Investigation of the asymmetric ionic Diels-Alder reaction for the synthesis of cis-decalins

The ionic Diels-Alder reaction, whereby an alpha,beta-unsaturated acetal in combination with a Lewis or Bronsted acid forms an equilibrium concentration of an activated dienophile, has been developed to provide an enantioselective synthesis of cis-decalins. Cyclohex-2-enone type chiral acetals of (2R,3R)-butane-2,3-diol have been screened against Lewis and Br?nsted acids with a variety of dienes and are efficient for the synthesis of a limited subset of cis-decalin structures. Diastereoselectivities of 73% and 82% have been found for the asymmetric ionic Diels-Alder reaction between the chiral acetal derivatives of cyclohex-2-enone (6) and 2-methylcyclohex-2-enone (18) with 2,3-dimethyl-1,3-butadiene (7). Terminal substituents on the diene partner in general render the system unreactive. However a synthetically useful cis-decalin 31, derived from the reaction of 2-methylcyclohex-2-enone and Z-3-t-butyldimethyl-silyloxypenta-1,3-diene has been prepared in enantiomerically pure form in 74% isolated yield using this asymmetric ionic Diels-Alder protocol.     

Viscosity dependence of intra- and intermolecular Diels-Alder reactions

The kinetics of the bimolecular Diels-Alder reaction between anthracene-9-carbinol and N-ethyl maleimide have been studied in a series of pyridinium-based ionic liquids with the tetrafluoroborate ([BF(4)](-)) and the bis(trifluorosulfonimide) ([NTf(2)](-)) anions and the viscosity dependence of the rate constants have been compared with the results for the intramolecular Diels-Alder reaction of (E)-1-phenyl-4-[2-(3-methyl-2-butenyloxy)benzylidene]-5-pyrazolone. The comparison leads to the surprising observation that the intermolecular reaction is less susceptible to viscosity variations of the ionic liquids as compared to the intramolecular reaction. The observed similarities and differences emphasize the complicated nature of solvent friction on the kinetics of cycloaddition reactions. The results are explained by considering the bimolecular and intramolecular processes as cases of translational and rotational diffusion, respectively. Plausible indicators of microviscosity consistent with the kinetic data for the Diels-Alder reactions are briefly discussed along with the constraints involved in designing a general microviscosity scale.     

On the Diels-Alder reactions of pentadienyl maleates and citraconates

Reactions between conjugated dienols and maleic anhydride provide either cis-fused or trans-fused bicyclic products as major products, depending upon how the reaction is carried out. Simply mixing the two reactants together generally leads to cis-fused lactone acids in thermal reactions which proceed viaintermolecular Diels-Alder reaction followed by intramolecular esterification. Pre-forming the maleate half ester derivative followed by heating affords predominantly trans-fused lactone acids in good yields by way of an intramolecular Diels-Alder (IMDA) reaction. Sorbyl citraconate half esters undergo a rapid thermolytic fragmentation in refluxing toluene to form the dienol and citraconic anhydride. The resulting diene-dienophile pair undergo an intermolecular cycloaddition followed by a rapid intramolecular esterification to give cis-fused bicyclic lactone acids as major products. The IMDA reaction of citraconic half esters is sufficiently rapid in DMSO to dominate over fragmentation: the exo-cycloadduct is formed almost exclusively. Nine literature reports of endo-selective IMDA reactions of triene acids are erroneous; the cycloadditions proceed in an intermolecular manner.     

Reactive dienes: intramolecular aromatic oxidation of 3-(2-hydroxyphenyl)-propionic acids

[reaction: see text] Treatment of 3-(2-hydroxyphenyl)-propionic acids with a hypervalent iodine reagent in the presence of a dienophile initiates a tandem intramolecular aromatic oxidation/Diels-Alder reaction. Herein we report (1) investigations on the scope and limitations of this novel reaction combination and (2) preliminary diastereoselectivity studies using alpha- and beta-substituted acids.     

Stereoselective ketal-tethered intramolecular diels-alder cycloadditions. An approach to the 2-oxadecalin spiroketal core of antifungal agent fusidilactone C

[reaction: see text] An approach toward the 2-oxadecalin spiroketal core of fusidilactone C via a rare ketal-tethered intramolecular Diels-Alder cycloaddition is described here. This intramolecular Diels-Alder cycloaddition is highly endo-selective and overall depended upon the nature of solvents and Lewis acids. We also observed some remarkable rate acceleration in MeOH.     

A New Intramolecular Reaction for the Regioselective Debenzylation or Protection of Alcohols

Strained benzylidene acetals such as 1 can be prepared with a new intramolecular reaction that allows the selective removal of benzyl protecting groups neighboring free OH groups, without attacking other benzyl groups. The mechanism of this reaction, which is useful for carbohydrate synthesis, probably proceeds via ionic intermediates with neighboring group participation.     

