Chiral dienophiles in Diels-Alder reaction

Cinchonine and cinchonidine form esters with their hydroxy functions. Such esters with unsaturated carboxylic acids were used as chiral dienophiles in Diels-Alder reactions (Section D. 1.6.1.1.1.). 

Modifications of these basic materials include the formation of the V-methanesu 1 tonate 36 which has been used for the synthesis of boronates used in allyl transfer reactions39 (Section D. 1.3.3.3.) and the attachment of the compounds to a chloromethylated polystyrene (Merrifield resin)40. The immobilized amino alcohol has been used as a catalyst for the addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.). 2,/ -Unsaturated dihvdrooxazoles have been prepared from such amino alcohols by reaction with imino ethers41 and used as chiral dienophiles in Diels-Alder reactions (Section D. 1.6.1.1.1.2.2.1.1.). 

The intermediate sulfonimide derived from saccharin by addition of an alkyllithium compound is also the starting material for sultams mimicking the behavior of camphorsultams. The sultams arc readily obtained from, e.g., 3-methylbenzisothiazole 1,1-dioxide, by ruthenium-catalyzed enantioselective reduction, using BINAP as a chiral ligand, in enantiomerically pure form 79. Thus, both enantiomers can be obtained by using the appropriate enantiomer of the control ligand. Like the camphorsultams, the saccharin derivatives readily form amides with carboxylic acids which can be alkylated via the carbanion (Section D.1.1.1.3.1.) or, if unsaturated carboxylic acids are used, may react as chiral dienophiles in Diels—Alder reactions (Section D.l.6.1.1.1.). 

Compound 817 behaves as an excellent chiral dienophile in Diels-Alder reactions. In three selected cases, reaction of 817 with an appropriate butadiene affords adduct 818 with high endo selectivity (Scheme 118). 

Amino-subsdnued dienes are also important dienophiles in Diels-Alder reactions Recently, chiral and achiral 2-amino-l,3-dienes have been prepared to snidy their reactivity Csee also asymmetric Diels-Alder reaction Section 8 1 2 The reaction of 2,3-diamino-l,3-butadienes v/ith nitrostyrene gives unusual [3t-2 carbocyclization products, 2-aminocyclopentanones, which are not formed by the direct cycloaddidon but derived from the Michael addidon products fsee secdon discussing the Michael addidon Secdon 4 1 3 "... 

As we have shown, the sulfinyl group has been widely used as a chiral inductor in Diels-Alder reactions when bonded to the dienophilic double bond, due to its strong ability to control the 7r-facial selectivity. However, only a small number of papers on the use of sulfinyl dienes in asymmetric synthesis have been written, perhaps due to the poor reactivity of many of these substrates and the complex course of their reactions (mainly in the case of 1-sulfinyl dienes, see later). Additionally, the fact that synthetic methods to obtain enantiomerically pure sulfinyl dienes have been available only in the last six years would also explain the low number of papers concerning these asymmetric Diels-Alder reactions. During the preparation of this account, an excellent review on the synthesis and asymmetric Diels-Alder reactions of chiral 1,3-sulfinyl dienes has been published [11]. 

Cationic ansa metallocenes can be utilized as chiral catalysts in Diels-Alder reactions. For example, in the presence of the cationic zirconocene complex [(ebthi)Zr(Ot-Bu) thf]+, the [4 + 2] cycloaddition of acrolein and cyclopentadiene proceeds efficiently to afford endo and exo cycloadducts (equation 71). In reactions in which methyl acrylate is used as the dienophile, cycloadditions occur with lower levels of enan-tioselection (23% ee), but with significantly higher degrees of diastereoselectivity (17 1 endo, exo). In these processes, recent studies demonstrated the great influence of chiral metallocene structure and the dramatic solvent effect. ... 

In an original publication which describes the addition of diphenylmethyl chloride to the enolate of ( + )-camphor [( + )-2] and subsequent reduction, it was claimed that the endo, tWoalcohol 24 was formed in such a reaction sequence23. However, other authors found the exo.e.xo-alcoho]24 using the same procedure, and attributed this to possible differences in the reaction and/or work-up methods which were not described precisely in the original article. The alcohols 24 thus obtained were used for the formation of chiral enol ethers and esters used as dienophiles in Diels - Alder reactions (Section D. 1.6.1.1.1.2.2.1.). 

Menthol [(—)-l] has been used as a chiral ligand for aluminum in Lewis acid catalyzed Diels-Alder reactions with surprising success2 (Section D.l.6.1.1.1.2.2.1). The major part of its application is as a chiral auxiliary, by the formation of esters or ethers. Esters with carboxylic acids may be formed by any convenient esterification technique. Esters with saturated carboxylic acids have been used for the formation of enolates by deprotonation and subsequent addition or alkylation reactions (Sections D.l.1.1.3.1. and D.l.5.2.3.), and with unsaturated acids as chiral dienes or dienophiles in Diels-Alder reactions (Section D. 1.6.1.1.1.), as chiral dipolarophiles in 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), as chiral partners in /(-lactam formation by [2 + 2] cycloaddition with chlorosulfonyl isocyanate (SectionD.l.6.1.3.), as sources for chiral alkenes in cyclopropanations (Section D.l.6.1.5.). and in the synthesis of chiral allenes (Section B.I.). Several esters have also been prepared by indirect techniques, e.g.,... 

