Chiral S(VI) platform unifies selective C-H amination of complex molecules and alkane feedstocks.

Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.

Small molecules have been used to explore many facets of biology for over a century. However, research in biology is not routinely performed using this approach, in the way that it is with biochemical, genetic, and increasingly, genomic approaches. Several problems limit the use of the former approach. Arguably, the primary one is the lack of routine access to structurally complex and diverse small molecules that can be used to modulate biological systems.[1] Diversityoriented organic synthesis, especially when coupled with an economical and efficient technology platform, offers the means to change this situation, as it aims to synthesize complex and diverse small molecules efficiently.[2] Diversityoriented synthesis is central to chemical genetics, which aims to explore biology with small molecules in a systematic way.[3] Although enantioselective catalysis is often used in targetoriented synthesis, it is still relatively underexplored in diversity-oriented synthesis.[4, 5] We have been interested in reactions catalyzed by bis(oxazoline)metal Lewis acid complexes because of their high efficiency, selectivity, and broad substrate tolerance.[6] We chose to concentrate on inverse electron demand heterocycloadditions of vinyl ethers and b,gunsaturated ketoesters (Scheme 1).[7, 8] An account of related cycloadditions on solid support has been described;[9] however, the reported reactions were performed in the presence of achiral catalysts and with the heterodiene bound to the PS solid support through the ester. We initially investigated this mode of cycloaddition and found it to be highly selective when the enantiomerically pure catalysts (S)or (R)-1 were used.[5, 8] However, in the interest of effectively functionalizing the cycloadduct, we found an alternative mode using support-bound vinyl ethers, linked to a macrobead through either carbon or oxygen, to be more effective.

Direct HPLC enantioseparation of chemopreventive chiral isothiocyanates sulforaphane and iberin on immobilized amylose-based chiral stationary phases under normal-phase, polar organic and aqueous conditions

Pathway Development and Pilot Library Realization in Diversity-Oriented Synthesis: Exploring Ferrier and Pauson-Khand Reactions on a Glycal Template

[EMBARGOED UNTIL 08/01/2025] The concept of micellar catalysis (Chemistry in water) and its applications in the development of various sustainable methodologies are discussed in this dissertation. It also discusses the synthesis of rationally designed amphiphiles and their multiple functions for sustainable synthesis. These novel methodologies reduce the reliance on expensive ligands and toxic organic solvents compared to traditional methods. Sustainable methodologies for the synthesis of valuable organic compounds, such as unsymmetrical biaryl ketones, and functionalized indoles, have been developed. In addition to this, a methodology for the functionalization of styrenes has been developed under aqueous conditions. Chapter 1 reviews the concept of Micellar catalysis (a reaction in water) and analytical techniques for probing the mechanism of reactions in a micellar environment. Chapter 2 discusses the development of a ligand-free protocol for the synthesis of asymmetrical biaryl ketones. The current methodologies suffer from the use of expensive multistep synthesized ligands and toxic organic solvents. With the developed methodology, biaryl ketones were developed without the use of ligands in aqueous conditions. Moreover, the new methodology is easy to execute. Chapter 3 highlights the synthesis of a novel surfactant for ligand-free gold-catalyzed synthesis of functionalized indoles. The methodology is easy to execute and does not require the use of toxic organic solvents. A wide variety of functionalized indoles were obtained, including the complex molecules from the Merck informer library. Chapter 4 discusses the sustainable protocol for the functionalization of styrenes with azides and carboxylic acids under aqueous micellar conditions using our rationally designed PS-750-M as an amphiphile. Under the shielding effect of micelles, styrenes, and azides can be used safely, even if they proceed through radical formation.

Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.

Total synthesis is the production of a molecule from commercially or readily available chemicals through a series of chemical reactions including bio‐mediated transformations. In the first quarter of the twenty‐first century, most complex molecules are, in principle, accesible through total synthesis. However, often, complex molecules can only be prepared in small amounts of a few milligrams. Therefore, the challenges of total synthesis in the XXIth century is the efficiency by which required amounts of a product can be prepared in the shorter time possible. In this article, different types of syntheses are discussed. These are divided into four classes: target‐oriented synthesis (TOS), combinatorial synthesis (CS), diversity‐oriented synthesis (DOS), and diverted total synthesis (DTS). The concepts, challenges, and requirements of each class are introduced and relevant examples, from classic to contemporary, including Woodward's synthesis of strychnine, are discussed.

