Cinchona alkaloid derivative

Cinchonine and Cinchonidine are Cinchona Alkaloids lacking the 6 -methoxy group. 

---

One of the most significant developmental advances in the Jacobsen-Katsuki epoxidation reaction was the discovery that certain additives can have a profound and often beneficial effect on the reaction. Katsuki first discovered that iV-oxides were particularly beneficial additives. Since then it has become clear that the addition of iV-oxides such as 4-phenylpyridine-iV-oxide (4-PPNO) often increases catalyst turnovers, improves enantioselectivity, diastereoselectivity, and epoxides yields. Other additives that have been found to be especially beneficial under certain conditions are imidazole and cinchona alkaloid derived salts vide infra). 

The actual catalyst is a complex formed from osmium tetroxide and a chiral ligand, e.g. dihydroquinine (DHQ) 9, dihydroquinidine (DHQD), Zj -dihydroqui-nine-phthalazine 10 or the respective dihydroquinidine derivative. The expensive and toxic osmium tetroxide is employed in small amounts only, together with a less expensive co-oxidant, e.g. potassium hexacyanoferrate(lll), which is used in stoichiometric quantities. The chiral ligand is also required in small amounts only. For the bench chemist, the procedure for the asymmetric fihydroxylation has been simplified with commercially available mixtures of reagents, e.g. AD-mix-a or AD-mix-/3, ° containing the appropriate cinchona alkaloid derivative ... 

Table 1.12 Cinchona alkaloid-derived phase-transfer catalysts for asymmetric Darzens reactions.

Scheme 10. Asymmetric synthesis of the a,a-dialkyl-a-amino acids 37 by use of the cinchona alkaloid derivative 12.

Scheme 19. Asymmetric Michael reaction by use of cinchona alkaloid derivatives.

R. S. E. Conn, A. V. Lovell, S. Karady, L. M. Weinstock, Chiral Michael Addition Methyl Vinyl Ketone Addition Catalyzed by Cinchona Alkaloid Derivatives , J. Org Chem. 1986, 51, 4710-4711. 

The first silica-supported CSP with a cinchona alkaloid-derived chromatographic ligand was described by Rosini et al. [20]. The native cinchona alkaloids quinine and quinidine were immobilized via a spacer at the vinyl group of the quinuclidine ring. A number of distinct cinchona alkaloid-based CSPs were subsequently developed by various groups, including derivatives with free C9-hydroxyl group [17,21-27] or esterified C9-hydroxyl [28,29]. All of these CSPs suffered from low enantiose-lectivities, narrow application spectra, and partly limited stability (e.g., acetylated phases). 

Meanwhile, a wide variety of cinchona alkaloid derivatives have been systematically developed as chiral selectors, which complement each other in their enantiomer discrimination profiles. Considering the variety of derivatives, an overall reasonably broad applicability spectrum, approximating for chiral acids a 100% success rate, is yielded and extreme enantiorecognition levels (a-values above 15) could be realized for some chiral solutes with certain selectors. Moreover, various studies carried out with the CHIRALPAK QD/QN-AX columns in industry and academia clearly document their practical usefulness for solving challenging real-life problems and this should be illustrated by the present review article as well. 

Some other cinchona alkaloid derivatives that have been synthesized and were evaluated as chiral selectors for liquid chromatographic enantiomer separation comprise CSPs based on cinchonan hydrazides [68], cinchonan ureas [42], cin-chonan amides [42], and urea-linked cinchonan-calixarene hybrid selectors [42]... 

A copolymerization approach of 0-9-[2-(methacryloyloxy)ethylcarbamoyl] cinchonine and cinchonidine with methacryl-modified aminopropylsilica particles was utilized by Lee et al. [71] for the immobilization of the cinchona alkaloid-derived selectors onto silica gel. The CSPs synthesized by this copolymerization procedure exhibited merely a moderate enantiomer separation capability and only toward a few racemates (probably because they were based on less stereodifferentiating cinchonine and cinchonidine). Moreover, the chromatographic efficiencies of these polymer-type CSPs were also disappointing. 

Since the cinchona alkaloid-derived selectors do possess two basic sites, the qui-nuclidine and quinoline nitrogens with the former being more basic, ion-pairs of 1 1 or 2 1 stoichiometry could be formed. To shed light on this issue, the binding stoichiometry was investigated by Maier et al. [92] and Czerwenka et al. [93]... 

Applicability Spectrum of Cinchona Alkaloid-Derived CSPs for Miscellaneous Chiral Acids... 

The separation mechanism is based on stereoselective ion-pair formation of oppositely charged cationic selector and anionic solutes, which leads to a difference of net migration velocities of the both enantiomers in the electric field. Thus, the basic cinchona alkaloid derivative is added as chiral counterion to the BGE. Under the chosen acidic conditions of the BGE, the positively charged counterion associates with the acidic chiral analytes usually with 1 1 stoichiometry to form electrically neutral ion-pairs, which do not show self-electrophoretic mobility but... 

Over more than 10 years, there have been a rather large number of people involved in the development and testing of the various cinchona alkaloid derivatives and CSPs,... 

Examines chiral stationary phases containing cinchona alkaloid-derived materials... 

Cinchona Alkaloid-Derived Enantioselective Separation Materials.. 

Moreover, looking for more effective ligands, Sharpless and his group prepared and tested a number of cinchona alkaloid derivatives, first in the stoichiometric ADH process [33] and then in the catalytic process. They found that aryl ethers of dihydroquinidine, as 4a and 4b, are excellent ligands for ADH of dialkyl substituted olefins (Table 10.3). 

Janda, Bolm and Zhang generated soluble polymer-bound catalysts for the asymmetric dihydroxylation by attaching cinchona alkaloid derivatives to polyethylene glycol monomethyl ether (MeO-PEG) [84—87]. Since these polymeric catalysts like (24) are soluble in many common solvents they are often as effective as their small homogenous counterparts. Janda et al. prepared catalyst (24) in which two dihydroquinidine (DHQD) units were linked together by phthalazine and finally were attached to MeO-PEG via one of the bicyclic ring system moieties (Scheme... 

While this manuscript was under preparation, a considerable number of examples of sohd-phase-attached catalysts appeared in the literature which is a clear indication for the dynamic character of this field. These include catalysts based on palladium [131, 132], nickel [133] and rhodium [134] as well applications in hydrogenations including transfer hydrogenations [135, 136] and oxidations [137]. In addition various articles have appeared that are dedicated to immobilized chiral h-gands for asymmetric synthesis such as chiral binol [138], salen [139], and bisoxa-zoline [140] cinchona alkaloid derived [141] complexes. 

O Donnell (1989), Corey/Lygo (1997) cinchona alkaloid-derived quaternary ammonium salts Lewis Base Cataiysis... 

---