Direct Catalytic Synthesis of Unprotected 2‐Amino‐1‐Phenylethanols from Alkenes by Using Iron(II) Phthalocyanine

Aryl‐substituted amino alcohols are privileged scaffolds in medicinal chemistry and natural products. Herein, we report that an exceptionally simple and inexpensive Fe^II complex efficiently catalyzes the direct transformation of simple alkenes into unprotected amino alcohols in good yield and perfect regioselectivity. This new catalytic method was applied in the expedient synthesis of bioactive molecules and could be extended to aminoetherification.     

Late-Stage Direct o-Alkenylation of Phenols by PdII-Catalyzed C−H Functionalization

o-Alkenylation of unprotected phenols has been developed by direct C−H functionalization catalyzed by Pd^II. This work features phenol group as a directing group and realizes highly site-selective C−H bond functionalization of phenols to achieve the corresponding products in moderate to excellent yields at 60 °C. The advantages of this reaction include unprecedented C−H functionalization using phenol as a directing group, high regioselectivity, good substrate scope, mild reaction conditions, and high efficiency. To the best of our knowledge, this is the first example of a regioselective C−H alkenylation of unprotected phenols utilizing phenolic hydroxyl group as a directing group. The alkenylation of unprotected tyrosine and intramolecular cyclization are also successfully carried out under this catalytic system in good yields. Furthermore, this novel method enables a late-stage modification of complex phenol-containing bioactive molecules toward a diversity-oriented drug discovery.     

Palladium(II)‐Mediated C−H Tritiation of Complex Pharmaceuticals

Tritium‐labeled molecules are critical tools for elucidating the binding and metabolic properties of bioactive compounds, particularly during pharmaceutical discovery. Direct tritiation of inert C?H bonds with T₂ gas is an ideal approach for tritium labeling, but significant gaps remain for direct tritiation of structurally complex molecules with diverse functional groups. Here we report the first application of palladium(II) C?H activation chemistry for tritiation with T₂ gas. This practical transformation exhibits novel substrate scope and greater functional group tolerance compared to previous state of the art tritiation methods, and has been applied to directly tritiate 9 complex pharmaceuticals and an unprotected dipeptide. The isolated tritium‐labeled products exhibit >15 Ci mmol^?1 specific activity, exceeding the typical requirements for application in studies of molecular interaction and metabolism.     

Synthesis of Unprotected β-Arylethylamines by Iron(II)-Catalyzed 1,2-Aminoarylation of Alkenes in Hexafluoroisopropanol

β-Arylethylamines are prevalent structural motifs in molecules exhibiting biological activity. Here we report a sequential one-pot protocol for the 1,2-aminoarylation of alkenes with hydroxylammonium triflate salts and (hetero)arenes. Unlike existing methods, this reaction provides a direct entry to unprotected β-arylethylamines with remarkable functional group tolerance, allowing key drug-oriented functional groups to be installed in a two-step process. The use of hexafluoroisopropanol as a solvent in combination with an iron(II) catalyst proved essential to reaching high-value nitrogen-containing molecules.     

Allenamides as Orthogonal Handles for Selective Modification of Cysteine in Peptides and Proteins

In this study, a remarkably simple and direct strategy has been successfully developed to selectively label target cysteine residues in fully unprotected peptides and proteins. The strategy is based on the reaction between allenamides and the cysteine thiol, and proceeds swiftly in aqueous medium with excellent selectivity and quantitative conversion, thus forming a stable and irreversible conjugate. The combined simplicity and mildness of the process project allenamide as robust and versatile handles to target cysteines and has potential use in biological systems. Additionally, fluorescent‐labeling studies demonstrated that the installation of a C‐terminal allenamide moiety onto various molecules of interest may supply a new methodology towards the site‐specific labeling of cysteine‐containing proteins. Such a new labeling strategy may thus open a window for its application in the field of life sciences.     

A General Approach to O-Sulfation by a Sulfur(VI) Fluoride Exchange Reaction

O-sulfation is an important chemical code widely existing in bioactive molecules, but the scalable and facile synthesis of complex bioactive molecules carrying O-sulfates remains challenging. Reported here is a general approach to O-sulfation by the sulfur(VI) fluoride exchange (SuFEx) reaction between aryl fluorosulfates and silylated hydroxy groups. Efficient sulfate diester formation was achieved through systematic optimization of the electronic properties of aryl fluorosulfates. The versatility of this O-sulfation strategy was demonstrated in the scalable syntheses of a variety of complex molecules carrying sulfate diesters at various positions, including monosaccharides, disaccharides, an amino acid, and a steroid. Selective hydrolytic and hydrogenolytic removal of the aryl masking groups from sulfate diesters yielded the corresponding O-sulfate products in excellent yields. This strategy provides a powerful tool for the synthesis of O-sulfate bioactive compounds.     

