Subject optical purity

Resolution of Racemic Amines and Amino Acids. Acylases (EC3.5.1.14) are the most commonly used enzymes for the resolution of amino acids. Porcine kidney acylase (PKA) and the fungaly3.spet i//us acylase (AA) are commercially available, inexpensive, and stable. They have broad substrate specificity and hydrolyze a wide spectmm of natural and unnatural A/-acyl amino acids, with exceptionally high enantioselectivity in almost all cases. Moreover, theU enantioselectivity is exceptionally good with most substrates. A general paper on this subject has been pubUshed (106) in which the resolution of over 50 A/-acyl amino acids and analogues is described. Also reported are the stabiUties of the enzymes and the effect of different acyl groups on the rate and selectivity of enzymatic hydrolysis. Some of the substrates that are easily resolved on 10—100 g scale are presented in Figure 4 (106). Lipases are also used for the resolution of A/-acylated amino acids but the rates and optical purities are usually low (107). 

Yugoslavia. An excellent monograph by Morrison and Mosher (38) provides a comprehensive review of the pre-1969 literature on this subject. The formation of sulfoxides in the asymmetric reaction shown above typically occurred with quite low optical purities (not higher than 10%). The detailed and extensive studies of Montanari and... 

The optically pure tricarbonyl chromium(O) complexes 116 have proven to offer an effective shielding of one of the faces of the alkene. Complex 116 was subjected to a 1,3-dipolar cycloaddition with the sterically crowded nitrile oxide 117 (Scheme 12.39) (172). The reaction proceeds at room temperature to give a 70% yield of 118. After removal of the tricarbonylchromium moiety by a light induced oxidation with air, compound 119 was obtained with an optical purity of 98% enantiomeric excess (ee). 

The 4-hydroxy-(S)-proline-derived acid (232) was subjected to electrophilic lactoni-zation either with J2-KJ-NaHC03 to yield the iodolactone (233a), or benzeneselenyl chloride to give the phenylselenolactone (23b). Reductive removal of X from these products was achieved with tri-n-butyl- or triphenyltin hydride, followed by hydro-genolysis to yield (234) with at least 99% optical purity 231 j). 

To 1.17 g of (-)-7,8-difluoro-2,3-dihydro-3-hydroxymethyl-4H-[l,4] benzoxazine was added 2.77 g of thionyl chloride in pyridine. The reaction mixture was concentrated and the concentrate was subjected to column chromatography using 40 g of silica gel and eluted with chloroform to obtain 1.18 g of the reaction product as a colorless oily product. This product was dissolved in 30 ml of dimethyl sulfoxide, and 0.41 g of sodium borohydride was added thereto, followed by heating at 80-90°C for 1 hour. The reaction mixture was dissolved in 500 ml of benzene, washed with water to remove the dimethyl sulfoxide, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography using 40 g of silica gel and eluted with benzene to obtain 0.80 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[l,4]benzoxazine as a colorless oily product [a]D25 = -9.6° (c = 2.17, CHCI3). Optical Purity >99% e.e. 

The asymmetric eiectroreduction of an imino group has also been the subject of several studies. The use of modified electrodes,or chiral additives that supposedly create a chiral environment close to the electrode surface, give only low optical yields. 49,so other strategies will have to be explored in order to obtain high optical purities useful for synthetic work. 

THC (27). [a]D +114° with absolute optical purity (Srebnik et al. 1984). These enantiomers have now been tested in human volunteers (Hollister et al., in press). Subjects received progressively increasing intravenous doses of (lS)-delta-3-THC (26) and (lR)-delta-3-THC (27), beginning with 1 mg (in 1 ml ethanol) followed by progressive doubling of doses until, definite effects were observed. Cannabimimetic effects with the (IS) epimer were noted at doses of 8 mg or higher. No effects were noted with the (IR) epimer. (lS)-delta-3-THC (26) is thus estimated to have a potency from one-third to one-sixth that of delta-1-THC. 

