special online event celebrates the impactful career and scientific legacy of Prof. Erick Carreira, through outstanding talks by leading researchers in the field: 🔹Prof. Tobias Ritter (Max-Planck-Institut Kohlenforschung, Germany)🔹Prof. Song Lin (Cornell University, USA)🔹Prof. Sarah Reisman (California Institute of Technology (Caltech), USA) Chaired by Prof. Mark Lautens, Editor-in-Chief of SynthesisDo not miss this unique and inspiring opportunity to explore groundbreaking chemistry and honor one of the field’s leading voices!Late-Stage FunctionalizationsTalk by Tobias Ritter, Mark LautensEnantioselective ElectrosynthesisTalk by Song LinNecessity is the Mother of Invention: Natural Products and the Chemistry They InspireTalk by Sarah Reisman

Late-Stage Functionalization

Late-stage functionalization (LSF) enables the direct, site-selective modification of complex molecules and has become a key strategy in sustainable drug discovery and chemical biology. While homogeneous photocatalysis has traditionally dominated this field, recent advances in materials engineering and catalyst design have triggered a new interest in heterogeneous photocatalysis. Although classical heterogeneous photocatalysts such as metal oxides and carbon nitrides are long established, their nanoscale re-engineering and integration into LSF have only recently enabled enhanced reactivity, selectivity, and recyclability. This review surveys the recent evolution of heterogeneous photocatalytic systems, from traditional semiconductors to covalent organic frameworks and metal-organic frameworks, for selective LSF. By connecting developments in materials chemistry with photoredox catalysis, this contribution highlights the growing potential of heterogeneous photocatalysts as scalable and sustainable platforms for complex molecule synthesis.

This overview discusses some highlights of iridium catalyzed CH functionalizations with hydrogen isotopes. The hydrogen isotope exchange (HIE) reaction has become the gold standard in late stage functionalization and synthesis of deuterium or tritium labelled organic, complex molecules. In particular, new highly selective and reactive protocols in the areas of acid/base, nanoparticle, metal‐ catalyzed or photoredox catalysis are reported.

Direct C–H bond functionalization to form C–N bonds via nitrenoid insertion is one of the most effective strategies to construct N-functionalized molecules of importance. In this context, metalloporphyrins have established themselves as effective catalytic systems for such transformation, following an outer-sphere pathway. In the past few years C(sp3)–H bond amination has progressed in leaps and bounds, tackling the chemo-/regioselectivity issue not only in small molecules but also in complex molecules through late-stage functionalization, furnishing valuable N-scaffolds. It is only very recently that the biocatalytic approach with metalloporphyrin-based enzymes has emerged as a promising research area demonstrating very good regio- and stereoselectivity toward the development of environmentally benign C–H amination processes. Importantly, the progress in aromatic C–H bond amination has also gained prominence lately under metalloporphyrin catalysis. This review covers development achieved to date in metal...

It has been more than 160 years since chemists first performed fluorination reactions on organic molecules. Scores of fluorination reagents and hundreds of worthwhile methods have been developed over the intervening years. Meanwhile, workers in the field are increasingly aware of the benefits of incorporating fluorine atoms into bioactive molecules. Therefore, the emergence of "late-stage fluorination" in the first decade of the 21st century is both natural and well-justified─an extant compound, off the shelf, can be converted more efficiently to a fluorinated product than through a de novo approach. It is worth noting that chemists' attempts to fluorinate complex molecules began sporadically decades ago before the concept of "late-stage" was first proposed. In this Perspective, we aim to present a comprehensive series of late-stage fluorination strategies, with the spotlight primarily focused on single-atom modifications of complex molecules (although incidental examples of polyfluorination are addressed), including natural products, analogues, and pharmaceuticals. Both the nucleophilic and electrophilic sources of fluorine are examined.

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

The development of synthetic tools to introduce saccharide derivatives into functionally complex molecules is of great interest, particularly in the field of drug discovery. Herein, we report a new route toward highly functionalized, arylated saccharides, which involves nickel-catalyzed cross-coupling of photoredox-generated saccharyl radicals with a range of aryl- and heteroaryl bromides, triggered by an organic photocatalyst. In contrast to existing methods, the mild reaction conditions achieve arylation of saccharide motifs while leaving the anomeric carbon available, thus providing access to a class of arylated glycosides that has been underexplored until now. To demonstrate the potential of this strategy in late-stage functionalization, a variety of structurally complex molecules incorporating saccharide moieties were synthesized.

