Pseudo-enantiomeric catalysts

Most recently, Kiindig has developed some related l,2-di(ferf-amine) catalysts which can be readily prepared from pseudo-enantiomeric quincoridines. These catalysts were shown to be more effective than those disclosed by Oriyama when applied to the ASD of a meso-Caol complex derived from [Cr(CO)3(q -5,8-naphthoquinone)] [188,189],... 

This asymmetric phase-transfer method has been applied to enantio-selective Robinson annelation as shown in Scheme 14 (41). First, alkylation of a 1-indanone derivative with the Wichtetie reagent as a methyl vinyl ketone equivalent in the presence of p-CF3BCNB gives the S-alkylation product in 92% ee and 99% yield. With 1 -(p-trifluoro-methylbenzyl)cinchonidinium bromide, a pseudo-enantiomeric diaste-reomer of p-CF3BCNB, as catalyst, the -alkylation product is obtained in 78% ee and 99% yield. These products are readily convertible to the... 

The MS assay has also been applied successfully in the directed evolution of enantioselective epoxide hydrolases acting as catalysts in the kinetic resolution of chiral epoxides [35]. Moreover, Diversa has recently employed the MS-based technique for desymmetrization of a prochiral dinitrile catalyzed by mutant nitrilases [36]. In this industrial application one of the nitrile moieties was labeled with 15N, which means that the two pseudo enantiomeric products differ by only one mass unit. 

A similar approach was reported by Lygo and co-workers who applied comparable anthracenylmethyl-based ammonium salts of type 26 in combination with 50% aqueous potassium hydroxide as a basic system at room temperature [26, 27a], Under these conditions the required O-alkylation at the alkaloid catalyst s hydroxyl group occurs in situ. The enantioselective alkylation reactions proceeded with somewhat lower enantioselectivity (up to 91% ee) compared with the results obtained with the Corey catalyst 25. The overall yields of esters of type 27 (obtained after imine hydrolysis) were in the range 40 to 86% [26]. A selected example is shown in Scheme 3.7. Because the pseudo-enantiomeric catalyst pairs 25 and 26 led to opposite enantiomers with comparable enantioselectivity, this procedure enables convenient access to both enantiomers. Recently, the Lygo group reported an in situ-preparation of the alkaloid-based phase transfer catalyst [27b] as well as the application of a new, highly effective phase-transfer catalyst derived from a-methyl-naphthylamine, which was found by screening of a catalyst library [27c],... 

It was mentioned at the beginning of this chapter that alkaloids were among the first catalysts to be used for asymmetric hydrocyanation of aldehydes. More recent work by Tian and Deng has shown that the pseudo-enantiomeric alkaloid derivatives 5/6 and 7/8 catalyze the asymmetric addition of ethyl cyanoformate to aliphatic ketones (Scheme 6.6) [50]. It is believed that the catalytic cycle is initiated by the alkaloid tertiary amine reacting with ethyl cyanoformate to form a chiral cyanide/acylammonium ion pair, followed by addition of cyanide to the ketone and acylation of the resulting cyanoalkoxide. Potentially, the latter reaction step occurs with dynamic kinetic resolution of the cyano alkoxide intermediate... 

As summarized in Scheme 6.6, the cyanohydrins of a,a-dialkylated and a-acetal ketones were obtained with quite remarkable enantiomeric excess. Clearly the pseudo-enantiomeric catalyst pairs 5/6 and 7/8 afford products of opposite configuration. Catalyst loadings were in the range 10-35 mol%. 

In a different ongoing study, a Bacillus subtilis lipase has been chosen as the catalyst in the asymmetric hydrolysis of the meso-diacetate 11 with formation of enantiomeric alcohols 12 (Fig. 11.19) [82]. This reaction does not constitute kinetic resolution and can thus be carried out to 100 % conversion. Screening is possible on the basis of the ESI-MS system [50] (see above) using the deuterium labeled pseudo-meso substrate 13 (Fig. 11.20). The ratio of the two pseudo-enantiomeric products 14 and 15 can easily be determined by integrating the two appropriate MS peaks. 

Homogeneous catalyst Na2PdCl4-K20s04-Naw04 H2O (DHQ)2-PHAL, pseudo enantiomeric ligand is used... 

Better levels of enantioselectivity have been achieved using different carbamates as nitrogen-atom source to perform this transformation. Hence, using N-chloro-N-sodium benzylcarbamate (6) and cinchoninium salt 7a, as a phase-transfer catalyst, in the aziridination of dimethylpyrazole acrylate 5 afforded the corresponding aziridine [12], which was further treated with N,N-dimethylaminopyridine (DMAP) to give the methyl-ester substituted aziridine 8 (Scheme 27.3). The use of the pseudo-enantiomeric cinchonidinium salt led to the aziridine with the opposite absolute configuration, as expected. 

