Epi-Cinchonine

Synthesis of optically enriched N-protected ethyl pipecolate 67 was achieved using EDP catalyzed by cinchona alkaloids [39]. Numerous bases were screened and 10 mol% of 9-epi-cinchonine 68 afforded selectivity up to 71% ee with the N-benzoyl piperidino hemimalonate 69 on a multigram scale (Scheme 7.31), offering... 

Nakamura et al. reported the first highly enantioselective desymmetrisation of aziridines with phosphites catalysed by Cinchona alkaloid amides in combination with Et2Zn (Scheme 15.15). The reaction proceeds in benzene with optimally 10 mol% of both Et2Zn and iV-(2-picolinoyl)-9-amino-9-deoxy-epi-cinchonine 2, affording p-aminophosphonates in up to 90% yield and in up to 99% ee. 

Chen and coworkers in 2007 reported the first conjugate addition of indoles to enones catalyzed by 9-amino-9-deoxy-epi-cinchonine (32) CF3SO2H salts (a primary amine derived from cinchona alkaloids) [76]. The reaction proceeds with aliphatic and aromatic ketones with moderate to excellent yields and moderate to good enantioselectivities (Scheme 33.25). Soon after this, Melchiorre and coworkers reported a similar system using a hydroquinine derivative [77]. 

The decarboxylation of aminomalonic acid derivatives constitutes a classical route to proteinogenic and non-proteinogenic amino acids. In 2003, Brunner et al. [16] explored the potential of the 9-ep/-cinchonine-benzamides previously designed [14], in the decarboxylation of A-acetylaminomalonic acid derivatives 22a-c. Selected examples presented in Scheme 3.8 indicate that a number of 9-epi-cinchonine-benzamides reached acceptable levels of enantioselectivity, up to 71%. hi contrast to 2-cyano-2-aryl propionic acids 14 and 20,9-ept-cinchonine-benzamides 19b, c and f gave rather disappointing results with A-acetylaminomalonic acids... 

The effect of change in the spatial relations at C and C is not clear since, as explained above, there is doubt as to the relative activities of the components of the two pairs, quinine and quinidine, and cinchonidine and cinchonine, but epf-C -quinine and epi-C -quinidine are only slightly active or, according to Dirscherl and Thron, inactive. This result supports Neeman s view that for anti-malarial activity the direction of rotation must be the same at C and C but that does not explain the... 

In 2005, Chen and coworkers found that the epi-cinchonidine/cinchonine-derived thiourea catalysts, 79a,b, can serve as highly active promoters of the Michael addition ofthiophenol to the a,P-unsaturated imide 80 however, the reaction proceeded with low enantioselectivity (up to 17% ee) (Scheme 9.28) [22]. 

Soon afterward, various types of carbon [40-44], oxygen [45], and phosphorous [46] Michael donors were successfully employed in the thiourea-catalyzed addition to nitroalkenes. In the presence of the bifunctional epi-9-amino-9-deoxy cinchonine-based thiourea catalyst 79a, the 5-aryl-l,3-dioxolan-4-ones 138 bearing an acidic a-proton derived from mandelic acid derivatives and hexafluoroacetone were identified by Dixon and coworkers as effective pronucleophiles in diastereo- and enantioselective Michael addition reactions to nitrostyrenes 124 [40]. While the diastereoselectivity obtained exceeded 98%, the enantiomeric excess recorded... 

For each configuration at C.8, two isomers are possible which differ in orientation at C.9. Since all of the alkaloids are identical in configuration except at C.8 and C.9, four isomeric substances are possible in each series. Li one series two of these substances are represented by cinchonine and cinchonidine. The other two members are eptcinchonine and eptcinchonidine. Quinine, quinidine, eptquinine and eptquinidine constitute another such series. The normal members of these series are the major natural alkaloids. The epi compounds may occur naturally... 

Moving to the use of 9-deo3gr-9-amino-epi Cinchona-, in 2007, shortly after the disclosure of their usefulness in conjugate additions, summarised in Section 14.2, Liu and coworkers demonstrated that these primaiy amines are also efficient in catalytic asymmetric 1,2-additions proceeding through enamine intermediates. The authors reported a highly enantioselective aldol addition of cyclic ketones to aromatic aldehydes catalysed by a primary amine derived from cinchonine (CNA) and proceeding in the absence of... 

In nearly aU cases, catalysts bearing the unnatural C9-epi configuration (e.g. SS, 9S for the quinine derivatives or R,9R for the quinidine-derived catalysts) have turned out to be more enantioselective [2]. A thorough review by Schreiner and Kotke discusses the developments in this area until 2009 [2, 13]. In spite of recent developments in the area, only a handful of X-ray crystal structures of the active catalysts have been reported. The X-ray stracture of a cinchonine-derived (8R, 9R configuration) squaramide catalyst is displayed in Fig. 6.3. 

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