Enantioselective Synthesis of Complex Fused Heterocycles through Chiral Phosphoric Acid Catalyzed Intramolecular Inverse-Electron-Demand Aza-Diels–Alder Reactions

A stable asymmetric intramolecular Povarov reaction has been established to provide an efficient method to access structurally diverse trans,trans-trisubstituted tetrahydrochromeno[4,3-b]quinolines in high stereoselectivities of up to >99:1 diastereomeric ratio and 99 % enantiomeric excess, without any purification step. Additionally, to facilitate large-scale application of this method, a low catalyst loading protocol was employed, 0.2 mol % chiral phosphoric acid, which provided the cycloadducts without any loss in yield and enantioselectivity. Theoretical studies revealed that the reaction occurred through a sequential Mannich reaction and an intramolecular Friedel–Crafts reaction, wherein the phosphoric acid acted as a bifunctional catalyst to activate the para-phenolic dienophile and N-2-hydroxy-2-azadiene simultaneously.     

Highly Enantioselective Diels–Alder Reaction Catalyzed by Chiral Imidazolidinone

New chiral imidazolidinone with an indole group was synthesized and used to catalyze the Diels–Alder reaction of α,β-unsaturated aldehyde with diene. High enantiomeric excesses and good yields were obtained. The reaction media were also surveyed. The best result in terms of enantioselectivity was achieved using acrolein and 2,3-dimethylbutdiene (up to 95% ee) in CH₃OH/H₂O.     

Synthesis of Chiral Bis-Thiazolines and Asymmetric Diels–Alder Reactions

Abstract

New chiral ligands, bis-thiazoline derivatives (sulfur analogues of known oxazolines) were prepared from chiral bis-(N-acylamino alcohols) with Lawesson's reagent. Bis-thiazolines thus obtained proved to be useful chiral ligands for metal in asymmetric Diels–Alder reaction.     

Highly Stereoselective Diels–Alder Reactions Catalyzed by Diboronate Complexes**

A highly enantioselective catalytic system for exo-Diels–Alder reactions was developed based on the newly discovered bispyrrolidine diboronates (BPDB). Activated by various Lewis or Brønsted acids, BPDB can catalyze highly stereoselective asymmetric exo-Diels–Alder reactions of monocarbonyl-based dienophiles. When 1,2-dicarbonyl-based dienophiles are used, the catalyst can sterically distinguish between the two binding sites, which leads to highly regioselective asymmetric Diels–Alder reactions. BPDB can be prepared as crystalline solids on a large scale and are stable under ambient condition. Single-crystal X-ray analysis of the structure for acid-activated BPDB indicated that its activation involves cleavage of a labile B←N bond.     

Chiral Phosphoric Acid Catalyzed Asymmetric Friedel–Crafts Alkylation of Indoles with Nitroolefins

Abstract

Asymmetric Michael-type Friedel–Crafts (F–C) alkylations of indoles with nitroolefins catalyzed by a chiral H₈-BINOL-based phosphoric acid were investigated. The reactions took place very smoothly in the presence of only 5 mol-% of catalyst at room temperature to afford the desired F–C alkylation products in good yields and with moderate enantioselectivities.

GRAPHICAL ABSTRACT      

How Lewis Acids Catalyze Diels–Alder Reactions

The Lewis acid(LA)-catalyzed Diels–Alder reaction between isoprene and methyl acrylate was investigated quantum chemically using a combined density functional theory and coupled-cluster theory approach. Computed activation energies systematically decrease as the strength of the LA increases along the series I₂<SnCl₄<TiCl₄<ZnCl₂<BF₃<AlCl₃. Emerging from our activation strain and Kohn–Sham molecular orbital bonding analysis was an unprecedented finding, namely that the LAs accelerate the Diels–Alder reaction by a diminished Pauli repulsion between the π-electron systems of the diene and dienophile. Our results oppose the widely accepted view that LAs catalyze the Diels–Alder reaction by enhancing the donor–acceptor [HOMO_diene–LUMO_dienophile] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.     

