Enantioselective catalysis of the hetero-Diels-Alder reaction between Brassard's diene and aldehydes by hydrogen-bonding activation: a one-step synthesis of (S)-(+)-dihydrokawain

The first catalytic enantioselective hetero-Diels-Alder reaction between Brassard's diene and aldehydes has been achieved through hydrogen-bonding activation using TADDOL derivatives as catalysts to afford the corresponding delta-lactone derivatives in moderate-to-good yields and with high enantioselectivities (up to 91 % ee). The reactions can be carried out either under solvent-free conditions or in toluene. On the basis of the absolute configurations of the products and the hydrogen-bonding interaction pattern between TADDOL (alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolan-4,5-dimethanol) and the carbonyl group disclosed by X-ray diffraction analysis, a possible mechanism for the catalytic reaction has been proposed. To demonstrate the usefulness of the methodology, a natural product, (S)-(+)-dihydrokawain, has also been prepared in 50 % isolated yield and with 69 % enantioselectivity in one step starting from 3-phenylpropionaldehyde by using this methodology. Therefore, this catalytic system is one of the most direct approaches to the construction of delta-lactone units, which will make the methodology very attractive for the synthesis of a variety of biologically important compounds and natural products.     

Asymmetric binary-acid catalysis with InBr3 in the inverse-electron-demanding hetero-Diels-Alder reaction of mono- and bis-substituted cyclopentadienes: remote fluoro-effect on stereocontrol

Remote F effect: Unprecedented hetero-Diels-Alder reactions of mono- and bis-substituted cyclopentadienes have been realized by an asymmetric binary-acid catalyst that synergistically combines a chiral phosphoric acid 1?h/InBr(3) with good periselectivity, high regioselectivity, and excellent stereoselectivity. Substituent mapping of the chiral phosphoric acid indicates a dramatic remote ortho-fluoro effect on the stereocontrol.     

The stepwise Diels-Alder reaction of 4-nitrobenzodifuroxan with Danishefsky's diene

The Diels–Alder reaction of 4‐nitrobenzodifuroxan (NBDF) with 1‐methoxy‐3‐trimethylsilyloxy‐1,3‐butadiene has been investigated experimentally and theoretically. Treatment of NBDF with excess diene in chloroform at room temperature was found to afford a single product that contained a carbonyl functionality. Based on an X‐ray structure and NMR spectroscopic data, the product appeared to be a result of the hydrolysis of the OSiMe₃ moiety of the thermodynamically more stable endo [2+4] cycloadduct, characterized by a cis arrangement of the MeO and NO₂ functionalities. In situ NMR investigations of the interaction were carried out at room temperature in CDCl₃ and at ?40 °C in deuterated acetonitrile. Calculations at the B3LYP/6‐31G* level in the gas phase and in acetonitrile were carried out under the assumption that the most stable cis conformation of the diene is also the most reactive in the interaction. The analysis revealed the NBDF/cis diene interaction involves the formation of a zwitterionic intermediate. Importantly, this intermediate is formed in two preferred conformations, which correspond to the endo and exo modes of approach of the reagents. Cyclization of these two identified conformations afforded the experimentally characterized endo and exo [2+4] cycloadducts. According to the calculations, the interconversion of the two conformers can either take place through a return to the pre‐reaction complexes or it can occur by rotation through an intermediate conformation of lesser stability. In view of the stepwise character of the interaction, the possibility that the intermediate zwitterion is the result of the interaction between NBDF and the trans diene could not be excluded. Calculations carried out with the most stable and more populated s‐trans conformer confirmed this idea and supported the role of the zwitterion in the overall interaction.     

Highly enantioselective hetero-Diels-Alder reaction of Brassard diene with aromatic aldehydes

[reaction: see text] Hetero-Diels-Alder reactions of Brassard diene with aromatic aldehydes were carried out smoothly in the presence of titanium(IV) tridentate Schiff base complexes to give the corresponding chiral delta-lactones in high enantioselectivities (up to 99% ee) under mild conditions.     

The nitrosocarbonyl hetero-Diels-Alder reaction as a useful tool for organic syntheses

Organic transformations that result in the formation of multiple covalent bonds within the same reaction are some of the most powerful tools in synthetic organic chemistry. Nitrosocarbonyl hetero-Diels-Alder (HDA) reactions allow for the simultaneous stereospecific introduction of carbon-nitrogen and carbon-oxygen bonds in one synthetic step, and provide direct access to 3,6-dihydro-1,2-oxazines. This Review describes the development of the nitrosocarbonyl HDA reaction and the utility of the resulting oxazine ring in the synthesis of a variety of important, biologically active molecules.     

