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.     

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.     

Diastereoselective synthesis of the top half of kijanolide

A highly diastereoselective synthesis of the top half (4) of kijanolide is described. The key step is the exo and diastereoface selective Diels-Alder reaction of triene 6 and chiral dienophile 6.     

Dienophile twisting and substituent effects influence reaction rates of intramolecular Diels-Alder cycloadditions: a DFT study

Intramolecular cycloadditions of 5-vinyl-1,3-cyclohexadienes were studied with B3LYP/6-31G(d) density functional calculations. The one-atom tether dictates that the Z substituent becomes exo and the E substituent becomes endo in the TS. The geometry of the cycloaddition TS is typical of a pericyclic transformation except unusual twisting of the dienophile places the endo substituent in a relatively steric-free position and the exo substituent in a highly crowded position. The experimental rate differences between isomeric pairs of vinylcyclohexadienes can be explained by comparing reactant destabilization when a bulky group occupies the Z position of the starting alkene and transition state stabilization when a bulky group is endo in the cycloaddition TS.     

Intramolecular Diels-Alder reactions using alpha-methylene lactones as dienophile

Several dienals were prepared and reacted in the presence of zinc metal with ethyl 2-bromomethylacrylate to provide in a Reformatsky-like reaction alpha-methylene lactones carrying a dienyl side chain. Thermolysis of these compounds (11, 21, 29, and 37) gave in an intramolecular Diels-Alder reaction the corresponding tricyclic cycloadducts (51, 52, 53, and 54). The cycloadditions took place with good diastereoselectivity and yields. The stereochemistry of the major isomer is in accordance with an endo transition state for cycloadducts 51, 52, and 54. In one instance (compound 58), the structure was supported by X-ray crystallography. In contrast to the other substrates, the nonatriene 29 cyclized to the exo product 53exo. The stereochemical situation could also be proven by NOESY NMR. However, the intramolecular Diels-Alder reaction did not work with furan as dienophile (compound 41) and substrate 50 featuring a densely functionalized tether connecting diene and alpha-methylene lactone.     

Exo selective enantioselective nitrone cycloadditions

We have developed a novel method for accessing exo adducts with high enantioselectivity in nitrone cycloadditions to enoates. Pyrazolidinones proved to be effective achiral templates in the cycloadditions, providing exo adducts typically in >15:1 selectivity and 90-98% ee. The use of Lewis acids that form square planar complexes, such as copper triflate, was important for obtaining high exo selectivity.     

Intramolecular Diels-Alder reactions of ester linked 1,3,9-decatrienes: cis/trans selectivity in thermal and Lewis acid promoted reactions of ethylene-tethered and benzo-tethered systems

High cis (i.e., endo) diastereoselectivities are witnessed in heat-promoted intramolecular Diels-Alder (IMDA) reactions of ethylene-tethered hexadienyl acrylates. The cis stereoselectivity is improved by promotion with Et2AlCl. The first examples of Et2AlCl catalyzed intramolecular Diels-Alder reactions of ester-activated dienophiles are reported. In contrast, the corresponding benzo-tethered hexadienyl acrylates undergo moderately trans (i.e., exo) selective IMDA reactions. Very high trans stereoselection is obtained upon promotion with ATPH. The outcomes of these reactions are essentially insensitive to dienophile (C10) geometry and substitution. DFT (B3LYP/6-31+G(d)) computed cis/trans product distributions-based on Boltzmann transition structure populations-are in good agreement with the experimental results. These computational investigations provide useful insights into the origins of stereoselection in these systems. The stereoselectivity exhibited by the ethylene-tethered hexadienyl acrylates is ascribed to stabilizing secondary orbital interactions at play in the cis-transition structures (TSs). In the benzo-tethered series, this effect is overridden by stabilizing pi-conjugative interactions, between the benzo moiety and the 1,3-diene component, which are stronger in trans TSs, compared to the cis TSs. The computed TS geometries generally exhibit advanced peripheral bond forming asynchronicity, with the tether carbonyl group in conjugation with the dienophile. Such TS features significantly weaken the stereodirecting influence of terminal dienophile substituents.     

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.     

Reversal of facial selectivity in complex Diels-Alder reactions

A complex Diels-Alder reaction between a semi-cyclic diene with allylic silyloxy substituents and a bromo enone presented an unusual diastereoselectivity: attack of the diene occured on its more hindered face, and this reversal of selectivity was shown to be induced by the presence of a bromo substituent in the dienophile.     

Ring closing enyne metathesis: control over mode selectivity and stereoselectivity

Ring closing enyne metathesis to form 10-15-membered rings was achieved by using a tartrate-derived linker to attach ene and yne subunits. The exo/endo selectivity of the ring closure reaction of these substrates was found to be a function of ring size, whereby larger rings (12-15) give endo-products selectively, while smaller rings (5-11) give exo-products. The E/Z selectivity of the resultant macrocyclic 1,3-dienes was not predictable except for 10- and 11-membered rings. However, both the exo/endo-mode selectivity of the ring closure and the E/Z selectivity of the 1,3-dienes were improved by performing these reactions under ethylene atmosphere. The presence of ethylene induces a selective cross metathesis between the alkyne moiety and ethylene to generate an acyclic 1,3-diene which can undergo ring closing diene metathesis between the isolated olefin and the distal monosubstituted double bond of the 1,3-diene to generate exclusively the endo-product with high E-selectivity.     

