A Minimal,Unstrained S‐Allyl Handle for Pre‐Targeting Diels–Alder Bioorthogonal Labeling in Live Cells

The unstrained S‐allyl cysteine amino acid was site‐specifically installed on apoptosis protein biomarkers and was further used as a chemical handle and ligation partner for 1,2,4,5‐tetrazines by means of an inverse‐electron‐demand Diels–Alder reaction. We demonstrate the utility of this minimal handle for the efficient labeling of apoptotic cells using a fluorogenic tetrazine dye in a pre‐targeting approach. The small size, easy chemical installation, and selective reactivity of the S‐allyl handle towards tetrazines should be readily extendable to other proteins and biomolecules, which could facilitate their labeling within live cells.     

A Pyrene‐Linked Cavity within a β‐Barrel Protein Promotes an Asymmetric Diels–Alder Reaction

A unique π‐expanded reaction cavity tethering a polycyclic moiety which provides a platform for substrate binding was constructed within the robust β‐barrel structure of nitrobindin (NB). NB variants with cavities of different sizes and shapes are coupled with N ‐(1‐pyrenyl)maleimide ( Pyr ) to prepare a series of NB‐ Pyr conjugates. The orientation of the pyrene moiety is fixed within the cavity by the coupling reaction. The fluorescent quenching analysis of NB‐ Pyr indicates that azachalcone ( aza ), which is a dienophile for a Diels–Alder (DA) reaction, is efficiently incorporated within the pyrene‐linked reaction cavity by the aromatic interaction. The DA reaction between aza and cyclopentadiene proceeds within the reaction cavity of NB‐ Pyr in the presence of Cu^II ion in high yield and high enantio‐ and regioselectivity.     

Pyrone Diels–Alder Routes to Indolines and Hydroindolines: Syntheses of Gracilamine,Mesembrine, and Δ7‐Mesembrenone

Although the Diels–Alder reaction has long been utilized for the preparation of numerous heterocycles, opportunities to extend its power remain. Herein, we detail a simple, modular, and robust approach that combines various amines regioselectively with 4,6‐dichloropyrone to create substrates which, under appropriate conditions, can directly deliver varied indolines and hydroindolines through [4+2] cycloadditions with substitution patterns difficult to access otherwise. As an initial demonstration of the power of the strategy, several different natural products have been obtained either formally or by direct total synthesis, with efforts toward one of these—the complex amaryllidaceae alkaloid gracilamine—affording the shortest route to date in terms of linear step count.     

Visible‐Light‐Irradiated Graphitic Carbon Nitride Photocatalyzed Diels–Alder Reactions with Dioxygen as Sustainable Mediator for Photoinduced Electrons

Photocatalytic Diels–Alder (D–A) reactions with electron rich olefins are realized by graphitic carbon nitride (g‐C₃N₄) under visible‐light irradiation and aerobic conditions. This heterogeneous photoredox reaction system is highly efficient, and the apparent quantum yield reaches a remarkable value of 47 % for the model reaction. Dioxygen plays a critical role as electron mediator, which is distinct from the previous reports in the homogeneous Ru^II complex photoredox system. Moreover, the reaction intermediate vinylcyclobutane is captured and monitored during the reaction, serving as a direct evidence for the proposed reaction mechanism. The cycloaddition process is thereby determined to be the combination of direct [4+2] cycloaddition and [2+2] cycloaddition followed by photocatalytic rearrangement of the vinylcyclobutane intermediate.     

A Cyclopropene Electrophile that Targets Glutathione S‐Transferase Omega‐1 in Cells

Cyclopropenes are an important new addition to the portfolio of functional groups that can be used for bioorthogonal couplings. The inert nature of these highly strained compounds in complex biological systems is almost counterintuitive given their established electrophilic properties in organic synthesis. Here we provide the first demonstration of a cyclopropene that is capable of direct conjugation to protein targets in cells and show that this compound preferentially alkylates the active site cysteine of glutathione S‐transferase omega‐1 (GSTO1).     

A Bioorthogonal Small‐Molecule‐Switch System for Controlling Protein Function in Live Cells

Chemically induced dimerization (CID) has proven to be a powerful tool for modulating protein interactions. However, the traditional dimerizer rapamycin has limitations in certain in vivo applications because of its slow reversibility and its affinity for endogenous proteins. Described herein is a bioorthogonal system for rapidly reversible CID. A novel dimerizer with synthetic ligand of FKBP′ (SLF′) linked to trimethoprim (TMP). The SLF′ moiety binds to the F36V mutant of FK506‐binding protein (FKBP) and the TMP moiety binds to E. coli dihydrofolate reductase (eDHFR). SLF′‐TMP‐induced heterodimerization of FKBP(F36V) and eDHFR with a dissociation constant of 0.12 μM . Addition of TMP alone was sufficient to rapidly disrupt this heterodimerization. Two examples are presented to demonstrate that this system is an invaluable tool, which can be widely used to rapidly and reversibly control protein function in vivo.     

