Regioselective Diels-Alder Reaction Research Articles

Unexpectedly Regioselective Diels-Alder Reactions of New Unsymmetrical Benzoquinones: A Convenient Synthetic Entry to Uniquely Substituted Decalins.

We report flexible synthesis of new unsymmetrically 2,6-disubstituted benzoquinones (33 examples) and a systematic study of their reactivity in the Diels-Alder reaction. The Diels-Alder reactions of selected unsymmetrical benzoquinones with seemingly similar substituents were found to proceed with high regioselectivity and the formation of selected experimentally observed main products was rationalized by theoretical (DFT) calculations. The findings can be exploited in the convenient preparation of densely substituted and stereochemically defined decalins with unique angular substituents at ring fusion. We also demonstrate the usefulness of this methodology in complex molecule synthesis through the total synthesis of a novel forskolin analog possessing an ethyl group at the fusion of the rings B and C.

Regioselective Diels-Alder Reactions of Anthracenes with Olefins via Visible Light Photocatalysis in a Homogeneous Solution.

Diels-Alder cycloaddition of anthracene with olefin is achieved in a homogeneous solution via energy transfer under visible light. A series of substrates including electroneutral styrene derivatives can be successfully converted into the corresponding cycloadducts in a head-to-head orientation with high to excellent yields. The high ortho-regioselectivity, mild condition, and broad substrate scope enable promising advances in organic transformation.

Regioselective Diels–Alder Reactions of C70 Directed by Endohedral Ca and Th Atoms

Regioselective Diels–Alder Reactions of C₇₀ Directed by Endohedral Ca and Th Atoms

A concise total synthesis of unprecedented tetranorsesquiterpenoids applanatumol Z5

A concise total synthesis of tetranorsesquiterpenoids applanatumol Z5 (3), possessing unique 6/5/5 ring system was disclosed with 7-step in 5-pot from commercially available starting materials. The key elements of the synthesis included an unexpected intramolecular dithiolane with alcohol oxidative coupling/deprotection sequence to create the unsaturated lactone as dienophile and a regioselective Diels-Alder reaction to assemble the 6/5/5 tricyclic scaffold including two vicinal quaternary carbon stereocenters. Late stage the diastereo- and regioselective carbonyl reduction led to achieve the total synthesis of (±) applanatumol Z5 (3).

BASF announces new product innovations in its selective hydrogenation catalysts portfolio

A concise total synthesis of tetranorsesquiterpenoids applanatumol Z5 (3), possessing unique 6/5/5 ring system was disclosed with 7-step in 5-pot from commercially available starting materials. The key elements of the synthesis included an unexpected intramolecular dithiolane with alcohol oxidative coupling/deprotection sequence to create the unsaturated lactone as dienophile and a regioselective Diels-Alder reaction to assemble the 6/5/5 tricyclic scaffold including two vicinal quaternary carbon stereocenters. Late stage the diastereo- and regioselective carbonyl reduction led to achieve the total synthesis of (±) applanatumol Z5 (3).

Regioselective IED Diels-Alder Reaction of Bis-(4,6-dichloro-[1,3,5]triazin- 2-yl)-diazene with Furan and Its Molecular Mechanism

The reaction of bis-(4,6-dichloro-[1,3,5]triazin-2-yl)-diazene with furan proceeds with the formation of inverse electron demand Diels-Alder product with a high yield. M06 2X/6 31G(d,p) calculations show thermodynamic instability of “normal” DA reaction product and predict its [3,3] sigmatropic rearrangement to the thermodynamically more favorable formal IEDDA reaction product. The obtained NMR spectra were in good agreement with GIAO calculations and were in accordance with DFT thermochemical data that confirmed the formation of the described product. IR and UV/Vis spectral data was also obtained and discussed.

Direct Synthesis of the Phenanthroviridone Skeleton Using a Highly Regioselective Nitroquinone Diels-Alder Reaction.

A variety of nucleophiles react efficiently with in situ generated nitroquinones. The reaction with substituted resorcinols led to the direct synthesis of the phenanthroviridinone and lagumycin skeleton via a highly regioselective Diels–Alder reaction.

Metal-Free Hyperbaric Multicomponent Approach to 4-Aryl[2.2]Paracyclophanes

Herein, we report the first metal-free synthesis of 4-aryl[2.2]paracyclophanes, an important scaffold in organic ligands and material science panorama. In order to avoid the use of toxic and expensive metal catalyst, a multicomponent hyperbaric protocol has been envisaged. First, easy-to-synthesize paracyclophane-substituted butenones underwent acid-catalyzed enol acetylation in the presence of isopropenyl acetate to generate in situ acetoxy-diene intermediates, which were then reacted with methyl propiolate in a hyperbaric regioselective Diels-Alder reaction. Oxidation of the resulting cycloadducts delivered the expected products showing the potential for further functionalization.

