Templated Diels-Alder reaction

A conceptually diHerent, convergent route was developed in 2006 by Nicolaou and Harrison [35, 146] for the enantioselective synthesis of 290 and 291. On the basis of an enantioselective Mg(II)-templated Diels-Alder reaction between chiral dienol 292 and methyl acrylate and on previous model studies to build the spirotetronic core [143c], Nicolaou prepared a ring-closing metathesis (RCM) precursor (296) that smoothly afforded atropoisomer 290 after oxidation and deprotection (Scheme 1.45). Nicolaou also observed that 290 and 291 participate in an acid-catalyzed intercorversion leading to equilibrium mixtures of various ratios depending on the acidic media. 

In another paper, the same authors investigated the 1,3-dipolar cycloaddition on 2-(lH)-pyrazine scaffolds 72 and electron-rich azides, using Cu(0) and CUSO4 as pre-catalysts. To demonstrate the versatility of this approach, they reported the generation of different templates (73 in Scheme 25) as an application of cUck chemistry . They also investigated the Diels-Alder reaction of the so obtained triazoles with dimethyl acetylenedicarboxylate (DMAD), under microwave irradiation. The latter reaction allowed obtaining various pyridinones in good yields (74 and 75 in Scheme 25) [57]. 

In 1990, Choudary [139] reported that titanium-pillared montmorillonites modified with tartrates are very selective solid catalysts for the Sharpless epoxidation, as well as for the oxidation of aromatic sulfides [140], Unfortunately, this research has not been reproduced by other authors. Therefore, a more classical strategy to modify different metal oxides with histidine was used by Moriguchi et al. [141], The catalyst showed a modest e.s. for the solvolysis of activated amino acid esters. Starting from these discoveries, Morihara et al. [142] created in 1993 the so-called molecular footprints on the surface of an Al-doped silica gel using an amino acid derivative as chiral template molecule. After removal of the template, the catalyst showed low but significant e.s. for the hydrolysis of a structurally related anhydride. On the same fines, Cativiela and coworkers [143] treated silica or alumina with diethylaluminum chloride and menthol. The resulting modified material catalyzed Diels-Alder reaction between cyclopentadiene and methacrolein with modest e.s. (30% e.e.). As mentioned in the Introduction, all these catalysts are not yet practically important but rather they demonstrate that amorphous metal oxides can be modified successfully. 

The catalysis of bimolecular reactions such as the Diels-Alder reaction can be realized effectively and specifically by abzymes such as 1E9. The antibody then acts as a template and maintains the two partners, diene and dienophile, in a position favorable to the formation of the TS that is in a boat conformation in this reaction (Figure 8). 

Certain transition metal complexes can serve as templates for the synthesis of chelating NHC ligands. For example, 1-phenylphosphole complexes of pal-ladium(II) are attacked in a Diels-Alder reaction by 1-vinylimidazole. If 1,2-dichloroethane is used as the solvent the imidazole is alkylated in situ and then subjected to a spontaneous carbometallation reaction [Eq. (37)]. 

Templates possessing two hydrogen bonding subunits bind two substrates forming a ternary complex in which the substrates are positioned so as to facilitate bond formation between them [5.64a]. In a related way, the rate and stereoselectivity of a bimolecular Diels-Alder reaction are substantially increased by binding both the diene and the dienophile within the cavity of a tris-porphyrin macrocycle [5.64b]. 

In 1997 the same group developed the first imprinted polymer able to catalyse a Diels-Alder reaction between tetrachlorothiophene dioxide (43) and maleic anhydride (44) to give the product (45). The imprinting strategy was inspired by previous work carried out by Hilvert et al. in 1989 for the development of catalytic antibodies with Diels-Alder capabilities [26]. The chlorendic anhydride (46) was used as a template because of its structural analogy with the transition state of the reaction (TSA). The resulting imprinted polymer showed a Michaelis-Menten behaviour and a ratio kcal/kunca equal to 270 (Scheme 8). 

Following the first reports in the literature of catalytic imprinted beads, a number of authors also reported applications of this polymer format to several imprinting systems. Busi et al. [64] reported the preparation of catalytic active beads for the Diels-Alder reaction using a TSA as a template. Jakubiak and co-workers developed imprinted beads for the oxidation of phenols based on a Cu(II) complex as catalytic centre [65]. Say and collaborators described the synthesis of microbeads also based on a Cu(II) complex with esterase activity towards paraoxon (60), a potent nerve agent [66]. The imprinted beads enhanced the rate of reaction over the non-imprinted polymer by a factor of 40, as resulted from the ratio of the corresponding kciil. 

