The role of the sulfinyl group on the course of the reactions of 3-p-tolylsulfinylfuran-2(5H)-ones with nitrones. synthetic uses of cycloreversion processes

[reaction: see text] The reaction of enantiopure 3-p-tolylsulfinylfuran-2(5H)-ones (2a and 2b) with cyclic (4) and acyclic (6) nitrones afforded furoisoxazolidines (5 and 7) in high yields under mild conditions. The reactivity of the dipolarophile was dramatically enhanced by the sulfinyl group, which modulated the pi-facial selectivity (it was complete for reactions from 2b, yielding only the anti adducts) and was the main controller of the endo/exo selectivity. Cycloreversion processes from the resulting sulfinyl furoisoxazolidines proceeded readily and were to be considered to account for an improvement in the selectivity (facial and endo/exo) and even for an inversion of it when the composition of the reaction mixtures obtained under kinetic and thermodynamic conditions were quite different.     

The role of steric and electronic interactions in the stereocontrol of the asymmetric 1,3-dipolar reactions of 5-ethoxy-3-p-(S)-tolylsulfinylfuran-2(5H)-ones with diazoalkanes: theoretical calculations and experimental evidences

The addition of diazomethane and diazoethane to (5S,SS)- and (5R,SS)-5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones (1a and 1b) and their 4-methylderivatives (2a and 2b) proceeded in almost quantitative yields and complete regioselectivity. The observed pi-facial selectivity is determined by the configurations at both C-5 and the sulfinyl group, the later being the most important. The syn adducts were almost exclusively obtained from 1a and 2a in apolar solvents but the pi-facial selectivity was strongly decreased in more polar solvents. On the other hand, the major adducts from 1b and 2b were the anti ones and such predominance was slightly increased with solvent polarity. The exo-selectivity was complete in all the cases except for the anti approach to compounds 2a (in polar solvents) and 2b. The role of the sulfinyl group in this behavior was inferred by comparison of these results with those obtained in reactions of diazoalkanes with 5-methoxyfuran-2(5H)-one (3). Steric interactions seem to be the main ones responsible for the observed exo selectivity of reactions with diazoethane, but electronic factors, which can be modulated by the solvent, are also significant in the pi-facial selectivity control. DFT computational methods are able to correctly predict the reactivity, regioselectivity, and pi-facial selectivity exhibited by 5-alkoxyfuranones as well as their changes with the solvent polarity. A C-H.O hydrogen bond, involving the oxygen atom of the 5-alkoxy group at dipolarophiles and the endo-hydrogen atom at dipoles, seems to play a key role in the electronic interactions influencing the stereochemical course of these reactions.     

Origins of stereoselectivity in the Diels-Alder addition of chiral hydroxyalkyl vinyl ketones to cyclopentadiene: a quantitative computational study

Modest basis set level MP2/6-31G(d,p) calculations on the Diels-Alder addition of S-1-alkyl-1-hydroxy-but-3-en-2-ones (1-hydroxy-1-alkyl methyl vinyl ketones) to cyclopentadiene correctly reproduce the trends in known experimental endo/exo and diastereoface selectivity. B3LYP theoretical results at the same or significantly higher basis set level, on the other hand, do not satisfactorily model observed endo/exo selectivities and are thus unsuitable for quantitative studies. The same is valid also with regard to subtle effects originating from, for example, conformational distributions of reactants. The latter shortcomings are not alleviated by the fact that observed diastereoface selectivities are well-reproduced by DFT calculations. Quantitative computational studies of large cycloaddition systems would require higher basis sets and better account for electron correlation than MP2, such as, for example, CCSD. Presently, however, with 30 or more non-hydrogen atoms, these computations are hardly feasible. We present quantitatively correct stereochemical predictions using a hybrid layered ONIOM computational approach, including the chiral carbon atom and the intramolecular hydrogen bond into a higher level, MP2/6-311G(d,p) or CCSD/6-311G(d,p), layer. Significant computational economy is achieved by taking account of surrounding bulky (alkyl) residues at 6-31G(d) in a low HF theoretical level layer. We conclude that theoretical calculations based on explicit correlated MO treatment of the reaction site are sufficiently reliable for the prediction of both endo/exo and diastereoface selectivity of Diels-Alder addition reactions. This is in line with the understanding of endo/exo selectivity originating from dynamic electron correlation effects of interacting pi fragments and diastereofacial selectivity originating from steric interactions of fragments outside of the Diels-Alder reaction site.     