Experimental and theoretical studies on the hydrogen-bond-promoted enantioselective hetero-Diels-Alder reaction of Danishefsky's diene with benzaldehyde

The enantioselective hetero-Diels-Alder (HDA) reaction of Danishefsky's diene with benzaldehyde has been achieved catalytically by a series of alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL) derivatives through hydrogen-bonding activation, affording 2-phenyl-2,3-dihydro-4H-pyran-4-one after trifluoroacetic acid workup in moderate yield and good enantioselectivity. The alpha,alpha'-aryl substituents in the TADDOL molecules are found to exert a significant impact on both the activity and the enantioselectivity of the catalysis. In combination with the experimental investigations, the mechanism of the present reaction has also been studied theoretically using the ONIOM (B3LYP/6-31G:PM3) method with trans-1,3-dimethoxy-1,3-butadiene as the model for Danishefsky's diene. In agreement with the experimental findings, the calculation results indicate that this TADDOL-catalyzed HDA reaction proceeds via a concerted mechanism through an asynchronous and zwitterionic transition structure (TS). The carbonyl group of benzaldehyde is activated by forming an intermolecular hydrogen bond with one of the hydroxy groups of TADDOL. Meanwhile, the intramolecular hydrogen bond between the two hydroxy groups in TADDOL is found to facilitate the intermolecular hydrogen bonding with benzaldehyde. The sense of asymmetric induction is well-rationalized by the analysis of the relative energies of TADDOL-complexed TSs, while the different stereocontrol capabilities exhibited by TADDOLs in the reaction can be qualitatively established on the basis of the structural features of their corresponding TSs.     

Site-recognition of one of the two alkoxy carbonyl groups present in the dienophile for Diels–Alder reaction

Recognition of one alkoxy carbonyl group from the two in a molecule by a Lewis acid was investigated using 1a–e in the Diels–Alder reaction with diene 6. Combination of 1a and BF₃·OEt₂ provided the highest efficiency to afford 7a, thus showing evidence for the site-selective coordination of BF₃·OEt₂ to the MOM-oxy carbonyl group in 1a. Furthermore, the generality and high reactivity of this combination were confirmed with dienes 11–14.     

Unsaturated aldehydes as alkene equivalents in the Diels-Alder reaction

A one-pot procedure is described for using alpha,beta-unsaturated aldehydes as olefin equivalents in the Diels-Alder reaction. The method combines the normal electron demand cycloaddition with aldehyde dienophiles and the rhodium-catalyzed decarbonylation of aldehydes to afford cyclohexenes with no electron-withdrawing substituents. In this way, the aldehyde group serves as a traceless control element to direct the cycloaddition reaction. The Diels-Alder reactions are performed in a diglyme solution in the presence of a catalytic amount of boron trifluoride etherate. Subsequent quenching of the Lewis acid, addition of 0.3% of [Rh(dppp)2Cl] and heating to reflux achieves the ensuing decarbonylation to afford the product cyclohexenes. Under these conditions, acrolein, crotonaldehyde and cinnamaldehyde have been reacted with a variety of 1,3-dienes to afford cyclohexenes in overall yields between 53 and 88%. In these transformations, the three aldehydes serve as equivalents of ethylene, propylene and styrene, respectively.     

Biocatalytic approaches to hetero-Diels-Alder adducts of carbonyl compounds

Very little information is available on hetero-Diels-Alderases for the assembly of heterocyclic products despite the synthetic value of these [4+2] cycloadditions. Hetero-Diels-Alderase antibodies raised against a bicyclic transition state analogue have been generated for the cycloaddition of ethylglyoxylate with an all-carbon diene. More recently, a conceptually novel biocatalytic approach to hetero-Diels-Alder (HDA) adducts derived from carbonyl dienophiles has been developed mirroring a stepwise aldol Michael mechanism instead of a concerted pathway. In this approach, the two key steps are an antibody-mediated kinetic resolution of beta-hydroxyenones and a subsequent ring-closure process. An attractive feature of this methodology is the possibility to convert the enantioenriched aldol intermediates into tetrahydropyranones or dihydropyranones. This bioorganic route is best applied for the preparation of enantioenriched HDA adducts derived from poorly electrophilic acceptors, therefore complementing existing catalytic routes to these adducts based on the use of small organocatalysts or chiral Lewis acids.     