Presents state-of-the-art strategies for the late-stage functionalization and diversity-oriented synthesis of challenging organic compounds Late-stage functionalization (LSF) and diversity-oriented synthesis have emerged as powerful approaches in contemporary organic chemistry, enabling the selective modification of complex molecules at advanced stages of synthesis. These strategies offer unique advantages in drug discovery, medicinal chemistry, and natural product derivatization, where access to structurally diverse analogues is crucial. By allowing transformations that would otherwise require lengthy synthetic routes, LSF and diversity-oriented synthesis open pathways to molecules of high biological, pharmaceutical, and material relevance, significantly streamlining discovery processes. Late-Stage Functionalization and Diversification in Organic Synthesis: Methods and Applications provides a comprehensive overview of the latest developments in this rapidly expanding field. Presenting both practical methodologies and mechanistic insights, the book covers transition metal catalysis, photo- and electrocatalysis, flow chemistry, and radioisotope insertion. In addition, the book: Places a unique focus on diversity-oriented synthesis, showcasing C-O, C-N, and C-S bond activationHighlights molecular editing and stereochemical editing as powerful new strategies for structural diversification Includes applications to natural products, pharmaceuticals, and radiopharmaceuticals Late-Stage Functionalization and Diversification in Organic Synthesis: Methods and Applications is essential reading for graduate students, postdoctoral researchers, and professionals in organic chemistry, medicinal chemistry, and natural products research. It is particularly suited for advanced courses in organic synthesis and catalysis, and also serves as a practical reference for chemists working in the pharmaceutical and biotechnology industries.

Late-stage functionalization reactions reliably functionalize already complex molecules to quickly access value-added molecular diversity. Late-stage functionalization is desirable in many areas of discovery such as in drug- or agrochemical development and protein modification, as well as a requirement in other areas such as the synthesis of positron-emission tomography (PET) tracers. I will describe the development of chemoselective reactions in late-stage functionalization, as well as their applications to modification of small and large molecules. In particular, I will describe the development of a broadly useful C-H thianthrenation reaction, as well as the conceptual differences and advances of thianthrenium chemistry when compared to conventional reaction chemistry, with development towards applications in catalysis, drug discovery, and medicine.

Oxidant-free cross-dehydrogenative oxyalkylation enables late-stage functionalization of drugs

The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential "late-stage functionalization" exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C-H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C-C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates, and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

Nickel-Catalyzed Enantioselective C(sp ³ )–H Arylation of Ketones with Aryl Ethers via Selective C _Ar –O Cleavage to Construct All-Carbon Quaternary Stereocenters

Ir-catalyzed deborylation can be used to selectively deuterate aromatic and heteroaromatic substrates. Combined with the selectivities of Ir-catalyzed C-H borylations, uniquely labeled compounds can be prepared. In addition, diborylation/deborylation reactions provide monoborylated regioisomers that complement those prepared by C-H borylation. Comparisons between Ir-catalyzed deborylations and Pd-catalyzed deborylations of diborylated indoles described by Movassaghi are made. The Ir-catalyzed process is more effective for deborylating aromatics and is generally more effective in the monodeborylation of diborylated thiophenes. These processes can be applied to complex molecules such as clopidogrel.

Using organic dyes as photocatalysts is an innovative approach to photocatalytic organic transformations. These dyes offer advantages such as widespread availability, adaptable absorption properties, and diverse chemical structures. Recent progress has led to the development of organic photocatalysts that can utilize visible light to modify chemically inert C-H bonds. These catalysts are sustainable, selective, and versatile, enabling mild reactions, late-stage functionalization, and various transformations in line with green chemistry principles. As catalysts in photoredox chemistry, they contribute to the development of efficient and environmentally friendly synthetic pathways. Acridinium-based organic photocatalysts have proved valuable in late-stage C-H functionalization, enabling transformative reactions under mild conditions. This review emphasizes their innovative features, such as organic frameworks, efficient light absorption properties, and their applications in modifying complex molecules. It provides an overview of recent advancements in the use of acridinium-based organic photocatalysts for late-stage C-H bond functionalization without the need for transition metals, showcasing their potential to expedite the development of new molecules and igniting excitement about the prospects of this research in the field.