Enantiomeric alcohol

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

Model (1) further suggests that, if the substrate is a secondary allylic alcohol (R4 / 11, R5 = H or r4=h, rVh), enantiomeric alcohols are epoxidized at different rates when (R,R)-DAT is used as the chiral auxiliary, (5)-allylic alcohol (R4 f H, R5 = H) suffers less steric hindrance from the tartrate ligand and is oxidized faster than (R)-allylic alcohol (R4 = H, R5 f H).37 As the ester alkyl group of DAT becomes bulkier, the hindrance becomes more intense and the relative... 

L. Lepri, M. Del Bubba, A. Cincinelli and M. Bracciali, Quantitative determination of enantiomeric alcohols by planar chromatography on tribenzoylcellulose. J. Planar Chromatogr.-Mod. TLC 15 (2002) 220-222. 

The four aldehydes studied were reduced in high optical yield and excellent synthetic yield. Either enantiomeric alcohol can be prepared using (S)- or (/ )-56. 

With the appropriate choice of enzyme, it has been found that only one enantiomer of the racemic mixture is hydrolysed, whilst the other remains unreacted. It is then a simple matter to separate the unreacted ester from the alcohol. The unreacted ester may then be hydrolysed chemically, thus achieving resolution of the enantiomeric alcohols. 

One of the first fluorescence-based ee assays uses umbelliferone (14) as the built-in fluorophore and works for several different types of enzymatic reactions 70,86). In an initial investigation, the system was used to monitor the hydrolytic kinetic resolution of chiral acetates (e.g., rac-11) (Fig. 8). It is based on a sequence of two coupled enzymatic steps that converts a pair of enantiomeric alcohols formed by the asymmetric hydrolysis under study (e.g., R - and (5)-12) into a fluorescent product (e.g., 14). In the first step, (R)- and (5)-ll are subjected separately to hydrolysis in reactions catalyzed by a mutant enzyme (lipase or esterase). The goal of the assay is to measure the enantioselectivity of this kinetic resolution. The relative amount of R)- and ( S)-12 produced after a given reaction time is a measure of the enantioselectivity and can be ascertained rapidly, but not directly. 

Two subsequent chemical transformations are necessary. First, the enantiomeric alcohols R)- and ( S)-12 are oxidized separately by horse-liver alcohol dehydrogenase... 

Figure 2.11 Transesterification of a racemic mixture of a secondary alcohol (1 -phenoxy-2-propanol, 1 in Table 2.1) with a butanoic acyl donor follows a ping-pong bi-bi mechanism in which Substrate 1 (acyl donor) enters the enzyme, forms an acyl enzyme expelling Product 1 (the leaving alcohol from the acyl donor). Then another Substrate 2 (the enantiomers of the alcohol to be resolved) reacts with the acyl enzyme to liberate Product 2 (the enantiomers of the produced esters), leaving the enzyme in its original form. In a kinetic resolution one of the enantiomeric alcohols reacts faster than the other to form an excess of one enantiomer of the esters (ideally enantiopure, for 1 the (R)-ester was formed with very high ee). The success of the resolution is expressed by the enantiomeric ratio E, which depends on the difference in free energy of activation of the two diastereomeric transition states. These are in turn related to the two tetrahedral intermediates.

Directed asymmetric reduction of a ketone has been brought about by the use of an intramolecular homochiral boronate ester250. The latter was readily introduced at a hydroxyl group in the molecule and has allowed the production of the enantiomeric alcohol, from the ketone by use of BH3-complex as the reductant (equation 64). The boronate ester may be readily removed by treatment with hydrogen peroxide-sodium hydroxide, using standard methodology. Other similar reductions have also been reported251-253. 

Figure 16 Chiral recognition based on a four-location model in the case of 3-methyl-2-butanol. (a) Two enantiomeric alcohol molecules in the channel of NDCA (b) an electron density map of the alcohol on a plane composed of Cl, C2 and C3 carbons.

Determination of Optical Yields. Optical yields of the siloxycyclopentenones derived from CPDK were determined by chiral HPLC (Chiracel OC column (J. T. Baker)) with the exception of the triphenylsilane derivative which was determined by optical rotation. 2-Butanol was derivatized to the corresponding diastereomeric urethanes with /Mnethylbenzylisocyanate according to literature procedures (32) the optical yield was then determined by G.C analysis using a Chirasil-L-Val column (Chrompack). The optical purity of the remaining alcohols (with the exception of a-tetralol optical rotation) was determined by chiral G.C. analysis of the underivatized alcohol using a CP-Cyclodextrin-B-2,3,6-M-19 column (Chrompack). Baseline resolution of the enantiomeric alcohols was achieved in all cases and it was observed that the / -isomer was eluted first without exception (confirmed by both optical rotation and G.C. analysis of independently prepared optically pure samples). 