S)-proline-catalyzed reaction is not sufficient therefore, a large number of (S)-proline-derived secondary amine catalysts have been developed. Primary amine catalysts derived from natural amino acids and cinchona alkaloids have also emerged as highly versatile and powerful catalysts [25]. For example, in the intramolecular 6-endo aldol reaction of diketone 43, quinine-derived primary amine 44 in acetic acid affords the cyclic ketone (S)-46 in 94% yield with 90% ee (Scheme 28.3) (S)-prohne gives the cycUzation product in low yield with moderate ee. In addition, the pseudo-enantiomeric quinidine-derived primary amine 45 deUvers the opposite product, the (R)-enantiomer 46, with similar yield and enantioselectivity [26]. 

Molybdenum catalysts that contain enantiomerically pure diolates are prime targets for asymmetric RCM (ARCM). Enantiomerically pure molybdenum catalysts have been prepared that contain a tartrate-based diolate [86], a binaph-tholate [87], or a diolate derived from a traris-1,2-disubstituted cyclopentane [89, 90], as mentioned in an earlier section. A catalyst that contains the diolate derived from a traris-1,2-disubstituted cyclopentane has been employed in an attempt to form cyclic alkenes asymmetrically via kinetic resolution (inter alia) of substrates A and B (Eqs. 45,46) where OR is acetate or a siloxide [89,90]. Reactions taken to -50% consumption yielded unreacted substrate that had an ee between 20% and 40%. When A (OR=acetate) was taken to 90% conversion, the ee of residual A was 84%. The relatively low enantioselectivity might be ascribed to the slow interconversion of syn and anti rotamers of the intermediates or to the relatively floppy nature of the diolate that forms a pseudo nine-membered ring containing the metal. 

Clearly, upon using the enantiomeric catalyst [(S,S) instead of (R,R)] the opposite enantioselectivity of the overall process results. However, this effect is also seen with catalysts that are of analogous configuration, but not derived from trans-1,2-diaminocyclohexane (DACH). For example, the pseudo-ephedrine derived catalyst shown in Scheme 5, having (5)-configuration at the centers of chirality, shows some preference for the (5)-azlactone kinetically favors the (5)-azlactone in alcoholytic ring opening [37]. 

The high-c/s polymer of 242 (see above), when made from enantiomeric monomer, has a mainly HH, TT structure and is therefore largely syndiotactic. On the other hand, the 96% Inins polymer made from enantiomeric monomer with RLiC.I(/i-C.I)(r 3 r 3-C. oHi6)]2 as catalyst (C10H16 = 2,7-dimethyloctadienediyl) has an HT structure and is therefore essentially isotactic. These tacticities are as predicted from the pseudo-octahedral model if the ligands are not labile and one site is available for coordination of monomer319 see Section VIII.A.5. 

Kinetic resolution of chiral, racemic anhydrides In this process the racemic mixture of a chiral anhydride is exposed to the alcohol nucleophile in the presence of a chiral catalyst such as A (Scheme 13.2, middle). Under these conditions, one substrate enantiomer is converted to a mono-ester whereas the other remains unchanged. Application of catalyst B (usually the enantiomer or a pseudo-enantiomer of A) results in transformation/non-transformation of the enantiomeric starting anhydride ). As usual for kinetic resolution, substrate conversion/product yield(s) are intrinsically limited to a maximum of 50%. For normal anhydrides (X = CR2), both carbonyl groups can engage in ester formation, and the product formulas in Scheme 13.1 are drawn arbitrarily. This section also covers the catalytic asymmetric alcoholysis of a-hydroxy acid O-carboxy anhydrides (X = O) and of a-amino acid N-carboxy anhydrides (X = NR). In these reactions the electrophilicity of the carbonyl groups flanking X is reduced and regioselective attack of the alcohol nucleophile on the other carbonyl function results. 

These nitrogen-containing natural products, often with powerful biological properties, are not usually incorporated into target molecules. However, they are important in asymmetric syntheses as the foundations of many reagents and catalysts. Quinine 119 is familiar as an anti-malarial and an ingredient in tonic water. Quinine and its twin cinchona alkaloid quinidine 118 are referred to as pseudo enantiomers. Each occurs naturally as one enantiomer only but the two structures are nearly enantiomeric only the vinyl side-chains disturb the symmetry and they act as enantiomers. The vinyl side-chains are reduced and two molecules of, say, dihydroquinine (DHQ) are joined... 

Examples of the modeling results at different experimental temperatures are presented in Fig. 9.13. A very good model fit to the experimental data was obtained, while kinetic models based on a pseudo-steady-state on the catalyst surface fail to describe the present system. The concentration versus the time-on-stream behavior is correctly predicted by the model, including the consumption of the reactant (A) as well as the formation of the two-product enantiomers (B and C). Consequendy, the model is able to describe the enantiomeric excess as a function of time-on-stream and provides valuable information about the behavior of complex organic reactions systems. The approach presented here is applicable to any catalytic three-phase system operated under transient conditions. 

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