Selective Diels Research Articles

Intermolecular exo-selective Diels–Alder reaction catalysed by dual-functional Brønsted acid: conformational restriction of transition states by hydrogen bonds as the key interaction

An exo-selective Diels–Alder reaction was predicted by a computational approach and was experimentally confirmed by the combined use of a dual-functional acid catalyst, such as phosphoric acid, and the conformationally restricted dienylcarbamate.

Inducing high exo selectivity in Diels–Alder reaction by dimethylborane substituent: a DFT study

In this work, the role of Lewis acid–base (LAB) interaction on the stereoselectivity of the Diels–Alder (DA) reaction has been studied by DFT in gas and solution (dichloromethane) phases. The calculations were performed at the B3LYP/6-311G++ (d, p) level. Two different series of DA reactions were investigated: (1)—three mono-substituted cyclopentadienes + dimethyl(vinyl)borane; (2)—five α,β-unsaturated carbonyl compounds + cyclopenta-2,4-dien-1-yldimethylborane. The reacting diene and dienophile pairs were chosen to restrict LAB interaction to the exo reaction pathway. It was found that in some of the examined cases, the favorable LAB interaction is so strong that it can lead to a completely exo-selective DA reaction. Furthermore, a novel multistep synthetic method was hypothesized for preparing exo cycloadduct with near 100% stereoselectivity. Our results can open up new avenues toward the rational design of exo-selective DA reactions for synthesizing novel bioorganic compounds.

Stereoselective Construction of Fluorinated Quaternary Stereogenic Centers via an Organocatalytic Asymmetric exo-Selective Diels-Alder Reaction in the Presence of Water.

A catalytic, asymmetric Diels-Alder reaction of α-fluoro α,β-unsaturated aldehydes and cyclopentadiene was developed using diarylprolinol silyl ether as an organocatalyst. The reaction proceeds in toluene with trifluoroacetic acid as an additive (condition A). Perchloric acid salt of diarylprolinol silyl ether also promotes the reaction using water as a reaction medium (condition B). In both cases, excellent exo-selectivity and enantioselectivity were obtained with generation of a fluorinated quaternary chiral center.

Highly Selective Synthesis of Seven-Membered Azaspiro Compounds by a Rh(I)-Catalyzed Cycloisomerization/Diels-Alder Cascade of 1,5-Bisallenes.

The synthesis of spiro compounds featuring seven- and six-membered rings in the spirobicyclic motif is successfully achieved through a cascade process encompassing a rhodium(I)-catalyzed cycloisomerization followed by a highly selective Diels–Alder homodimerization. The scope of the reaction is analyzed based on a series of synthetic substrates, and control experiments and DFT calculations led us to justify the exquisite degree of selectivity observed.

Generation of Cyclopentadiene for Diels–Alder Reactions by Visible‐Light Irradiation of Iron Sandwich Complexes

AbstractCyclopentadienes readily undergo fast and selective Diels–Alder reactions which can be used for conjugation of biomolecules and polymers. Herein we present a new method for the photochemical generation of cyclopentadienes by the visible light irradiation of the iron complexes [(C5H4R)Fe(arene)]+. This reaction proceeds at room temperature, in water, and in the presence of potentially interfering amino acids. Free cyclopentadiene is trapped by dienophiles to give the corresponding Diels–Alder adducts in 72–95 % yield.

High-Pressure-Promoted and Facially Selective Diels-Alder Reactions of Enzymatically Derived cis-1,2-Dihydrocatechols and Their Acetonide Derivatives: Enantiodivergent Routes to Homochiral and Polyfunctionalized Bicyclo[2.2.2]octenes.

cis-1,2-Dihydrocatechols 5 (X = Me and Cl), which are available in the homochiral form through the whole-cell biotransformation of toluene and chlorobenzene, respectively, undergo Diels-Alder cycloaddition reactions with a range of electron-deficient dienophiles at 19 kbar (1.9 GPa). The favored products of such reactions are adducts of the general form 7 and that arise through the operation of a contrasteric or syn-addition pathway. In contrast, the acetonide derivatives of metabolites 5 undergo anti-selective addition reactions under the same conditions and so producing adducts of the general form 11. Bicyclo[2.2.2]octenes 7 and 11, which embody carbocyclic frameworks of opposite enantiomeric form, are useful scaffolds for chemical synthesis. Computational studies reveal that syn-adduct formation is kinetically and normally thermodynamically favored over anti-adduct formation when the free diols 5 are involved, but the reverse is so when the corresponding acetonides participate as the 4π-addend. Furthermore, the reactions become more exothermic as pressure increases while, concurrently, the activation barrier diminishes and at 6 GPa (60 kbar) almost vanishes.

Solvation effects drive the selectivity in Diels-Alder reaction under hyperbaric conditions.