Dual Activation of Aromatic Diels–Alder Reactions

The unusually fast Diels–Alder reactions of [5]cyclophanes were analyzed by DFT at the BLYP-D3(BJ)/TZ2P level of theory. The computations were guided by an integrated activation-strain and Kohn–Sham molecular orbital analysis. It is revealed why both [5]metacyclophane and [5]paracyclophane exhibit a significant rate enhancement compared to their planar benzene analogue. The activation strain analyses revealed that the enhanced reactivity originates from 1) predistortion of the aromatic core resulting in a reduced activation strain of the aromatic diene, and/or 2) enhanced interaction with the dienophile through a distortion-controlled lowering of the HOMO–LUMO gap within the diene. Both of these physical mechanisms and thus the rate of Diels–Alder cycloaddition can be tuned through different modes of geometrical distortion (meta versus para bridging) and by heteroatom substitution in the aromatic ring. Judicious choice of the bridge and heteroatom in the aromatic core enables effective tuning of the aromatic Diels–Alder reactivity to achieve activation barriers as low as 2 kcal mol⁻¹, which is an impressive 35 kcal mol⁻¹ lower than that of benzene.     

Aluminosilicate Catalysis of Chalcone Diels–Alder Reactions

Previously unreported Diels–Alder adducts of substituted chalcones with isoprene and myrcene have been formed at more than 0°C by employing a nanoporous aluminosilicate catalyst. This catalyst eliminates problems with diene polymerization that are encountered with many other Lewis acids. The chalcone component has some size restrictions.     

Diels–Alder Reactions of β-Acylacrylic Acids

The Diels–Alder reaction of β-acylacrylic acids with dienes gave good yields and good regio- or stereoselectivity of the corresponding cycloaddition products with the use of Lewis acids.     

Chiral Phosphoric Acid Catalyzed Atroposelective C−H Amination of Arenes

N-arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C−H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition-metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C–N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N-arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N-arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal-catalyzed C–N cross-coupling, but also brings about opportunities for the exploitation of structurally diverse N-aryl atropisomers and OLED materials.     

Diels–Alder Reactions During the Biosynthesis of Sorbicillinoids

The sorbicillinoids are a class of biologically active and structurally diverse fungal polyketides arising from sorbicillin. Through co-expression of sorA, sorB, sorC, and sorD from Trichoderma reesei QM6a, the biosynthetic pathway to epoxysorbicillinol and dimeric sorbicillinoids, which resemble Diels–Alder-like and Michael-addition-like products, was reconstituted in Aspergillus oryzae NSAR1. Expression and feeding experiments demonstrated the crucial requirement of the flavin-dependent monooxygenase SorD for the formation of dimeric sorbicillinoids, hybrid sorbicillinoids, and epoxysorbicillinol in vivo. In contrast to prior reports, SorD catalyses neither the oxidation of 2′,3′-dihydrosorbicillin to sorbicillin nor the oxidation of sorbicillinol to oxosorbicillinol. This is the first report that both the intermolecular Diels–Alder and Michael dimerization reactions, as well as the epoxidation of sorbicillinol are catalysed in vivo by SorD.     

Enantioselective Copper(I)/Chiral Phosphoric Acid Catalyzed Intramolecular Amination of Allylic and Benzylic C−H Bonds

Radical-involved enantioselective oxidative C−H bond functionalization by a hydrogen-atom transfer (HAT) process has emerged as a promising method for accessing functionally diverse enantioenriched products, while asymmetric C(sp³)−H bond amination remains a formidable challenge. To address this problem, described herein is a dual Cu^I/chiral phosphoric acid (CPA) catalytic system for radical-involved enantioselective intramolecular C(sp³)−H amination of not only allylic positions but also benzylic positions with broad substrate scope. The use of 4-methoxy-NHPI (NHPI=N-hydroxyphthalimide) as a stable and chemoselective HAT mediator precursor is crucial for the fulfillment of this transformation. Preliminary mechanistic studies indicate that a crucial allylic or benzylic radical intermediate resulting from a HAT process is involved.     

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 uti...     

Imino Diels–Alder Reactions: Efficient Synthesis of Pyrano and Furoquinolines Catalyzed by ZrCl4

Abstract

Anhydrous zirconium tetrachloride is found to be an efficient catalyst for the Imino Diels–Alder reactions of N‐benzylideneanilines with 3,4‐dihydro‐2H‐pyran and 2,3‐dihydrofuran to afford pyrano and furo [3,2‐c] quinolines in good yields.     

