Synthesis of Chiral Polyethers Containing Imidazolidinone Repeating Units and Application as Catalyst in Asymmetric Diels–Alder Reaction

In this study, enantiopure imidazolidinones containing two hydroxyphenyl groups were synthesized, and the Williamson synthesis of the chiral bisphenols thus prepared with dihalides afforded polyethers containing chiral imidazolidinone repeating units. These chiral imidazolidinone polyethers exhibited excellent catalytic activity in the asymmetric Diels–Alder reaction. With the use of these polymeric catalysts, enantioselectivities up to 99% were obtained, higher than those obtained by the corresponding monomeric imidazolidinone catalyst in homogeneous solution. The polymeric catalysts were found to be insoluble in commonly used organic solvents, and they could be repeatedly used without the loss of activity.

     

Ionic Liquid Effect on the Reversal of Configuration for the Magnesium(II) and Copper(II) Bis(oxazoline)‐Catalysed Enantioselective Diels–Alder Reaction

Ionic liquids have been used to support a range of magnesium‐ and copper‐based bis(oxazoline) complexes for the enantioselective Diels–Alder reaction between N‐acryloyloxazolidinone and cyclopentadiene. Compared with reaction performed in dichloromethane or diethyl ether, an enhancement in ee is observed with a large increase in reaction rate. In addition, for non‐sterically hindered bis(oxazoline) ligands, that is, phenyl functionalised ligands, a reversal in configuration is found in the ionic liquid, 1‐ethyl‐3‐methylimidazolium bis[(trifluoromethanesulfonyl)imide], compared with molecular solvents. Supported ionic liquid phase catalysts have also been developed using surface‐modified silica which show good reactivity and enantioselectivity for the case of the magnesium‐based bis(oxazoline) complexes. Poor ees and conversion were observed for the analogous copper‐based systems. Some drop in ee was found on supporting the catalyst due a drop in the rate of reaction and, therefore, an increase in the contribution from the uncatalysed achiral reaction.     

Bio‐orthogonal Fluorescent Labelling of Biopolymers through Inverse‐Electron‐Demand Diels–Alder Reactions

Bio‐orthogonal labelling schemes based on inverse‐electron‐demand Diels–Alder (IEDDA) cycloaddition have attracted much attention in chemical biology recently. The appealing features of this reaction, such as the fast reaction kinetics, fully bio‐orthogonal nature and high selectivity, have helped chemical biologists gain deeper understanding of biochemical processes at the molecular level. Listing the components and discussing the possibilities and limitations of these reagents, we provide a recent snapshot of the field of IEDDA‐based biomolecular manipulation with special focus on fluorescent modulation approaches through the use of bio‐orthogonalized building blocks. At the end, we discuss challenges that need to be addressed for further developments in order to overcome recent limitations and to enable researchers to answer biomolecular questions in more detail.     

Synthesis of NOBIN Derivatives for Asymmetric Catalysis

This account highlighted the recent advances of our research on the synthesis of enantiopure 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN) and its derivatives as well as their applications in asymmetric catalysis, including diethyl zinc addition to aldehydes, allylic addition to aldehydes, allylic substitutions, and hetero-Diels–Alder reactions.     

Recycling Chiral Imidazolidin‐4‐one Catalyst for Asymmetric Diels–Alder Reactions: Screening of Various Ionic Liquids

Various imidazolium ionic liquids such as [Bmim]PF₆, [Bmim]SbF₆, [Bmim]OTf and [Bmim]BF₄ were screened for recycling an organic catalyst [(5S)‐5‐benzyl‐2,2,3‐trimethylimidazolidin‐4‐one ( 1 )] for asymmetric Diels–Alder reactions. Good yields and enantioselectivies (up to 85% yield and 93% ee) were obtained from reactions in [Bmim]PF₆ or [Bmim]SbF₆. However, reactions in [Bmim]OTf or [Bmim]BF₄ gave racemic products in low yields. Isolation of the products by simple extraction using diethyl ether allowed recycling of the ionic liquid containing the immobilized catalyst in subsequent reactions without significant decrease of yields and enantioselectivities.     

Exploring the Potential of Norbornene‐Modified Mannosamine Derivatives for Metabolic Glycoengineering

Metabolic glycoengineering (MGE) allows the introduction of unnaturally modified carbohydrates into cellular glycans and their visualization through bioorthogonal ligation. Alkenes, for example, have been used as reporters that can react through inverse‐electron‐demand Diels–Alder cycloaddition with tetrazines. Earlier, norbornenes were shown to be suitable dienophiles; however, they had not previously been applied for MGE. We synthesized two norbornene‐modified mannosamine derivatives that differ in the stereochemistry at the norbornene (exo/endo linkage). Kinetic investigations revealed that the exo derivative reacts more than twice as rapidly as the endo derivative. Through derivatization with 1,2‐diamino‐4,5‐methylenedioxybenzene (DMB) we confirmed that both derivatives are accepted by cells and incorporated after conversion to a sialic acid. In further MGE experiments the incorporated sugars were ligated to a fluorophore and visualized through confocal fluorescence microscopy and flow cytometry.     

