Diels-Alder, Ene, and Related Reactions

The Diels-Alder reaction is one of the most fundamental means of preparing cyclic compounds. Since discovery of the accelerating effect of Lewis acids on the Diels-Alder reaction of a,)3-unsaturated carbonyl compounds [341-344], its broad and fine application under mild reaction conditions has been amplified. Equations (140) [341] and (141) [345], respectively, illustrate typical dramatic effects from an early reaction and from one reported more recently. Lewis acid-promoted Diels-Alder reactions have been reviewed [7,8,346-353]. In addition to the acceleration of the reaction, other important feature is its alteration of chemo-, regio-, and diastereoselectivity this will be discussed below. The titanium compounds used in Diels-Alder reaction are titanium halides (TiX4), alkoxides (Ti(OR)4), or their mixed salts (TiX (OR)4 n = 1-3). A cyclopentadienyl complex such as Cp2Ti(OTf)2 is also documented as a very effective promoter of a Diels-Alder reaction [354], In addition to these titanium salts, a few compounds such as those in Eq. (142) [355] have recently been reported to effect the Diels-Alder reaction. The third, [(/-PrO)2Ti(bpy)(OTf)(i-PrOH)] (OTf), was estimated to be a more active catalyst than Cp2Ti(OTf)2. 

Other investigations of titanium Lewis acids include a study of the molecular imprinting of a titanium salt according to Eq. (143) [356]. In the Diels-Alder reaction of Eq. (144), this polymer-immobilized titanium salt has catalytic activity only 3-5 times less that of the analogous complex of the type (ArO)2TiCl2 in solution. 

The Diels-Alder reaction of a relatively unreactive dienophile such as cyclopente-none can be effected with TiCU at a low temperature, although the exocyclic double bond of the product migrates to the more stable endo position (Eq. 145) [357]. A weaker Lewis acid, Ti(0-r-Pr)2Cl2, resulted in no reaction even under forcing conditions. Acceleration of reaction and the improvement of diastereoselectivity were achieved in a titanium Lewis acid-mediated intramolecular reaction as shown in Eq. (146) [358]. Other relevant Diels-Alder reactions promoted by titanium Lewis acids are summarized in Table 12. 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

Hetero-Diels-Alder reactions starting with unsaturated compounds with heteroatom-carbon or heteroatom-heteroatom multiple bond(s) are also enhanced by Lewis acids [374-381]. Aldehydes and imines work as dienophiles under the influence of TiCU- Electron-rich dienes are generally a preferable partner, as shown in Eq. (149), in which the product was obtained virtually as a single isomer [382,383]. The importance of the choice of the Lewis acid in determining the stereochemical outcome of the reaction is illustrated in Eq. (150) [384]. The notion of chelation and of Felkin-Anh models, respectively, is valid for these Diels-Alder reactions. Diastereoi-somers other than those shown in Eq. (150) were not detected. The stereochemistry of the product in Eq. (149) could be also explained by the chelation model. 

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