Optical purity, enhancement

Optical purity enhancement A 1-L, three-necked flask equipped as described... 

Optically active hydroperoxides 244 were found285 to oxidize prochiral sulphides into the corresponding sulphoxides in higher optical yields (up to 27%) in comparison with those observed with peracids (equation 132). Moreover, the optical purity of the sulphoxides formed may be enhanced by addition of Ti(OPr-i)4. The oxidation of racemic 2-methyl-2,3-dihydrobenzothiophene 246 with these peroxides gave a mixture of cis and trans-sulphoxides 247 (equation 133). In all cases of the oxidation with the hydroperoxide alone the formation of the trans-isomer was strongly preferred and the e.e. value (up to 42%) of the cis-isomer was always higher than that of the trans-isomer. Moreover, the addition of Ti(OPr-i)4 furthermore promoted the selective formation of the frans-sulphoxide 247 and remarkably enhanced the e.e. value of both isomers. 

In contrast to these results, a preference for rearrangement through an exo-transition state has been detected in the rearrangement of several cyclic allylic sulfoxides. For example, while sulfoxide 36 rearranged to alcohol 37 with 60% ee, introduction of bulky substituents at the (i position of the ring enhanced the optical purity to 90%, as a result of further destabilization of the endo conformation (equation 21)82,84. 

The DKRs of (J-azido alcohols and p-hydroxy nitriles were also accomplished hy employing 1 and CALB with PCPA as the acyl donor. The DKRs of p-azido alcohols were performed at 60°C while those of (3-hydroxy nitriles required higher temperature (100°C) primarily to enhance the racemization rate. The optical purities of products were satisfactory in all cases. In the case of p-hydroxy nitriles, dehydrogenation lowered the yield. 

The lipase-catalyzed DKRs provide only (/ )-products to obtain (5 )-products, we needed a complementary (5 )-stereoselective enzyme. A survey of (5 )-selective enzymes compatible to use in DKR at room temperature revealed that subtilisin is a worthy candidate, but its commercial form was not applicable to DKR due to its low enzyme activity and instability. However, we succeeded in enhancing its activity by treating it with a surfactant before use. At room temperature DKR with subtilisin and ruthenium catalyst 5, trifluoroethyl butanoate was employed as an acylating agent and the (5 )-products were obtained in good yields and high optical purities (Table 3)P... 

Alcohols will serve as hydrogen donors for the reduction of ketones and imi-nium salts, but not imines. Isopropanol is frequently used, and during the process is oxidized into acetone. The reaction is reversible and the products are in equilibrium with the starting materials. To enhance formation of the product, isopropanol is used in large excess and conveniently becomes the solvent. Initially, the reaction is controlled kinetically and the selectivity is high. As the concentration of the product and acetone increase, the rate of the reverse reaction also increases, and the ratio of enantiomers comes under thermodynamic control, with the result that the optical purity of the product falls. The rhodium and iridium CATHy catalysts are more active than the ruthenium arenes not only in the forward transfer hydrogenation but also in the reverse dehydrogenation. As a consequence, the optical purity of the product can fall faster with the... 

The application of a chiral auxiliary or catalyst, in either stoichiometric or catalytic fashion, has been a common practice in asymmetric synthesis, and most of such auxiliaries are available in homochiral form. Some processes of enantiodifferentiation arise from diastereomeric interactions in racemic mixtures and thus cause enhanced enantioselectivity in the reaction. In other words, there can be a nonlinear relationship between the optical purity of the chiral auxiliary and the enantiomeric excess of the product. One may expect that a chiral ligand, not necessarily in enantiomerically pure form, can lead to high levels of asymmetric induction via enantiodiscrimination. In such cases, a nonlinear relationship (NLE) between the ee of the product and the ee of the chiral ligand may be observed. 

In her initial investigation, Lundquist studied the monolayer behavior of racemic and optically active forms of both tetracosan-2-ol and its acetate derivative on 0.0 lA aqueous HCl over a considerable range of temperature (77). In each case, it was possible to demonstrate chiral discrimination between pure enantiomers versus the racemic substance. Furthermore, the extent of enantiomer discrimination was significantly temperature dependent, being enhanced at lower temperatures and frequently disappearing at higher ones. Under favorable conditions of temperature, however, the appearance of the force-area curves could be very sensitive to the optical purity... 

Such resolution could be readily optimized by use of an appropriate acyl group which reacts efficiently with the enzyme employed [29]. For example, the acetate prepared from monofluorinated a-phenetyl alcohol was hydrolyzed with lipase MY at 34% conversion to afford the product only with 26% . Enhancement of optical purity to 73% was observed when the corresponding isobutyrate was hydrolyzed. The best results were obtained for hydrolysis of the isobutyrate by lipase PS, which afforded the product in 82% at 47% hydrolysis. Experience has shown (see Table 3) that one of the best combinations was hydrolysis of acetate with lipase MY or isobutyrate with lipase PS [30]. 

Table 5 shows selected examples of the enzymatic resolution of esters with various structures. As discussed above, enhancement of the optical purity was... 

Sublimation. Such effects can also be seen in solid-gas interphase. Scheme 30 shows the consequences of fractional sublimation of partially resolved L-mandelic acid (47). The optical purity could be enhanced or reduced, depending on the optical purity of the starting material. Since the eutectic point of mandelic acid is obtained with about a 75 25 enantiomer ratio, such a mixture is more readily sublimed than the racemate or conglomerate. Scheme 30 gives other examples of optical enrichment by sublimation. Phenyl 1-phenyl-1-propyl sulfide in 6% ee affords the sublimed compound in 74% ee, but the residue is... 

