Enantioselective Diels Research Articles

Enantioselective Diels–Alder Approach to Cannabinoids

Enantioselective Diels–Alder Approach to Cannabinoids

Organocatalytic Enantioselective Diels–Alder Reaction of 2‐Trifluoroacetamido‐1,3‐dienes with α,β‐Unsaturated Ketones

AbstractWe report herein the first examples of chiral phosphoric acid‐catalyzed enantioselective Diels–Alder reactions between 2‐trifluoroacetamido‐1,3‐dienes 1 and α,β‐unsaturated carbonyl compounds 2. Polysubstituted 1‐acetamido cyclohexenes 3 were formed in high yields with excellent diastereo‐ and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three‐component reaction of 1, 2 and ortho‐hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters.

Organocatalytic Enantioselective Diels-Alder Reaction of 2-Trifluoroacetamido-1,3-dienes with α,β-Unsaturated Ketones.

We report herein the first examples of chiral phosphoric acid-catalyzed enantioselective Diels-Alder reactions between 2-trifluoroacetamido-1,3-dienes 1 and α,β-unsaturated carbonyl compounds 2. Polysubstituted 1-acetamido cyclohexenes 3 were formed in high yields with excellent diastereo- and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three-component reaction of 1, 2 and ortho-hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters.

Asymmetric syntheses of (–)-hedyosumins A–C via enantioselective Diels–Alder reaction of (E)-Hex-3-en-5-yn-2-one and platinum(II)-catalyzed [3+2]-cyclization

Enantioselective construction of the central [3.2.1] oxa-bicyclic core of hedyosumins A–C was achieved via an enantioselective Diels–Alder reaction and a platinum(II)-catalyzed 1,3-dipolar [3+2] cycloaddition as key steps, which leads to the asymmetric total synthesis of hedyosumins A-C.

Expanding the Chiral Monoterpene Pool: Enantioselective Diels-Alder Reactions of α-Acyloxy Enones.

An enantioselective Diels-Alder (DA) reaction of α-acyloxy enones has been developed to synthesize chiral oxidized cyclohexenes. Yttrium(III) triflate, in conjunction with a chiral pyridinebisimidazoline (PyBim) ligand, was found to catalyze the asymmetric [4 + 2] cycloaddition with a variety of dienes and α-acyloxy enone dienophiles. Using this method, terpinene-4-ol, a key intermediate in the synthesis of commercial herbicide cinmethylin, can be prepared in four steps from isoprene. A combination of kinetic data and NMR studies support a mechanism involving reversible binding of a dienophile to a yttrium catalyst followed by cycloaddition with a diene as the rate-determining step.

Catalytic Asymmetric Spirocyclizing Diels-Alder Reactions of Enones: Stereoselective Total and Formal Syntheses of α-Chamigrene, β-Chamigrene, Laurencenone C, Colletoic Acid, and Omphalic Acid.

We disclose a general catalytic enantioselective Diels–Alder reaction of exo-enones with dienes to give spirocyclanes. The obtained products feature highly congested quaternary stereogenic spirocenters and are used in concise total and formal syntheses of several sesquiterpenes, including of α-chamigrene, β-chamigrene, laurencenone C, colletoic acid, and omphalic acid. The stereo- and regioselectivities of our spirocyclizing cycloaddition are effectively controlled by strongly acidic and confined imidodiphosphorimidate catalysts. Computational studies shed light on the origin of reactivity and selectivity.

Catalytic Enantioselective Diels Alder Reaction: Application in the Synthesis of Antiviral Agents

The Diels–Alder reaction (DAR) is one of the most effective and reliable strategies for the construction of six-membered carbocyclic and heterocyclic rings, and it is widely used in the synthesis of organic molecules and drugs. Due to the high regio- and stereo-selectivity and its versatility, DARs have represented a powerful tool for organic chemistry for many years. In addition, the asymmetric DAR has become a fundamental synthetic approach in the preparation of optically active six-membered rings and natural compounds. The COVID-19-related pandemic requires continuous research; DAR represents an useful method to obtain optically active intermediates for the synthesis of antiviral agents under different catalytic conditions. We would like to highlight an intriguing synthetic procedure applied to the development of novel synthetic protocols that are potentially useful against a large panel of viruses and other unmet diseases.