Enantioselective Friedel–Crafts Alkylation Reaction of Heteroarenes with N-Unprotected Trifluoromethyl Ketimines by Means of Chiral Phosphoric Acid

An enantioselective Friedel–Crafts alkylation reaction of pyrroles and indoles with N-unprotected trifluoromethyl ketimines by use of chiral phosphoric acid provided α-trifluoromethylated primary amines bearing chiral tetrasubstituted carbon centers in high yields and with high to excellent enantioselectivities. The present reaction is unique to N-unprotected trifluoromethyl ketimines. No reaction took place with N-p-methoxyphenyl (PMP)-substituted ketimine. Corresponding α-trifluoromethylated amines were transformed without loss of enantioselectivity.     

Tailoring Magnetic Features in Zigzag-Edged Nanographenes by Controlled Diels–Alder Reactions

Nanographenes (NGs) with tunable electronic and magnetic properties have attracted enormous attention in the realm of carbon-based nanoelectronics. In particular, NGs with biradical character at the ground state are promising building units for molecular spintronics. However, most of the biradicaloids are susceptible to oxidation under ambient conditions and photolytic degradation, which hamper their further applications. Herein, we demonstrated the feasibility of tuning the magnetic properties of zigzag-edged NGs in order to enhance their stability via the controlled Diels–Alder reactions of peri-tetracene ( 4-PA ). The unstable 4-PA (y₀=0.72; half-life, t_1/2=3 h) was transformed into the unprecedented benzo-peri-tetracenes ( BPTs ) by a one-side Diels–Alder reaction, which featured a biradical character at the ground state (y₀=0.60) and exhibited remarkable stability under ambient conditions for several months. In addition, the fully zigzag-edged circumanthracenes ( CAs ) were achieved by two-fold or stepwise Diels–Alder reactions of 4-PA , in which the magnetic properties could be controlled by employing the corresponding dienophiles. Our work reported herein opens avenues for the synthesis of novel zigzag-edged NGs with tailor-made magnetic properties.     

Enantioselective Alkynylation of Benzaldehyde Catalyzed by New Chiral Lewis Acid Ligand: Zinc-Amide Complex

The enantioselective alkynylzinc addition to aldehydes is very useful for the synthesis of chiral propargyl alcohols which are important versatile building blocks of many biologically active compounds and natural products1. A series of chiral oxazolidines were conveniently synthesized from amino acids in three steps with good yields. The use of chiral Lewis acid ligand: zinc-amide complex in situ generated from this oxazolidine with alkylzinc as chiral catalysts for the enantioselective alkyny…     

Recent Advances in Asymmetric Nitroso Diels—Alder Reactions

Russian Journal of Organic Chemistry - The nitroso Diels—Alder (NDA) reaction has occupied an important place in organic synthesis, and numbers of important compounds and bioactive skeletons...     

Inverse-Electron-Demand Diels–Alder Reactions of 2-Pyrones: Bridged Lactones and Beyond

Inverse-electron-demand Diels–Alder (IEDDA) reactions of electron-poor 2-pyrones as electrophilic dienes have been extensively studied in the past fifty years. These reactions provide an efficient access to bridged bicyclic lactones and their derivatives, such as densely functionalized 1,3-cyclohexadienes after CO₂ extrusion and polysubstituted aromatic compounds through elimination. This reaction has been used for the synthesis of many biologically active natural products and drug candidates. In this review, the developments of these IEDDA reactions including non-catalytic, Lewis acid-catalyzed and organocatalytic IEDDA reactions, and their applications in total synthesis are discussed in detail.     

Inverse Electron Demand Hetero Diels–Alder Reactions of Solid Supported α-Acilthiones

Abstract

A solid supported dienic α,α′-dioxothione, obtained from the corresponding resin-linked β-chetoester, is able to react with vinyl ethers to give chemo- and regiospecifically the expected oxathiin cycloadducts. Trans-esterification allowed a quantitative and very clean cleavage of the products from the solid support.