Asymmetric Carbon‐Carbon Bond Forming Reactions Catalysed by Metal(II) Bis(oxazoline) Complexes Immobilized using Supported Ionic Liquids

A series of bis(oxazoline) metal(II) complexes has been supported on silica and carbon supports by non‐covalent immobilisation using an ionic liquid. The catalytic performance of these solids was compared for the enantioselective Diels–Alder reaction between N‐acryloyloxazolidinone and cyclopentadiene and the Mukaiyama‐aldol reaction between methyl pyruvate and 1‐methoxy‐1‐trimethylsilyloxypropene. In both reactions the enantioselectivity was strongly influenced by the choice of support displaying enantioselectivies (ee values) up to 40% higher than those conducted under homogeneous reaction conditions.     

Asymmetric Diels–Alder and Cascade Reaction of Quinone Imine Ketals and 2,4‐Dienals: Construction of Chiral Benzo[de]quinolone Derivatives

An asymmetric Diels–Alder cycloaddition reaction of quinone imine ketals and 2,4‐dienals has been investigated via trienamine catalysis of a secondary chiral amine. A series of chiral tricyclic benzo[de]quinolone derivatives were efficiently constructed in moderate to good yields and with high to excellent enantioselectivity after a cascade aromatization/intramolecular hemiaminal formation sequence (up to 98% ee, >19:1 dr). The methodology and the useful product scaffolds could be further utilized in both synthetic and medicinal fields.

     

[4+2] Cycloaddition of ortho‐Quinone Methides Promoted by Ionic Liquids: an Efficient and Mild Protocol for the Synthesis of Tetrahydropyranobenzopyrans

The stereoselective synthesis of trans‐annelated pyrano[3,2‐c]benzopyrans has been achieved by intramolecular [4+2] cycloaddition of o‐benzoquinone methides that are generated in situ from o‐hydroxybenzaldehydes and unsaturated alcohols using an air‐ and moisture‐stable ionic liquid, i.e., 1‐butyl‐3‐methylimidazolium tetrafluoroborate [bmim]BF₄ under mild and neutral conditions.     

Efficient Asymmetric Synthesis of 2,6‐Disubstituted 2H‐Dihydropyrans via a Catalytic Hetero‐Diels–Alder/Allylboration Sequence

[4+2] Cycloaddition of (E)‐3‐borylacrolein 1 with ethyl vinyl ether, catalysed by chromium complex (1R,2S) or (1S,2R) 2 , led to the corresponding cycloadducts with high diastereo‐ and enantioselectivities. Further reaction with aldehydes offers an attractive asymmetric route to synthetically useful substituted 3,4‐dihydro‐2H‐pyrans.     

N,N′‐Dioxide/Zinc Bis(trifluoromethylsulfonyl)imide Complex Catalyzed Enantioselective Diels–Alder Reaction of Cyclopentadiene with Alkynones

An N,N′‐dioxide/zinc bis(trifluoromethylsulfonyl)imide complex has been developed as an efficient catalyst for the highly enantioselective Diels–Alder reaction of cyclopentadiene with alkynones. Various 2‐acyl substituted norbornadiene derivatives were obtained in moderate to high yields (up to 99 %) with good enantiomeric excesses (up to 95 %).

     

Hafnium Chloride Tetrahydrofuran Complex‐Catalyzed Diels–Alder Cycloadditions of 3‐Ethoxycarbonylcoumarins with 1,3‐Dienes under Solvent‐Free Conditions

Hafnium chloride tetrahydrofuran complex (HfCl₄⋅2 THF) is an efficient catalyst for the Diels–Alder cycloadditions of 3‐ethoxycarbonylcoumarins 1a – c and 1,3‐butadienes 2x – z under solvent‐free conditions furnishing the corresponding cycloadducts in excellent yields. This salt is an air stable Lewis acid and therefore the reactions can be performed in air atmosphere making the procedure simple to be carried out.     

Retro‐Diels–Alder Reactions of Masked Cyclopentadienones Catalyzed by Heterogeneous Brønsted Acids

The zeolite H‐Beta catalyzes the retro‐Diels–Alder reaction of a range of cyclopentadiene cyclo‐adducts at moderate temperatures and ambient pressure, in the presence of an active dienophile. The active catalyst was identified and optimum reaction conditions established after screening a range of zeolites in the retro‐Diels–Alder reaction of the cyclopentadiene adduct of cyclopentenone. Our results suggest that retro‐Diels–Alder reactions of tricyclodecadienones are catalyzed by Brønsted acids and the high catalytic performance of H‐Beta catalysts can be ascribed to the optimal balance between the number of acid sites and their strength as well as to the accessibility of these sites. The methodology was then applied to a series of alkyl derivatives of cyclopentadienylcyclopentenones to provide a viable alternative synthetic route to 4‐alkylcyclopentenones and the versatility of the approach was demonstrated by the successful cycloreversion of N‐cyclohexyl‐2‐azanorborn‐5‐ene.     

