Enantiomeric purity of alcohols

Acylation of various oxygen functions by use of common and commercially available fluonnated carboxylic acid denvatives such as trifluoroacetic anhydride or the corresponding acyl halides have already been discussed sufficiently in the first edition [10] Therefore only exceptional observations will be described in this section In the past 15 years, many denvatizations of various nonfluonnated oxygen compounds by fluoroacylation were made for analytical purposes. Thus Mosher s acid chlorides for example became ready-to-use reagents for the determination of the enantiomeric purity of alcohols and amines by NMR or gas-liquid chromatographic (GLC) techniques [//] (equation 1)... 

The enantiomeric purity of alcohol 5 was determined by conversion to the silyl ether 8via the following sequence ... 

Various chiral derivatizing agents have been reported for the determination of enantiomer compositions. One example is determining the enantiomeric purity of alcohols using 31P NMR.28 As shown in Scheme 1-8, reagent 20 can be readily prepared and conveniently stored in tetrahydrofuran (THF) for long periods. This compound shows excellent activity toward primary, secondary, and tertiary alcohols. To evaluate the utility of compound 20 for determining enantiomer composition, some racemic alcohols were chosen and allowed to react with 20. The diastereomeric pairs of derivative 21 exhibit clear differences in their 31P NMR spectra, and the enantiomer composition of a compound can then be easily measured (Scheme 1-8). 

I. Simple and Efficient Determination of Enantiomeric Purity of Alcohols and Amines... 

Camphorsulfonyl chloride has been widely used as a chiral deriva-tizing agent for the assay of enantiomeric purity of alcohols and amines by NMR techniques. A typical procedure for the preparation of the sulfonate ester or sulfonamide involves mixing a solution of the alcohol or amine in CH2CI2 with camphorsulfonyl chloride in the presence of an amine base (EtsN, py, or DMAP). This reagent has been particularly valuable for determining the enantiomeric purity of secondary alcohols (1, 2) and p-hydroxy esters (3). ... 

Determination of the Enantiomeric Purity of Alcohols, Amines, and Other Compounds by Derivatization. The enan-... 

Alcohok. When using the H NMR spectra of MTPA esters to determine the enantiomeric purity of alcohols, the MTPA methoxy peaks tend to be most useful. This technique can be sensitive enough to detect as little as 1% of the minor alcohol enantiomer. The enantiomeric purity of chiral alcohols (1) and (2) has been determined this way. The enantiomeric purity of primary alcohols (3) and (4), in which the asymmetric center is not the carbinol carbon, has also been determined by H NMR analysis of their MTPA esters. A slight variation of this methodology is the use of shift reagents like Eu(fod)3 to increase the chemical shift separation between diastereotopic MeO peaks this procedure has been used in the analysis of alcohols (S) and (6). ... 

MOSHER S ACID for Chirality Determination Synthesis and use of a-methoxy-a-(trifluoromethyl)phenylacetic acid (MTPA) 4, a chiral reagent for determination of enantiomeric purity of alcohols or amines by NMR. 

Camphorsulfonyl chloride has been widely used as a chiral deriva-tizing agent for the assay of enantiomeric purity of alcohols and amines by NMR techniques. A typical procedure for the... 

Silyl acetals have been used in the assay of the enantiomeric purity of alcohols. A dichlorosilane is first reacted with an alcohol of 100% enantiomeric excess, such as methylmandelate, quinine or menthol, to give a CDA which is then used to derivatise a second alcohol of unknown enantiomeric purity (Scheme 3.2). H, C and 29Si NMR... 

Reagent for synth. of chiral monothiophosphate esters and for detn. of enantiomeric purity of alcohols and amines by P nmr. Cryst. (diisopropyl ether or cyclohexane). Mp 125-128°. [a] —121° (CHCI3), [a]p -123° (CgHg). Has 25-config. 

Improved methods for the preparation of reagents such as isopinocampheyl(l-isopinocam-pheyl-2-alkenyl)borinic acids will certainly lead to a more enantioselective synthesis of anti-homoallylic alcohols, since the enantiomeric purity of the reagent is the only significant limitation to the synthetic utility of this reagent system. 