Cycloadditions are useful for the preparation of cyclic ompounds. Several thermal and photoactivated cycloadditions, typically [4+2] (Diels-Alder reaction), are known. They proceed with functionalized electronically activated dienes and monenes. However, various cycloaddition reactions of alkenes and alkynes without their electronical activation, either mediated or catalysed by transition metal complexes under milder conditions, are known, offering a useful synthetic route to various cyclic compounds in one step. Transition metal complexes are regarded as templates and the reactions proceed with or without forming metallacycles [49]. 

The non-selective thermal Diels-Alder reaction of hexa-2,4-dienol with methyl acrylate is made enantioselective by using the Lewis acid template (86) to assemble the reagents for cycloaddition.91 The Me2AlCl-catalysed intramolecular Diels-Alder... 

Microwave-assisted Diels-Alder reactions of 9-substituted anthracenes with 2-acetamidoacrylate in DMF generate conformationally constrained bicyclic bisaryl a-amino acid derivatives with high regioselectivity.138 The Sc(OTf)3-catalysed Diels-Alder reaction of anthracenes with methyl vinyl ketone does not proceed via an electron-transfer process from anthracenes to the MVK-Sc(OTf)3 complex.139 (-)-(/ )-9-(l,2-Dimethoxyethyl)anthracene has been used as a chiral template in the Diels-Alder/retro-Diels-Alder sequence for the synthesis of a,j3-unsaturated lactams.140... 

The phosphino functionalised carbene is generated in the coordination sphere of palladium(II) in a template [4+2] Diels-Alder reaction between a coordinated 1-phenyl-... 

Kunz, H, Mueller, B, Schanzenbach, D, Diastereoselective Diels-Alder reactions using carbohydrate templates, Angew. Chem. Int. Ed., 26, 267- 269, 1987. 

Nouguier, R, Gras, J L, Giraud, B, Virgili, A, Methyl 3,4-p-D-arabinoside as a new chiral template for the asymmetric Diels-Alder reaction. Tetrahedron Lett., 32, 5529-5530, 1991. 

Pfrengle, W, Kunz, H, Hetero Diels-Alder reactions on a carbohydrate template stereoselective... 

Chiral (helical) Lewis acids for asymmetric Diels-Alder catalysis are prepared from titanium tetraisopropoxide 5 and a chiral binaphthol ligand 4 [13]. The titanium reagent 6 plays an important role as chiral template for the fixation of a,fi-unsaturated aldehydes and thereby for the enantioface recognition of substrates. The asymmetric Diels-Alder reaction, e. g., of cyclopentadiene 7 and acrolein 8, is effected in the presence of catalytic (P)-6 (10 mol%), producing the endo adduct 9 (R =R2=H) in 88% ee (Scheme 1). 

Scheme 1. In the presence of the asymmetric titanium catalyst (f)-6, which acts as chiral template for the fixation of a,y9-unsaturated aldehydes, the Diels-Alder reaction of cyclopentadiene 7 and acrolein 8 leads to the enr/o-adduct 9 (Ri=R2=H) in...

A multipurpose template is the oxazolidinone 19 which is endo-fused to a norbomane skeleton. Proper A-acyl derivatives are useful for asymmetric alkylation, conjugate addition, and Diels-Alder reactions. 

Compared with the Diels-Alder reaction, the [2+2+2]-cycloaddition is potentially more powerful since the number of new bonds as well as chirality centers that are formed is higher. Unfortunately, the reaction seems to be entropically or kinetically unfavorable. This disadvantage can, however, be overcome by the use of transition metal catalysts (templates). Among the most successful examples of this reaction type, the nickel(II) catalyzed Reppe reactions 96), the cobalt(I) catalyzed cocyclizations of a,to-diynes with alkynes 97), the cobalt(I) catalyzed pyridine synthesis 985 and last but not least the palladium(0) catalyzed cyclotrimerizations of 3,3-dialkylcyclopropenes to frans-cr-tris-homobenzenes must be mentioned. The latter has been known for ten years 99>. 

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