High pressure effects on the Diels-Alder reaction in condensed phase are investigated by means of theoretical methods, employing advanced multiscale modeling approaches based on physically grounded models. The simulations reveal how the increase of pressure from 1 to 10 000 atm (10 katm) does not affect the stability of the reaction products, modifying the kinetics of the process by lowering considerably the transition state energy. The reaction profile at high pressure remarkably differs from that at 1 atm, showing a submerged TS and a pre-TS structure lower in energy. The different solvation between endo and exo pre-TS is revealed as the driving force pushing the reaction toward a much higher preference for the endo product at high pressure.

Understanding exo-selective Diels-Alder reactions involving Fischer-type carbene complexes.

The factors controlling the selectivity of the Diels-Alder cycloaddition reactions involving Fischer-type carbene complexes and cyclopentadiene have been explored computationally by means of density functional theory calculations. To this end, the influence of the substituents directly attached to the carbene ligand on the endo : exo ratio has been compared to the available experimental data and quantitatively analysed in detail by means of the combination of the activation strain model of reactivity and energy decomposition analysis methods. The insight gained in this computational study may be important for the rational design of exo-selective Diels-Alder reactions.

Efficient Access to the Functionalized Bicyclic Pharmacophore of Spirolide C by Using a Selective Diels–Alder Reaction

AbstractA functionalized bicyclic lactam that was used as a key intermediate in an efficient synthesis of the pharmacophore of potent marine toxin spirolide C was synthesized by using a highly selective Diels–Alder reaction. To improve the reactivity of this transformation without loss of selectivity, substrates that contained a silyl ether or silatrane moiety were elaborately designed and converted into the spirobicyclic core structure with stereochemical control over the two asymmetric centers at the C7 and C29 positions. Moreover, a further C−C bond formation by using a Hiyama cross‐coupling reaction of the vinyl silatrane derivative facilitated versatile modification at the C5 position with an aryl or alkenyl substituent.

A concise Diels–Alder strategy leading to congeners of the ABC ring system of the marine alkaloid ‘upenamide

A second-generation approach to the BC spirocycle of ‘upenamide is reported. Central to the synthesis is an endo selective Diels–Alder reaction between 1-(t-butyldimethylsiloxy)-1,3-butadiene and bromomaleic anhydride followed by a radical mediated allylation of the ring fusion bromide. Functional group manipulation provides three (9–11) advanced synthetic intermediates ready for coupling with the remaining half (DE bicycle) of ‘upenamide.

Irreversible endo-selective diels-alder reactions of substituted alkoxyfurans: a general synthesis of endo-cantharimides.

The [4+2] cycloaddition of 3-alkoxyfurans with N-substituted maleimides provides the first general route for preparing endo-cantharimides. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2-substitued furans including alkyl, aromatic, and heteroaromatic groups. The cycloaddition products were converted into a range of cantharimide products with promising lead-like properties for medicinal chemistry programs. Furthermore, the electron-rich furans are shown to react with a variety of alternative dienophiles to generate 7-oxabicyclo[2.2.1]heptane derivatives under mild conditions. DFT calculations have been performed to rationalize the activation effect of the 3-alkoxy group on a furan Diels–Alder reaction.

Diastereo- and Facially Selective Imino-Diels–Alder Cycloaddition of 2-Azeditinone-Tethered 1-Azadiene: Synthesis of Functionalized (2-Oxo-4-styrylazetidin-3-yl)–Pyridine Hybrids

Highly diastereo- and π-facially selective imino Diels–Alder cycloadditions of 3-allylideneamino-2-azetidinones having stereocentres at its α- and β-positions, with symmetrical dienophiles leading to the formation of biologically potent (2-oxo-4-styrylazetidin-3-yl)–pyridine hybrids have been reported.

Stereoselective Synthesis of Tricyclo[6.2.2.02,7]dodecane-3,6,9,10-tetrol via Selective Reduction of α,β-Unsaturated 1,4-DIKetone

Stereoselective synthesis of tricyclo[6.2.2.02,7]dodecane-3,6,9,10-tetrol was developed starting from p-benzoquinone. The endo selective Diels–Alder cycloaddition of p-benzoquinone and 1,3-cyclohexadiene afforded the corresponding bicyclic diketone. The synthesis of the title compound was based on the cycloadduct by selective reduction with NaBH4, acetylation with AcCl, and hydroxylation with OsO4-NMO. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource: Full experimental and spectral details.]

