Cinchona alkaloid-derived enantioselective development

A new cinchona alkaloid-derived catalyst has been developed for the enantioselective Strecker reaction of aryl aldimines via hydrogen-bonding activation. For reference, see Huang, J. Corey, E. J. Org. Lett. 2004, 6, 5027-5029. 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

Currently, this area is not as well developed as the use of cinchona alkaloid derivatives or spiro-ammonium salts as asymmetric phase-transfer catalysts, and the key requirements for an effective catalyst are only just becoming apparent. As a result, the enantioselectivities observed using these catalysts rarely compete with those obtainable by ammonium ion-derived phase-transfer catalysts. Nevertheless, the ease with which large numbers of analogues - of Taddol, Nobin, and salen in particular- can be prepared, and the almost infinite variety for the preparation of new, chiral metal(ligand) complexes, bodes well for the future development of more enantioselective versions of these catalysts. 

The Cinchona alkaloid-derived thiourea (112), has been developed as an organocat-alyst for conjugate addition of a wide range of nucleophilic enol species to enones. The reaction is characterized by high enantioselectivities and mild reaction condition.160... 

Another important asymmetric epoxidation of a conjugated systems is the reaction of alkenes with polyleucine, DBU and urea H2O2, giving an epoxy-carbonyl compound with good enantioselectivity. The hydroperoxide anion epoxidation of conjugated carbonyl compounds with a polyamino acid, such as poly-L-alanine or poly-L-leucine is known as the Julia—Colonna epoxidation Epoxidation of conjugated ketones to give nonracemic epoxy-ketones was done with aq. NaOCl and a Cinchona alkaloid derivative as catalyst. A triphasic phase-transfer catalysis protocol has also been developed. p-Peptides have been used as catalysts in this reaction. ... 

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]. 

Jew and Park have also utilized the dimerization effect, as observed in the development of Sharpless asymmetric dihydroxylation, where ligands with two independent cinchona alkaloid units attached to heterocyclic spacers led to a considerable increase in both the enantioselectivity and scope of the substrates, to design dimeric and trimeric cinchona alkaloid-derived phase-transfer catalysts 12 [12] and 13 [13]. These authors investigated the ideal aromatic spacer for optimal dimeric catalysts, and found that the catalyst 14 with a 2,7-bis(bromomethyl) naphthalene spacer and two cinchona alkaloid units exhibited remarkable catalytic and chiral efficiency (Scheme 11.3) [14]. 

Jorgensen developed a catalytic regioselective and enantioselective nucleophilic aromatic substitution reaction of activated aromatic compounds with 1,3-dicarbonyl compounds under phase-transfer conditions. This was crucial for obtaining the C-arylated product 61 predominantly with high enantioselectivity by replacing a benzyl with a benzoate group in the cinchona alkaloids-derived phase-transfer catalyst (Scheme 11.13) [49]. 

An enantioselective dichlorination of allylic alcohols using (dichloroiodo)arenes as chlorine sources in the presence of catalytic amounts of a dimeric cinchona alkaloid derivative (DHQ)2PHAL has been developed [57]. For example, the dichlorination of frans-cinnamyl alcohols 71 with 4-Ph(C6H4)ICl2 catalyzed by (DHQ)2PHAL affords products 72 in good yields and enantioselectivities (Scheme 3.24). 

The addition of nitroalkanes to chalcones is more attractive since the Michael adducts are useful intermediates for a variety of further elaborated stmctures such as chiral aminocarbonyls, pyrrolidines, y-lactams, and y-amino acids. Thus, many elegant organocatalysts such as cinchona alkaloid-derived chiral tertiary amine thiourea 69 [67] or suqaramide 70 [68] and bisquaternary ammonium salts [69] 71a or 71b have been developed for such a reaction in recent years (Scheme 5.33). In addition, a,(3-unsaturated A -acylpyrroles [70] and 4-oxo-enoates [71] were also applicable in the highly enantioselective conjugated addition with nitroalkanes (Scheme 5.34). 