An inexpensive fluorescent labeling protocol for bioactive natural products utilizing Cu(I)-catalyzed Huisgen reaction

Labeling of bioactive small molecules with organic dyes for various applications in cell biology has been emerging as an attractive research field. Using an easily prepared and inexpensive fluorescein derivative 1 and a Cu(I)-catalyzed Huisgen reaction, an efficient fluorescent labeling strategy is developed generally for bioactive natural products. Essentials of a successful labeling include the personalized introduction of an azido functionality to specific targets by a selective and efficient manner, and the strategic adjustment of reaction sequence to avoid possible side reactions under the ‘click’ reaction conditions. Such a protocol has been successfully applied to the fluorescent labeling of four bioactive small molecules in different chemical categories in this study. Advantages of this labeling protocol include the use of inexpensive reagents, ease of operation, free-of-protections at the ‘click’ step, and suiting a wide range of bioactive molecules bearing the reactive functionalities.     

Highly Chemoselective Aerobic Oxidation of Amino Alcohols into Amino Carbonyl Compounds

The direct oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has often posed serious challenges in organic synthesis and has constrained chemists to adopting an indirect route, such as a protection/deprotection strategy, to attain their goal. Described herein is a highly chemoselective aerobic oxidation of unprotected amino alcohols to their amino carbonyl compounds in which 2‐azaadamantane N‐oxyl (AZADO)/copper catalysis is used. The catalytic system developed leads to the alcohol‐selective oxidation of various unprotected amino alcohols, carrying a primary, secondary, or tertiary amino group, in good to high yield at ambient temperature with exposure to air, thus offering flexibility in the synthesis of nitrogen‐containing compounds.     

Substituted guanidines: introducing diversity in combinatorial chemistry

The guanidine moiety is an important motif present in many biologically active compounds. Fully substituted guanidines are of key importance for the development of bioactive molecules. The present paper reports on an efficient procedure for the direct solid-phase conversion of amines to fully substituted guanidines under very mild conditions.     

Synthesis of Nucleoside Derivatives Containing Benzophenoxazinone Moiety

Two new nucleoside derivatives containing benzophenoxazinone moiety were synthesized. Their luminescence spectra show that they have strong near infrared fluorescence.Our study provides a new method for direct introduction of near infrared fluorescent probe to bioactive molecules.     

Photorelease of Pyridines Using a Metal-Free Photoremovable Protecting Group

The photorelease of bioactive molecules has emerged as a valuable tool in biochemistry. Nevertheless, many important bioactive molecules, such as pyridine derivatives, cannot benefit from currently available organic photoremovable protecting groups (PPGs). We found that the inefficient photorelease of pyridines is attributed to intramolecular photoinduced electron transfer (PET) from PPGs to pyridinium ions. To alleviate PET, we rationally designed a strategy to drive the excited state of PPG from S₁ to T₁ with a heavy atom, and synthesized a new PPG by substitution of the H atom at the 3-position of 7-dietheylamino-coumarin-4-methyl ( DEACM ) with Br or I. This resulted in an improved photolytic efficiency of the pyridinium ion by hundreds-fold in aqueous solution. The PPG can be applied to various pyridine derivatives. The successful photorelease of a microtubule inhibitor, indibulin, in living cells was demonstrated for the potential application of this strategy in biochemical research.     

Rhodium(III)‐Catalyzed CH Activation and Indole Synthesis With Hydrazone as an Auto‐Formed and Auto‐Cleavable Directing Group

An efficient, practical, and external‐oxidant‐free indole synthesis from readily available aryl hydrazines was developed, by using hydrazone as a directing group for Rh^III‐catalyzed C?H activation and alkyne annulation. The hydrazone group was formed by in situ condensation of hydrazines and C?O source, whereas its N?N bond was served as an internal oxidant, for which we termed it as an auto‐formed and auto‐cleavable directing group (DG^auto). This method needs no step for pre‐installation and post‐cleavage of the directing group, making it a quite easily scalable approach to access unprotected indoles with high step economy. The DG^auto strategy was also applicable for isoquinoline synthesis. In addition, synthetic utilities of this chemistry for rapid assembly of π‐extended nitrogen‐doped polyheterocycles and bioactive molecules were demonstrated.     