Uranium iodides as catalysts for Diels–Alder reactions

Uranium triiodide is found to be an efficient Lewis acid catalyst for various Diels–Alder reactions which are performed in mild conditions and with low amounts of catalysts. The replacement of an iodide by a dihydrobis(pyrazolyl)borate ligand does not increase activity or selectivity.     

(R)-bis-Binaphthoxy iodo lanthanides as catalysts for Diels–Alder reactions

[(R)-1,1′bi-2,2′-Naphthoxy]LnI(THF)₂ (Ln: Yb, Sm, La) 5 have been prepared by reaction of the bispotassium salt of (R)-binaphthol with lanthanide triiodides, and characterized. They are active catalysts for Diels–Alder reactions although with low asymmetric inductions. The lanthanum iodo bisbinaphthoxide gives a slightly higher enantiomeric excess than the two other complexes.     

Bifunctional Schiff base/Ti(IV) catalysts for enantioselective cyanoformylation of aldehydes with ethyl cyanoformate

A new bifunctional titanium/Schiff base catalyst was developed for the enantioselective cyanoformylation of aldehydes with ethyl cyanoformate. The reaction proceeded smoothly with a mild reaction condition to afford the cyanohydrin ethyl carbonates in high yields (up to 96%) and good enantioselectivities (up to 85% enantiomeric excess). Copyright © 2013 John Wiley & Sons, Ltd.     

Self-supported heterogeneous titanium catalysts for enantioselective carbonyl-ene and sulfoxidation reactions

A new strategy for the heterogenization of chiral titanium complexes was developed by the in situ assembly of bridged multitopic BINOL ligands with [Ti(OiPr)4] without using a support. The assembled heterogeneous catalysts (self-supported) showed excellent enantioselectivity in both the carbonyl-ene reaction of alpha-methylstyrene with ethyl glyoxylate (up to 98 % ee) and the oxidation of sulfides (up to >99 % ee). The catalytic performance of these heterogeneous catalytic systems was comparable or even superior to that attained with their homogeneous counterparts. The spacers between the two BINOL units of the ligands in the assembled catalysts had significant impact on the enantioselectivity of the carbonyl-ene reaction. This demonstrates the importance of the supramolecular structures of the assemblies on their catalytic behavior. In the catalysis of sulfoxidation, the self-supported heterogeneous titanium catalysts were highly stable and could be readily recycled and reused for over one month (at least eight cycles) without significant loss of activity and enantioselectivity (up to >99.9 % ee). The features of these self-supported catalysts, such as facile preparation, robust chiral structure of solid-state catalysts, high density of the catalytically active units in the solids, as well as easy recovery and simple recycling, are particularly important in developing methods for the synthesis of optically active compounds in industrial processes.     

Ruthenium-Lewis acid catalyzed asymmetric Diels-Alder reactions between dienes and alpha,beta-unsaturated ketones

The complex [Ru(Cp)(R,R-BIPHOP-F)(acetone)][SbF(6)], (R,R)-1 a, was used as catalyst for asymmetric Diels-Alder reactions between dienes (cyclopentadiene, methylcyclopentadiene, isoprene, 2,3-dimethylbutadiene) and alpha,beta-unsaturated ketones (methyl vinyl ketone (MVK), ethyl vinyl ketone, divinyl ketone, alpha-bromovinyl methyl ketone and alpha-chlorovinyl methyl ketone). The cycloaddition products were obtained in yields of 50-90 % and with enantioselectivities up to 96 % ee. Ethyl vinyl ketone, divinyl ketone and the halogenated vinyl ketones worked best and their reactions with acyclic dienes consistently provided products with >90 % ee. alpha-Chlorovinyl methyl ketone performed better than alpha-bromovinyl methyl ketone. The reaction also provided a [4.3.1]bicyclic ring system in 95 % ee through an intramolecular cycloaddition reaction. Crystal structure determinations of [Ru(Cp)((S,S)-BIPHOP-F)(mvk)][SbF(6)], (S,S)-1 b, and [Ru(Cp)((R,R)-Me(4)BIPHOP-F)(acrolein)][SbF(6)], (R,R)-2 b, provided the basis for a rationalization of the asymmetric induction.