Enantioselective quinidine

This technology was extended to the preparation of chiral capillary columns [ 138 -141 ]. For example, enantioselective columns were prepared using a simple copolymerization of mixtures of O-[2-(methacryloyloxy)ethylcarbamoyl]-10,11-dihydro quinidine, ethylene dimethacrylate, and 2-hydroxyethyl methacrylate in the presence of mixture of cyclohexanol and 1-dodecanol as porogenic solvents. The porous properties of the monolithic columns can easily be controlled through changes in the composition of this binary solvent. Very high column efficiencies of 250,000 plates/m and good selectivities were achieved for the separations of numerous enantiomers [140]. 

Overall, the /er/-butyl carbamates of quinine and quinidine evolved as the most effective chiral selectors among this family because of their broad enantioselectivity spectmm and exceptional degree of selectivity for a wide variety of chiral acids. On... 

The calorimetric binding isotherms of the carbamoylated quinine and quinidine selectors clearly reveal that the heats released upon binding are strongly different for 5- and R-enantiomers of DNB-Leu, which is commensurate with the remarkable enantioselective molecular recognition capability of these selectors (Figure 1.14a,b). As can be seen from Table 1.4, the binding constants for R- and 5-enantiomers differ by about one order of magnitude in case of the carbamate-type selectors. Furthermore,... 

Ultrapurification of 50 mmolL DNB-D,L-Leucine in a Cascade of Five Stages with Two Modules and Two Enantiomeric Carrier (Quinine and Quinidine Derivative with 5 vol% Polysiloxane-supported Carrier) Transmembrane Material Stream J, Enantioselectivity a, Enantiomer Excess ee, Purity, and Yield of DNB-D-Leucine... 

The use of compounds with activated methylene protons (doubly activated) enables the use of a mild base during the Neber reaction to 277-azirines. Using ketoxime 4-toluenesulfonates of 3-oxocarboxylic esters 539 as starting materials and a catalytic quantity of chiral tertiary base for the reaction, moderate to high enantioselectivity (44-82% ee) was achieved (equation 240). This asymmetric conversion was observed for the three pairs of Cinchona alkaloids (Cinchonine/Cinchonidine, Quinine/Quinidine and Dihydro-quinine/Dihydroquinidine). When the pseudoenantiomers of the alkaloid bases were used, opposite enantioselectivity was observed in the reaction. This fact shows that the absolute configuration of the predominant azirine can be controlled by base selection. 

A simple method for asymmetric synthesis of 2//-azirine-2-phophonates 540 was described, using various alkaloids as bases (equation 241). Moderate to good asymmetric induction was observed (69-94% yield, 33-72% ee) when quinidine was used as the base (the S isomer was obtained). A solid-phase asymmetric synthesis was also performed (541 and 542 used as bases) and good yields were usually obtained (43-88%) but only low enantioselectivity was achieved (3-11%). 

As with other ester enolate rearrangements, the presence of chiral ligands can render the reaction enantioselective. Use of quinine or quinidine with the chelating metal leads to enantioselectivity (see entry 21 in Scheme 6.12). 

Asymmetric ring opening of achiral monocyclic, bicyclic and tricyclic anhydrides under formation of the corresponding chiral monoesters can be accomplished in high yield with modest enantioselectivity with methanol in the presence of less than stoichiometric amounts of cinchona alkaloids in toluene or diethyl ether (Table 9)91 94. As expected the use of cinchonine A or quinidine C, and of cinchonidine B or quinine D gives opposite enantiomers. Recrystallization of the monoesters and lactones affords material of considerably higher enantiomeric purity (Table 9, entries 15, 16, 21, and 23). 

The tetracyclic alkaloid quinine 1 and the diastereomeric alkaloid quinidine 2 share a storied history. Eric Jacobsen of Harvard recently completed (J. Am. Chem. Soc. 2004, 126, 706) syntheses of enantiomerically-pure 1 and of 2. For each synthesis, the key reaction for establishing the asymmetry of the target molecule was the enantioselective conjugate addition developed by the Jacobsen group. 

Addition to olefins of the form RCH=CH2 has been made enantioselective, and addition to RCH=CHR both diastereoselective724 and enantioselective, by using optically active amines, such as 72, 73 (derivatives of the naturally occurring quinine and quinidine). 