Asymmetric Diels-Alder reactions of a nitroso compound derived from D-bornane-10,2-sultam

Acylnitroso dienophile 3 derived from D-bornane-10,2-sultam undergoes cycloaddition with high yields and complete facial selectivity to cyclopentadiene and cyclohexadiene. When the nitroso group is attached to the sultam nitrogen, it is no longer reactive in Diels-Alder reactions.     

Rate acceleration and subsequent retardation of Diels-Alder reactions in LiClO4-diethyl ether: an experimental investigation.

The experimental kinetic data for several Diels-Alder reactions show why a 5 M LiClO(4)-diethyl ether (LPDE) solution offers maximum enhancement of reaction rates, endo/exo ratios, and yields. These reactions, if carried out in LPDE solutions of concentrations higher than 5 M, show a substantial decrease in these kinetic parameters. This decrease is attributed to the very high viscosity of LPDE solutions near saturation, though this interpretation is not consistent when considered in terms of sizes of the diene and dienophile. The monoetherates, dietherates, and higher other clusters in LPDE solutions and their relationship with the Lewis acid catalysis by Li+ offer a more plausible explanation of both the enhancement and the decrease of the rate of Diels-Alder reactions in this medium.     

exo-selective asymmetric Diels-Alder reaction catalyzed by diamine salts as organocatalysts

[reaction: see text] A novel binaphthyl-based diamine (R)-2 was designed and synthesized. A protonic acid-(R)-2 salt catalyst has the advantage of exhibiting unprecedented high exo selectivity in the asymmetric Diels-Alder reaction of alpha,beta-unsaturated aldehydes. For instance, the reaction between cinnamaldehyde and cyclopentadiene in the presence of 12 mol % of binaphthyl-based diamine (R)-2 and 10 mol % of p-TsOH.H(2)O in alpha,alpha,alpha-trifluorotoluene at -20 degrees C gave the corresponding exo cycloadduct with 92% ee as a major diastereomer (exo/endo = 13/1).     

1,3-dipolar cycloadditions of diazoalkanes to activated sulfoxides: influence of Lewis acids

[reaction: see text] The reactions of diazomethane and diazoethane with (S)-3-p-tolylsulfinylfuran-2(5H)-one (3) and its 4-methyl derivative (4) have been studied. The sulfinyl group was able to completely control the pi-facial selectivity of all these reactions, which decreased when the polarity of the solvent increased and could be inverted in the presence of Lewis acids, Yb(OTf)(3) being the most efficient catalyst. This behavior made possible the stereodivergent synthesis of diastereoisomeric pyrazolines in almost quantitative yields and de's higher than 98%. The endo/exo selectivity was also complete in reactions of 3 with diazoethane, whereas 4 afforded an easily separable 1:1 mixture of diastereoisomers. Steric factors accounts for the endo/exo selectivity, whereas electrostatic interactions must also be considered to explain the facial selectivity.     

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.     

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.     

Diastereo-controlled Diels–Alder cycloadditions of erythrose benzylidene-acetal 1,3-butadienes by 4-substituted-1,2,4-triazoline-3,5-dione: Evidence for the stereoelectronic effects on the dienes

Erythrose benzylidene-acetal 1,3-butadienes are studied as partners in Diels–Alder cycloadditions. A high diastereofacial improvement is found in cases where both the alcohol function is protected and a π–π interaction between the diene and dienophile is possible. Several competing factors have been studied independently in order to explain its influence on the selectivity of the cycloadditions.     

Practical synthesis and Diels-Alder chemistry of [4]dendralene

Spectacular new atom efficient domino cycloaddition sequences involving [4]dendralene, the simplest cross-conjugated tetraene, are reported. Up to eight stereocenters, three new rings, and six C-C bonds are generated in one synthetic operation. The site selectivity of dienophile addition to cross-conjugated trienes and tetraenes is controlled with a simple Lewis acid.     

(Z)-3-p-tolylsulfinylacrylonitrile as a chiral dienophile: diels-alder reactions with furan and acyclic dienes

The behavior of (Z)-3-p-tolylsulfinylacrylonitrile (1) as a chiral dienophile has been evaluated from its reactions with furan and acyclic dienes. Electrostatic interactions of the cyano group with the sulfinyl one restrict the conformational mobility around the C-S bond, thus controlling the pi-facial selectivity, which is almost complete in all cases, the approach of the diene from the less-hindered face of the dienophile (that bearing the lone electron pair) in the predominant rotamer being the favored one. The regioselectivity is also completely controlled by the cyano group. Additionally, the reactivity of compound 1 as well as its endo-selectivity are both higher than those observed for the corresponding (Z)-3-sulfinylacrylates, thus proving the potential of sulfinylnitriles as chiral dienophiles.