Cinchona dimerization

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

Osmium tetroxide hydroxylations can be highly enantioselective in the presence of chiral ligands. The most highly developed ligands are derived from the cinchona alkaloids dihydroquinine and dihydroquinidine.40 The most effective ligands are dimeric derivatives... 

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

The development of polymeric cinchona-derived PTCs was triggered by the group of Jew and Park in 2001 [8]. The group paid particular attention to the fact that the cinchona alkaloids have demonstrated great utility in the Sharpless asymmetric dihydroxylation. Especially, it was noted that the significant improvements in both stereoselectivity and scope of the asymmetric dihydroxylation were achieved when the dimeric ligands of two independent cinchona alkaloid units attached to heterocyclic spacers were used, such as (DHQ)2-PHAL or (DHQD)2-PYR (Figure 4.4) [9]. 

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.

Scheme 4.2 General synthetic scheme for cinchona-derived dimeric quaternary ammonium salts, (a) bis(Bromomethyl)-linkers (0.5 equiv.), EtOH-DMF-CHCI3 (5 6 2), r.t. or reflux, (b) Allyl bromide or benzyl bromide (6.0 equiv.), 50% KOH (10.0 equiv.), CH2CI2, r.t.

The lack of any difference in enantioselectivity between the 1,4-phenyl-dimeric PTC S and the monomeric PTC M implies that the two cinchona alkaloid units of the 1,4-phenyl-dimeric PTC do not sterically affect each other. In the case of 1,2-phenyl-dimeric PTC 3, the severe steric repulsion between the two cinchona alkaloid units may lead to an unfavorable conformation, thereby affording poor enantioselectivity. 

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]. 

The probable structure of the 1,3-phenyl-dimeric catalyst 4 is shown in Figure 4.7. This is based on the results of an X-ray crystallographic study in which the conformation of the two cinchona alkaloid units are placed in a direction of anti-relationship to each other. The figure also shows that each cinchona alkaloid unit... 

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).

Based on the fact that the meta-relationship in catalyst 7 showed good activity in asymmetric alkylation, the same concept was applied to the 1,3,5-trimeric catalyst 36, in which all cinchona units on the phenyl ring were placed in the meta-position to each other hence, it would be expected this relationship might increase or maintain the catalytic efficiency of the meta-dimeric effect. Compared with the result from 7, the effect of trimerization could be regarded as quite similar to that of the metadirecting-dimerization in chemical and optical yields [14]. 

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

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%). 

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... 

During the search for the optimal dimeric PTC for this epoxidation, the Park-Jew group found an interesting result, namely that the functional groups of 9-0 H and 6 -OMe in the cinchona unit, along with 2-F group in the phenyl linker, were critical factors for high enantioselectivity of the reaction (Scheme 4.16). 

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

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