Development and Applications of Water-Compatible Reactions: A Journey to Be Continued.

ConspectusThe pursuit of novel and eco-friendly methods in organic synthesis is gaining prominence, with a strong emphasis on green transformations using renewable and sustainable resources. Among these environmentally conscious approaches, water-compatible reactions stand out for their many advantages. Water, as a solvent, offers unmatched abundance, cost-efficiency, and environmental compatibility compared to organic solvents. Its use eliminates the need for complex protection and deprotection steps for reactive functional groups in multistep synthesis and enables the use of water-soluble substrates like proteins and carbohydrates. Water-compatible reactions also provide opportunities to combine with enzymes, resulting in chemoenzymatic transformations that can increase efficiency. Additionally, these reactions facilitate site-specific modification and the bioconjugation of biomolecules, leading to bioconjugate therapeutics.Over nearly three decades, our research group has been dedicated to developing innovative water-compatible methodologies and concepts. This Account provides a comprehensive overview of our contributions since 1994. Our central strategy revolves around integrating green chemistry principles into our methods, focusing on (i) developing reactions that can operate under mild conditions, including room temperature, atmospheric pressure, and physiological pH; (ii) designing atom-economical reactions that minimize waste production; (iii) replacing toxic and flammable organic solvents with eco-friendly alternatives like water and ethanol; and (iv) reducing reliance on metals or halogenated compounds in specific reactions.In this Account, we detail our achievements in developing efficient methodologies in aqueous media, highlighting their scope, limitations, asymmetric control, and applications for synthesizing complex molecules and functionalizing peptides and proteins. Mechanistic investigations underlying these developments are also discussed when applicable. Furthermore, we offer insights into the reasoning behind our work and address future opportunities and challenges in this area of research. We hope that this Account will inspire continued interest and foster new breakthroughs. By exploring innovative and broadly applicable strategies that expand the water-compatible synthetic toolbox, we aim to pave the way for the truly green and sustainable synthesis of complex molecules and pharmaceuticals.

Silicon-Containing Thiol-Specific Bioconjugating Reagent.

A new bioconjugation reagent containing silicon has been developed for the selective reaction with thiols. The inclusion of silicon significantly improves chemoselectivity and suppresses retro processes, thereby exceeding the capabilities of traditional reagents. The method is versatile and compatible with a broad range of thiols and unsaturated carbonyl compounds and yields moderate to high results. These reactions can be conducted under biocompatible conditions, thereby making them suitable for protein bioconjugation. The resulting conjugates display good stability in the presence of various biomolecules, which suggests their potential application for the synthesis of antibody-drug conjugates. Furthermore, the presence of a silicon moiety within the conjugated products opens up new avenues for drug release and bridging inorganics with other disciplines. This new class of silicon-containing thiol-specific bioconjugation reagents has significant implications for researchers working in bioanalytical science and medicinal chemistry and leads to innovative opportunities for advancing the field of bioconjugation research and medicinal chemistry.

Recent Advances in Alkenyl sp2 C-H and C-F Bond Functionalizations: Scope, Mechanism, and Applications.

Alkenes and their derivatives are featured widely in a variety of natural products, pharmaceuticals, and advanced materials. Significant efforts have been made toward the development of new and practical methods to access this important class of compounds by selectively activating the alkenyl C(sp2)-H bonds in recent years. In this comprehensive review, we describe the state-of-the-art strategies for the direct functionalization of alkenyl sp2 C-H and C-F bonds until June 2022. Moreover, metal-free, photoredox, and electrochemical strategies are also covered. For clarity, this review has been divided into two parts; the first part focuses on currently available alkenyl sp2 C-H functionalization methods using different alkene derivatives as the starting materials, and the second part describes the alkenyl sp2 C-F bond functionalization using easily accessible gem-difluoroalkenes as the starting material. This review includes the scope, limitations, mechanistic studies, stereoselective control (using directing groups as well as metal-migration strategies), and their applications to complex molecule synthesis where appropriate. Overall, this comprehensive review aims to document the considerable advancements, current status, and emerging work by critically summarizing the contributions of researchers working in this fascinating area and is expected to stimulate novel, innovative, and broadly applicable strategies for alkenyl sp2 C-H and C-F bond functionalizations in the coming years.

Ionogels: recent advances in design, material properties and emerging biomedical applications.