The methods for the determination of enantiomeric purity have been the subject of reviews (92-95). If the maximum rotation of an optically active compound is known, measurement of the specific rotation of a given sample indicates its optical purity, provided the sample is chemically pure. The maximum specific rotation of most chiral organosilanes (in given solvents) is now known since their enantiomeric purity has been determined independently. 

The addition of aldehydes to carbenoids derived from the Cu-catalyzed decomposition of ArCHNj to form stilbene epoxides is subject to asymmetric induction by 1,3-oxathiane 47 prepared from 10-mercaptoisobomeol and acetaldehyde. The attack of sulfonium ylides derived from 48 on aldehydes also affords epoxides of high optical purity. The same principle underlies a synthesis of chiral aziridines. ... 

Another Bristol-Meyers Squibb process represents an enzymatic route for the production of side-chain precursors of Paclitaxel (33, Scheme 10) [69]. Racemic czs-azetidinone acetate (rac-31) is subjected to the hydrolytic treatment of Pseudomonas cepacia lipase (PCL), which is used in its immobilized form on polypropylene beads. Thus, (3R,4S)-acetate 31 can be obtained in high ee as well as the remaining alcohol 32. The process takes place in 150 1 reactors where 1.2 kg mc-31/batch can be resolved with a hydrolysis rate of 0.12 g/lh. Lowering the reaction temperature to 5 °C after full conversion causes (3R,4S)-31 subsequently to crystallize. Due to the immobilization, the enzyme can be reused for at least ten cycles without any loss of activity, productivity, or optical purity of the product. Paclitaxel is finally accessible by further chemical steps. 

Scheme 40 describes the second part of the Hoechst Marion Roussel process of 7-AC A (129) manufacture - the first enzymatic transformation has already been described in Scheme 6. Glutaric acid derivative 20 is now subjected to treatment with immobilized Pseudomonas sp, cu-amidodicarboxylate amido-hydrolase (recombinant in Escherichia coli). The enzyme catalyzes the chemo-and stereoselective hydrolysis of the amide and gives the free amine 129 in reasonable yield and optical purity. The whole process has also been established in several other companies, with minor modifications. Anbics, for example, is presently setting up a fermentation process with its subsidiary Bioferma Murcia in Spain for the production of 7-AC A. A typical isolated yield of 82% has been reported for 129, which can be further optimized to >85% by applying techniques such as reversed osmosis on the production scale [115].

The stereoselectivity of the reaction was determined by converting both p-lactams 204 and 205 into the corresponding hydroxy compounds 206 and 207, followed by removal of the chiral auxiliary under Birch reduction conditions and further benzoylation. The resulting P-lactams 208 and 209 were subjected to HPLC analysis indicating that the ratio of cis and trans isomers was 95 5 for both compounds. After purification by column chromatography the optical purity of the major isomer was found to be 70% ee. 

Despite its utihty, the mechanistic details of the vinylcyclopropane rearrangement have been the subject of controversy. However, the stereochemical outcome of the rearrangement has now been established by Baldwin and Andrews. The rearrangement of unconstrained and optically pure (-hH 1 S,2S)-trans,trans-2-methyl-1 -propenyl-cyclopropane (236) leads to the 3,4-dimethylcyclopentenes (+)- and ( —)-(237) and ( +)- and (—)-(238) with an enthalpy of activation of 47.1 2.3 kcal mol (log.4 = 14.3 + 0.8) (cf. tra/is-2-methyl-l-vinylcyclopropane, 48.6 and 45.7 kcal mol 1. From the optical purities of the products and their distributions, the percentage contributions of each of the four possible stereochemical outcomes for the vinylcyclopropane rearrangement have been obtained (Scheme 28). The supra- and antara-... 

While the ultimate aim should remain to provide a catalytic solution for every stereoselective synthetic endeavor, this ideal is still some way off. The fundamental dichotomy remains that unless a catalytic process achieves better than a 95% ee, serious problems and losses can attend the final achievement of optical purity. Since diastereomers are not subject to the same restrictions of separation as enantiomers, diastereoselection as low as 70-80% can still afford optically pure products, albeit with some potential waste. 

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