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

AbstractRegioselectivity 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.

Total Synthesis of γ-Indomycinone and Kidamycinone by Means of Two Regioselective Diels-Alder Reactions.

An efficient access for the synthesis of pluramycinones is described. Total syntheses of racemic γ-indomycinone and kidamycinone were achieved by means of two Diels-Alder reactions. A first Diels-Alder condensation followed by a Stille cross-coupling is used for the elaboration of the desired substituted dienes which will be involved in the second pericyclic reaction with juglone to construct the tetracyclic core of pluramycinones.

Regioselective Diels-Alder reaction to open-cage ketolactam derivatives of C60.

Open-cage ketolactam fullerenes reacted with dienes on the rim of the orifice both regio- and stereoselectively. Unequivocal evidence for the structure of the Diels-Alder adduct was provided by 2D INADEQUATE 13C NMR studies on 13C enriched material, as well as via DFT-GIAO calculations. The theoretical calculations successfully model the regioselective and the endo stereoselective reaction, predicting molecular orbital control along with a repulsive steric interaction between the substituents on the nitrogen atom and those on the diene.

Synthesis of the Reported Pyranonaphthoquinone Structure of the Indoleamine-2,3-dioxygenase Inhibitor Annulin B by Regioselective Diels–Alder Reaction

Annulin B, isolated from the marine hydroid isolated from Garveia annulata, is a potent inhibitor of the tryptophan catabolizing enzyme indoleamine-2,3-dioxygenase (IDO). A synthesis of the reported pyranonaphthoquinone structure is described, in which the key step is a regioselective Diels-Alder reaction between a pyranobenzoquinone dienophile and a silyl ketene acetal diene.

A Platform of Regioselective Methodologies to Access Polysubstituted 2‐Methyl‐1,4‐naphthoquinone Derivatives: Scope and Limitations

AbstractA platform of synthetic methodologies has been established to access a focused library of polysubstituted 3‐benzylmenadione derivatives functionalized on the aromatic ring of the naphthoquinone core. Two main routes were explored: 1) The naphthol route, starting from either an α‐tetralone or a propiophenone, and 2) the regioselective Diels–Alder reaction, starting from various dienes and two 2‐bromo‐5(or 6)‐methyl‐1,4‐benzoquinones. 6‐Substituted 2‐methylnaphthols were synthesized by using a xanthate‐mediated free‐radical addition/cyclization sequence for the construction of the 6‐substituted menadione subunit. Furthermore, an efficient and simple new pathway that allows the formation of 6‐ or 7‐substituted 3‐(substituted‐benzyl)menadione regioisomers from a common commercial scaffold has also been developed by the naphthol route, advantageous with regard to step economy. Our synthetic methodologies exemplified by 34 compounds have allowed structure–activity relationships to be deduced for use as the basis for the development of new antimalarial redox‐active polysubstituted benzylmenadione derivatives.

Diels–Alder Reactions of γ-Hydroxybutenolides: Approach to the Himbacine Tricyclic Core

The Diels–Alder reaction of γ-hydroxybutenolides with dienes gave good yields of cycloadducts under thermal and Lewis acid catalyzed conditions. The application of this methodology to a more complex system was demonstrated by the synthesis of a model system for the tricyclic himbacine core. The stereo- and regioselective Diels–Alder reaction established three of the stereogenic centers, with the fourth stereogenic center secured by diastereoselective alkylation of the cycloadduct.

ChemInform Abstract: Synthesis of Conformationally Constrained α‐Amino Acid Derivatives Containing Bicyclo[2.2.2] Unit via the Diels—Alder and Suzuki—Miyaura Cross‐Coupling Reactions as Key Steps.