Remote asymmetric induction in an intramolecular ionic Diels-Alder reaction: application to the total synthesis of (+)-dihydrocompactin

The total synthesis of (+)-dihydrocompactin via an intramolecular ionic Diels-Alder reaction that proceeds with remote stereocontrol is described. This reaction proceeds by an intermediate vinyl-oxocarbenium ion (6), the conformational constraints of which lead to the observed asymmetric induction. The sense of asymmetric induction appears contrasteric and is explained by the proposed reactive conformation shown in Figure 1.     

Asymmetric synthesis of the hydronaphthalene moieties of mevinic acids

The hydronaphthalene moieties of mevinic acids are synthesized enantioselectively by using the asymmetric intramolecular Diels-Alder reaction catalyzed by a chiral titanium reagent.     

A mechanistic study on the intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol and 2,11-dimethyl-1,3,9,11-dodecatetraene

Intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol (1) was studied under acidic conditions. Treatment of 2-methyl-3,9,11-tridecatriene-2-ol (1) with trifluoromethanesulfonic acid yielded 7-methyl-8-isopropenyl-1,2,3,4,4aR^∗,7R^∗,8R^∗,8aS^∗-octahydronaphthalene (4) and (1Z)-1-((E)-but-2-enylidene)-2-(2-methylpropenyl)cyclohexane (5) through regioselective intramolecular ionic Diels-Alder reaction. The reaction appeared to proceed partly through a stepwise mechanism involving a carbocation intermediate. However, a concerted pathway rather than a stepwise one is suggested to be involved in the acid-catalyzed intramolecular Diels-Alder reaction of 2,11-dimethyl-1,3,9,11-dodecatetraene (13).     

Cyclic allene intermediates in intramolecular dehydro Diels-Alder reactions: labeling and theoretical cycloaromatization studies

A comprehensive theoretical and experimental investigation of dehydro Diels-Alder reactions examining the evolution of the cyclic allene intermediates under conditions for intramolecular and ionic and radical intermolecular cycloaromatization processes is reported. Theoretical calculations showed that the most favored intramolecular path for cycloaromatization of 1,2,4-cyclohexatriene 4 and its benzoannulated derivative 14, strained cyclic allenes, consists of a pair of successive [1,2] H shifts rather than a [1,5] shift. Cycloaromatization of cyclic allenes may follow both inter- and intramolecular pathways, depending on the experimental conditions (use of protic or aprotic solvents). For synthetic purposes, the best procedure is to use a protic solvent to promote the ionic intermolecular route, the fastest and highest yielding. When the reaction is carried out in CCl4, intermolecular radical addition of chlorine to the cyclic allene competes with intramolecular aromatization paths. Theoretical calculations predict a low barrier for the reaction of cyclic allenes with carbon tetrachloride, and that the cyclic allenes act as nucleophiles in this reaction.     

Conversion of 2-alkylcinnamaldehydes to 2-alkylindanones via a catalytic intramolecular Friedel-Crafts reaction

The preparation of indanones by the intramolecular acylation of 3-arylpropanoic acids or halides requires the use of noncatalytic acid promoters. In the presence of 5-10 mol % FeCl(3), in situ generated dimethyl acetals of (E)-2-alkylcinnamaldehydes cyclize to 1-methoxy-2-alkyl-1H-indenes in good-to-high yields. The 1-methoxyindenes were converted in high yield into 2-alkylindanones by treatment with triethylamine, to effect isomerization to the isomeric enol ethers, followed by acid-catalyzed hydrolysis. Thus, a catalytic, intramolecular Friedel-Crafts reaction leading to 2-alkylindanones from 2-alkylcinnamaldehydes was developed.     

Thermal and palladium-catalyzed [3 + 2] synthesis of cyclopentadienone acetals from cyclopropenone acetals and acetylenes

[reaction: see text] Substituted cyclopentadienone acetals (CPDAs) were synthesized by a thermal or palladium-catalyzed [3 + 2] cycloaddition reaction of a substituted cyclopropenone acetal to an electron-deficient acetylene. The synthesis afforded di-, tri-, and tetra-substituted CPDAs of considerable structural varieties that undergo Diels-Alder reaction to produce bicyclo[2.2.1]heptenes.     

Intramolecular Diels-Alder reaction in ionic liquids: effect of ion-specific solvent friction

The present work aims at understanding the role of viscosity or solvent friction in ionic liquids for an intramolecular Diels-Alder (IMDA) reaction of (E)-1-phenyl-4-[2-(3-methyl-2-butenyloxy)benzylidene]-5-pyrazolone (1). The results have been analyzed on the basis of the current theoretical models, and their failure to account for the observed trends is discussed in terms of "effective" viscosity or microviscosity. The rates of the reaction decrease with the increasing viscosity of the ionic liquids. As evident from the anionic effect, the solute-solvent specific interactions play a role in governing the kinetics of the reaction. The lower viscosities of the bistrifluoromethanesulfonimide [NTf2](-) based ionic liquids as compared to those based on tetrafluoroborate [BF4](-) anion fail to result in a corresponding acceleration in the rates of the reaction. These contradictory results indicate that solvent microviscosity, rather than the bulk macroscopic viscosity, should be the criteria for selecting the ionic liquids as reaction media.     