Diastereoselective Diels-Alder reactions of N-sulfonyl-1-aza-1,3-butadienes with optically active enol ethers: an asymmetric variant of the 1-azadiene Diels-Alder reaction

The first detailed study of a room-temperature asymmetric Diels-Alder reaction of N-sulfonyl-1-aza-1,3-butadienes is reported enlisting a series of 19 enol ethers bearing chiral auxiliaries, with many providing highly diastereoselective (endo and facial diastereoselection) reactions, largely the result of an exquisitely organized [4+2] cycloaddition transition state. Three new, readily accessible, and previously unexplored auxiliaries rationally emerged from the studies and provide remarkable selectivities (two of these give 49:1 endo:exo and 48:1 facial selectivity) that promise to be useful in systems beyond those detailed.     

Optically active 1,2-bis(1-arylhydroxymethyl) ferrocene: a new, efficient chiral ligand for scandium-catalyzed asymmetric Diels-Alder reaction

[reaction: see text] The Sc(OTf)3/FERRODIOL (2) complex was prepared at -78 degrees C in CH2Cl2 in the presence of 2,6-lutidine and MS 4A. The chiral scandium Lewis acid-catalyzed asymmetric Diels-Alder reaction of cyclopentadiene (3) with 3-acyloxazolidin-2-ones (4) effectively produced the adduct (5) in a high yield with good selectivity, i.e., endo/exo = 90:10 up to 91% ee (endo).     

Counterions of BINAP-Pt(II) and -Pd(II) complexes: novel catalysts for highly enantioselective Diels-Alder reaction

[formula: see text] Platinum and palladium chiral bisphosphine complexes and their counterion effects in asymmetric Diels-Alder reactions have been investigated. The reaction of cyclopentadiene and various bidentate dienophiles in the presence of a catalytic amount of Pt(II)- or Pd(II)-BINAP complex proceeds with excellent endo/exo selectivity as well as endo enantioselectivity (up to 99% ee).     

Diels-Alder reactions of 3-substituted coumarins in water and under high-pressure condition. An uncatalyzed route to tetrahydro-6H-benzo[c]chromen-6-ones

[reaction: see text] Diels-Alder reactions of 3-substituted coumarins 1a-g with methyl-1,3-butadienes 2a-c carried out in water alone and in CH2Cl2 under 9 kbar pressure are reported. In aqueous medium satisfactory results were obtained by operating at 150 degrees C, whereas under high pressure the cycloadditions were complete at 60-70 degrees C with excellent yields (85-95%). The reactions with isoprene (2b) always resulted in the exclusive formation of para cycloadducts, whereas with (E)-piperylene (2c) only ortho products were detected. The cycloaddition of 3-phenylsulfonylcoumarin (1a) with (E)-piperylene (2c) allowed the endo adduct to be obtained exclusively, whereas 3-carboxycoumarin (1b) reacted with 2c to give a mixture of the corresponding endo/exo adducts in a 58:42 ratio in water and in a 45:55 ratio under high-pressure condition.     

Synthesis and Diels-Alder reactions of 4-vinylimidazoles

[structure in text] The synthesis of several 4-vinylimidazoles via Stille cross-coupling reactions of the corresponding protected 4-iodoimidazoles with tributylvinylstannane is described. These heterocyclic dienes are shown to be effective partners in the Diels-Alder reaction, providing adducts in good yield and exhibiting useful levels of isomer selectivity and stereoselectivity (endo/exo).     