Conformationally constrained α-amino acid (AAA) derivatives 1,2 play a significant role in designing peptidomimetics and peptide modifications. Constrained AAAs such as 2-aminoisobutyric acid (Aib) 1 is found to be useful in the peptide design, when it incorporates into the peptide; the resulting peptides adopt α-helical or β-sheet conformation. To design various peptidomimetics and peptide catalysts, these racemic or meso constrained AAAs are important because when they are coupled with optically pure proteinogenic AAA, two diastereoisomers are formed which can be easily separated by conventional methods. Various synthetic methodologies have been developed where the Diels–Alder (DA) reaction is a useful tool to prepare bicyclic AAA derivatives 3 . These bicyclic AAAs 1b such as 2a,b are prepared by the Bucherer–Bergs reaction or Strecker synthesis. Highly constrained bicyclic AAA derivative (e.g. 3a) (Ref 4a) has been synthesized by the DA reaction of methyl 2-acetamidoacrylate 11 and the anthracene 10. It is worth mentioning that, this strategy is useful to design non-steroidal biologically relevant molecules 4b-i . There-fore, a systematic investigation has been undertaken to design the synthesis of bicyclo[2.2.2]octane related AAA derivatives. Later, this strategy has been extended to 9-substituted anthracene derivatives to generate the substituted bicyclic constrained AAA derivatives 3b (Ref 5) by a regioselective DA reaction (Figure 1).

Model studies on construction of the oxabicyclic [3.3.1] core of the mulberry Diels–Alder adducts morusalbanol A and 441772-64-1

Preparation of the oxabicyclic [3.3.1] cores of morusalbanol A and 441772-64-1 was achieved via the intramolecular cyclization of cis–trans (endo) mulberry Diels–Alder adducts. The latter were derived from a hydrogen bond-assisted regioselective Diels–Alder reaction between a chalcone dienophile and a dehydroprenyl diene. Results from these studies provide important insights into the syntheses of morusalbanol A and related mulberry Diels–Alder adducts.

Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine‐2,3‐dioxygenase (IDO) as Potential Target for Anticancer Activity

AbstractNatural quinones, often linked with cellular oxidation processes, exhibit pronounced biological activity. In particular, the structurally unique isothiazolonaphthoquinone aulosirazole, isolated from blue‐green alga, possesses selective antitumor cytotoxicity, although its mechanism of action is unknown. The first synthesis of aulosirazole uses a route centered upon a late‐stage regioselective Diels–Alder reaction. The structurally related natural product pronqodine A, an inhibitor of prostaglandin release, and analogues thereof, were also prepared for comparison. Biological evaluation of the compounds identified one potential target as the immunoregulatory enzyme indoleamine‐2,3‐dioxygenase (IDO). The isothiazoloquinones are also efficient substrates for the human quinone reductase NQO1, and undergo intracellular NQO1‐dependent redox cycling resulting in the generation of reactive oxygen species, and at lower doses have the potential to alter the ratio of intracellular oxidized to reduced pyridine nucleotides.

Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine-2,3-dioxygenase (IDO) as Potential Target for Anticancer Activity.

Natural quinones, often linked with cellular oxidation processes, exhibit pronounced biological activity. In particular, the structurally unique isothiazolonaphthoquinone aulosirazole, isolated from blue-green alga, possesses selective antitumor cytotoxicity, although its mechanism of action is unknown. The first synthesis of aulosirazole uses a route centered upon a late-stage regioselective Diels-Alder reaction. The structurally related natural product pronqodine A, an inhibitor of prostaglandin release, and analogues thereof, were also prepared for comparison. Biological evaluation of the compounds identified one potential target as the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO). The isothiazoloquinones are also efficient substrates for the human quinone reductase NQO1, and undergo intracellular NQO1-dependent redox cycling resulting in the generation of reactive oxygen species, and at lower doses have the potential to alter the ratio of intracellular oxidized to reduced pyridine nucleotides.

Regioselective inverse Diels-Alder reaction of unsymmetrical tetrazines with aldehydes and ketones

The amine-catalyzed inverse electron demand Diels-Alder reaction of unsymmetrical tetrazines with aldehydes and ketones was investigated. We found that only one regioisomer could be observed when pyrrolidine was applied as the catalyst. Using this reaction, fluorogenic dyes could be developed with a tetrazine unit as the “triggering group”.

ChemInform Abstract: Concise Synthesis of Multisubstituted Isoquinolines from Pyridines by Regioselective Diels—Alder Reactions of 2‐Silyl‐3,4‐pyridynes.

A four-step regioselective synthesis of multisubstituted isoquinoline derivatives from 3-bromopyridines was developed by the Diels-Alder (DA) reactions of 2-silyl-3,4-pyridynes with furans, followed by functional-group transformations. In particular, the silyl group at the C2-position of the 3,4-pyridynes played two important roles: firstly, it functioned as the directing group for the DA reaction, and secondly, it served to introduce diverse substituents at the C1-position of the isoquinolines by electrophilic ipso-substitution.