Ionic liquid (IL)-based gels (ionogels) have received considerable attention due to their unique advantages in ionic conductivity and their biphasic liquid-solid phase property. In ionogels, the negligibly volatile ionic liquid is retained in the interconnected 3D pore structure. On the basis of these physical features as well as the chemical properties of well-chosen ILs, there is emerging interest in the anti-bacterial and biocompatibility aspects. In this review, the recent achievements of ionogels for biomedical applications are summarized and discussed. Following a brief introduction of the various types of ILs and their key physicochemical and biological properties, the design strategies and fabrication methods of ionogels are presented by means of different confining networks. These sophisticated ionogels with diverse functions, aimed at biomedical applications, are further classified into several active domains, including wearable strain sensors, therapeutic delivery systems, wound healing and biochemical detections. Finally, the challenges and possible strategies for the design of future ionogels by integrating materials science with a biological interface are proposed.

Triaryl Carbenium Ion Pair Mediated Electrocatalytic Benzylic C-H Oxygenation in Air.

The selective oxidation of benzylic C-H bonds is a pivotal transformation in organic synthesis. Undoubtedly, achieving efficient and highly selective aerobic oxidation of methylarenes to benzaldehydes has been highly challenging due to the propensity of benzaldehyde to undergo overoxidation under typical aerobic conditions. Herein, we propose an innovative approach to address this issue by leveraging electrocatalytic processes, facilitated by ion-pair mediators [Ph3C]+[B(C6F5)4]-. By harnessing the power of electrochemistry, we successfully demonstrated the effectiveness of our strategy, which enables the selective oxidation of benzylic C-H bonds in benzylic molecules and toluene derivatives. Notably, our approach exhibited high efficiency, excellent selectivity, and compatibility with various functional groups, underscoring the broad applicability of our methodology.

Recent advances in ligand-enabled palladium-catalyzed divergent synthesis.

Developing efficient and straightforward strategies to rapidly construct structurally distinct and diverse organic molecules is one of the most fundamental tasks in organic synthesis, drug discovery and materials science. In recent years, divergent synthesis of organic functional molecules from the same starting materials has attracted significant attention and has been recognized as an efficient and powerful strategy. To achieve this objective, the proper adjustment of reaction conditions, such as catalysts, solvents, ligands, etc., is required. In this review, we summarized the recent efforts in chemo-, regio- and stereodivergent reactions involving acyclic and cyclic systems catalyzed by palladium complexes. Meanwhile, the reaction types, including carbonylative reactions, coupling reactions and cycloaddition reactions, as well as the probable mechanism have also been highlighted in detail.

Thiol-Specific Silicon-Containing Conjugating Reagent: ß-Silyl Alkynyl Carbonyl Compounds.

Site-specific modification of thiol-containing biomolecules has been recognized as a versatile and powerful strategy for probing our biological systems and discovering novel therapeutics. The addition of lipophilic silicon moiety opens up new avenues for multi-disciplinary research with broad applications in both the medicinal and material sciences. However, adhering to the strict biocompatibility requirements, and achieving the introduction of labile silicon handle and high chemo-selectivity have been formidable. In this paper, we report silicon-based conjugating reagents including ß-trialkylsilyl and silyl ether-tethered alkynones that selectively react with thiols under physiological conditions. The pH-neutral, metal-free and additive-free reaction yields stable products with broad substrate compatibility and full retention of silicon handles in most cases. Besides simple aliphatic and aromatic thiols, this approach is applicable in the labeling of thiols present in proteins, sugars and payloads, thereby expanding the toolbox of thiol conjugation.

Fluoride Anion Catalyzed Mukaiyama-Aldol Reaction: Rapid Access to α-Fluoro-ß-hydroxy Esters.

The Mukaiyama-aldol reaction is probably one of the most efficient strategies to prepare synthetically useful ß-hydroxy carbonyl compounds. However, only several reported methods were concerned with the accesses to α-fluoro-ß-hydroxy esters. Herein, we report a protocol for a fluoride anion-mediated Mukaiyama aldol reaction with low catalytic loading in a short reaction time to incorporate fluorine at the α position into ß-hydroxy esters. The method shows good functional-group tolerance and scale-up potential, moreover, is applicable to the late-stage modification of natural products and small molecular drugs.

Targeting RNA editing of antizyme inhibitor 1: A potential oligonucleotide-based antisense therapy for cancer.

Dysregulated adenosine-to-inosine (A-to-I) RNA editing is implicated in various cancers. However, no available RNA editing inhibitors have so far been developed to inhibit cancer-associated RNA editing events. Here, we decipher the RNA secondary structure of antizyme inhibitor 1 (AZIN1), one of the best-studied A-to-I editing targets in cancer, by locating its editing site complementary sequence (ECS) at the 3' end of exon 12. Chemically modified antisense oligonucleotides (ASOs) that target the editing region of AZIN1 caused a substantial exon 11 skipping, whereas ECS-targeting ASOs effectively abolished AZIN1 editing without affecting splicing and translation. We demonstrate that complete 2'-O-methyl (2'-O-Me) sugar ring modification in combination with partial phosphorothioate (PS) backbone modification may be an optimal chemistry for editing inhibition. ASO3.2, which targets the ECS, specifically inhibits cancer cell viability in vitro and tumor incidence and growth in xenograft models. Our results demonstrate that this AZIN1-targeting, ASO-based therapeutics may be applicable to a wide range of tumor types.