Different solid-phase techniques for the synthesis of C-terminal peptide aldehydes have gained much attention and allowed greater accessibility to such compounds. Solid-phase techniques have been used to synthesize peptide aldehydes from semicarbazones, Weinreb amides, phenyl esters, acetals, and a, 3-unsaturated y-amino acids)47-50,60 63 The examples presented below use unique linkers to enhance the automated efficiency of C-terminal peptide aldehyde synthesis)47 For instance, the reduction of phenyl esters led to the aldehyde as the major product, but also a small amount of alcohol)50 The cleavage of u,p-unsaturated y-amino acids via ozonolysis yielded enantiomeric pure C-terminal peptides)49,61 The semicarbazone from reduction of peptide esters technique laid the initial foundation for solid-phase synthesis. Overall, Weinreb reduction is an ideal choice due to its high yields, optical purity, and its adaptability to a solid-phase platform)47 ... 

The optical purity of 91-93% was too low for downstream chemistry. The physical properties of 170 made enantiomeric enhancement by crystallization. The formation of a DABCO inclusion complex 171 in heptane and crystallization under thermodynamic control provided material that was 99% ee, 98% purity, and 79% recovery. This procedure produced 90 kg of 170, which was used to prepare an NK-1 receptor antagonist, Aprepitant (172), used for the treatment of chemotherapy-induced emesis.213... 

Resolution of a cheap racemate at the start of a synthesis is economically advantageous if it can be demonstrated that chirality is not lost in the subsequent stages. Moreover, optical purity can be enhanced by purification of intermediates during the total synthesis. This strategy of resolution at the beginning has been applied to a new synthesis of optically active methadones and levo-a-acetylmethadol (LAAM) (16). 

Nucleophilic substitution with lithium hexamethyldisilazane (LiHMDS) proceeds with inversion to give silylated amino boronic ester 19.26 A solution of 19 is passed through a short plug of silica before its use in the desilylation reaction. Due to the instability of underivatized a-amino boronic esters,26 trifluoroacetic acid (TFA) is used to furnish the corresponding TFA salt 20.27 A second recrystallization from TFA and isopropylether further enhances the optical purity. A diastereomeric ratio (dr) > 97 3 is typically obtained from the process route. 

The large-scale production of esomeprazole is now successfully achieved by asymmetric oxidation of the same sulfide intermediate as is used in the production of omeprazole (Scheme 2.5). Using the titanium-based catalyst originally developed by K. Barry Sharpless for allyl alcohol oxidation [56] and by H.B. Kagan for certain sulfide oxidations [57], a process was developed that could achieve initial enantiomeric excesses of about 94% [53]. During the production process, the optical purity is further enhanced by the preparation of esomeprazole magnesium salt, with subsequent re-crystallization. 

In order to provide a better estimate of the enantioselectivity of the catalyst, we prepared an authentic sample of (+)-chorismate by kinetic resolution of the racemate with 1F7 (37). Circular dichroism spectroscopy confirmed the identity and high optical purity of the recovered, HPLC-purified compound. Initial rate measurements with the individual isomers show that (-)-chorismate is favored over (+)-chorismate by the antibody by a factor of at least 90 to 1 at low substrate concentrations. The slight rate enhancements above background observed for the (+)-isomer may be due to general medium effects rather than interaction with a specific locus on the antibody surface. To test this possibility we are currently examining the ability of the transition state analog 3 to inhibit rearrangement of this optical isomer. 

In an attempt to enhance the optical purities of oxiranes via the above method the use of the ylide derived from (-)-Af-tosyl-S-methyl-S-neomenthylsulfoximine 86 has been investigated. The enantiomeric purities of the oxirane products 87 ranged from 56 to 86% 62 A related study using S-exo-2-bomylsulfoximines gave oxiranes in similar enantiomeric purities.63... 

Essentially, nitrilases NIT-106 and NIT-107 were the most efficient catalysts, whereas NIT-lOl and NIT-105 turned out to be less suitable for the synthesis of Y-amino adds. cts-3-Aminocyclopentanecarboxylic acid (-h)-13c was prepared by Nrr-104, whereas (-)-13c was produced by NIT-106 in an enantiocomplementary manner in a high e.e. (97%) dose to the theoretical yield of a kinetic resolution. The respective trans-isomer (-)-14c was obtained in only 55% e.e. by the same enzyme. All other nitrilases examined could not enhance this result NrT-106 revealed similar outstanding sdectivities in the transformation of six-membered aminonitrile cts-( )-15a to (-)-15c in almost optical purity (>99% e.e.) and in a 29% isolated yield [43]. 

As an example of the use of SC-CO2 in an enzymatic reaction, the lipase-catalyzed esterification of oleic acid with racemic ( )-citronellol should be mentioned. At 31 °C and 8.4 MPa, the (—)-(5)-ester is formed enantioselectively in SC-CO2 with an optical purity of nearly 100% [924]. The reaction rate is enhanced by increasing pressure, i.e. by increasing the solvation capability or solvent polarity of SC-CO2. A linear correlation has been found between reaction rate and the solvatoehromie solvent polarity parameter 1(30) see Section 7.4 for the definition of t(30). 

Other nuclei besides H or have been used to monitor enantiomeric discrimination with chiral lanthanide chelates. This includes the NMR spectra of chiral 2-thiabicyclo[4.3.0]nonane 2,2-dioxides (14) and 8,8-dioxides (15) with Pr(hfc)3 . The Si NMR spectrum of a-C-silylated amines and alcohols (38) in the presence of Eu(tfc)3 was used to monitor the optical purity of these compounds . A refocused-decoupled INEPT (insensitive nuclei enhanced by polarization transfer) pulse sequence was used to circumvent the long spin-lattice relaxation times of the silicon. 

Additives such as water, carboxylic and other organic acids, and some inorganic salts enhance the optical purity of the product. Table 4 shows the effect of supplementary reagents in the modification... 

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