The key attribute of the thiol-Michael addition reaction that makes it a prized tool in materials science is its modular “click” nature, which allows for the implementation of this highly efficient, ...“green” reaction in applications that vary from small molecule synthesis to in situ polymer modifications in biological systems to the surface functionalization of material coatings. Over the past few decades, interest in the thiol-Michael addition reaction has increased dramatically, as is evidenced by the number of studies that have been dedicated to elucidating different aspects of the reaction that range from an in-depth analysis aimed at understanding the mechanistic pathways of the reaction to synthetic studies that have examined modifying molecular structures with the aim of yielding highly efficient thiol-Michael reaction monomers. This review examines the reaction mechanisms, the substrates and catalysts used in the reaction, and the subsequent implementation of the thiol-Michael reaction in materials science over the years, with particular emphasis on the recent developments in the arena over the past decade.
The liver plays a central role in glucose homeostasis and hepatic insulin resistance constitutes a key feature of type 2 diabetes. However, platforms that accurately mimic human hepatic glucose ...disposition and allow for rapid and scalable quantification of glucose consumption dynamics are lacking. Here, we developed and optimized a colorimetric glucose assay based on the glucose oxidase‐peroxidase system and demonstrate that the system can monitor glucose consumption in 3D primary human liver cell cultures over multiple days. The system was highly sensitive (limit of detection of 3.5 µM) and exceptionally accurate (R2 = 0.999) while requiring only nanoliter input volumes (250 nL), enabling longitudinal profiling of individual liver microtissues. By utilizing a novel polymer, off‐stoichiometric thiol‐ene (OSTE), and click‐chemistry based on thiol‐Michael additions, we furthermore show that the assay can be covalently bound to custom‐build chips, facilitating the integration of the sensor into microfluidic devices. Using this system, we find that glucose uptake of our 3D human liver cultures closely resembles human hepatic glucose uptake in vivo as measured by euglycemic‐hyperinsulinemic clamp. By comparing isogenic insulin‐resistant and insulin‐sensitive liver cultures we furthermore show that insulin and extracellular glucose levels account for 55% and 45% of hepatic glucose consumption, respectively. In conclusion, the presented data show that the integration of accurate and scalable nanoliter glucose sensors with physiologically relevant organotypic human liver models enables longitudinal profiling of hepatic glucose consumption dynamics that will facilitate studies into the biology and pathobiology of glycemic control, as well as antidiabetic drug screening.
Clinical percutaneous delivery of synthetically engineered hydrogels remains limited due to challenges posed by crosslinking kinetics—too fast leads to delivery failure, too slow limits material ...retention. To overcome this challenge, supramolecular assembly is exploited to localize hydrogels at the injection site and introduce subsequent covalent crosslinking to control final material properties. Supramolecular gels are designed through the separate pendant modifications of hyaluronic acid (HA) by the guest–host pair cyclodextrin and adamantane, enabling shear‐thinning injection and high target site retention (>98%). Secondary covalent crosslinking occurs via addition of thiols and Michael‐acceptors (i.e., methacrylates, acrylates, vinyl sulfones) on HA and increases hydrogel moduli (E = 25.0 ± 4.5 kPa) and stability (>3.5 fold in vivo at 28 d). Application of the dual‐crosslinking hydrogel to a myocardial infarct model shows improved outcomes relative to untreated and supramolecular hydrogel alone controls, demonstrating its potential in a range of applications where the precise delivery of hydrogels with tunable properties is desired.
Injectable hyaluronic acid hydrogels with high target site retention, tunable properties, and potential for percutaneous delivery are developed through a tandem crosslinking approach. Supramolecular crosslinking provides initial hydrogel formation and shear‐thinning delivery, while secondary covalent crosslinking stabilizes the hydrogel in situ. Material properties and treatment of myocardial infarct are examined.
Cascading like dominos: An efficient and highly enantioselective synthesis of 2,3,4‐trisubstituted tetrahydroquinolines through cascade aza‐Michael–Michael reactions was developed. ...Tetrahydroquinolines were obtained in excellent yields, high enantioselectivities, and good diastereoselectivities, and could be easily transformed into ring‐fused tetrahydroquinolines (see scheme).
