Cycloadditions cinchona alkaloids

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 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. 

To improve the position selectivity in the AD of oligoprenyl compounds bis-cinchona alkaloid ligand 8 was introduced by Corey 15,6]. Its design was based on the [3+2]-cycloaddition model for the AD mechanism, which will be discussed in Section 6E. 1.2. The two 4-heptyl ether substituents of the quinolines are supposed to assist fixation of the substrate in the binding cleft. Additionally, the jV-methylquinuclidinium unit and the linking naphthopyridazine were introduced to rigidify the osmium tetroxide complex of 8 [6],... 

CYCLOADDITIONS Alkylaluminum halides. Cinchona alkaloids. Trifluoromethanesulfonic anhydride. 

Cinchona alkaloid derivatives catalysed the enantioselective 4 + 2-cycloaddition of o-quinones with ketene enolates to produce chiral o-quinone cycloadducts in high ee... 

Polymer-supported organocatalysts have been used for cycloaddition of ketene, 127, to chloral, 128 [141]. Use of homo-acrylate polymers of cinchona alkaloids led to formation of the desired /Mactone (S)-130 with enantioselectivity up to... 

A series of (1-lactams (64) have been synthesized through the use of an immobilized cinchona alkaloid catalyst. This is postulated to proceed via the cycloaddition of an imine, and a ketene formed in situ through deprotonation of an acid chloride (Scheme 4.81). Different system configurations were described in the paper however, a column filled with a 5 1 mixture of solid K2C03 and immobilized-quinine derivative 65 cooled to —45 °C was found to be the most practical. The solution of the acid chloride and imine was dripped through the column and then directed... 

Cinchona alkaloids possess a nucleophilic quinuclidine structure and can perform as versatile Lewis bases to react with ketenes generated in situ from acyl halides in the presence of an acid scavenger. The resulting ketene enolates can react with electrophilic C=0 or C=N bonds to deliver chiral [i-lactones [5] or [i-lactams [6], respectively, in a [2 + 2] cycloaddition manner, which is discussed in Chapter 5 in detail. Gaunt et al. also developed practical one pot cydopropanation processes mediated by the modified cinchona alkaloids via ammonium ylide intermediates [7]. Although the catalytic strategy has been well established, the utilization of ammonium enolate based [4 + 2] cycloaddition is rare probably because of the relative unreactivity of the... 

Later, Lectka et al. reported a detailed synthetic and mechanistic study of unusual [4 + 2] cycloaddition of ketene enolates and o-quinones by the bifunctional catalysis of cinchona alkaloids BQD la (or BQN lb) and Lewis adds. The undertaken investigations based on the integration of experimental and calculated data itself demonstrated a surprising cooperative LA/LB interaction on a ketene enolate. It showed that the reaction of o-quinone undergoes a mechanistic switch in which the mode of activation changes from Lewis acid (LA) complexation of the quinone to metal complexation of the chiral ketene enolate. 

Asymmetric Cycloadditions Catalyzed by QumucM me Tertiary Amim 303 Table 10.2 Cinchona alkaloid catalyzed ketene-N-thioacyl imine [4 + 2] cycloadditions ... 

Apart from acting as effective Lewis base catalysts, the quinuclidine structure of cinchona alkaloids can also participate in the other cycloaddition reaction by a different catalytic mechanism. Calter et al. described an interesting asymmetric interrupted Feist-Benary reaction between ethyl bromopyruvates and cyclohexadione. They proposed that the protonated cinchona alkaloid would perform as a Bronsted acid to form hydrogen-bonding interaction with a-ketoester moiety, rendering it more electrophilic toward attack by either the enol or enolate of cydohexandione. Then intramolecular alkylation would afford the formal [3 + 2] cycloadduct (Scheme 10.12) [16]. 

Azomethine ylides are very important 1,3-dipoles, and they are usually used to react with alkenes leading to the formation of the highly substituted pyrrolidine derivatives [17]. A novel and practical process for the 1,3-dipolar cycloaddition of azomethine ylides with alkenes had been reported by j0rgensen and coworkers [18]. They proposed that a dipol-chiral base ion pair would be generated between a-imino ester-metal complex and a cinchona alkaloid, and subsequent cycloaddition with dipolarophile would take place in a stereoselective manner (Scheme 10.13). 

Asymmetric Cycloadditions Catalyzed by Bifiinctional Cinchona Alkaloids... 

Asymmetric Cycloadditions Catalyzed by Bifunctional Cinchona Alkaloids 309... 