Cyclic vinyl p-tolyl sulfilimines as chiral dienophiles: Diels-Alder reactions with furan and acyclic dienes

The dienophilic behavior of the sulfilimine 2, synthesized from (Z)-3-p-tolylsulfinylacrylonitrile 1, in its Diels-Alder reactions with furan and acyclic dienes has been investigated. A complete pi-facial selectivity for 2, opposite to that observed from its precursor 1, is the main feature of all these cycloadditions. Moreover, the high exo selectivity observed in reactions of 2 with furan (not observed for 1) contrasts with the almost complete endo selectivity with other cyclic and acyclic dienes. Additionally, the opposite regioselectivities obtained for 2 with Dane's diene and 1-substituted butadienes (not observed for 1) are also noteworthy. This behavior allows dienophiles 1 and 2 to be considered as complementary precursors from a synthetic point of view.     

Stereoselectivity in Diels-Alder reactions of diene-substituted N-alkoxycarbonyl-1,2-dihydropyridines

Diene substituent effects on the regiochemical and stereochemical outcomes of uncatalyzed Diels-Alder reactions of N-alkoxycarbonyl-1,2-dihydropyridines with both styrene and methyl vinyl ketone (MVK) were studied. Alkyl substitution on the diene in all cases examined resulted in a kinetic preference for 7-endo isomers (7-phenyl 51-96% exo and 7-acetyl 54-96% exo). For both dienophiles, the highest stereoselectivities (>or=89% endo) were observed with 5-methyl or 6-methyl substituents in the dihydropyridine. Theoretical calculations of the energies of gas phase endo and exo transition states at the RHF/3-21G(*) predict that total entropy, DeltaStotal, considerations favor endo cycloadducts for both dienophiles with DHP, while total energy considerations, DeltaEo, favor endo cycloadducts for styrene and exo cycloadducts for MVK. At this level, favored endo-phenyl isomers are correctly predicted for styrene reactions, but the calculation of 7-acetyl exo or endo isomer dominance is diene-substituent-dependent for MVK reactions. The preference for endo addition of MVK to the parent, 5-methyl, and 6-methyl-DHPs was successfully predicted by calculations at the B3LYP/6-31G* theory level.     

Allylic stereocontrol of the intramolecular Diels-Alder reaction

The stereochemical outcome of the intramolecular Diels-Alder reaction of ester-linked 1,3,8-nonatrienes can be controlled by substituents about a stereogenic center attached to C1. The scope and limitations of this approach have been investigated, with variation in substrate structure about the allylic stereocenter and the dienophile. The stereochemical outcomes of these reactions are explained by reference to B3 LYP/6-31G(d) transition structures. New insights into the conformational preferences of allylic alcohol derivatives are reported, results which allow an explanation of the differing levels of pi-diastereofacial selectivity and cis/trans (i.e. endo/exo) selectivity from the reaction.     

Formal intermolecular 4 + 4 approach to cyclooctanoids: 4 + 3 capture of the Nazarov oxyallyl intermediate with simple 1,3-dienes

[reaction: see text] Simple 1,4-dien-3-ones and 1,3-dienes react in the presence of BF(3).OEt(2) via a domino Nazarov electrocyclization/intermolecular [4 + 3]-cycloaddition sequence to furnish keto-bridged cyclooctenes in good yield. Most cases showed high diastereofacial selectivity and/or endo/exo selectivity, and surprising levels of regioselectivity were observed when isoprene was used as the diene partner.     

A computational study of the Diels-Alder reaction of ethyl-S-lactyl acrylate and cyclopentadiene. Origins of stereoselectivity

The eight diastereoisomeric transition structures of the Diels-Alder addition of ethyl-S-lactyl acrylate and cyclopentadiene have been investigated in the gas phase and in solution by HF, MP2, and density functional theory (B3LYP and B3PW91) methods with the 6-31G(d,p) basis set. At all levels of theory used, the s-cis transition structures are more stable than the s-trans ones. The contribution of the s-trans transition structures increases in solution and, although still small, has to be taken in consideration for correct prediction of stereoselectivity. Diastereofacial selectivity is interpreted in terms of electrostatic (weak hydrogen bonding) C=O...H(C) interactions between the carbonyl group(s) of the dienophile and cyclopentadiene in the energetically favored transition structures. Endo/exo reaction selectivity is attributed to positive orbital interactions between the diene and the acrylate carbonyl oxygen in the endo s-cis transition structures. Ab initio methods reproduce well the experimentally observed trends in both endo/exo and diastereofacial selectivity. Density functional calculations in the gas phase correctly reproduce the observed trends in diastereofacial selectivity but single-point MP2 calculations are necessary to reproduce the experimental trend in endo/exo selectivity.     

