Chiral additives also

Chiral additives, however, do pose some unique problems. Many chiral agents are expensive or are not commercially available, and therefore, must be synthesized. The presence of the chiral additive in the bulk Hquid phase may also interfere with detection or recovery of the analytes. Finally, the presence of enantiomeric impurity in the chiral additive may add analytical complications (10). 

Other substrates were tested the results are summarized in Table 5.2. Vinyl ethers (2b-2d) also worked well to afford the corresponding tetrahydroquinoline derivatives (3a-3e) in good to high yields with good to excellent diastereo- and en-antioselectivity (entries 1-10). Use of 10 mol% of the chiral catalyst also gave the adducts in high yields and selectivity (entries 2 and 6). As for additives, 2,6-di-t-bu-... 

In addition to the development of the powerful chiral additive, this study also demonstrated that the often tedious deconvolution process can be accelerated using HPLC separation. As a result, only 15 libraries had to be synthesized instead of 64 libraries that would be required for the full-scale deconvolution. A somewhat similar approach also involving HPLC fractionations has recently been demonstrated by Griffey for the deconvolution of libraries screened for biological activity [76]. Although demonstrated only for CE, the cyclic hexapeptides might also be useful selectors for the preparation of chiral stationary phases for HPLC. However, this would require the development of non-trivial additional chemistry to appropriately link the peptide to a porous solid support. 

For the separation of racemic mixtures, two basic types of membrane processes can be distinguished a direct separation using an enantioselective membrane, or separation in which a nonselective membrane assists an enantioselective process [5]. The most direct method is to apply enantioselective membranes, thus allowing selective transport of one of the enantiomers of a racemic mixture. These membranes can either be a dense polymer or a liquid. In the latter case, the membrane liquid can be chiral, or may contain a chiral additive (carrier). Nonselective membranes can also... 

The proline derived diamines 2 and 4 (vide supra) are also suitable chiral additives in enantiose-lective additions of a-unsubstituted enolates. Best results are obtained with the naphthyl derivative, as demonstrated in the tin(II) triflate mediated addition of the O-silylketene thio-acetal l-toT-butylthio-l-trimethylsilyloxyethane to aldehydes which delivers 3-hydroxythio esters in optical purities of up to 95% ee and chemical yields between 50 and 90 %24... 

In general the chiral additive (l/ ,2/J)-l,2-dimethoxy-l,2-diphenylethane was the most effective while (.S )-2.2 -diniethoxy-1,1 -binaphthalene and (1 / ,27 )-/V,/V,/V, A"-tetramethyl-1,2-diphcnyl-ethylenediamine induced only very low levels of enantiofacial differentiation. In the case of the acyclic enimines competing 1,2-addition products were also obtained7. 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

The titanium reagent also dimethylates aromatic aldehydes." Triethylaluminum reacts with aldehydes, however, to give the mono-ethyl alcohol, and in the presence of a chiral additive the reaction proceeds with good asymmetric induction." A complex of Me3Ti-MeLi has been shown to be selective for 1,2 addition with conjugated ketones, in the presence of nonconjugated ketones." ... 

Mukaiyama aldol reactions have been reported, usually using chiral additives although chiral auxiliaries have also been used. This reaction can also be run with the aldehyde or ketone in the form of its acetal R R C(OR )2> in which case the product is the ether R COCHR2CR R OR instead of 27. Enol acetates and enol ethers also give this product when treated with acetals and TiCLi or a similar catalyst. When the catalyst is dibutyltin bis(triflate), Bu2Sn(OTf)2, aldehydes react, but not their acetals, while acetals of ketones react, but not the ketones themselves. 

The hydrogenation of a cinnamate was also investigated as a first step to determine kinetics and finally to come to a quantitative determination of kinetic models and parameters in asymmetric catalysis [64]. The enantiomeric excess of enantioselective catalytic hydrogenations is known to be dependent on pressure, chiral additives and mixing. Such dependences are often due to kinetics, demanding appropriate studies. 