Cancer Biomarker-Triggered Disintegrable DNA Nanogels for Intelligent Drug Delivery.

Even though various techniques have been developed thus far for targeted delivery of therapeutics, design and fabrication of cancer biomarker-triggered disintegrable nanogels, which are exclusively composed of nucleic acid macromolecules, are still challenging nowadays. Here, we describe for the first time our creation of intelligent DNA nanogels whose backbones are sorely disintegrable by flap endonuclease 1 (FEN1), an enzymatic biomarker that is highly overexpressed in most cancer cells but not in their normal counterparts. It is the catalytic actions of intracellular FEN1 on bifurcated DNA structures that lead to the cancer-specific disintegration of our DNA nanogels and controlled release of drugs in target cancer cells. Consequently, the brand-new strategies introduced in the current report could break new ground in designing drug carriers for eliminating unwanted side effects of chemotherapeutic agents and live-cell probes for cancer risk assessment, diagnosis, and prognosis.

Buckyball-Based Spherical Display of Crown Ethers for De Novo Custom Design of Ion Transport Selectivity.

Searching for membrane-active synthetic analogues that are structurally simple yet functionally comparable to natural channel proteins has been of central research interest in the past four decades, yet custom design of the ion transport selectivity still remains a grand challenge. Here we report on a suite of buckyball-based molecular balls (MBs), enabling transmembrane ion transport selectivity to be custom designable. The modularly tunable MBm-Cn (m = 4-7; n = 6-12) structures consist of a C60-fullerene core, flexible alkyl linkers Cn (i.e., C6 for n-C6H12 group), and peripherally aligned benzo-3m-crown-m ethers (i.e., m = 4 for benzo-12-crown-4) as ion-transporting units. Screening a matrix of 16 such MBs, combinatorially derived from four different crown units and four different Cn linkers, intriguingly revealed that their transport selectivity well resembles the intrinsic ion binding affinity of the respective benzo-crown units present, making custom design of the transport selectivity possible. Specifically, MB4s, containing benzo-12-crown-4 units, all are Li+-selective in transmembrane ion transport, with the most active MB4-C10 exhibiting an EC50(Li+) value of 0.13 µM (corresponding to 0.13 mol % of the lipid present) while excluding all other monovalent alkali-metal ions. Likewise, the most Na+ selective MB5-C8 and K+ selective MB6-C8 demonstrate high Na+/K+ and K+/Na+ selectivity values of 13.7 and 7.8, respectively. For selectivity to Rb+ and Cs+ ions, the most active MB7-C8 displays exceptionally high transport efficiencies, with an EC50(Rb+) value of 105 nM (0.11 mol %) and an EC50(Cs+) value of 77 nM (0.079 mol %).

Palladium-Catalyzed Cascade Intramolecular Cyclization and Allylation of Enynoates with Allylic Alcohols.

A Pd(II)-catalyzed mild and highly regioselective 6- endo cyclization/allylation reaction of enynoates with simple allylic alcohols has been developed. Under mild reaction conditions, the vinyl palladium species generated in situ after cyclization could insert C-C double bond of allylic alcohol through cross-coupling reaction and lead to the formation of allyl pyrone via ß-OH elimination. This cascade cross-coupling reaction represents a direct and atom economic methodology for the construction of novel allyl pyrones in moderate to good yields.

Reactions of 5-Aminoisoxazoles with α-Diazocarbonyl Compounds: Wolff Rearrangement vs N-H Insertion.

A highly chemoselective reaction between 5-aminoisoxazoles and α-diazocarbonyl compounds has been described. Both Wolff rearrangement and N-H insertion products can be obtained selectively by the judicious choice of reaction conditions. In the case of the Wolff rearrangement reactions, the N-isoxazole amides are accessed as the sole products under thermal conditions. On the other hand, α-amino acid derivatives of N-isoxazolescan be obtained through N-H insertion reactions in the presence of catalytic Rh2(Oct)4. Both reactions proceed under mild reaction conditions and feature a broad substrate scope.

Palladium-Catalyzed Cycloaromatization/Alkylation of o-(Alkynyl)styrenes.