Zhang et al. investigated the asymmetric 1,3-dipolar cycloaddition of tert-butyl 2-(diphenylmethyleneamino)acetate and nitroalkenes promoted by bifunctional thiourea compounds derived from cinchona alkaloids, affording chiral pyrrolidine derivatives 13 with multisubstitutions. Catalyst lm delivered the best results in terms of catalytic activity, diastereoselectivity and enantioselectivity. Nevertheless, only moderate ee values could be obtained while the diastereoselectivities were generally good (Scheme 10.18) [22]. 

Drawing from their success with catalytic [4 + 2] cycloaddition, Lectka group developed another highly enantioselective cycloaddition of o-quinone methide (o-QM) with silyl ketene acetals, using a chiral cinchona alkaloid derived ammonium, N-(3-nitrobenzyl)quinidinium fluoride Is, as a precatalyst. The free hydroxyl group of the cinchona alkaloid moiety was crucial to high optical induction. A variety of silyl ketene acetals had been screened to afford the cycloadducts 22 with good ee (72-90%) and excellent yield (84—91%) (Scheme 10.26) [35]. 

As discussed above, the vast synthetic potential of cinchona alkaloids and their derivatives in the asymmetric cycloadditions has been well demonstrated over the past few years. Cinchona-based organocatalysts possess diverse chiral skeletons and are multifunctional. There is no doubt that the further development of cinchona-based organocatalysts and their catalyzed cycloaddition reactions will continue to provide exciting results in the near future. 

Keywords [2-1-2] Cycloaddition, Cyclobutane, Chiral titanium catalyst, Propionolactone, Cinchona alkaloid... 

The hetero [2+2] cycloaddition reaction is a synthetically important reaction for the construction of 4-membered heterocyclic compounds. As far as the catalytic asymmetric reaction is concerned, however, only the cycloaddition between ketenes and aldehydes has been reported. The thus synthesized chiral oxetan-2-ones are employed as monomer precursors for the biologically degradable co-polyesters and also as chiral building blocks for natural product synthesis. Two types of catalysts. Cinchona alkaloids and a chiral Lewis acid, are known to promote this reaction. 

Cinchona alkaloids are the effective asymmetric catalysts in the [2+2] cycloaddition reaction of ketenes and aldehydes [47]. That is, the reaction between ketenes and chloral proceeds with a catalytic amount (2.5 mol %) of quinidine in toluene at -50 °C to provide the P-propionolactone (-)-18 in quantitative yield with 98% ee (Scheme 17). 

In an effort to improve asymmetrical induction, Okamura and co-workers investigated the cinchona-alkaloid-promoted reaction of 3-hydroxy-2-pyrone with enantiomerically pure -acryloyloxazolid-inone dienophiles. These cycloadditions proceed smoothly at 0 °C to give bicyclic lactone adducts in good yields and with good to excellent levels of diastereocontrol. The diastereoselectivities depend... 

Nelson and co-workers reported cinchona alkaloid-catalyzed [4-1-2] cycloaddition of ketenes and N-thioacyl imine, affording the 4,5-cw-disubstituted l,3-thiazin-6-one derivatives 146 with high enantioselectivities (>95% ee) and diastereoselectivities (>95 5 cis. trans). Scheme 3.47 [63], Ketene, in situ generated from acyl halide 143 and base, followed by addition to imine which was generated in situ via basic elimination of a-amido sulfone 144, providing the ketene-imine addition pathway toward the cycloadducts. 

Scheme 3.47 Cinchona alkaloid-catalyzed [4-1-2] cycloadditions of ketenes with a-amido...

Nelson and co-workers reported a cinchona alkaloid-Lewis acid-catalyzed acycl chloride aldehyde reaction, an extension of ketene-aldehyde cycloaddition, providing 3,4-cw-p-lactones 168 with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (>96% de), [69], The methodology was later applied by the group in the enantioselective total synthesis of (-)-pironetin (Scheme 3.53). 

Scheme 3.53 Cinchona alkaloid 145/LiC10,-catalyzed ketene-aldehyde cycloadditions...

Peters and Zajac reported the cinchona alkaloids, e.g. quinine, catalyzed formal [2+2] cycloadditions of sulfonylchlorides 177 and highly reactive non-nucleophiUc iminesl78, affording the P-sultams 180, Scheme 3.56 [72]. 

An organocatalytic asymmetric formal [3 + 2] cycloaddition reaction of isocya-noesters 218 to nitroolefins 210 leading to highly optically active dihydropyrroles 220 was reported by Gong, et al., Scheme 3.70 [87], The proposed mechanism is depicted in Scheme 3.70 the cinchona alkaloid chiral base 219 promote an asymmetric Michael addition of isocyanoesters to electron-deficient olefins (nitroolefins), and subsequent intramolecular cyclization of the intermediate to afford the dihydropyrroles 220. 

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