Role of Anion in Determining the Stereoselectivity of Mg-Ph-BOX-Catalyzed Diels–Alder Reactions: A Computational Study

In the realm of enantioselective Diels–Alder reactions, a role of primary importance is held by Mg-BOX catalysis. The main features of both catalysts and ligand in directing the stereoselective outcome have been extensively studied in several papers mainly through 1H NMR and X-ray diffraction (XRD) techniques. However, over the years, no computational studies have been reported to support the models proposed to rationalize the observed stereoselectivity for the reaction between 3-acryloyl-1,3-oxazolidin-2-one and cyclopentadiene catalyzed by the BOX ligand (R,R)-(+)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline) and Mg(II) salts. To approach the problem, we performed a density functional theory (DFT) computational study, aiming to locate the preferred transitions states deriving from these proposed models, but we only found a correspondence in selectivities for the reaction catalyzed by Mg(OTf)2, where the model suggests an octahedral complex with the two triflate anions coordinating magnesium. For the other cases [i.e., Mg(ClO4)2, Mg(ClO4)2·2H2O, and MgI2·I2], the commonly accepted tetrahedral or octahedral models suggest no involvement of the perchlorate or iodide anions, but the corresponding calculations did not reproduce the experimental selectivities. Only when we considered also in these cases coordination complexes involving their presence, the observed selectivities were reproduced, thus opening new insights to better understand the role and the action of the counterion to determine the stereochemical outcome of these reactions.

Synthesis of chiral-at-metal rhodium complexes from achiral tripodal tetradentate ligands: resolution and application to enantioselective Diels-Alder and 1,3-dipolar cycloadditions.

An improved synthesis of the racemic rhodium compound [RhCl2(κ4 C,N,N',P-L1)] (1) containing an achiral tripodal tetradentate ligand is reported. Their derived solvate complexes [Rh(κ4 C,N,N',P-L1)(Solv)2][SbF6]2 (Solv = NCMe, 2; H2O, 3) are resolved into their two enantiomers. Complexes 2 and 3 catalyze the Diels-Alder (DA) reaction between methacrolein and cyclopentadiene and the 1,3-dipolar cycloaddition reaction between methacrolein and the nitrone N-benzylidenphenylamine-N-oxide. When enantiopure (A Rh,R N)-2 was employed as the catalyst, enantiomeric ratios >99/1, in the R at C2 adduct, and up to 94/6, in the 3,5-endo isomer, were achieved in the DA reaction and in the 1,3-dipolar cycloaddition reaction, respectively. A plausible catalytic cycle that accounts for the origin of the observed enantioselectivity is proposed.

Asymmetric Inverse-Electron-Demand Diels–Alder Reactions of 2-Pyrones by Lewis Acid Catalysis

AbstractDiels–Alder reactions of 2-pyrones with alkenes can provide highly functionalized [2,2,2]-bicyclic lactones under mild reaction conditions. Synthetic utilizations of these reactions have been well demonstrated in natural-product synthesis. Although several catalytic asymmetric strategies have been realized, current research in this area is still largely underdeveloped. Recent advances in enantioselective inverse-electron-demand Diels–Alder reactions with Lewis acid catalysis are reviewed.1 Introduction2 State of the Art of Enantioselective Diels–Alder Reactions of 2-Pyrones by Lewis Acid Catalysis3 Enantioselective Synthesis of Arene cis-Dihydrodiols by Diels–­Alder/Retro-Diels–Alder Reactions of 2-Pyrones4 Enantioselective Synthesis of cis-Decalin Derivatives by Diels–­Alder Reactions of 2-Pyrones5 Conclusions

3-(Methoxycarbonyl)Cyclobutenone as a Reactive Dienophile in Enantioselective Diels-Alder Reactions Catalyzed by Chiral Oxazaborolidinium Ions.

Cyclobutenone has been used as a highly reactive dienophile in Diels-Alder reactions, however, no enantioselective example has been reported. We disclose herein a chiral oxazaborolidine-aluminum bromide catalyzed enantioselective Diels-Alder reaction of 3-alkoxycarbonyl cyclobutenone with a variety of dienes. Furthermore, a total synthesis of (-)-kingianin F was completed for the first time via enantioenriched cycloadduct bicyclo[4.2.0]octane derivative.

3‐(Methoxycarbonyl)Cyclobutenone as a Reactive Dienophile in Enantioselective Diels–Alder Reactions Catalyzed by Chiral Oxazaborolidinium Ions

AbstractCyclobutenone has been used as a highly reactive dienophile in Diels–Alder reactions, however, no enantioselective example has been reported. We disclose herein a chiral oxazaborolidine‐aluminum bromide catalyzed enantioselective Diels–Alder reaction of 3‐alkoxycarbonyl cyclobutenone with a variety of dienes. Furthermore, a total synthesis of (−)‐kingianin F was completed for the first time via enantioenriched cycloadduct bicyclo[4.2.0]octane derivative.