Aldehydes, ketones, and quinones react with ketenes to give p-lactones, diphenylketene being used most often. The reaction is catalyzed by Lewis acids, and without them most ketenes do not give adducts because the adducts decompose at the high temperatures necessary when no catalyst is used. When ketene was added to chloral Cl3CCHO in the presence of the chiral catalyst (+ )-quinidine, one enantiomer of the p-lactone was produced in 98% enantiomeric excess.777 Other di- and trihalo aldehydes and ketones also give the reaction enantioselectively, with somewhat lower ee values.778 Ketene adds to another molecule of itself ... 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

The first example of the use of a polymer-bound cinchona alkaloid in the AD was described in 1990 by Sharpless [48,49], The polymer was readily obtained by radical co-polymerization of 9-(p-chlorobenzoyl)quinidine acrylate with acrylonitrile. First applications in dihydroxylations of frans-stilbene using NMO as co-oxidant yielded products with enantioselectivities in the range of 85 -93 % ee. It is interesting that a repetitive use of the polymer was possible without great loss of reactivity, indicating that the metal was retained in the polymeric array. 

Balan and Adolfsson [28] reported a direct catalytic enantioselective three-component aza Baylis-Hillman reaction between arylaldehydes, tosylamides, and Michael acceptors using the quinidine-based Hatekayama catalyst 96 [29] together with titanium isopropoxide as a Lewis acid cocatalyst (Scheme 9.18). High chemical yields and stereoselectivity ranging between 49 and 74% ee were obtained using various substituted arylaldehydes. 

The first examples of asymmetric Michael additions of C-nudeophiles to enones appeared in the middle to late 1970s. In 1975 Wynberg and Helder demonstrated in a preliminary publication that the quinine-catalyzed addition of several acidic, doubly activated Michael donors to methyl vinyl ketone (MVK) proceeds asymmetrically [2, 3], Enantiomeric excesses were determined for addition of a-tosylnitro-ethane to MVK (56%) and for 2-carbomethoxyindanone as the pre-nudeophile (68%). Later Hermann and Wynberg reported in more detail that 2-carbomethoxy-indanone (1, Scheme 4.3) can be added to methyl vinyl ketone with ca 1 mol% quinine (3a) or quinidine (3b) as catalyst to afford the Michael-adduct 2 in excellent yields and with up to 76% ee [2, 4], Because of their relatively low basicity, the amine bases 3a,b do not effect the Michael addition of less acidic pre-nucleophiles such as 4 (Scheme 4.3). However, the corresponding ammonium hydroxides 6a,b do promote the addition of the substrates 4 to methyl vinyl ketone under the same mild conditions, albeit with enantioselectivity not exceeding ca 20% [4],... 

A detailed study of the effect of modified quinidine derivatives was conducted by the same group [103]. In particular the effects on enantioselectivity of several substituents at the C9 position and of catalyst conformation were investigated, with interesting results - the enantioselectivity was almost unaffected by the O-acyl substituent at the C9 carbon atom (Scheme 6.41). For example, use of catalysts 90, 91, and 92, which are based on structurally different acyl substituents, gave the product (1 R,2S)-( I )-89a with enantioselectivity in the narrow range 89-92% ee. The yields, however, differed substantially, and did not exceed 54%. Interestingly, a more rigid quinidine derivative resulted in complete reversal of enantioselectivity... 

The enantioselective nitroaldol reaction in the presence of alkaloid-based organo-catalysts has been investigated by the Matsumoto group [127]. A further focus of this study was investigation of the effect of high pressure on the course of the reaction. Addition of nitromethane to benzaldehyde at atmospheric pressure resulted in a low (4%) yield and 18% ee when a catalytic amount (3 mol%) quinidine was... 

All catalytic enantioselective versions of the Darzens condensation are based on the use of chiral phase-transfer agents, e.g. the cations 184a,b derived from ephed-rine, quinine/quinidine-based ammonium ions such as 185a,b, or the crown ether 186. 

THF, ethyl acetate, and methanol. In contrast, use of other chlorinated solvents, e.g. CCI4, and cyclohexane resulted in higher enantioselectivity, comparable with that for chloroform. The range of dienophile substrates was also studied. Replacing N-methylmaleimide by N-phenylmaleimide, in the presence of quinidine as a catalyst, also led to a good yield, although enantioselectivity was lower (20% ee compared with 61% ee). Much slower reaction rates were observed when methyl acrylate and methyl fumarate were used and enantioselectivity was low (0% ee for methyl acrylate and 30% ee for methyl fumarate). With methyl maleate as a dienophile no reaction was observed. Mechanistic studies were also conducted by Kagan et al. results were in accordance with a concerted [4+2]-cycloaddition process. 

Pracejus and co-workers also described an alternative method for preparing suitable enolates in situ, Michael addition of a thiol to an acrylate [8]. A selected example of this reaction, for which enantioselectivity is in the range 20-54% ee, is shown in Scheme 9.3, Eq. (a). Use of a catalytic amount (5 mol%) of quinidine, 7, gave the (R)-cysteine derivative 6 with 54% ee. Benzyl thiol, benzhydryl thiol, or triphenylmethyl thiol were used as the thiol component. In addition to acrylates, nitroalkenes were used as a starting material. 

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