Cinchona alkaloids carbonyl compounds

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

A different mechanism operates in the direct a-heteroatom functionalization of carbonyl compounds when chiral bases such as cinchona alkaloids are used as the catalysts. The mechanism is outlined in Scheme 2.26 for quinine as the chiral catalyst quinine can deprotonate the substrate when the substituents have strong electron-withdrawing groups. This reaction generates a nucleophile in a chiral pocket (see Fig. 2.6), and the electrophile can thus approach only one of the enantiotopic faces. 

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. ... 

The indium-promoted allylation of carbonyl compounds in the presence of cinchona alkaloids (2 equiv), as a route to chiral allylic alcohols, was recently reported by Loh [20, 21]. The reaction is applicable to a variety of aldehydes and ketones. The enantioselectivities obtained with allyl bromides as the substrate are at the best moderate (up to 75% ee) [20]. However, the use of prenyl bromides as substrates... 

In 2003, Caron and coworkers enhanced the stereoselectivity by introducing a bulky subunit at the quinudidine nitrogen atom of cinchona alkaloids [66], By using only 4 mol% of catalyst 143, the desired product 145 was obtained with up to 92% ee (Scheme 8.55). However, this catalyst proved not to be generally applicable to other carbonyl compounds. 

In 2007, Connon and McCooey developed highly efficient, asymmetric syn-selective addition reactions of enolizable carbonyl compounds to nitroolefins by adopting the enamine catalysis approach [48]. The 9-epi-amino cinchona alkaloid derivative (160,9 -epi-DHQDA) as an aminocatalyst promoted the addition ofa variety... 

These points will be further illustrated in three specific cases (1) reductions of carbonyl compounds by chiral oxazaborolidines-borane complexes ( 2.3), (2) reactions of carbonyl compounds with dialkylzinc reagents in the presence of chiral ligands ( 2.5.4), and (3) dihydroxylation of olefins by OSO4 in the presence of cinchona alkaloids ( 2.9). 

Aza-Henry reaction is rendered asymmetric by quaternary salts of Cinchona alkaloids. Addition reactions. Changing the 9-hydroxy group of Cinchona alkaloids to a 9-epiamino group not only is synthetically expedient, such products often show excellent catalytic activities in many asymmetric reactions. Those derived from dihydrocinchona alkaloids mediate Michael reactions to good results, including addition of indole to enones, and carbonyl compounds to nitroalkenes. Salt 4 has also been successfully employed in the alkenylation of t-butyl a-aryl-a-cyanoacetate. ... 

The potential of Cinchona alkaloids as nucleophilic catalysts was also demonstrated in Gaunl s cyclopropanation approach by reacting a-halo carbonyl compounds with Michael acceptors in the presence of catalytic amounts of 0-protected Cinchona alkaloids (468—470). This reaction is thought to proceed... 

The organocatalyzed condensation of arenes (i.e., phenols) with a model carbonyl compound, 3,3,3-trifluoropyruvate 6a, was first described in 2008 in the presence of Cinchona alkaloid 42a (10mol%). Crucial aspect to guarantee high levels of stereoinductions (ee up to 94%) Ued on blocking the C9—OH with a hindered group (i.e., phenanthrene, PHEN) and leaving unprotected the C6 —OH function (Scheme 5.13) [23]. 

SCHEME 5.13 Asymmetric alkylation of phenols with carbonyl compounds in the presence of chiral Cinchona alkaloids (PH 9-phenanthryl). 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

Asymmetric Michael addition of optically active perhydro-l,4-oxazepin-5,7-diones, and of thioglycollic acid in the presence of a cinchona alkaloid as catalyst, to a-nitro-olefins yields y-nitrocarboxylic acids and 2-nitrothio ethers, respectively, with reasonable enantiomeric excess. Allylsilanes add to a-nitro-olefins in the presence of aluminium chloride to give unsaturated nitronic acids, which are further transformed in a Nef-type reaction to give y,5-enones (Scheme 36).Nitro-compounds are also converted into the corresponding carbonyl compounds upon treatment with base and MoOs pyHMPA, a new modified Nef reaction. 

Non-fluoride initiators have been employed satisfactorily as well, including Lewis bases (amines, amine A-oxides, carbonates and phosphates," LiOAc," " f-BusF ), Lewis acids," A-heterocyclic carbenes, or even without initiator in DMSO as solvent. The addition of TMSCF3 to carbonyl compounds in the presence of a chiral initiator allows the enantioselective preparation of trifluoromethyl alcohols. For this purpose, quaternary ammonium fluorides derived from cinchona alkaloids (1) have been employed, affording moderate (up to 51% ee) " to high enantioselectivities (up to 92% ee). Also, the corresponding bromides were used in combination with an external fluoride source (KF or TMAF, up to 94% ee) or with disodium (R)-binaphtholate (up to 71% ee), or simply a cinchonidine-derived ammoniumphenoxide (up to 87% ee). Moreover, the use of a chiral TASF derivative (2) has also been reported (up to 52% ee). ... 

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... 

Different groups reported in 2007 on the use of C9 amino cinchona alkaloids as catalysts for the stereoselective functionaUzation of branched carbonyl compounds. Connon and coworkers demonstrated that the C9 amino derivative of epidihydro-quinine (40) and epidihydroquinidine (41) were effective catalysts for the conjugate addition of aldehydes and (cyclic) ketones to nitroalkenes via enamine catalysis [99] (Scheme 6.46). The catalysts with the same configuration at C9 as in the natural cinchona alkaloid gave poor results, in line with the results obtained for... 

The versatile nature of cinchona alkaloid ammonium salts for phase-transfer catalysis can be illustrated by recent reports on conjugate additions [118] and a nitro-Mannich reachon [119]. Dimeric catalysts derived from quinine and quini-dine were applied in the conjugate addition of cyclic (l-ketoesters to a, 3-unsaturated carbonyl compounds. The reaction proceeded in the presence of a tertiary amine as base and afforded the products in moderate to high yield and enantioselectivity (Scheme 6.56). 

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