Highly Efficient Organocatalysts

The opposite enantiomers can be obtained easily simply by changing from the cinchonine-derived catalyst to the cinchonidine analog [21], This contribution by O Donnell et al. served as a starting point for impressive studies from several groups with regard to detailed optimization of the process. 

Optimization of the alkaloid phase-transfer catalysts included both the development of improved reaction conditions and the design of more efficient organocatalysts. Addressing this latter issue, O Donnell observed the first remarkable improvement of the enantioselectivity on use of modified alkaloid organocatalysts with an O-substituent, in particular an O-allyl or O-benzyl substituent, for example 23 and 24, respectively. This positive effect of O-alkylated structures was discovered during a detailed mechanistic study [22]. In this study it was found that O-alkylation of the previously used alkaloid catalysts, e.g. 21, and N-alkylated derivatives thereof, e.g. 22, by reaction with an alkyl halide (which is used in 1.2-5 

The development of dimeric cinchona alkaloids as very efficient and practical catalysts for asymmetric alkylation of the N-protected glycine ester 18 was reported 

Dimeric phase-transfer catalysts were also reported by Najera et al., who used cinchonidine- and cinchonine-derived ammonium salts bearing a dimethyl-anthracenyl bridge as a spacer [32]. In the presence of these catalysts high enantioselectivity of up to 90% ee was obtained. 

A new class of suitable optically active organocatalyst for enantioselective alkylations has recently been developed by Maruoka and co-workers [le, 33-37]. This catalyst is not based on an alkaloid-related quaternary ammonium salt but consists of a C2 -symmetric compound of type 29 (or derivatives thereof bearing other types of substituent on the 3,3 positions of the binaphthyl unit) [33, 34], In the presence 

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Several organocatalysts have been recycled efficiently (selected examples are shown in Scheme 14.2). For example, the Jacobsen group has reported results from an impressive study of the recycling of the immobilized urea derivative 6, a highly efficient organocatalyst for asymmetric hydrocyanation of imines (Scheme 14.2) [11]. It was discovered that the catalyst can be recycled and re-used very efficiently - over ten reaction cycles the product was obtained with similar yield and enantioselectivity (96-98% yield, 92-93% ee). 

Zheng X, Qian YB, Wang Y (2010) 2-Pytrotidinecarboxyhc add ionic liquid as a highly efficient organocatalyst for the asymmetric one-pot Mannich reaction. Eur J Org Chem 515-522... 

On the other hand, modified-imidazoHdinones endowed with imidazole (125) [149] or a fluorous tag in the side chain (126) [150] proved to be active in the Diels-Alder cycloaddition in the presence of 5 vol.% water (Figure 24.40). The highly efficient organocatalyst 127 promoted, in the presence ofp-(trifluoromethyl) benzoic acid, the asymmetric Diels-Alder reaction of cyclohexenones with aromatic nitroolefins in seawater and brine with excellent chemo-, regjo-, and stereoselectivities [151], It has been postulated that the cychzation was involved in a concerted addition process and that seawater and brine significantly promoted the... 

Zhao HQ, Shen J, Guo JJ, Ye RJ, Zeng HQ (2013) A macrocyclic aromatic pyridone pentamer as a highly efficient organocatalyst for the direct arylations of unactivated arenes. Chem Commun 49 2323-2325... 

Miscellaneous Reactions Berkessel " has identified peptide-like urea-based bifiinctional organocatalysts for the highly efficient dynamic kinetic resolution of azalactones (Scheme 11.14a). Another selective hydrogen-bonding activation mechanism that enables the addition of pyrroles to ketenes using catalytic quantities of azaferrocene 36 has been introduced by Fu and coworkers (Scheme 11.14b). ° ... 

Finally, a highly efficient organocatalytic asymmetric approach was described by Gong et al. in 2006, using chiral phosphoric acids as catalysts. These results opened a window for the development of new optically active DHPMs synthesis (Scheme 19) [96, 97]. More recently, chiral organocatalysts such as Cinchona... 

Zhou, L. and Wang, L. (2007) Chiral ionic liquid containing L-proline unit as a highly efficient and recyclable asymmetric organocatalyst for aldol reaction. Chem. Lett., 36 (5), 628-629. 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

On the basis of their observation that achiral 2,2 -bipyridyl promotes the reaction between crotyltrichlorosilane and benzaldehyde, the Barrett group screened chiral pyridine molecules as Lewis-base catalysts for this reaction [175]. The pyridinylox-azoline 164a was identified as the most efficient organocatalyst. In the presence of this catalyst, which was, however, used in stoichiometric amounts, asymmetric addition of (E)-crotyltrichlorosilane 158b to aldehydes gave the anti products (S,S)-159 in yields of 61-91% and with enantioselectivity from 36 to 74% ee (Scheme 6.76) [175], Diastereoselectivity is high, because only the anti diastereomers were obtained. Aromatic aldehydes and cinnamylaldehyde were used as substrates. 

The asymmetric catalytic Strecker reaction is an elegant means of synthesis of optically active a-amino acids. The Jacobsen group developed optimized organocata-lysts [21, 44-48], optically active urea or thiourea derivatives, which were found to be the most efficient type of catalyst yet for asymmetric hydrocyanation of imines (see also Section 5.1 on the hydrocyanation of imines). Because of its high efficiency, Jacobsen hydrocyanation technology has already been used commercially at Rodia ChiRex [49]. The concept of the reaction is shown in Scheme 14.7. In the presence of a catalytic amount (2 mol%) of the readily available organocatalyst... 

Recently, Mukaiyama and co-workers prepared cinchona alkaloid-derived chiral quaternary ammonium phenoxide-phenol complex 23 and used it as an efficient organocatalyst for the tandem Michael addition and lactonization between oc,f-unsaturated ketones and a ketene silyl acetal 24 derived from phenyl isobutyrate. This approach permits the highly enantioselective synthesis of a series of 3,4-dihydropyran-2-ones (25), as shown in Scheme 4.11 [17]. 

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