In Step D another thiazoline chiral auxiliary, also derived from cysteine, was used to achieve double stereodifferentiation in an aldol addition. A tin enolate was used. The stereoselectivity of this reaction parallels that of aldol reactions carried out with lithium or boron enolates. After the configuration of all the centers was established, the synthesis proceeded to P-D lactone by functional group modifications. 

Similar additions also occurred on vinylphosphine oxides. When the optically active vinylphosphine oxide was used, P-chiral alkylphosphine oxide was obtained with retention of the configuration (Eq. 10.27)60... 

Similar to the addition of secondary phosphine-borane complexes to alkynes described in Scheme 6.137, the same hydrophosphination agents can also be added to alkenes under broadly similar reaction conditions, leading to alkylarylphosphines (Scheme 6.138) [274], Again, the expected anti-Markovnikov addition products were obtained exclusively. In some cases, the additions also proceeded at room temperature, but required much longer reaction times (2 days). Treatment of the phosphine-borane complexes with a chiral alkene such as (-)-/ -pinene led to chiral cyclohexene derivatives through a radical-initiated ring-opening mechanism. In related work, Ackerman and coworkers described microwave-assisted Lewis acid-mediated inter-molecular hydroamination reactions of norbornene [275]. 

Chiral active pharmaceutical ingredients, 18 725-726. See also Enantio- entries Chiral additives, 6 75—79 Chiral alcohols, synthesis of, 13 667-668 P-Chiral alcohols, synthesis of, 13 669 Chiral alkanes, synthesis of, 13 668-669 Chiral alkenes, synthesis of, 13 668—669 Chiral alkoxides, 26 929 Chiral alkynes, synthesis of, 13 668-669 Chiral ammonium ions, enantiomer recognition properties for, 16 790 Chiral ansa-metallocenes, 16 90 Chiral auxiliaries, in oxazolidinone formation, 17 738—739... 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

Based on the theory, the separation of enantiomers requires a chiral additive to the CE separation buffer, while diastereomers can also be separated without the chiral selector. The majority of chiral CE separations are based on simple or chemically modified cyclodextrins. However, also other additives such as chiral crown ethers, linear oligo- and polysaccharides, macrocyclic antibiotics, chiral calixarenes, chiral ion-pairing agents, and chiral surfactants can be used. Eew non-chiral separation examples for the separation of diastereomers can be found. 

Additives are often used to increase selectivity. They are paramount in chiral separations, but they are also frequently used in non-chiral separations, e.g., cyclodextrins (CDs). In our lab, BGEs with and without a cyclodextrin are part of our generic protocol. Figure 8 demonstrates that although one can more or less predict interaction with the additive from the chemical structures, it is still difficult to predict separation.Batch-to-batch variability and variability between suppliers can be a problem of (chiral) additives and a check of different batches has to be part of the robustness test (e.g., reference 56). If the additive is charged and has one or more pK s around the pH of the BGE, extra care should be taken to control the pH. Alternatively, better robustness might be obtained with another uncharged additive, even if this results in lower resolution. 

Harwood and co-workers (105) utihzed a phenyloxazine-3-one as a chiral derived template for cycloaddition (Scheme 4.50). An oxazinone template can be formed from phenylglycinol as the template precursor. The diazoamide needed for cycloaddition was generated by addition of diazomalonyl chloride, trimethyl-dioxane-4-one, or succinimidyl diazoacetate, providing the ester, acetyl, or hydrogen R group of the diazoamide 198. After addition of rhodium acetate, A-methylmaleimide was used as the dipolarophile to provide a product that predominantly adds from the less hindered a-face of the template in an endo fashion. The cycloaddition also provided some of the adduct that approaches from the p-face as well. p-Face addition also occurred with complete exo-selectivity. Mono- and disubstituted acetylenic compounds were added as well, providing similar cycloadducts. 

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