Catalysts cinchona

There are two views on the origin of enantiodifferentiation (ED) using Pt-cinchona catalyst system. In the classical approach it has been proposed that the ED takes place on the metal crystallite of sufficient size required for the adsorption of the chiral modifier, the reactant and hydrogen [8], Contrary to that the shielding effect model suggest the formation of substrate-modifier complex in the liquid phase and its hydrogenation over Pt sites [9],... 

A cursory examination of the Cinchona catalysts used in O Donnell-type alkylation [90] of methyl (diphenylimino)glycinate (Appendix 7.A) reveals that only minor modifications to the Cinchona scaffold are required for the synthesis of a catalyst the 8-substituent on the quinuclidine core may either be a vinyl group (as in the parent alkaloids, quinine and quinidine) or can be an ethyl substituent, introduced by hydrogenation. The quinoline system at the 2-position ofthe quinuclidine ring can be unsubstituted if the catalyst is derived from quinine or quinidine, but can contain a 6-methoxy group ifit is derived from cinchonine or cinchonidine. The 3-position ofthe quinuclidine ring may contain either a hydroxy group or else a vinyloxy or benzyloxy... 

Cinchona catalysts that fulfill one of these criteria acceptably well have the entry related to that criterion (i.e. either relative molecular mass, number of steps required to make the catalyst, reaction yield, , mole percentage of catalyst, or biodegradability prediction based on rules of thumb broken) represented in bold in Appendix 7. A. Notably, in spite of their natural origin, none of the Cinchona catalysts is completely benign in terms of the rules of thumb for biodegradability, with the best examples (Entries 4 [108] and 31-33 [109, 116]) breaking only two of the rules. 

For the Pt/cinchona catalysts only preliminary adsorption studies have been reported [30]. From the fact that in situ modification is possible and that under preparative conditions a constant optical yield is observed we conclude that in this case there is a dynamic equilibrium between cinchona molecules in solution and adsorbed modifier. This is supported by an interesting experiment by Margitfalvi [63] When cinchonine is added to the reaction solution of ethyl pyruvate and a catalyst pre-modified with cinchonidine, the enantiomeric excess changes within a few minutes from (R)- to (S)-methyl lactate, suggesting that the cinchonidine has been replaced on the platinum surface by the excess cinchonine. 

A number of other types of compounds have been used as chiral catalysts in phase-transfer reactions. Many of these compounds embody the key structural component, a P-hydroxyam-monium salt-type structure, which has been shown to be crucial to the success of the above described cinchona-derived quats. Although they have not been as successful as the cinchona catalysts, the ephedra-alkaloid derived catalysts (see 20, 22, 23 and 25 in Charts 3 and 4) have been used effectively in several reactions. In general, quats with chirality derived only from a single chiral center, which cannot participate in a multipoint interaction with other reaction species, have not been effective catalysts [80]. 

Carbon-Nitrogen Bonds. Several groups have studied the synthesis of optically active a-amino acids from inexpensive and readily available a-haloesters by displacement with phthalimide in the presence of chiral cinchona catalysts [1 le,24h,24i,47e,60d,77]. Early studies, with chiral, non-racemic starting material, showed that this reaction occurs with partial... 

Significant progress in the substrate scope of the Pt-cinchona systems has been made in the last 5 years. Besides a-keto acids and esters, a-keto acetals, a-keto ethers, and some trifluoromethyl ketones have been shown to give high ee s. It is now possible to classify ketones concerning their suitability as substrates for the Pt-cinchona catalyst system, as depicted in Figure 18.6. Nevertheless, for the synthetic chemist, the substrate scope is still relatively narrow, and it is not expected that new important substrate classes will be found in the near future. However, the chemoselectivity of this system has not yet been exploited to its full value, and this might be a potential for future synthetically useful applications. 