This type of reaction has been explored in detail as the chemical character of the conjugated system and reactivity of levoglucosenone is highly suitable for functionalization though cycloaddition reactions. Horton s laboratory (43,44) was the first to explore the potential of levoglucosenone as a chiral dienophile in Diels-Alder cycioadditions. 

A final example of the use of carbohydrate-derived dienophiles in Diels-Alder reactions involves the role of the carbohydrate as a chiral auxiliary. Shing and coworkers have described the Diels-Alder reaction of arabinose-derived dienophile 31 with butadiene under Lewis acid catalyzed conditions (Scheme 5). A mixture of cycloadducts 32 with R and S configurations at the cyclohexane ring stereocenter was obtained in 68% yield. The ratio was 73 27 in favor of the / -product when a benzyl glycoside was used lower selectivities were observed with the corresponding methyl glycoside (77). 

In stereoselective reactions, Zn11 Lewis acids work well to achieve high selectivities (Scheme 54). Chiral complexes of Zn11 with chiral bis(oxazoline) ligands act as effective catalysts in Diels-Alder reactions of reactive dienes with dienophiles having bidentate chelating moieties such as... 

Lewis acids of chiral metal aryloxides prepared from metal reagents and optically active binaphthol derivatives have played a significant role in asymmetric synthesis and have been extensively studied.23 However, in Diels-Alder reactions, the asymmetric induction with chiral metal aryloxides is, in most cases, controlled by steric interaction between a dienophile and a chiral ligand. This kind of interaction is sometimes insufficient to provide a high level of enantioselectivity. 

The most important development within the field of Diels-Alder chemistry during the past two decades must be considered to be the design and application of chiral Lewis acid catalysts. From the mid 80s on, the number of literature reports about the design and application of chiral Lewis acids in the synthesis of chiral Diels-Alder adducts from achiral precursors grew exponentially, but it started to level off and decrease again in the mid 90s. Several excellent reviews about the application of chiral Lewis acids in Diels-Alder reactions have been published41,43 44. In this section, the recent literature about the chiral Lewis acid catalyzed all-carbon Diels-Alder reactions of dienes with dienophiles is reviewed, which, as such, has not been reviewed before. 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

In addition to Lewis acid catalysts, chiral bases catalyze the Diels-Alder reaction.100101 Although the use of bases as catalysts does show promise, especially for acid-sensitive functionality, the current level of asymmetric induction may not be acceptable for scale up. In addition, only a limited number of dienes and dienophiles have been shown to undergo the chiral-base catalyzed Diels-Alder reaction. 

Ru-catalysed enyne metathesis offers a short approach to chiral derivatives of 3-vinyl-5,6-dihydro-2//-pyrans. Some epimerisation can occur at the pyranyl C atom at elevated temperatures (Scheme 3) <02T5627>. The bispropargyloxynorbomene derivative 6 undergoes a cascade of metathesis reactions in the presence of alkenes and Grubbs catalyst incorporating an enyne-RCM that leads to fused cyclic dienes. A dienophile can be added to the reaction mixture, resulting in Diels-Alder reactions and the formation of functionalised polycyclic products <02TL1561>. 

Ketene equivalents have found widespread use as partners in Diels-Alder reactions for the construction of cyclic, fused, and bridged unsaturated ketones. However, ketene equivalents based on simple vinyl sulfoxides are poor dienophiles and show low levels of diastereocontrol. Recently, Aggarwal and colleagues reported that (l/ ,3/ )-2-methylene-l,3-dithiolane 1,3-dioxide (187) was a highly reactive and highly selective chiral ketene equivalent.116 Diels-Alder cycloaddition of this... 

In an effort to develop enantioselective methods for azirine cycloadditions, azirine 87 was added to chiral diene 99 <1998TL7579, 2003TL6561>. Diene 99 has previously shown facial selectivity in Diels-Alder reactions with a number of dienophiles. Reaction of Z equiv of azirine 87 with 99 provides aziridine 100 in excellent yield as a single isomer (Equation 24). 

The possibility that metallocenes might function as Lewis acids in Diels-Alder reactions was probed with ferrocenium hexafluorophosphate [184]. The answer is affirmative the cycloadditions studied include methacrolein, crotonaldehyde, and methyl vinyl ketone as dienophiles and butadienes and cyclopentadienes as diene components. Yields are in the range 60-80 % with reaction times of 3-36 h at 0 to 20 °C. Fair to good yields were also obtained in reactions of isoprene and cyclopentadiene with acrolein and methyl vinyl ketone in the presence of 1 % [Pd(PPh3)2(MeCN)2](BF4)2 (in CH2CI2, room temperature). Methyl acrylate resulted in low yields, and chiral modification with (5)-BINAP is reported to give the cycloadducts with modest enantioselectivity [164]. 

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