Enantioselective Carbo Diels-Alder Reactions

The enantioselective Diels-Alder reaction is now of great interest because of its usefulness for simultaneous introduction of asymmetric centers during carbon-carbon bond formation. 

Yamamoto et al. have found that the action of a controlled amount of diborane on a carboxylic acid leads to an (acyloxy)borane RC02BR 2, which behaves as a Lewis acid [17]. The chiral (acyloxyjborane (CAB) complex 2 that is formed in situ from monoacyl tartaric acid and diborane is an excellent asymmetric catalyst (Equation 18) for the Diels-Alder reaction of cyclopentadiene with acrylic acid [17] or methacrolein (Equation 19) [18]. 

The reaction with acrylic acid deserves special attention, since it is usually not a good component in Diels-Alder reactions. The fact that the reaction proceeds cat- 

The CAB process is quite general for simple dienes and aldehydes. The a-sub-stituent on the dienophile increases the enantioselectivity (acrolein vs methacrolein). When there is a P-substitution in the dienophile, as in crotonaldehyde, the cycloadduct is nearly racemic. Conversely, for a substrate with substituents at both a-and P-positions, high ees are observed, as with 2-methylcrotonaldehyde and cy-clopentadiene (90% ee, exo endo = 97 3). a-Bromoacrolein is a useful dienophile in the Diels-Alder process because of the exceptional synthetic versatility of its resulting adducts e.g., an important intermediate for prostaglandin synthesis [19a]. In the presence of 10 mol% of 3a, a-bromoacrolein and cyclopentadiene in dichloro-methane undergo a smooth Diels-Alder reaction to give the (S)-bromoaldehyde cycloadduct in quantitative yield, 95% ee and 94 6 (exo endo CHO) diastereoselectivity (Equation 20). Similar results are obtained for the catalyst 3b in propionitrile. Other examples are listed below [20]. 

Hawkins et al. have reported a simple, efficient catalyst for the Diels-Alder reaction based on a chiral alkyldichloroborane (4, Equation 21) [21]. A molecular complex between methyl crotonate and the chiral catalyst has been isolated for the first time. 

A crystal structure study of the complex allowed the authors to propose a model to predict the approach of the diene on one of the faces of the methyl crotonate, since the other face is inaccessible due to rt-n donor-acceptor interactions involving the naphthyl unit. This secondary attractive substrate-catalyst interaction is key to the stereocontrol. 

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A frequently used catalytic system used for the catalytic enantioselective carbo-Diels-Alder reaction of N-alkenoyl-l,3-oxazolidin-2-one 4 is the chiral TADDOL-Ti(IV) 6 [14] complexes (Scheme 8.2 see Ghapter 1 in this book, by Hayashi) [15]. 

Yamamoto et al. have developed a catalytic enantioselective carbo-Diels-Alder reaction of acetylenic aldehydes 7 with dienes catalyzed by chiral boron complexes (Fig. 8.10) [23]. This carbo-Diels-Alder reaction proceeds with up to 95% ee and high yield of 8 using the BLA catalyst. The reaction was also investigated from a theoretical point of view using ab-initio calculations at a RHF/6-31G basis set. 

Fig. 8.10 The catalytic enantioselective carbo-Diels-Alder reaction of acetylenic aldehydes 7 with cyclopentadiene 2 catalyzed by chiral...

Catalytic enantioselective hetero-Diels-Alder reactions are covered by the editors of the book. Chapter 4 is devoted to the development of hetero-Diels-Alder reactions of carbonyl compounds and activated carbonyl compounds catalyzed by many different chiral Lewis acids and Chapter 5 deals with the corresponding development of catalytic enantioselective aza-Diels-Alder reactions. Compared with carbo-Diels-Alder reactions, which have been known for more than a decade, the field of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds and imines (aza-Diels-Alder reactions) are very recent. 

A simple, commercially available chiral alcohol, a,a,a a -tetraaryl-l,3-dioxo-lane-4,5-dimethanol (TADDOL, 7a), catalyzes the hetero- and carbo-Diels-Alder reactions of aminosiloxydienes with aldehydes and a-substituted acroleins to afford the dihydropyrones and cyclohexenones, respectively, in good yields and high enan-tioselectivities. More recently, it was reported that axially chiral biaryl diols 7b and 7c were more highly effective catalysts for enantioselective hetero-Diels-Alder reactions (Scheme 12.5). ... 

The development and application of catalytic enantioselective 1,3-dipolar cycloadditions is a relatively new area. Compared to the broad application of asymmetric catalysis in carbo- and hetero-Diels-Alder reactions (337,338), which has evolved since the mid-1980s, the use of enantioselective metal catalysts in asymmetric 1,3-dipolar cycloadditions remained almost unexplored until 1993 (5). In particular, the asymmetric metal-catalyzed reactions of nitrones with alkenes has received considerable attention during the past 5 years. 

Marko and co-workers applied chiral Yb catalysts to enantioselective Diels-Alder reactions of electron-deficient dienes (Table 10) [35]. When the reaction of 3-carbo-methoxy-2-pyrone with phenyl vinyl sulfide was conducted in the presence of THE (5 mol equiv. to Yb), the bicyclic lactone was obtained in 92% yield and in more than 95% ee (entry 5). Vinyl ethers could also be used as dienophiles, affording the corresponding products with excellent selectivities. 

Enantioselective vanadium and niobium catalysts provide chemists with new and powerful tools for the efficient preparation of optically active molecules. Over the past few decades, the use of vanadium and niobium catalysts has been extended to a variety of different and complementaiy asymmetric reactions. These reactions include cyanide additions, oxidative coupling of 2-naphthols, Friedel-Crafts-type reactions, pinacol couplings, Diels-Alder reactions, Mannich-type reactions, desymmetrisation of epoxides and aziridines, hydroaminations, hydroaminoalkylations, sulfoxida-tions, epoxidations, and oxidation of a-hydroxy carbo) lates Thus, their major applications are in Lewis acid-based chemistiy and redox chemistry. In particular, vanadium is attractive as a metal catalyst in organic synthesis because of its natural abundance as well as its relatively low toxicity and moisture sensitivity compared with other metals. The fact that vanadium is present in nature in equal abundance to zinc (albeit in a more widely distributed form and more difficult to access) is not widely appreciated. Inspired by the activation of substrates in nature [e.g. bromoperoxidase. 

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