Chiral catalysts Enantioselective variation

If the above research is an indication, the catalytic enantioselective variants of many of these exciting transformations will soon be disclosed in our leading journals. Another challenge in this area remains the difficulty encountered in preparing chiral zirconocene catalysts, particularly since many of the reactions promoted by this group of chiral catalysts cannot be effected by the non-metallocene variants. Thus, the development of more practical, but equally or even more selective and efficient variations of existing methods should not be viewed as any less significant. 

Further attempts by introducing Y + R and Y + S interactions showed that both the enantioselectivity reversal in the presence of competing chiral or achiral catalysts as well as the experimentally observed variation of the transition step as a function of the structure of the chiral catalyst can be addressed by the same approach [82],... 

A variation of the Sharpless asymmetric epoxidation is to employ chiral hydroperoxides. The chiral iminium salt 89 has moderate enantiocontrol for epoxidation. Quatemized cinchona alkaloids can serve as chiral catalyst and phase-transfer agents in epoxidation of enones with NaOCl. Enones are also epoxidized by oxygen in the presence of diethylzinc and A-methylpseudoephedrine, whereas IZj-enones are submitted to enantioselective epoxidation by t-BuOOH-O-PrO),Yb and the BINOL 90. 

The 3-amino alcohols 35a-g represent the latest variation on the theme of chiral promoters for the enantioselective addition of dialkylzinc reagents to im-ines (Scheme 17) [38]. Andersson and co-workers interest in the use of chiral, sterically constrained P-amino alcohols with the 2-azanorbornyl skeleton led them to consider such bicychc P-amino alcohols as chiral catalysts in the above-mentioned addition reaction. One important feature of these ligands is the fact that both enantiomers are equally available. The common precursor for all the ligands was 34 which could be constructed via an aza-Diels-Alder reaction. The synthesis of the bicychc amino alcohols 35a-g is depicted in Scheme 17. 

In all of the examples considered so far, the chiral element has been employed in stoichiometric quantities. Ultimately, it would be desirable to require only a small investment from the chirality pool. This is only possible if the chiral species responsible for enantioselectivity is catalytic. It is worth stating explicitly that, in order to achieve asymmetric induction with a chiral catalyst, the catalyzed reaction must proceed faster than the uncatalyzed reaction. One example of an asymmetric aldol addition that has been studied is variations of the Mukaiyama aldol reaction [110] whereby silyl enol ethers react with aldehydes with the aid of a chiral Lewis acid. These reactions proceed via open transition structures such as those shown in Figure... 

This reduction method has a number of advantages that include wide scope, predictable absolute stereochemistry, ready availability of the chiral catalyst in both enantiomeric forms, high yields, experimental ease, recovery of the catalyst (as the amino alcohol), and low cost of goods. The most common form of the chiral oxazaborolidine is derived from prolinol and has a methyl substituent on the boron atom (B-Me-CBS) 1. When one conducts a reduction on a novel system for the first time, this catalyst provides a good compromise of cost, enantioselectivity, and experimental ease. If sufficient control is not observed with this reagent, one can then systematically evaluate the numerous variations of this framework. 

Jurczak and co-workers have developed an enantioselective variation of the Friedel-Crafts reaction to produce hydroxyl(thiophene-2-yl)acetates from the reaction of thiophenes with glyoxylates in the presence of a chiral BINOL-titanium catalyst. The desired thiophenes can be produced in high enantiomeric excess and can be utilized as a key intermediates in the synthesis of duloxetine. 

The a-amino acids prepared by the synthetic methods just described are racemic unless a resolution step is included, enantiomerically enriched reactants are used, or the reaction is modified so as to become enantioselective. Considerable progress has been made in the last of these methods, allowing chemists to prepare not only L-amino acids, but also their much rarer D-enantiomers. We have already seen one example of this approach in the synthesis of the anti-parkinsonism drug L-dopa by enantioselective hydrogenation (see Section 14.14). A variation of the Strecker synthesis using a chiral catalyst has recently been developed that gives a-amino acids with greater than 99% enantioselectivity. 

A more efficient approach to control the stereochemical outcome for the Robinson annulation can be through the use of chiral catalysts such as in the case of the enantioselective Hajos-Wiechert variation introduced earlier. There are other chiral agents other than the popular (S)-proline-mediated annulation reaction that are used for these transformations—for example the use of (Bronsted acid such as trifluoroacetic (TFA). This new catalyst for the Robinson annulation was reported in 2007 by Endo et. al., where the Bronsted acid, contrary to Hajos-Wiechert reaction, gives the (i )-isomer of the Wieland-Miescher ketone 44 in a moderate yield of 47% and 75% ee. 

The results indicate that non-systematic variation of the structure of chbal ligands leads to a casual degree of enantioselectivity. This statement is valid for aU enantioselective catalytic processes. Systematic study of chiral catalysts and reaction conditions is required to reach high enantioselectivity. 

No discussion is offered, concerning the sense of the observed enantioselectivity in this reaction because of a need to be cautious We have observed that the sense of the enantioselectivity can be reversed simply by a variation of the procedure used for catalyst modification [15], and this has been confirmed by others [16] Thus it appears that the state of the Pd surface, as well as the nature of the species adsorbed upon it and their spatial relationship, contributes to chiral direction in this reaction. 

Variation in catalyst and ligand can lead to changes in both regio- and enantio-selectivity. For example, the hydroboration of vinyl arenes such as styrene and 6-methoxy-2-vinylnaphthalene can be directed to the internal secondary borane by use of Rh(COD)2BF4 as a catalyst.166 These reactions are enantioselective in the presence of a chiral phosphorus ligand. 

Systematic variation in chirality at both the chelate backbone and the terminal groups revealed a remarkable effect on the enantioselectivity of the catalysts. Ligand (109) generates chiral cooperativity between the backbone and the terminal moieties in Pt-catalyzed hydroformylation. The highest ee (65%) for 2-phenylpropanal was found for the ligand R-bis(S)-(110) in combination with Pt. The chemoselectivities with all ligands described in association with Pt were rather low. The comparative... 

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