Diels-Alder reaction, heteroatom asymmetric

Heteroatom Diels-Alder reactions that proceed with good to excellent asymmetric induction are well known. Chiral 1-aza-dienes have been developed as substrates, for example. ... 

The carbo- and hetero-Diels-Alder reactions are excellent for the constmction of six-membered ring systems and are probably the most commonly applied cycloaddition. The 1,3-dipolar cycloaddition complements the Diels-Alder reaction in a number of ways. 1,3-Dipolar cycloadditions are more efficient for the introduction of heteroatoms and are the preferred method for the stereocontrolled constmction of five-membered heterocycles (1 ). The asymmetric reactions of 1,3-dipoles has been reviewed extensively by us in 1998 (5), and recently, Karlsson and Hogberg reviewed the progress in the area from 1997 and until now (6). Asymmetric metal-catalyzed 1,3-dipolar cycloadditions have also been separately reviewed by us (7-9). Other recent reviews on special topics in asymmetric 1,3-dipolar cycloadditions have appeared. These include reactions of nitrones (10), reactions of cyclic nitrones (11), the progress in 1996-1997 (12), 1,3-dipolar cycloadditions with chiral allyl alcohol derivatives (13) and others (14,15). 

The vast majority of work on asymmetric Diels-Alder reactions deals with additions of 1,3-dienes to a, -alkenic carbonyl derivatives XXI) where the chirophore R is attached to the carbonyl group eiAer directly or via a heteroatom X, permitting subsequent removal of the auxiliary (e.g. by attack of a nucleophile Nu Scheme 75). 

The first report of a chiral aluminum Lewis acid employed in a heteroatom Diels-Alder reaction utilized Koga s mentholoxy dichloroaluminum catalyst 4 [75]. trans-Piperylene and 1-methoxybutadiene were reacted with n-butyl glyoxalate and diethyl mesoxalate the results are summarized in Sch. 46. The asymmetric induction and chemical yield in these reactions are quite poor but the authors did find that moderate asymmetric induction could be obtained from reactions catalyzed by Eu(hfc)3. 

Table 18. Asymmetric catalytic heteroatom Diels-Alder reactions of alkoxydienes.

Table 5) [28], and heteroatom Diels-Alder reactions (Sch. 50) [79,80] but no X-ray structure had ever been reported for it or for the 3,3 -disubstituted derivatives which were first introduced as an asymmetric Claisen catalyst [24-27]. Although compound 435 was found not to induce any reaction between cyclohexenone and phosphonate 425 under the standard conditions for catalyst 428, consistent with the proposed equilibrium of species 394, 431, 432, 433, and 434 is the finding that catalysis of the reactions between cyclohexenone or cyclopentenone and phosphonate 425 with a 2 1 mixture of 434 (M = Li) and 435 gave only the Michael adducts 426 and 427 in 96 % ee and 92 % ee, respectively. Because 394 and 432 are inactive catalysts and 434 results in much lower induction and some 1,2-adduct, it was proposed that the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone was the species 431 resulting from association of ALB catalyst with a metal alkoxide. It was proposed that the stereochemical determining step involved intramolecular transfer of the enolate of 425 to the coordinated cyclohexenone in species 436. 

Azo compounds, such as A-phenyl- or iV-methyltriazoline-dione, have been applied as dienophiles in thermal asymmetric hetero Diels-Alder reactions with heteroatom-substituted dienes, leading to cycloadducts with excellent diastereoselectivities. 

The hetero -Diels-Alder (HDA) reaction provides the opportunity to incorporate a heteroatom into the Diels-Alder product. Most commonly the catalytic asymmetric version of this reaction involves the reaction between an aldehyde (8.122) and a reactive diene (8.123) (typically with one or two oxygen substituents attached). Normally, the isolated products, after acidic work-up, are the enones (8.124). The products can either be formed by a direct cycloaddition or via a two step aldol-Michael sequence, according to Figure 8.5. 

Regardless of the precise structure of the chosen half southern synthon, the two main problems to be solved are the establishment of the carbon skeleton and the introduction of the necessary chirahty into the molecule. The published approaches have introduced chirality either by resolution, by starting with a chiral precursor, or via use of asymmetric synthesis techniques. The carbon skeleton has been established by use of a wide variety of techniques including the Diels-Alder and other cycloaddition reactions, heteroatom induced cyclizations, intramolecular Michael or Aldol cyclizations, intramolecular ether formation, and radical cyclization. 

---