An experimental and theoretical study of stereoselectivity of furan-maleic anhydride and furan-maleimide diels-alder reactions

The stereoselectivity of the reaction of furan (1) with maleic anhydride (2) and maleimide (3) was studied experimentally and theoretically. Although the two reactions are highly similar with regard to their preference for endo and exo steroisomers, notable differences were experimentally observed and explained on the basis of calculated reaction-free energies and transition-state barriers. The experimental values of rate constants (k(1+2endo) = (1.75 +/- 0.48) x 10(-5); mol(-1) l s(-1); k(1+2exo) = (3.10 +/- 0.55) x 10(-5); mol(-1) l s(-1); k(1+3endo) = (1.93 +/- 0.082) x 10(-5); mol(-1) l s(-1), k(1+3exo) = (1.38 +/- 0.055) x 10(-5); mol(-1) l s(-1) all at 300 K) and the observed reaction course clearly confirm that neither of these reactions are prototypical examples of Diels-Alder [4 + 2] cycloadditions, whose dominant preference is for endo isomers. However, only by comparing their energetics-calculated at the CCSD(T) level of theory-with the analogous reactions involving cyclopentadiene (8) as a diene can these observations be understood. The low thermodynamic stability of furan [4 + 2] adducts opens retro-Diels-Alder reaction channels and overrules the very small kinetic preference (calculated and measured here) of initial formation for endo stereoisomers. On a macroscopic scale "an irregular"-thermodynamically more stable-exo stereoisomer was consequently observed as a dominant species.     

Selectivity in the electron transfer catalyzed Diels-Alder reaction of (R)-alpha-phellandrene and 4-methoxystyrene

Electron transfer catalysis is an effective method for the acceleration of Diels-Alder reactions between two substrates of similar electron density. The dependence of the selectivity of the Diels-Alder reaction between (R)-alpha-phellandrene and 4-methoxystyrene catalyzed by photoinduced electron transfer with tris(4-methoxyphenyl) pyrylium tetrafluoroborate is studied. Despite the fact that the radical ions involved are highly reactive species, complete regioselectivity favoring attack on the more highly substituted double bond is observed. The endo/exo selectivity and the periselectivity between [4 + 2] and [2 + 2] cycloaddition is found to be solvent-dependent. Stereochemical analysis showed that the periselectivity is correlated with the facial selectivity, with attack trans to the isopropyl group leading to the [4 + 2] product and cis attack leading to the formation of the [2 + 2] product. A good correlation between the dielectric constant of the solvent and the endo/ exo ratio is found, but more polar solvents lead to lower periselectivity. The effect of reactant and catalyst concentrations is found to be smaller. These results are rationalized in the context of the relative stability of the ion-molecule complexes and the singly linked intermediate of the reaction.     

Optimising stereoselectivity in intramolecular Diels-Alder reactions of pentadienyl acrylates: synthetic and computational investigations into the "steric directing group" approach

Experimental conditions for the intramolecular cycloaddition of four related pentadienyl acrylates 3, 4, 5 and 6 are reported. In contrast with several previous reports, pentadienyl acrylates do undergo synthetically useful intramolecular Diels-Alder reactions: 3, 4, 5 and 6 cyclise at reasonable rates at temperatures of 132-180 degrees C at atmospheric pressure in moderate to good yields. The stereochemical outcome of each of these reactions was accurately measured and the results are in good agreement with transition structure populations predicted using B3LYP/6-31+G(d) theory. The parent system 3 cyclises with moderate endo selectivity; the presence of either a C5-methyl substituent or a C3-bromine atom results in a slight shift towards the trans-fused exo stereoisomer but--overall--a less selective reaction. The presence of both C3-Br and C5-CH3 substituents results in a marked improvement in stereoselectivity with the exo,lk-product predominating. Interpretation of B3LYP/6-31+G(d) transition structures allows insights into the improvement in stereoselectivity obtained by incorporating a removable "steric directing group" into a 5-methyl-1,3,8-nonatriene precursor.     