A Single Molecular Diels–Alder Crosslinker for Achieving Recyclable Cross‐Linked Polymers

A triol‐functional crosslinker combining the thermoreversible properties of Diels–Alder (DA) adducts in one molecule is designed, synthesized, and used as an ideal substitute of a traditional crosslinker to prepare thermal recyclable cross‐linked polyurethanes with excellent mechanical properties and recyclability in a very simple and efficient way. The recycle property of these materials achieved by the DA/retro‐DA reaction at a suitable temperature is verified by differential scanning calorimetry and in situ variable temperature solid‐state NMR experiments during the cyclic heating and cooling processes. The thermal recyclability and remending ability of the bulk polyurethanes is demonstrated by three polymer processing methods, including hot‐press molding, injection molding, and solution casting. It is notable that all the recycled cross‐linked polymers display nearly invariable elongation/stress at break compared to the as‐synthesized samples. Further end‐group functionalization of this single molecular DA crosslinker provides the potential in preparing a wide range of recyclable cross‐linked polymers.

     

Electropolymerizable Terthiophene S,S‐Dioxide‐Fullerene Diels‐Alder Adduct for Donor/Acceptor Double‐Cable Polymers

The preparation of a novel fullerene‐thiophene derivative by Diels‐Alder addition of terthiophene S,S‐dioxide was demonstrated. Extrusion of SO₂ from the adduct is an effective process that yields a stable cyclohexadiene‐1,4‐bisthiophene–C₆₀ adduct in good isolable yield. The product has been accurately characterized and opens the way to synthesize new C₆₀ derivatives “via” Diels‐Alder methodology without the possibility of cycloreversion. Electrochemical and spectroscopic properties of this macromolecule were studied and supported by theoretical calculations to interpret its electronic structure. The first approach to the electropolymerization of this macromonomer produces donor‐acceptor molecular wires providing a new and versatile way to fullerene‐based double cable polymers.

     

Azido‐Functionalized 5′ Cap Analogues for the Preparation of Translationally Active mRNAs Suitable for Fluorescent Labeling in Living Cells

The 7‐methylguanosine (m⁷G) cap structure is a unique feature present at the 5′ ends of messenger RNAs (mRNAs), and it can be subjected to extensive modifications, resulting in alterations to mRNA properties (e.g. translatability, susceptibility to degradation). It also can provide molecular tools to study mRNA metabolism. We developed new mRNA 5′ cap analogues that enable the site‐specific labeling of RNA at the 5′ end using strain‐promoted azide–alkyne cycloaddition (SPAAC) without disrupting the basic function of mRNA in protein biosynthesis. Some of these azide‐functionalized compounds are equipped with additional modifications to augment mRNA properties. The application of these tools was demonstrated by labeling translationally active mRNAs in living cells.     

Iminium Ions as Dienophiles in Aza‐Diels–Alder Reactions: A Closer Look

This review highlights the state of the art of the use of iminium ions as dienophiles in Aza‐Diels–Alder (ADA) cycloadditions. An historical survey spanning the very first discovery of the reaction to modern developments, mechanistic studies and synthetic applications of the iminium variant of the ADA (iADA) reaction are presented. The discussion is focused on the intermolecular and intramolecular versions of the iADA reactions that are conducted in aqueous solutions to generate, in situ, the reactive dienophile from an amine hydrochloride and either aliphatic or aromatic aldehydes in the presence of a variety of dienes. The retro‐ADA reaction is also presented as an interesting method for the protection of amines. The use of Lewis acid catalysis in these reactions was thoroughly studied by the reactions of different amines and aldehydes conducted in the presence of lanthanide(III) complexes.     

A Well‐Defined Aluminum‐Based Lewis Acid as an Effective Catalyst for Diels–Alder Transformations

A catalytically active aluminum‐based system for Diels–Alder transformations is reported. The system was generated by mixing a β‐diketiminate‐stabilized aluminum bistriflate compound with Na[BAr^Cl₄] (Ar^Cl=3,5‐Cl₂C₆H₃). Solid‐state analysis of the catalytic system reveals a unique structure incorporating a two‐dimensional coordination polymer. According to the experimental results obtained from several Diels–Alder transformations, the aluminum‐based system appears to be a more practical and more robust alternative to the recently reported compounds based on carbon and silicon cations.     

A theoretical study for the regioselective Diels–Alder reaction of 5,6‐fulleroid with strained anti‐Bredt olefins

Regioselectivity of Diels–Alder reaction of the anti‐Bredt olefin of fulleroid, the 5,6‐methylene‐bridged fullerene derivative, is theoretically clarified by DFT calculations. In transition state calculations, the addition of a noncyclic diene 2,3‐dimethyl‐1,3‐butadiene (DMBD) at the anti‐Bredt olefin has considerably lower activation energy than those at the other sixteen olefins, while the reaction of a rigid cyclic diene cyclohexadiene (CHD) has similar activation energy at both anti‐Bredt and another nontwisted olefin. The changes in strain and interaction of the reactants are estimated along its reaction coordinate by activation strain model. Noncyclic diene shows asynchronous C? C bond formation with a significant gain of interaction energy, while the rigid cyclic diene shows a large growth of strain energy canceling out the interaction energy between diene and fulleroid.     

Dynamic Covalent Chemistry: A Facile Room‐Temperature,Reversible, Diels–Alder Reaction between Anthracene Derivatives and N‐Phenyltriazolinedione

A series of readily accessible, dynamic Diels–Alder reactions that are reversible at room temperature have been developed between anthracene derivatives as dienes and N‐phenyl‐1,2,4‐triazoline‐3,5‐dione as the dienophile. The adducts formed undergo reversible component exchange to form dynamic libraries of equilibrating cycloadducts. Furthermore, reversible adduct formation allows temperature‐dependent modulation of the fluorescent properties of anthracene components; a feature of potential interest for the design of optodynamic polymeric materials by careful selection and manipulation of these simple dienes and dienophiles.