Development of efficient Lewis acid catalysts for intramolecular cycloaddition reactions of ester-tethered substrates

We have developed novel bidentate Lewis acids that efficiently promote the intramolecular cycloaddition reactions of ester-tethered substrates. Bis-aluminated triflic amide derivatives [TfN(AlR(1)R(2))2], which are generated by simply mixing triflic amide and 2 equiv of methyl aluminum or aluminum hydride, catalyzed intramolecular Diels-Alder (DA) reactions of ester-tethered 1,7,9-trienes and intermolecular DA reactions of alpha,beta-unsaturated lactones. We also found that bimetallic Lewis acid derived from 1,1'-biphenyl-2,2'-di(triflyl)amide and dimethylaluminum chloride promoted the intramolecular [3 + 2] cycloaddition reaction of acrylate derivatives having an allylsilane part.     

Copper(II)-catalyzed room temperature aerobic oxidation of hydroxamic acids and hydrazides to acyl-nitroso and azo intermediates, and their Diels-Alder trapping

CuCl(2), in the presence of a 2-ethyl-2-oxazoline ligand, is an effective catalyst for the room temperature, aerobic oxidation of hydroxamic acids and hydrazides, to acyl-nitroso and azo dienophiles respectively, which are efficiently trapped in situ via both inter- and intramolecular hetero-Diels-Alder reactions with dienes. Both inter- and intramolecular variants of the Diels-Alder reaction are suitable under the reaction conditions using a variety of solvents. Under the same conditions, an acyl hydrazide was also oxidized to give an acyl-azo dienophile which was trapped intramolecularly by a diene.     

Hosomi-Sakurai reactions of silacyclohexenes

Silacyclic allyl silanes, derived from silene-diene Diels-Alder reactions, combine with acetals in the presence of Lewis acids to afford, following oxidation of the intermediate fluorosilane, either butane-1,4-diols or tetrahydronaphthalenes containing four contiguous chiral centres with moderate to good diastereoselectivity.     

Synthesis of Antitumor Lycorines by Intramolecular Diels-Alder Reaction

Pharmacologically interesting lycorines were obtained by a short, efficient method based on an intramolecular Diels-Alder reaction between an alpha-pyrone and an alkyne, followed by loss of CO(2) in a retro Diels-Alder reaction. The cyclization precursors (pyrones 9) were obtained in good yields in two or three steps from the corresponding homophthalic acid or anhydride.     

Intramolecular Diels-Alder reactions using chiral ruthenium Lewis acids and application in the total synthesis of ent-ledol

One-point binding chiral ruthenium Lewis acids incorporating the C(2)-symmetric electron-poor bidentate phosphinite ligand BIPHOP-F and a Cp or an indenyl 'roof' can efficiently catalyze asymmetric intramolecular Diels-Alder reactions of trienes to form bicyclic adducts with good to excellent asymmetric induction. This reaction forms the key step in a total synthesis of ent-ledol in 96% ee. The synthesis also helps to clarify the stereochemical assignment of ledol and inconsistencies in the measured optical rotation.     

A new 3-(phenylseleno)allylic cation: its regioselective C-C bond formation reaction with nucleophiles

Highly useful C-C bond formation using 2-ethoxy-3-(phenylseleno)prop-2-enal acetal 2 was examined with various Lewis acids. The reaction of 2 with the silyl enol ether in the presence of BF(3)*Et2O, ZnBr2, or SnBr4 regioselectively provided (Z)-3,4-diethoxy-5-(phenylseleno)pent-4-enophenone 5a in high yields. On the other hand, the reaction with other Lewis acids such as EtAlCl2 or SnCl4 gave 5-(phenylseleno)- 6 or non-selenopentane-1,4-dione 7, respectively. Novel prop-2-enal acetals 2-4 and 13-15 reacted with various nucleophiles to give pent-4-enophenones 5a,b, 10a, 12, and 16-18, S-ethyl pent-4-enoate 5b, alkylated vinylic sulfide 10b, 3-pentenenitrile 5d, and 10c. A versatile pent-4-enophenone 5a could be converted to tetrahydrofuran 20 and penta-2,4-dienophenone 19, the Diels-Alder reactions of which with dienophiles gave the adducts 24 and 25.     

Coupling reactions of alpha-bromoalkenyl phosphonates with aryl boronic acids and alkenyl borates

[reaction: see text] Transition metal-catalyzed arylation and alkenylation of the alpha-bromoalkenyl phosphonates were investigated with organoboranes and -borates. Arylation was successful with the aryl boronic acids and a palladium catalyst, while alkenylation was found to proceed with alkenyl borates and a nickel catalyst. In addition, an intramolecular Diels-Alder reaction of the diene prepared by the alkenylation afforded the corresponding adduct.