Chemical and Enantiomeric Purity

Lewis acids, results in the formation of isopulegol (43) with greater than 98% diastereoselectivity isopulegol (43), wherein all of the ring substituents are equatorially oriented, arises naturally from a chairlike transition state structure in which the C-3 methyl group, the coordinated C-l aldehyde carbonyl, and the A6,7 double bond are all equatorial (see 48). A low-temperature crystallization raises the chemical and enantiomeric purity of isopulegol (43) close to 100%. Finally, hydrogenation of the double bond in 43 completes the synthesis of (-)-menthol (1). 

The very short reaction times required for the alkylation of substrate 11a with benzylic bromides using Nobin as an asymmetric phase-transfer catalyst are important for the synthesis of 18F-fluorinated amino adds for use in positron-emission tomography (PET)-imaging studies. Thus, Krasikova and Belokon have developed a synthesis of 2-[18F]fluoro-L-tyrosine and 6-[18F]fluoro-L-Dopa employing a (S)-Nobin-catalyzed asymmetric alkylation of glycine derivative 11a as the key step, as shown in Scheme 8.14 [29]. The entire synthesis (induding semi-preparative HPLC purification) could be completed in 110 to 120 min, which corresponds to one half-life of18 F. Both the chemical and enantiomeric purity of the final amino acids were found to be suitable for clinical use. 

Preparative enrichment of enantiomers should be followed by determination of their chemical and enantiomeric purities, e.g., by enantioselective liquid chromatography.25,26 In addition to the sorbents mentioned above, others may be used which are available in only smaller amounts. In our laboratory, this is true for (+)-poly(trityl methacrylate) on silica,35 which can be used for analytical purposes. Preparative separations on a column 0.5 cm in diameter, however, would require many injections of small amounts of racemate. In the case of a baseline chromatogram like that in Figure 2, the determination of enantiomeric purity by measurement of the two peak areas of the enantiomers is straightforward. An analytical chromatogram showing some separation by photometric detection in spite of peak overlap (Figure 4) can still be used for optical purity determina-tion. The simultaneous use of both photometric and chiroptical detection as... 

For the further reduction of the reaction volume we tested even higher substrate concentrations and higher concentrated titrating solutions. As to the former, it turned out that the enzyme worked smoothly even at 20 to 30% (w/v) substrate concentration and, in addition, at substrate to buffer ratio of 1 1 (w/v) the enzyme still showed a useful activity. In all cases the product was obtained with excellent chemical and enantiomeric purity (both >99%). 

It has been shown that the enantioselectivity of the reduction of ketones by the photosynthetic cyanobacterium Synechococcus elongatus PCC 7942 is regulated by light. In the case of the ketone (28), the enantioselectivity is reduced by over 50% in the absence of light (Nakamura and Yamanaka, Chapter 5). It was also shown that a known photosynthesis inhibitor decreases both the chemical and enantiomeric purities of the products, which suggests that physiological changes on irradiation alfect the enzymatic activity of cyanobacteria. 

Treatment of crude 9 with methyl chloroformate in the presence of triethylamine gave crude hydantoin 8 in 91% yield. Methylation [LiN(TMS)2, Mel, DMF, rt] of 8 followed by a single recrystallization of the crude product from EtOAc/hexane afforded BIRT-377 (1) in 74% yield. The drug substance prepared by this method possessed excellent chemical and enantiomeric purity (both >99.9% by HPLC). 

The addition of the lithium enolates of various acetic add esters to (S)-3-(4-methylphcnyl-sulfmyl)-2(5//)-liiranone and (,S)-5,6-dihydro-3-(4-methylphenylsulfinyl)-2//-pyran-2-one gives, after desulfurization with Raney nickel, 4-substituted dihydro-2(3//)-furanoncs and 4-substituted tetrahydro-2//-pyran-2-ones, respectively, in good to quantitative enantiomeric excess. Addition of the enolate occurs via the nonchelate mode. The enolate of methyl (phenylthio)acetatc is best overall in regards to chemical yields and enantiomeric purity of the final lactone product13. 

Since tryptophan synthase does not (or poorly) tolerate the substitution of indoles by large groups (iodo- and nitro-groups), such cases have lead to the development of a facial chemical synthesis of racemic A-oc-acetyltryptophan derivatives from 5- and 6-monosubstituted indoles and L-serine, followed by an enzymatic resolution step using acylase Amano resulting in substituted L-tryptophans in high yields and enantiomeric purity of 91-100% ee [66] (Fig. 4). 

There are four diastereomeric menthols according to the relative orientations of the methyl, isopropyl, and hydroxyl groups. They are known as menthol, isomenthol, neomenthol, and neoisomenthol, each of which exists in two enantiomeric forms. The most abundant and readily available is /-menthol, or (/A 2.S, 5iZ)-(-)-menthol (23), whereas other stereoisomers, although available from nature, are more economically produced through chemical derivatizations from menthone, limonene, and a-pinene. Commercial (-)-menthol from natural sources can be as pure as 99% in both chemical and optical purities. Synthetic menthol is currently made by an asymmetric isomerization (see Chapters 12 and 31).34... 

During the development of rivaroxaban 1, Pleiss et al. at Bayer Health Care prepared [14C]-radiolabeled rivaroxaban,22 which was required for clinical studies of drug absorption, distribution, metabolism, and excretion (ADME studies). The approach taken for the synthesis of l4C labeled rivaroxaban 38 relies on the previously reported synthesis. In the presence of EDC HCl and HOBT, 4- 4-[5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl -morpholin-3-one 22 was coupled with 5-chloro-2-thiophene [14C]-carboxylic acid 37 and was purified using chiral HPLC to afford the [l4C]-radiolabelled rivaroxaban 38 in 85% yield with high chemical and radiochemical purity and with an enantiomeric excess of > 99% ee (Scheme 5). Meanwhile, the metabolite M-4 of rivaroxaban (compound 39) was prepared from 5-chlorothiophenecarboxylic acid chloride 23 and [14C]glycine in 77% yield (Scheme 6). 

For the preparation of enantiomeric drugs with a high chemical and stereochemical purity (> 99%), often required nowadays for drugs and for pharmacological investiga-... 

Besides quantitative determinations of endogenous PGs, HPLC techniques have been used for some special features in clinical, chemical, or pharmaceutical research, including investigations of stability, metabo-lization and enantiomeric purity, thermodynamic characterizations of chemical equilibria, validating im-... 

These are given wherever possible, and normally refer to what the Carbohydrates contributor believes to be the best characterised sample of highest chemical and optical purity. Where available an indication of the optical purity (op) or enantiomeric excess (ee) of the sample measured follows the specific rotation value. 

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