Chiral auxiliaries in Diels-Alder reaction

Nitroalkenes with Chiral Auxiliaries The use of carbohydrates as chiral auxiliary in Diels-Alder reactions for the stereoselective preparation of carbocyclic and heterocyclic chiral rings is well documented.48 For example, D-manno-nitroalkene reacts with 2,3-dimethyl-1,3-butadiene to give a 65 35 mixture of adducts, as shown in Eq. 8.29. The configurations at C-4 and C-5 have been determined to be (4R,5R) and (45,55), respectively. Hydrolysis of the product followed by degradative oxidation of the sugar side chains leads to enantiomerically... 

Scheme 6.2 gives some other examples of use of chiral auxiliaries in Diels-Alder reactions.60... 

Ghosh has also shown that cis- l-(arylsulfonamido)-2-indanols could be used as excellent chiral auxiliaries in Diels-Alder reaction.85 Reaction of 80 with cyclopentadiene using a variety of Lewis acids led to 81 in good yield, with endo. exo ratios superior to 99 1 and diastereoselectivities ranging from 72% to 92%. The best selectivities were observed using titanium tetrachloride as the Lewis acid. The high degree of diastereoselection was presumed to result from effective metal chelation (Scheme 24.17). 

There are other considerations than mere analogy. If R represents some chiral auxiliary, a Diels-Alder reaction on 124 gives a product 125 with two new chiral centres, one, at C-2 in exactly the same place as in the aldol products such as 107. Michael (conjugate) addition to 124 on the other hand gives a compound 122 with only one new chiral centre (C-3) one atom further away from the chiral auxiliary. Another substitution pattern 128 still creates a new chiral centre at C-2 in the Diels-Alder adduct 129 but this time Michael addition does the same. However, the new centre is not created in the conjugate addition step, as that gives the enolate 127, but in the protonation of 127, an inherently less well controlled and probably reversible step. We shall therefore consider Diels-Alder reactions first and tackle the more troublesome Michael additions in the next section. 

Chiral Auxiliaries for Diels-Alder Reactions The highly ordered cyclic TS of the Diels-Alder reaction permits design of reactants and catalysts that lead to a preference between diastereomeric or enantiomeric adducts. (See Section 2.4) to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve diastereoselectivity is to install a chiral auxiliary. The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature and the greater stereoselectivity, the best diastereoselectivity is often observed in Lewis acid-catalyzed reactions. Chiral esters and amides of acrylic acid are particularly useful because the chiral auxiliary can be easily recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. 

Among the pinene-derived mono-alcohols, only (-)-isopinocampheol [(— )-33] has been used as an auxiliary. Its enantiomer ( + )-33 is commercially available or is readily prepared by a hydroboration/oxidation sequence from (+)-a-pinene (for a detailed procedure, see ref 34). The phenyl ether of (—)-33 has been used as a starting material for cyclic enol ethers 35. obtained by Birch reduction of the phenyl group3s, which are used as chiral dienes in Diels-Alder reactions (Section D.1.6.1.1.1.), although no description of the synthesis of the ether has been given. The alcohol has also been used for the synthesis of di(isopinocampheyloxy)-2-propenylborane 3433 (Section D.2.3.5.). 

Carbohydrates are inexpensive and renewable natural products which contain numerous functional groups and chiral centers. Utilizing their pronounced complexing abilities and their content of chiral information, carbohydrates are applied as chiral auxiliaries in Diels-Alder and aza-Diels-Alder reactions. The method involves the use of Lewis acid catalysts with different complexing properties. Thus, dienes of low reactivity can be transformed to their cycloadducts with high asymmetric induction. The use of N-glycosyl imines as the dienophiles offers stereoselective access to enantiomerically pure piperidine derivatives, e.g. the alkaloids coniin and anabasin. 

Next, we investigated an asymmetric Diels-Alder reaction of o-quinodimethanes generated in situ from benzocyclobutenols utilizing a tartaric acid ester as a chiral auxiliary. The Diels-Alder reaction of o-quinodimethane with olefins is a useful method to construct tetrahydronaph-thalene frameworks bearing up to four stereocenters, which are key intermediates for the synthesis of polycyclic... 

Asymmetric Diels-Alder reactions using a dienophile containing a chiral auxiliary were developed more than 20 years ago. Although the auxiliary-based Diels-Alder reaction is still important, it has two drawbacks - additional steps are necessary, first to introduce the chiral auxiliary into the starting material, and then to remove it after the reaction. At least an equimolar amount of the chiral auxiliary is, moreover, necessary. After the discovery that Lewis acids catalyze the Diels-Alder reaction, the introduction of chirality into such catalysts has been investigated. The Diels-Alder reaction utilizing a chiral Lewis acid is truly a practical synthetic transformation, not only because the products obtained are synthetically useful, but also because a catalytic amount of the chiral component can, in theory, produce a huge amount of the chiral product. 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

The reactivity of 47/-benzopyran-4-ones in Diels-Alder reactions is well documented <1987T3075>, and recently high asymmetric induction has been achieved in the reaction of 3-alkoxycarbonyl-substituted chromones with chiral auxiliaries and Danishefsky s diene <1991JOC2058>. It should be noted that 3-formylchromones can react as heterodienes in the stereoselective inverse electron Diels-Alder reaction with enol ethers <1994T11755> to provide a route to pyrano[4,3-A][l]benzopyrans a heterocyclic nucleus which occurs naturally in the fungal metabolite fulvic acid <1984CC1565>. The thermal Diels-Alder reaction of 477-pyran-4-one 405 in the presence of an excess of Danishefsky s diene 404 provided cycloadduct 406 (Equation 32) <1996H(43)745>. 

SMP is a useful chiral auxiliary in various cycloaddition reactions. Chiral 2-amino-1,3-dienes have been used in the Diels-Alder reaction with 2-aryl-1 -nitroethylenes, and 5-ary 1-2-methyl-substituted 4-nitrocyclohexanones were obtained in excellent enantiomeric purities (ee=95-99%) and diastereoselectiv-ities (ds = 75-95% eq 6). The photo-Diels-Alder reaction of SMP acrylonitrile with 1-acetylnaphthalene has been carried out. After hydrolysis of the adduct, the 1,4-diketone was obtained in excellent enantiomeric purity (ee > 97% eq 7). 

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.,... 

Ghosez and co-workers showed that changing the catalyst in Diels-Alder reactions using a chiral auxiliary can influence selectivity. When 285 reacted with diene 286, in the presence of a silyl triflate catalyst, an 88 12 mixture of 287/288 was obtained in 96%. 37 Changing the catalyst to europium [Eu(fod)3], however, gave... 

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). 

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