Azepino3,4,5‐cdindole derivatives represent the core scaffold of important natural products and biologically relevant compounds. Therefore, the establishment of step‐ and atom‐economic strategies to ...access this class of compounds is of paramount importance. To this end, complexity‐to‐diversity (CtD) strategy has become one of the most important tools that transforms complex molecules into diverse skeleta. However, many of the reactions that could be employed in CtD are restricted by the functional handles exist in these molecules. This limits the achievement of the desired skeletal diversity. Herein, an efficient and step‐economic strategy to access a diverse collection of azepino‐3,4,5‐cdindole architectures through a cascade that combines Pictet‐Spengler with Michael addition, is described. This was achieved by reacting cyclohexadienone acetaldehydes 2 a–2 d with indolyl‐4‐ethyl amine 1. Employing a CtD strategy on the developed azepino‐3,4,5‐cdindoles, a rapid rearrangement reaction that provided a modular, chemo‐ and diastereoselective access to diverse collection of spiro azepinocarbazole nature‐inspired frameworks, was encountered.
An efficient and step‐economic strategy was established that enables a facile access to highly functionalized azepino3,4,5‐cdindole architectures through a cascade combining Pictet‐Spengler and Michael addition. Employing a late‐stage transformation strategy on the developed azepino‐3,4,5‐cdindoles, provided a modular, chemo‐ and diastereoselective access to diverse collection of nature‐inspired frameworks, namely spiroazepino2,3,4,5‐defcarbazole‐5,1′‐cyclohexan‐2′‐ene systems.
Photomediated Giese reactions are at the forefront of radical chemistry, much like the classical tin‐mediated Giese reactions were nearly forty years ago. With the global recognition of ...organometallic photocatalysts for the mild and tunable generation of carbon‐centered radicals, chemists have developed a torrent of strategies to form previously inaccessible radical intermediates that are capable of engaging in intermolecular conjugate addition reactions. This Review summarizes advances in photoredox‐mediated Giese reactions since 2013, with a focus on the breadth of methods that provide access to crucial carbon‐centered radical intermediates that can engage in radical conjugate addition processes.
This Review summarizes advances in photoredox‐mediated Giese reactions since 2013, with a focus on the breadth of methods that provide access to crucial carbon‐centered radical intermediates that can engage in radical conjugate addition processes.
Display omitted
•The enantioselective Michael addition of malonates with unsaturated ketones.•Catalyzed by samarium amide SmN(SiMe3)23 together with the chiral phenoxy-functionalized amino alcohol ...proligands.•The products with good group tolerance, mostly in high to excellent yields (85–98%) and good to excellent ee values (50– >99%).•A possible mechanism was proposed.
A combination of rare-earth metal amides REN(SiMe3)23 and chiral phenoxy-functionalized amino alcohol proligands was developed to realize the enantioselective Michael addition of malonates with unsaturated ketones. The reactions catalyzed by samarium amide SmN(SiMe3)23 were performed best together with the chiral proligand H3L1 (H3L1 = 2,4-di-tert-butyl-6-(((1S,2R)-2-hydroxy-1,2-diphenylethyl) amino)methyl)phenol) in DCE with good group tolerance, mostly in high to excellent yields (85–98 %) and good to excellent ee values (50− >99 %). The possible mechanism was also proposed.
Abstract
This account describes the strategies for the synthesis of functionalized spirooxindole polycycles, including enantiomerically enriched forms, that we have developed and reported. The ...syntheses of these complex molecules were accomplished in a few steps starting from relatively simple oxindole derivatives and other reactants. Organocatalytic reactions involved in kinetic resolution or in dynamic kinetic transformation led to the formation of products with high diastereo- and/or enantioselectivities. Cyclic 1,3-diones, such as 1,3-cyclohexanedione, were used as reactants to provide two reaction sites for the construction of polycyclic ring systems. To tune the reaction conditions, 2-methyl-1,3-cyclohexanedione was employed. The developed methods enabled the synthesis of complex functionalized spirooxindole polycycles bearing up to seven stereogenic centers, and will be useful for the synthesis of potentially bioactive molecules.
1 Introduction
2 Formal (4+1) Cycloaddition and Enantioselective Michael/Henry Cascade Reactions
3 Dynamic Stereoselective Aldol/Oxacyclization Cascade Reactions
4 Dynamic Kinetic Asymmetric Transformation: Diastereo- and Enantioconvergent Michael/Henry Reactions
5 Dimerization Reactions
6 Conclusion
PDF