The preparation of enantiomerically pure chemicals is also the theme of the next group of four procedures. The biopolymer polyhydroxybutyric acid, which is now produced on an industrial scale, serves as the starting material for the large scale synthesis of (R)-3-HYDROXYBUTANOIC ACID and (R)-METHYL 3-HYDROXYBUTANOATE. Esters of (-)-camphanic acid are useful derivatives for resolving and determining the enantiomeric purity of primary and secondary alcohols. An optimized preparation of (-)-(1S,4R)-CAMPHANOYL CHLORIDE is provided. The preparation of enantiomerically pure a-hydroxyketones from ethyl lactate is illustrated in the synthesis of (3HS)-[(tert)-BUTYL-DIPHENYLSILYL)OXY]-2-BUTANONE. One use of this chiral a-hydroxyketone is provided in the synthesis of (2S,3S)-3-ACETYL-8-... 

A chiral bis(oxazolinyl)phenylrhodium complex was found to catalyze the asymmetric hydrosilylation of styrenes with hydro(alkoxy)silanes such as HSiMe(OEt)2 (Scheme 7).47 Although the regioselectivity in forming branched product 27 is modest, the enantiomeric purity of the branched product 27 is excellent for styrene and its derivatives substituted on the phenyl group. The hydrosilylation products were readily converted into the corresponding benzylic alcohols 29 (up to 95% ee) by the Tamao oxidation. 

A major advantage that nonenzymic chiral catalysts might have over enzymes, then, is their potential ability to accept substrates of different structures by contrast, an enzyme will select only its substrate from a mixture. Striking examples are the chiral phosphine-rhodium catalysts, which catalyze die hydrogenation of double bonds to produce chiral amino acids (10-12), and the titanium isopropoxide-tartrate complex of Sharpless (11,13,14), which catalyzes the epoxidation of numerous allylic alcohols. Since the enantiomeric purities of the products from these reactions are exceedingly high (>90%), we might conclude... 

The BINAP derivative of the ort/io-cyclometallated iridium catalyst has been characterized by single crystal X-ray diffraction analysis [280]. Remarkably, although the reaction sequence depends upon oxidation of either the reactant alcohol or isopropanol, the enantiomeric purity of the homoallylic alcohol product... 

In what appears to be a particularly irmovative development in the area of UV/ Vis-based ee screening systems, the determination of the enantiomeric purity of chiral alcohols 9 is based on a new concept of using two enantioselective enzymes to modify the product (84). The method allows the determination of ee values independent of the concentration, which may be of significant advantage in directed evolution projects. It can be used in three different biocatalytic processes, namely biohydroxylation of alkanes, reductase-catalyzed reduction of ketones, and lipase-or esterase-catalyzed ester hydrolysis. 

A typical example that illustrates the method concerns the lipase- or esterase-catalyzed hydrolytic kinetic resolution of rac-1-phenyl ethyl acetate, derived from rac-1-phenyl ethanol (20). However, the acetate of any chiral alcohol or the acetamide of any chiral amine can be used. A 1 1 mixture of labeled and non-labeled compounds (S)- C-19 and (f )-19 is prepared, which simulates a racemate. It is used in the actual catalytic hydrolytic kinetic resolution, which affords a mixture of true enantiomers (5)-20 and (J )-20 as well as labeled and non-labeled acetic acid C-21 and 21, respectively, together with non-reacted starting esters 19. At 50% conversion (or at any other point of the kinetic resolution), the ratio of (5)- C-19 to (1 )-19 correlates with the enantiomeric purity of the non-reacted ester, and the ratio of C-21 to 21 reveals the relative amounts of (5)-20 and (J )-20 (98). 

In work concerning the directed evolution of enantioselective enzymes, there was a need for fast and efficient ways to determine the enantiomeric purity of chiral alcohols, which can be produced enzymatically either by reduction of prochiral ketones (e.g., 26) using reductases or by kinetic resolution of rac-acetates (e.g., 19) by lipases (111). In both systems, the CD approach is theoretically possible. In the former case, an LC column would have to separate the educt 26 from the product (A)/(J )-20, whereas in the latter, (5)/(J )-20 would have to be separated from (S)/(R)-19. 

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