Poly(ethylene glycol)‐Supported Chiral Imidazolidin‐4‐one: An Efficient Organic Catalyst for the Enantioselective Diels–Alder Cycloaddition

A tyrosine‐derived imidazolidin‐4‐one was immobilized on a modified poly(ethylene glycol) and converted in situ into a soluble polymer‐supported catalyst for the enantioselective Diels–Alder cycloaddition of acrolein to 1,3‐cyclohexadiene (up to 92% ee) and 2,3‐dimethyl‐1,3‐butadiene (73% ee). Catalyst recycling (up to four cycles) was accompanied by some loss of the chemical efficiency and marginal erosion of the enantioselectivity.     

Second Generation CaSH (Camphor Sulfonyl Hydrazine) Organocatalysis. Asymmetric Diels–Alder Reactions and Isolation of the Catalytic Intermediate

In one step, the well known chiral auxiliary, Oppolzer’s camphor sultam, is turned into the new generation camphor sulfonyl hydrazine (CaSH II) organocatalyst. With the primary hydrazine functionality external to the tricyclic structure, CaSH II is active towards ketone substrates in asymmetric Diels–Alder reactions. The iminium intermediate of the catalytic cycle was isolated. When it was put back into the solution reaction system, the same level of yield and stereoselectivity was observed. Based on these observations, we argue that organocatlyst is actually an in situ chiral auxiliary.     

Copper‐Free Postsynthetic Labeling of Nucleic Acids by Means of Bioorthogonal Reactions

Postsynthetic modification of nucleic acids has the advantage that the chemical development of only a few building blocks is necessary, each bearing a chosen reactive functional group that is applicable to its reactive counterpart for a variety of different labeling types. The reactive group is either linked to phosphoramidites for chemical synthesis on solid phase or attached to nucleoside triphosphates for application in primer extension experiments and PCR. Chemoselectivity is required for this strategy, together with bioorthogonality to perform these labelings in living cells or even organisms. Currently, the copper‐free reactions include strain‐promoted 1,3‐dipolar cycloadditions, “photoclick” reactions, Diels–Alder reactions with inverse electron demand, and nucleophilic additions. The majority of these modification strategies show good to excellent reaction kinetics, an important prerequisite for labeling inside cells and in vivo in order to keep the concentrations of the reacting partners as low as possible.     

Enantioselective Synthesis of Cyclopentadienes by Gold(I)‐ Catalyzed Cyclization of 1,3‐Dien‐5‐ynes

An asymmetric synthesis of elusive chiral cyclopentadienes has been developed by gold(I)‐catalyzed alkoxycyclization of 1,3‐dien‐5‐ynes. The application of these substrates in completely diastereoselective Diels–Alder cycloaddition reactions, which can be carried out in one pot from achiral 1,3‐dien‐5‐ynes, allows the preparation of highly functionalized products bearing five stereogenic centers with high enantiomeric excesses.     

Chiral Phosphoric Acid‐Catalyzed Enantioselective Three‐ Component Aza‐Diels–Alder Reactions of Aminopyrroles and Aminopyrazoles

A highly stereoselective three‐component Povarov reaction, catalyzed by (R)‐ and (S)‐BINOL hydrogen phosphate, was achieved for the first time with aminopyrroles and aminopyrazoles as 2‐azadiene precursors. A variety of aldehydes, enecarbamates, amino‐substituted azines participated in the reaction to afford the tetrahydropyrrolopyridines and tetrahydropyrazolopyridines in good yields with excellent diatereo‐ and enantioselectivities. A stereochemical model is proposed to account for the observed absolute stereochemistry.

     

Rhodium‐Catalyzed Enantioselective Intramolecular [4+2] Cycloaddition using a Chiral Phosphine‐Phosphite Ligand: Importance of Microwave‐Assisted Catalyst Conditioning

The use of modular α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐ and 1,1′‐bi‐2‐naphthol (BINOL)‐derived phosphine‐phosphite ligands (L₂*) in the asymmetric rhodium‐catalyzed intramolecular [4+2] cycloaddition (“neutral” Diels–Alder reaction) of (E,E)‐1,6,8‐decatriene derivatives (including a 4‐oxa and a 4‐aza analogue) was investigated. Initial screening of a small ligand library led to the identification of a most promising, TADDOL‐derived ligand bearing a phenyl group adjacent to the phosphite moiety at the arene backbone. In the course of further optimization studies, the formation of a new, more selective catalyst species during the reaction time was observed. By irradiating the pre‐catalyst with microwaves prior to substrate addition high enantioselectivities (up to 93% ee) were achieved. The new cyclization protocol was successfully applied to all three substrates investigated to give the bicyclic products in good yield and selectivity. ³¹P NMR and ESI‐MS measurements indicated the formation of a [Rh(L₂*)₂]⁺ species as the more selective (pre‐) catalyst.