Electrostatic effects on nanofiber formation of self-assembling peptide amphiphiles

Self-assembling peptide amphiphile molecules have been of interest to various tissue engineering studies. These molecules self-assemble into nanofibers which organize into three-dimensional networks to form hydrocolloid systems mimicking the extracellular matrix. The formation of nanofibers is affected by the electrostatic interactions among the peptides. In this work, we studied the effect of charged groups on the peptides on nanofiber formation. The self-assembly process was studied by pH and zeta potential measurements, FT-IR, circular dichroism, rheology, atomic force microscopy, scanning electron microscopy and transmission electron microscopy. The aggregation of the peptides was triggered upon neutralization of the charged residues by pH change or addition of electrolyte or biomacromolecules. Understanding the controlled formation of the hydrocolloid gels composed of peptide amphiphile nanofibers can lead us to develop in situ gel forming bioactive collagen mimetic nanofibers for various tissue engineering studies including bioactive surface coatings.     

Triphosgene: An Efficient Catalyst for Synthesis of Isothiocyanates

Isothiocyanates are bioactive molecules that show various biological activities such as antifungal and anathematic activities. They play a vital role in the synthesis of various heterocyclic compounds. Various isothiocyanates were prepared in good to high yield using triphosgene.     

The synthesis of PROTAC molecule and new target KAT6A identification of CDK9 inhibitor iCDK9

Cyclin-dependent kinases (CDKs) have become potential targets for treating various diseases, especially cancer. Compound iCDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC (proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of iCDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism. The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore, KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation (IP) assay confirmed a direct interaction between KAT6A and iCDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of iCDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.     

Amination of Poly(ethylene-terephthalate) polymer surface for biochemical applications

Amine functionalization of Poly(ethylene-terephthalate) (PET) films for covalent binding of peptides is described. Ammonia plasma treatments have been used to graft nitrogen-containing functional groups onto the PET surface. The samples were then analyzed by X-ray photoelectron spectroscopy (XPS) and a parametric study was performed to define the best plasma grafting conditions. For biological tests, samples were sterilized by steam autoclaving: this induces a four to fivefold loss of the nitrogen functional groups on the polymer surface. XPS does not differentiate easily between the various nitrogen groups present on the surface so it is difficult to estimate the amount of surface amine groups available for direct coupling of bioactive molecules (proteins, peptides, nucleic acids, ...). To obtain a direct measurement of the amines present, we assayed for cysteine fixation through its carboxylic group by detection of the thiolaminoacid by XPS. We obtained cysteine fixation, showing the presence of grafted primary amine functions on PET surface after ammonia plasma treatment. Radiochemical assays were also made to quantify the amount of amine groups on plasma treated PET. XPS, cysteine fixation and radiochemical assays all show the presence of amine functions on ammonia plasma treated PET.     

Myoglobin‐Catalyzed C−H Functionalization of Unprotected Indoles

Functionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal‐catalyzed carbene transfer has provided an attractive route to afford C3‐functionalized indoles, these protocols are viable only in the presence of N‐protected indoles, owing to competition from the more facile N−H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C−H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α‐diazoacetate to give the corresponding C3‐functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti‐inflammatory drug indomethacin.     

Molecular topology analysis of the differences between drugs, clinical candidate compounds, and bioactive molecules

A new method to decompose molecules is proposed and used to analyze drugs, clinical candidate compounds and bioactive molecules. The method classifies a set of molecules into a few well-defined classes based on their molecular framework. It is then possible to use these classes to investigate differences between drugs, clinical candidates and bioactive molecules. The analysis shows that in comparison with clinical candidates and bioactive compounds, drugs have a higher fraction of compounds with only one ring system. This conclusion is still valid after correcting for lipophilicity (ClogP) and molecular size, as well as any potential protein target bias in the data sets. Furthermore the molecular bridge part of compounds in the drug set has on average fewer ring systems than molecules from the other sets. The ring system complexity (RSC) was also investigated and for most topological classes drugs have a lower RSC than the clinical candidates and bioactive molecules. Hence, this study highlights differences in topology between drugs, clinical candidate compounds and bioactive molecules.     

Trifluoromethylation of Alkenes with Concomitant Introduction of Additional Functional Groups

The trifluoromethyl group is found in many synthetic bioactive compounds, and the difunctionalization of a C?C bond, as a powerful strategy for the construction of compounds with various functional groups, has been intensively investigated. Therefore, the difunctionalizing trifluoromethylation of alkenes has attracted growing interest because of the potential of the products as building blocks for bioactive molecules. In this review, we focus on recent advances in the trifluoromethylation of alkenes with concomitant introduction of additional functional groups.     

Trichlorosilane mediated asymmetric reductions of the C=N bond

Chiral amines are key components in numerous bioactive molecules. The development of efficient and economical ways to access molecules containing this functional group still remains a challenge at the forefront of synthetic chemistry. Of the methods that do exist, the trichlorosilane mediated organocatalytic reduction of ketimines offers significant potential as an alternative strategy. In this perspective, we wish to highlight the progress made in the past decade in this field and offer a direct quantitative comparison to transition-metal mediated process.