Peroxycarbenium-mediated C-C bond formation: applications to the synthesis of hydroperoxides and peroxides

The Lewis acid-mediated reaction of alkene nucleophiles with peroxyacetals provides an effective route for the synthesis of homologated peroxides and hydroperoxides. In the presence of Lewis acids such as TiCl(4), SnCl(4), and trimethylsilyl triflate, peroxyacetals and peroxyketals undergo reaction with allyltrimethylsilane, silyl enol ethers, and silyl ketene acetals to afford homoallyl peroxides, 3-peroxyketones, and 3-peroxyalkanoates, respectively. Reactions of peroxyacetals are Lewis acid dependent; TiCl(4) promotes formation of ethers while SnCl(4) and trimethylsilyl triflate promote formation of peroxides. Lewis acid-promoted reactions of silylated hydroperoxyacetals furnish silylated hydroperoxides, which can be deprotected to homologated hydroperoxides. Hydroperoxyketals undergo Lewis acid-mediated allylation to furnish 1,2-dioxolanes via attack of hydroperoxide on the intermediate carbocation. Lewis acid-mediated cyclization of unsaturated peroxyacetals furnishes 1,2-dioxanes, 1,2-dioxepanes, and 1,2-dioxacanes through 6-endo/exo, 7-endo/endo, and 8-endo/endo pathways. The corresponding reactions involving 6-endo/endo and 5-endo/exo pathways were unsuccessful.     

A DFT study of the domino inter

The molecular mechanism of the domino inter [4 + 2]/intra [3 + 2] cycloaddition reactions of nitroalkenes with enol ethers to give nitroso acetal adducts has been characterized using density functional theory methods with the B3LYP functional and the 6-31G basis set. The presence of Lewis acid catalyst and solvent effects has been taken into account to model the experimental environment. These domino processes comprise two consecutive cycloaddition reactions: the first one is an intermolecular [4 + 2] cycloaddition of the enol ether to the nitroalkene to give a nitronate intermediate, which then affords the final nitroso acetal adduct through an intramolecular [3 + 2] cycloaddition reaction. The intermolecular [4 + 2] cycloaddition can be considered as a nucleophilic attack of the enol ether to the conjugated position of the nitroalkene, with concomitant ring closure and without intervention of an intermediate. For this cycloaddition process, the presence of the Lewis acid favors the delocalization of the negative charge that is being transferred from the enol ether to the nitroalkene and decreases the activation energy of the first cycloaddition. The [4 + 2] cycloaddition presents a total regioselectivity, while the endo/exo stereoselectivity depends on the bulk of the Lewis acid used as catalyst. Thus, for small Lewis acid catalyst, modeled by BH(3), the addition presents an endo selectivity. The [3 + 2] cycloaddition reactions present an total exo selectivity, due to the constraints imposed by the tether. Inclusion of Lewis acid catalyst and solvent effects decrease clearly the barrier for the first [4 + 2] cycloaddition relative to the second [3 + 2] one. Calculations for the activation parameters along this domino reaction allow to validate the results obtained using the potential energy barriers.     

First asymmetric cycloaddition of carbonyl ylides to vinyl sulfoxides and furan-2(5H)-ones

The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)-alpha-diazoacetophenone with enantiomerically pure 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones 1a and 1b afford 4,10-epoxybenzo[4,5]cyclohepta[1,2-c]furan-3,9-diones 6a and 6b, in good or moderate yields and in a completely regioselective way. The pi-facial selectivity is complete for 1a, which only yields anti-6a adducts, and very high for 1b. The endo stereoisomers are favored with respect to the exo ones in both reactions. The sulfinyl group significantly increases the reactivity of the dipolarophile as it has been demonstrated by studying the behavior of 5-methoxyfuran-2(5H)-one (3).