In contrast to asymmetric oxidation chemistry, cinchona-catalyzed asymmetric reduction reactions have been explored very little, despite the importance of this reaction. Previous reports on this topic are restricted to the reduction of aromatic ketones, and the enantioselectivities achieved to date remain far from satisfactory when compared with metal catalysis. Moreover, Hantsch esters, another type of useful organic hydrides, have not yet been studied in combination with cinchona catalysts. However, as is well known, the structures of cinchona alkaloids are easily modifiable, thus permitting the easy tuning of the reaction course. The successful use of cinchona catalysts for this reaction will therefore likely be reported in the very near future. 

In 2005, Lectka and coworkers also reported a-cMorination of acid halide by using polymer-supported cinchona catalyst via a column-based flush and flow system (Scheme 6.37) [66]. To a column of quinine-bound Wang resin 126 were added 120 and 123, then the eluent (THF) was flowed by flushing to afford the corresponding a-chloroesters 125 up to 94% ee. 

In 2006, Lectka and coworkers upgraded the enantioselective a-bromination with (R)-prolinc incorporated cinchona catalyst 129 and new bromination agent 127 (Scheme 6.38) [67]. It was notable that (R)-proline incorporated cinchona catalyst gave quite higher enantioselectivity (95% ee) than that of (S)-proline incorporated cinchona catalyst (88% ee) and their previous catalyst 122 in a-bromination of phenylacetyl chloride. 

Scheme 4.7 Influence of cinchona catalysts structure on the yield and enantioselec-tivity of the Michael reaction of dimethyl malonate with nitrostyrene.

Although dimeric Sharpless ligands, as another kind of cinchona catalyst, showed impressive results in related organocatalytic transformations, they provided only limited success in asymmetric MBH reactions (Scheme 2.78). These compounds can act as bifunctional catalysts in the presence of acid... 

The conceptually different activation of carbonyl substrates through the formation of a nucleophilic enamine or an electrophilic iminium ion is achieved by use of 9-deo>q -ep/-9-amino Cinchona catalysts. In contrast to typical secondary amine-based catalysts i.e. derived from proline), the primary amine of these modified Cinchona alkaloids can combine also with sterically biased substrates, such as ketones and hindered aldehydes. This class of catalyst has thus allowed the scope of aminocatalysis to be extended beyond unhindered aldehydes/enals, and has proved to be remarkably powerful and general. 

Scheme 14.7 Catalytic asymmetric conjugate Friedel-Crafts-type addition of indoles to enones catalysed by primaiy amine Cinchona catalysts, and reaction transition state.

However, the enantioselectivities remained unsatisfactory. In 2003, Park and coworkers designed new substrates to increase the enantioselectivities of a,a-diallq l-ot-amino acids. After systematic optimisation of the aldimine substrates and reaction conditions, allqrlation of the 2-naphthyl aldimines of alanine tert-butyl esters (17) with rubidium hydroxide and the electronically optimised Cinchona catalyst 8d, at 35 °C, was shown to afford the corresponding (5)-a-allqrl-alanines, 18, with up to 96% enantiomeric excess (Scheme 16.10). ... 

Cinchona catalyst inactivation via a Friedel-Crafts-type reaction with the dicarboxylate esters has been invoked to explain eroded yields and selectivities... 

Whereas the chalcones represent model substrates for the evaluation of new oxidations protocols, many authors have applied these exact or similar conditions to the epoxidation of naphthoquinones and quinone derivatives. Thus, Taylor s group epoxidized quinone-acetal 97 (Scheme 12.23) in good ee (89%) and moderate yield (32%). Epoxide 98 was used in the synthesis of (+)-Manumycin A [154]. Other naphthoquinones have been oxidized in good yields using similar conditions and slight modifications on the cinchona catalyst [155]. 

Additionally, some non-cinchona catalysts have also been applied for the epoxidation of chalcones and electron-deficient olefins. Maruoka s group [156] demonstrated that 3 mol% of ammonium salt 96 with NaOCl as oxidant allows the epoxidation of chalcones with excellent yields and enantioselectivities (Scheme 12.24). 

The use of dimeric cinchona catalyst 97 for the epoxidation of enones in the presence of surfactants (span 20) is highly effective for the epoxidation of chalcones (Scheme 12.25). Only 1 mol% of the catalyst was needed to obtain excellent enantioselectivities (97-99%) [157]. 

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