Cinchona alkaloids Diels-Alder reactions

Base-catalyzed Diels-Alder reactions are rare (Section 1.4). A recent example is the reaction of 3-hydroxy-2-pyrone (145) with chiral N-acryloyl oxazolidones 146 that uses cinchona alkaloid as an optically active base catalyst [97] (Table 4.25). Only endo adducts were obtained with the more reactive dienophile 146 (R = H), the best diastereoselectivity and yields being obtained with an i-Pr0H/H20 ratio of 95 5. The reaction of 146 (R = Me) is very slow, and a good adduct yield was only obtained when the reaction was carried out in bulky alcohols such as t-amyl alcohol and t-butanol. 

Table 4.25 Diels-Alder reactions of 3-hydroxy-2-pyrone (145) catalyzed by cinchona alkaloids...

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

An asymmetric Diels-Alder reaction of 2-pyrones 57 and a,P-unsaturated ketones 34 with a bifunctional organic catalyst, e.g., cinchona alkaloid derivative 58, was reported by Deng, et al. Scheme 3.23. [37]. 

Scheme 3.23 Enantioselective Diels-Alder reaction of a,p-unsaturated ketones and 2-pyrones with cinchona alkaloid catalyst 58...

In addition to metal-based catalysts, organocatalysts are also selective promoters of asymmetric Diels-Alder reactions. Several groups reported the use of cinchona alkaloid catalysts in standard Diels-Alder reactions. Deng combined 2-pyrones with a,P unsaturated ketones, while Bernard and Ricci focused on the reactions of vinylindoles with quinones and maleimides. Lectka reported enantioselective inverse electron demand hetero Diels-Alder reactions of ketene enolates and o-benzoquininone diimides catalyzed by a combination of benzoylquinidine and zinc triflate. For example, subjecting diimide 51 to the standard reaction conditions yields cycloadduct 52 as a single stereoisomer, which can be easily converted to... 

Scheme 6.3 Cinchona alkaloid-catalysed Diels-Alder reactions of 2-pyrones.

A readily available 9-NH2 cinchona alkaloid has proved to efficiently catalyse the asymmetric Diels-Alder reaction of simple a,p-unsaturated ketones with 2-pyrones. In the presence of TFA as an additive, the reaction afforded the exo-cycloadduct as the major product in good enantiomeric excess of up to 99% ee in almost all cases of substrates, as shown in Scheme 6.3. Moderate to excellent diastereoselectivities of 50-94% de were obtained, but it is important to note that both the diastereoselectivity and the enantioselectivity of the reaction did not fluctuate significantly when the aromatic substituent of the a,p-unsaturated ketone was changed to an aliphatic substituent. 

There are only few examples of asymmetric inverse hetero-Diels Alder reactions using a,P-unsaturated aldehydes. As a recent example, a cinchona alkaloid was successfully used to catalyse the oxa-Diels Alder reaction of heterodienes such as 3-formylchromones with acetylene dicarboxylates, providing the corresponding tricyclic benzopyrones in moderate to high yields (54-87%) and enantioselectivities (46-84% ee), as shown in Scheme 6.12. ... 

Chiral oxazaborolidine catalysts were applied in various enantioselective transformations including reduction of highly functionalized ketones/ oximes or imines/ Diels-Alder reactions/ cycloadditions/ Michael additions, and other reactions. These catalysts are surprisingly small molecules compared to the practically efficient chiral phosphoric acids, cinchona alkaloids, or (thio)ureas hence, their effectiveness in asymmetric catalysis demonstrates that huge substituents or extensive hydrogen bond networks are not absolutely essential for successful as5unmetric organocatalysis. 

Benzoate salt of the vicinal diamine (249) has been found to catalyse a domino reaction of enones R CH=CHCOR with R CH=CHCOR that affords cyclic products containing three to four contiguous stereocentres (with 92-99% ee and >30 1 dr) " The self-assembly of proline and cinchona alkaloid-derived thioureas has been reported to dramatically improve the enantioselectivity of the inverse-electron-demand hetero-Diels-Alder reactions between aldehydes R R CHCH=0 and electron-deficient enones R CH=CHCOR , affording (250) after subsequent oxidation with PCC. °... 

In 2006, Lectka and coworkers reported an asymmetric inverse electron demand hetero-Diels-Alder reaction (HDAR) of acyl chlorides (Bekele et al. 2006 Wolfer et al. 2006) and o-benzoquinone diimides to deliver chiral quinoxalinones (Abraham et al. 2006). In spite of perfect ee values observed by the catalysis of Lewis bases derived from cinchona alkaloids, the reaction conditions were somewhat harsh and metal triflates had to be used as co-catalysts to activate the electrophilic o-benzoquinone diimides (Abraham et al. 2006 Pauli et al. 2(X)8). 

In 2003, Rawal reported the use of TADDOLs 177 as chiral H-bonding catalysts to facilitate highly enantioselec-tive hetero-Diels-Alder reactions between dienes 181 and different aldehydes 86 (Scheme 6.29A) [82], and also BINOL-based catalysts 178 were found to facilitate this reaction with excellent selectivities [83]. TADDOLs were also successfully used as organocatalysts for other asymmetric transformations like Mukaiyama aldol reactions, nitroso aldol reactions, or Strecker reactions to mention a few examples only [84]. In addition, also BINOL derivatives have been employed as efficient chiral H-bonding activators as exemplified in the Morita-Baylis-Hilhnan reaction of enone 184 with different carbaldehydes 86 [85]. The use of chiral squaramides for asymmetric reactions dates back to 2005 when Xie et al. first used camphor-derived squaric amino alcohols as ligands in borane reductions [86]. The first truly organocatalytic application was described by Rawal et al. in 2008 who found that minute amounts of the bifunctional cinchona alkaloid-based squaramide 180 are... 

The influence of pressure on organic reactions catalyzed by chiral metal-free organic molecules was studied for selected asymmetric Michael, Baylis-Hillman, aldol, Mannich, Friedel-Crafls, and Diels-Alder reactions-the essential part of this work was done in Japan. In the early stages of those investigations the high-pressure technique was applied to reactions catalyzed by cinchona alkaloids and in most cases low or moderate enantioselectivities were observed. Since 2002 some examples of high-pressure reactions catalyzed by proUne, thioureas, and modified cinchona alkaloids have appeared. 

The reported organic bifunctional catalysts possessing both hydrogen bond donor and acceptor moieties are often derived from the cinchona alkaloids. Tan and coworkers developed the simple and readily available amino-indanol 95 as an efficient bifunctional organocatalyst for the enantioselective Diels-Alder reaction of 3-hydroxy-2-pyridones 94 (Scheme 38.26) [40]. Besides maleimides 80, alkyl vinyl ketones were also suitable dienophiles for this catalytic system. 

An interesting expansion to the scope of dienes that could be adopted as partners within the Diels-Alder cycloaddition was reported by Deng (Scheme 57) [193]. Reaction of 3-hydroxypyrones 145 with a broad range of a,p-unsaturated ketones in the presence of the primary cinchona alkaloid 144 (5 mol%) provided the Diels-Alder adducts with exceptional levels of asymmetric induction (up to 99% ee). Within this report it was also shown that the related alkaloid 146 provided access to the enantiomeric adducts with similar levels of asymmetric induction. 

---