Oxazolidinone polycyclitols. Stereospecific synthesis of novel aminocarbasugars with oxazolidinone ring

Two new oxazolidinone polycyclitols, 4,5,7,8,9-pentahydroxy-3-tosyldecahydronaphtho [2,1-d]oxazol-2(9bH)-one and 4,5,6,7,8-pentahydroxy-3-tosyldecahydronaphtho [2,1-d]oxazol-2(9bH)-one were synthesized starting from p-benzoquinone. An endo selective Diels–Alder cycloaddition between p-benzoquinone and 1-acetoxybutadiene followed by stereoselective reduction with NaBH4–CeCl3·7H2O led to the formation of an allylic cis-diol. The obtained diols were protected with p-TsNCO to yield bis-carbamates and then a palladium-catalyzed ionization/cyclization reaction produced two oxazolidinone derivatives. Oxidation of the two double bonds in either oxazolidinones with OsO4 followed by acetylation produced oxazolidinone-pentaacetates whose exact configurations were determined by X-ray diffraction analysis. Controlled removal of the acetate groups furnished the desired two new oxazolidinone polycyclitols.

Accurate prediction of rate constants of Diels–Alder reactions and application to design of Diels–Alder ligation

Bioorthogonal reactions are useful tools to gain insights into the structure, dynamics, and function of biomolecules in the field of chemical biology. Recently, the Diels-Alder reaction has become a promising and attractive procedure for ligation in bioorthogonal chemistry because of its higher rate and selectivity in water. However, a drawback of the previous Diels-Alder ligation is that the widely used maleimide moiety as a typical Michael acceptor can readily undergo Michael addition with nucleophiles in living systems. Thus, it is important to develop a nucleophile-tolerant Diels-Alder system in order to extend the scope of the application of Diels-Alder ligation. To solve this problem, we found that the theoretical protocol M06-2X/6-31+G(d)//B3LYP/6-31G(d) can accurately predict the activation free energies of Diels-Alder reactions with a precision of 1.4 kcal mol(-1) by benchmarking the calculations against the 72 available experimental data. Subsequently, the electronic effect and ring-strain effect on the Diels-Alder reaction were studied to guide the design of the new dienophiles. The criteria of the design is that the designed Diels-Alder reaction should have a lower barrier than the Michael addition, while at the same time it should show a similar (or even higher) reactivity as compared to the maleimide-involving Diels-Alder ligation. Among the designed dienophiles, three substituted cyclopropenes (i.e. 1,2-bis(trifluoromethyl)-, 1,2-bis(hydroxylmethyl)- and 1,2-bis(hydroxylmethyl)-3-carboxylcyclopropenes) meet our requirements. These substituted cyclopropene analogs could be synthesized and they are thermodynamically stable. As a result, we propose that 1,2-bis(trifluoromethyl)-, 1,2-bis(hydroxylmethyl)- and 1,2-bis(hydroxylmethyl)-3-carboxylcyclopropenes may be potential candidates for efficient and selective Diels-Alder ligation in living systems.

Synthesis of a diversifiable cis-dehydrodecalin scaffold based on meiogynin A

A highly endo selective Diels–Alder reaction provides efficient access to the substituted cis-dehydrodecalin core structure of meiogynin A. Elaboration into the fully functionalized scaffold was achieved in three steps from cycloadduct 20a. This strategy is amenable to the synthesis of diversely substituted meiogynin analogs for the discovery of novel inhibitors of Bcl-xL and related anti-apoptotic proteins.

The Catalytic Asymmetric Diels–Alder Reactions and Post‐cycloaddition Reductive Transpositions of 1‐Hydrazinodienes

The Catalytic Asymmetric Diels–Alder Reactions and Post‐cycloaddition Reductive Transpositions of 1‐Hydrazinodienes

Selective Diels–Alder cycloaddition on semiconducting single-walled carbon nanotubes for potential separation application

Selectivity for the Diels-Alder cycloaddition reaction of the electron-rich diene with single-walled carbon nanotubes was first investigated. This chemistry is a complete departure from the curvature-dependent reactivity based on the carbon pyramidalization angle.

ChemInform Abstract: Catalytic Enantioselective Cycloadditions: A Readily Available Diels-Alder Catalyst.

Abstract A highly selective Diels–Alder catalyst has been prepared from a commercially available tetrahydronaphthalene diol. Stereocontrol is enhanced by introduction of a planar chiral arene chromium tricarbonyl group.

Erbium triflate in ionic liquids: A recyclable system of improving selectivity in Diels–Alder reactions

The efficiency of Er(OTf) 3 in promoting the Diels–Alder reactions between different dienes and dienophiles in ionic liquids has been investigated. Compared with the analogous cycloadditions performed in conventional solvents shorter reaction times are required to obtain good/excellent yields. In most cases an enhancement of regio- and endo:exo selectivity was observed. The role of the ionic liquid, as a function of the cationic part, i.e. the imidazolium based or the pyridinium based, is discussed well. The ILs containing the catalyst can be readily separated from the reaction products and recovered in very high purity for direct reuse, up to six cycles.