Bryostatins are a family of marine natural products that have garnered significant interests, as evidenced by over 40 clinical trials. However, their extremely low natural abundance has severely limited further research. Despite significant efforts, which have led to the total synthesis of seven bryostatin members by eight independent research groups, these complex molecules present persistent challenges for stereocontrolled, large-scale, and especially divergent synthesis. Here, we report the divergent total syntheses of bryostatins 1, 7, 9 and 9-N3. Notably, 1.5 g of bryostatin 1 was obtained in a single sequence of the final three steps. Key transformations include Ni-catalyzed reductive cross-coupling to rapidly assemble the northern fragment, the flow chemistry-assisted visible light-induced alkyl radical conjugate addition to convergently construct the southern fragment, and an intramolecular geminal bis(silyl) Prins cyclization to establish the cis-Z selectivity on the B-ring. The syntheses consist of 20-22 steps in the longest linear sequence and 33-35 total steps, with overall yields ranging from 3.3 % to 4.5 %.

Bryostatins are a family of marine natural products that have garnered significant interests, as evidenced by over 40 clinical trials. However, their extremely low natural abundance has severely limited further research. Despite significant efforts, which have led to the total synthesis of seven bryostatin members by eight independent research groups, these complex molecules present persistent challenges for stereocontrolled, large‐scale, and especially divergent synthesis. Here, we report the divergent total syntheses of bryostatins 1, 7, 9 and 9‐N3. Notably, 1.5 g of bryostatin 1 was obtained in a single sequence of the final three steps. Key transformations include Ni‐catalyzed reductive cross‐coupling to rapidly assemble the northern fragment, the flow chemistry‐assisted visible light‐induced alkyl radical conjugate addition to convergently construct the southern fragment, and an intramolecular geminal bis(silyl) Prins cyclization to establish the cis‐Z selectivity on the B‐ring. The syntheses consist of 20–22 steps in the longest linear sequence and 33–35 total steps, with overall yields ranging from 3.3 % to 4.5 %.

A one-bead, one-stock solution approach to chemical genetics: part 1

Diversity-Oriented Synthesis (DOS) aims to broaden the frontier of accessible collections of complex and diverse small molecules. This review endeavours to dissect the DOS concept through three elements of diversity: building block, stereochemistry, and skeleton. Recent examples in the literature that emphasize the efficient combinations of these elements to generate diversity are reported.

The morpholine motif is valued in medicinal chemistry, but C-substituted morpholine derivatives remain challenging to access. Here we report a general strategy to address that challenge: annulative heterocoupling of aziridines and epoxides to synthesize highly substituted, N-unprotected morpholine derivatives via aziridinyl alcohols. Due to the accessibility of complex, stereodefined aziridines and epoxides, this approach allows for facile and combinatorial synthesis of substituted morpholine derivatives with handles for further elaboration. Stereochemical outcomes are dictated by the preset stereogenic centers in the strained-ring coupling partners. Our method expands access to morpholine derivatives bearing multiple substituents α to oxygen and densely substituted morpholine derivatives bearing up to six C substituents. Moreover, our formal 3 + 3 synthetic approach can be used to join two complex molecules through the carbon atoms of a morpholine ring, affording rapid access to diverse molecular skeletons for use in medicinal chemistry and diversity-oriented synthesis.

This work presents an efficient and sustainable protocol for the direct Csp-H thiolation of terminal alkynes with N-thiosuccinimides via silver catalysis. The reaction proceeds under mild, base-, and ligand-free conditions, enabling the construction of alkynyl sulfides in good to excellent yields. The key advantages of this protocol are that it enables the omission of external bases and ligands, offers operational simplicity, and maintains broad functional group tolerance. This method offers a simple and effective alternative for synthesizing versatile alkynyl sulfide derivatives, with potential applications in pharmaceutical and materials chemistry.

Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

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.