Cinchona-PTCs

Development of Dimeric Cinchona-PTCs by the Park-Jew Croup 51... 

Despite such numerous and fruitful studies having been conducted on the asymmetric phase-transfer catalytic reactions, the development of cinchona-PTCs has, until the start of the 21st century, been mainly focused on the monomeric cinchona-PTCs (Figure 4.3). 

Dimeric Cinchona-PTCs with Phenyl Linker... 

The first series of the dimeric cinchona-PTCs (3-8) to have a phenyl ring as a linker was designed to examine the primary effect according to the relationship of the attached position (Figure 4.6). One of the two independent cinchona alkaloid units can be located at the ortho-, meta-, or para-position against the other, respectively. The group envisaged that, both chemical yield and enantioselectivity of the asymmetric alkylation of 1 should be affected by the direction of each of the cinchona units. 

Figure 4.5 General structure of dimeric cinchona-PTCs.

Figure 4.6 The dimeric cinchona-PTCs with phenyl linker.

As (—)-cinchonidine-derived ammonium salts have been mainly used as chiral PTCs in monomeric cinchona-PTCs via the asymmetric alkylation of 1, and have generally shown better results than those of others [e.g., derived from (+)-cinchonine, (—(-quinine, and (+)-quinidine], the Park-Jew group primarily prepared (—) -cinchonidine derivatives to identify both the optimal linker and best relationship of attachment for the two cinchona units, and to compare catalytic efficiency with that of monomeric cinchona-PTCs. 

By screening solvent and inorganic bases to establish the optimal reaction conditions for dimeric chiral PTCs, a toluenexhloroform (7 3, v/v) solvent system and a 50% aqueous KOH base were found to afford the best enantioselectivity and chemical yield within a reasonable reaction time. As dimeric cinchona-PTCs are very poorly soluble in toluene (one of the popular solvents in asymmetric alkylation), this might act as an obstacle for the catalyst to show its maximum ability. However, the addition of chloroform to toluene provided better results due to an improved solubility of the dimeric PTC. This difference in ability to dissolve the dimeric PTC might be heavily associated not only with the reaction rate but also with the chemical/ optical yield. However, the use of chloroform alone proved to be inadequate as an optimal solvent [10]. 

Figure 4.7 The probable structure of the dimeric cinchona-PTC 4 (top), and a stereoview of a plausible model ofthe preferred three-dimensional arrangement of the ion pair from 7 and one (ortwo) l -eriolate(s) ofl, based on an understanding of the enantioselectivity (bottom).

Polymeric Cinchona-PTCs with Other Linkers... 

Phenyl- and 2,7-Naphthyl-Linked Dimeric Cinchona-PTCs... 

Figure 4.8 Polymeric cinchona-PTCs with other linkers.

With these anthracene-linked dimeric cinchona-PTCs, the Najera group investigated the counterion effect in asymmetric alkylation of 1 by exchanging the classical chloride or bromide anion with tetrafluoroborate (BF4 ) or hexafluorophosphate (PF6-) anions (Scheme 4.10) [17]. They anticipated that both tetrafluoroborate and hexafluorophosphate could form less-tight ionic pairs than chloride or bromide, thus allowing a more easy and rapid complexation of the chiral ammonium cation with the enolate of 1, and therefore driving to a higher enantioselectivity. However, when... 

The Siva group reported another type of dimeric cinchona-PTC containing an aliphatic tetra-azacyclotetradecane-based-linker (56 and 57), and their application to the asymmetric alkylation of 1 (Scheme 4.12) [19]. In general, high chemical and optical yields were obtained, even with a lower dimeric PTC loading of (1.5 mol%) compared to the more commonly used level (5.0mol%). 

Asymmetric Epoxidation with Polymeric Cinchona-PTCs 63... 

Besides the asymmetric alkylation of 1 for the synthesis of higher a-amino acid derivatives, the Park-Jew group applied their dimeric cinchona-PTCs to the... 

Quite recently, one of the most efficient phase-transfer-catalyzed epoxidation methods for chalcone-type enones was developed by the Park-Jew group [11], A series of meta-dimeric cinchona PTCs with modified phenyl linkers were prepared. Among this series, the 2-fluoro substituted catalyst 5, exhibited unprecedented activity and enantioselectivity for the epoxidation of various trans-chalcones in the... 

In 1984, the first successful monumental use of cinchona PTC for asymmetric a-substitution of carbonyls was reported by Dolling and coworkers of the Merck research group (Scheme 6.1) [8], In this work, cinchoninium salt (1) was employed in the catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone (2) under phase-transfer conditions. The methylated product 3, which was finally transformed to (+ )-indacrinone through three further steps, was obtained in 95% conversion with 92% enantiomeric excess (ee). Through the systematic investigation, the group reported the relationship between the chemical/optical yield and the reaction variables (e.g., amount or concentration of each chemical species, halide of... 

The Merck group s report has undoubtedly sparked the development of efficient catalytic organic reaction systems using structurally well-defined chiral organocata-lysts. Cinchona alkaloids have taken the lead in this research area, and, as a matter of course, a variety of cinchona PTCs have been newly developed and applied to diverse... 

---