The development of the first highly enantioselective cyanocarbonation of prochiral ketones promoted by a chiral base catalyst, such as a cinchona alkaloid derivative, was reported by Tian and Deng in 2006. " Importantly, the reaction complemented known enzyme- and transition metal based methods in substrate scope via its unique ability to promote highly enantioselective cyanocarbonation of sterically hindered simple dialkyl ketones. Mechanistic studies provided experimental evidence to shed significant light on the asymmetric induction step in which the modified cinchona alkaloid acted as a chiral nucleophilic catalyst. Moreover, experimental evidence supported the mechanistic proposal that the enantioselectivity determination step in the cyanocarbonation was a DKR of the putative intermediates G and H via asymmetric transfer of the alkoxycarbonyl group (Scheme 2.105). 

On the other hand, Yang etal. [33] have developed an organocatalyzed enantioselective FC-type addition reaction of 2-naphthol 212 with p,y-unsaturated a-ketoesters 209 using a cinchona alkaloid-derived thiourea catalyst 213 (Scheme 2.30). The resulting product 214 is in rapid equilibrium with the cyclic hemiketal 215, which was dehydrated with a catalytic amount of concentrated H SO in a one-pot fashion, providing the naphthopyran derivatives 216 with moderate to good yields (51-91%) and enantioselectivities (57-90% ee). 

In addition, several organocatalysts other than cinchona alkaloid derivatives have been developed very recently. As an example, a chiral bicyclic guanidine was found by Tan et al. to be an excellent catalyst for enantioselective Michael additions of malonates or ethyl benzoylacetates to cyclopentenone or... 

Cooperative catalysis using cinchona alkaloid derivatives in combination with metals such as silver have also been widely developed. On the basis of this concept, Escolano et al. have disclosed an enantioselective domino Michael-cyclisation reaction. This formal [3 + 2] cycloaddition occurred between isocyanoacetates and enones in the presence of a combination of a chiral hifunctional cinchona alkaloid, such as cupreine, and AgNOs to provide the corresponding chiral 2,3-dihydropyrroles in low to high yields and... 

In 2010, Jorgensen et al. developed an enantioselective tandem reaction of propargylated malononitriles with cyclic enones sequentially catalysed by a cinchona alkaloid-derived primary amine catalyst in the presence of (J )-mandelic acid as an additive for the first Michael step, and a gold catalyst for the second tandem exo-dig cyclisation-isomerisation reaction. " As shown in Scheme 7.62, the corresponding chiral bicyclic enones were achieved in good yields and high enantioselectivities of up to 96% ee, albeit low to moderate diastereoselectivities (34-66% de). 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

List and coworkers reported an oxa-Michael reaction with aliphatic acyclic enones 94 using hydrogen peroxide as oxygen source [111]. Treatment of enones with catalytic amounts of cinchona alkaloid derived primary amine 33 (as its salt), followed by excess hydrogen peroxide furnished the intermediate peroxy-hemiketals with high yields and stereoselectivities. Subsequent reduction of these compounds led to the corresponding p-hydroxyketones 124 without loss of enantioselectivity (Scheme 33.36). The same research group developed the asymmetric epoxidation of enones with excellent results [112],... 

A subsequent study by Jprgensen et al. also demonstrated the enantioselective a-sulfenylation of (S-dicarbonyl compounds 420 using l-alkylsulfanyl[l,2,4]triazole derivatives 419 in the presence of a catalytic amount of cinchona alkaloid derivative 421. The use of cyclic (S-dicarbonyl compounds ensured the introduction of a quaternary sulfur center however, the observed enantioselectivity was modest in 51-89%. In 2009, Zhu and co-workers reported that a chiral a,a-diaryl prolinol 424 efficiently catalyzed the enantioselective sulfenylation of (S-ketoesters 420 using N-(phenylthio)phthalimide 423 as a sulfur electrophile. The absence of racemizable C—H bonds led to the optically enriched a-sulfenylated products 425 in excellent enantio-selectivities. In 2010, Fu developed a method for catalytic asymmetric 7-sulfenylation of carbonyl compounds using 2,3-allenoates 426 in the presence of a chiral bisphos-phine, TangPhos 427, and a bulky carboxylic acid 428. ... 

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