A Pd(II)-catalyzed mild and highly regioselective 6-endo cyclization/alkylation reaction of o-(alkynyl)styrenes with simple allylic alcohols has been developed. Under mild reaction conditions, the vinyl palladium species generated in situ after cyclization could insert a C-C double bond of allylic alcohol through a cross-coupling reaction and led to the formation of (alkyl)naphthalenes. This cascade cross-coupling reaction represents a direct and atom economic method for the construction of functionalized naphthalene derivatives in moderate to good yields.

Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct Indium Insertion and Their Applications in Cross-Coupling Reactions.

An efficient method for the synthesis of alkyl indium reagent by means of an iodine-catalyzed direct indium insertion into alkyl iodide in THF is reported. The thus-generated alkyl indium reagents effectively underwent Pd-catalyzed cross-coupling reactions with various aryl halides, exhibiting good compatibility to a variety of sensitive functional groups. By replacing THF with DMA and using 0.75 equiv of iodine, less reactive alkyl bromide could be used as substrate for indium insertion with equal ease.

Lead-Mediated Highly Diastereoselective Allylation of Aldehydes with Cyclic Allylic Halides.

Lead was found to efficiently mediate the allylation reactions of carbonyl compounds with cyclic allylic halides in the presence of stoichiometric amounts of lithium chloride and a catalytic amount of GaCl3 (20 mol %), leading to the desired homoallylic alcohols in modest to high yields with excellent diastereocontrol (>99:1 syn/anti) and good functional group tolerance. In contrast, the use of either 2-pyridinecarboxaldehyde as the carbonyl substrate or ( E)-cinnamyl bromide as the allylating agent produced the corresponding product with reversed diastereoselectivity (>99:1 anti/syn).

Copper-catalyzed regiodivergent 1,4- and 1,6-conjugate silyl addition to diendioates: access to functionalized allylsilanes.

A copper-catalyzed regioselective 1,4- and 1,6-conjugate addition of a silyl reagent to diendioates was established. Various 1,4- and 1,6-protosilylation products were obtained in good yields and with high regioselectivity via tuning the ligands used in the reactions. This protocol has provided a simple and efficient method for the synthesis of multisubstituted functionalized allylsilanes.

Synthesis of Functionalized α-Vinyl Aldehydes from Enaminones.

An efficient RhII -catalyzed synthesis of functionalized α-vinyl aldehydes with high E/Z stereoselectivity was developed. The reaction mediates the cyclopropanation of enaminones with vinyl carbenoids that are generated from cyclopropenes in situ to give the aminocyclopropane intermediates. Selective C-C bond cleavage of the cyclopropane intermediates leads to formation of α-vinyl aldehyde derivatives with high E/Z selectivity. This method proceeds at room temperature under very mild reaction conditions and works with a broad substrate scope.

Copper-Catalyzed Asymmetric Silylation of Propargyl Dichlorides: Access to Enantioenriched Functionalized Allenylsilanes.

A copper-catalyzed silylation of propargyl dichlorides was developed to access chloro-substituted allenylsilanes under mild reaction conditions. Moreover, enantioenriched chloro-substituted allenylsilanes can be synthesized in moderate to high yields and good enantioselectivities with this protocol.

Selective Binding to mRNA Duplex Regions by Chemically Modified Peptide Nucleic Acids Stimulates Ribosomal Frameshifting.

Minus-one programmed ribosomal frameshifting (-1 PRF) allows the precise maintenance of the ratio between viral proteins and is involved in the regulation of the half-lives of cellular mRNAs. Minus-one ribosomal frameshifting is activated by several stimulatory elements such as a heptameric slippery sequence (X XXY YYZ) and an mRNA secondary structure (hairpin or pseudoknot) that is positioned 2-8 nucleotides downstream from the slippery site. Upon -1 RF, the ribosomal reading frame is shifted from the normal zero frame to the -1 frame with the heptameric slippery sequence decoded as XXX YYY Z instead of X XXY YYZ. Our research group has developed chemically modified peptide nucleic acid (PNA) L and Q monomers to recognize G-C and C-G Watson-Crick base pairs, respectively, through major-groove parallel PNA·RNA-RNA triplex formation. L- and Q-incorporated PNAs show selective binding to double-stranded RNAs (dsRNAs) over single-stranded RNAs (ssRNAs). The sequence specificity and structural selectivity of L- and Q-modified PNAs may allow the precise targeting of desired viral and cellular RNA structures, and thus may serve as valuable biological tools for mechanistic studies and potential therapeutics for fighting diseases. Here, for the first time, we demonstrate by cell-free in vitro translation assays using rabbit reticulocyte lysate that the dsRNA-specific chemically modified PNAs targeting model mRNA hairpins stimulate -1 RF (from 2% to 32%). An unmodified control PNA, however, shows nonspecific inhibition of translation. Our results suggest that the modified dsRNA-binding PNAs may be advantageous for targeting structured RNAs.