Fe-BPsalan complex catalyzed highly enantioselective Diels–Alder reaction of alkylidene β-ketoesters

A practical Fe-BPsalan-catalyzed asymmetric Diels–Alder reaction of various alkylidene β-ketoesters and dienes was developed to afford estrone analogues in excellent yields, good to high diastereoselectivities and excellent enantioselectivities.

Organocatalytic enantioselective Diels–Alder reaction between hydroxymaleimides and in situ generated nitrosoalkenes for direct preparation of chiral hemiketals with 1,2-oxazine skeleton

Organocatalytic Enantioselective IEDDA reaction between hydroxymaleimides and in situ generated nitrosoalkenes has been disclosed, a series of chiral hemiketals containing 5,6-dihydro-4H-l,2-oxazines and succinimide frameworks have been prepared.

Enantioselective Diels–Alder reactions with left-handed G-quadruplex DNA-based catalysts

Since the discovery of left-handed G-quadruplex (L-G4) structure formed by natural DNA, there has been a growing interest in its potential functions. This study utilised it to catalyse enantioselective Diels-Alder reactions, considering its different optical rotation compared to an ordinary G4. It was determined that when L-G4 was used with a combination of copper(II) ions, there was a good enantioselectivity (−52% ee) without further addition of ligands. When further consideration was given by adding G4 ligands, G4 was further stabilised, even obtaining a better enantioselectivity (up to −80% ee). Moreover, when using ligands that have regulatory effects on G4, the ee value can be adjusted. In this work, a minimal left-handed G4 was reported. A follow-up study was also conducted, which recovers that the minimal left-handed G4 remains its catalytic effect and enantioselectivity, but is not so effective as the former case. This indicates that a complete G4 structure is relatively conducive to chiral catalysis.

Enantioselective Diels–Alder Reaction of 3-Nitrocoumarins Promoted by Chiral Organoammonium Salt Catalysts

AbstractAn enantioselective Diels–Alder reaction of 3-nitrocoumarins has been developed. A tryptophan-derived C 1-symmetric organoammonium thiourea catalyst promoted the reaction of 3-nitrocoumarins with Danishefsky’s diene to give the corresponding adducts with good enantioselectivity (up to 94% ee). One of the resulting adducts was converted into a chiral carbocyclic quaternary β-amino alcohol.

An Efficient Cyclic Di‐AMP Based Artificial Metalloribozyme for Enantioselective Diels–Alder Reactions

The diverse structures of nucleic acids as scaffolds have brought the significant advancement for DNA‐based enantioselective catalysis, yet RNA‐based enantioselective catalysis is lacking investigation. Herein, we report a small, natural RNA of cyclic di‐AMP (c‐di‐AMP) and Cu2+ ions assemble into an artificial metalloribozyme (c‐di‐AMP·Cu2+), that could effectively catalyze the enantioselective Diels–Alder reactions with up to 80 % ee. The enantioselective catalytic performance of c‐di‐AMP·Cu2+ has been studied by thorough investigations of different metal cofactors, c‐di‐AMP/Cu2+ molar ratios, additives, buffers and c‐di‐AMP analogues. In addition, the assembly of c‐di‐AMP·Cu2+ gives rise to 300‐fold and 5‐fold rate acceleration compared to the uncatalyzed reaction and Cu2+ ions, respectively. This work provides a simple and efficient strategy to construct the RNA‐based catalysts that would expand the current nucleic acids‐based catalysis and might hint the possible catalytic RNA in primordial chemistry.

Enantioselective Redox-Divergent Diels–Alder Reaction of Quinones with Diene Carbamates

Enantioselective Redox-Divergent Diels–Alder Reaction of Quinones with Diene Carbamates

Optically Active Helical Lanthanide Complexes: Storable Chiral Lewis Acidic Catalysts for Enantioselective Diels-Alder Reaction of Siloxydienes.

Lanthanide triflates and a series of hexadentate chiral ligand complexes were synthesized. X-ray-quality crystals were obtained from mixtures of the lanthanide complexes, which were helical in shape. The complexes showed Lewis acidity and catalyzed the enantioselective Diels-Alder reaction of electron-rich siloxydienes. The complexes were stable enough to be stored at ambient temperature on a laboratory bench and retained their Lewis acidity even after a month.

Enantioselective Diels-Alder reaction of anthracene by chiral tritylium catalysis.

The combination of the trityl cation and a chiral weakly coordinating Fe(III)-based bisphosphate anion was used to develop a new type of a highly active carbocation Lewis acid catalyst. The stereocontrol potential of the chiral tritylium ion pair was demonstrated by its application in an enantioselective Diels–Alder reaction of anthracene.