Enantiomers can be separated in an analogous manner after reaction with 2-phenyl-propionyl chloride [40], Brooks et al. [41] used drimanoyl and chrysanthemoyl chlorides as chiral reagents for series of enantiomeric alcohols. The alcohol (1 mg) in dry toluene (20 pi) was treated with 10 pi of a solution of freshly prepared drimanoyl chloride (3 molar excess) in dry toluene and the mixture was heated at 60°C for 1 —2 h. The injection was performed without using any other purification. Good separation of enantiomers of chrysanthemoyl esters, which are prepared in an analogous manner, was achieved on a 5-m column packed with 1% of SE-30 on Gas-Chrom Q (100-120 mesh) at 143°C. 

Each diastereomer was converted to the enantiomeric alcohols by zinc borohydride reduction, followed by chromatography of the Cls-epimeric mixtures. Saponification of the diolester gave the enantiomeric 9,9-dioxy-9-thia-prostanoids 96. 

In a different ongoing study, a Bacillus subtilis lipase has been chosen as the catalyst in the asymmetric hydrolysis of the meso-diacetate 11 with formation of enantiomeric alcohols 12 (Fig. 11.19) [82]. This reaction does not constitute kinetic resolution and can thus be carried out to 100 % conversion. Screening is possible on the basis of the ESI-MS system [50] (see above) using the deuterium labeled pseudo-meso substrate 13 (Fig. 11.20). The ratio of the two pseudo-enantiomeric products 14 and 15 can easily be determined by integrating the two appropriate MS peaks. 

The substrate, 4-(6-methoxy-2-benzoxazolyl)acetophenone, the R and S enantiomers of the product, 4-(6-methoxy-2-benzoxazolyl)phenethyl alcohol, and the internal standard, 3-acetyl-7-(dimethylamino)coumarin, were separated by chromatography on a cellulose-based chiral column (Chiracel OD from Daicel). The mobile phase was a 93 7 mixture (v/v) of n-hexane and 2-propanol, which was used at ambient temperature and a flow rate of 1.2 mL/ min. Detection of the enantiomeric alcohols and the internal standard was by fluorescence, with excitation and emission wavelengths of 315 and 375 nm, respectively. 

In the hydrogenation of racemic allylic alcohols catalyzed by a chiral Rh catalyst, at most, 20 1 discrimination has been attained for some acyclic substrates. BINAP-Ru complexes have been used for kinetic resolution of chiral acyclic and cyclic secondary alcohols with up to 74 1 differentiation between the enantiomeric alcohols (equation 15). ... 

Initial studies on the GLC separation of enantiomeric alcohols as esters of various chiral adds used packed columns (1,4). A major advance in GLC separations was the advent of capillary columns, and most of the recently published indirect GLC separations used capillary columns. 

This reaction was amrmg the earliest used for the GLC resolution of enantiomeric alcohols Studies 20 years ago showed that the reaction of (—)-menthyI chloroformate, [17], with chiral alcohols produced dia-stereomeric carbonates that could be resolved on packed columns (71,162). Despite its commercial availability, this CDA has been little used for the resolution of alcohols, Prelusky et al. (163) used [17] in a study of enantio-selecrive metabolic ketone reductions. The metabolite alcohols were deri-vatized with [17] and the derivatives were separated by capillary GLC. Good resolution was obtained under the chromatographic conditions used (163). The derivatization of warfarin with [17] and LC of the derivatives was described, but the peaks were not fully separated, even with retention times of 80-100 min (164). Brash et al. used CDA [17] to determine the enantiomeric composition of several enantiomeric pairs of hydroperoxy-eicosatetraenoic acids using silica LC, but some of the derivatives could not be resolved (165). It appears that [17] may be useful in the resolution of hydroxyl compounds and the evaluation of capillary GLC in the separations deserves attention. 

Used for synthesis of diastereomeric derivatives of enantiomeric alcohols. 

The priority number for an alcohol product was determined by the relative rate and the stereoselectivity of reduction. The priority number for each substrate surrogate was calculated from the rates of production of each enantiomeric alcohol product using the total relative rate of reduction vs cyclohexanol and the enantiomeric ratio (E) formula derived by Sih (Table 5). ... 

Bioreduction of ketones often leads to (he creation of an asymmetric center and. thereby, two possible stereoisomeric alcohols. " For example, reduction of acetophenone by a soluble rabbit kidney reductase leads to the enantiomeric alcohols (5)(-)- and (R)( + )-mcthylphen lcarbinol. with the (.V)(-) isomer predominating (3 1 ratio). The preferential formation of one stereoisomer over the other is termed product stereoselectivity in drug metabolism. " Mechanistically, ketone reduction involves a "hydride" transfer from the reduced nicotinamide moiety of the cofactor NADPH or NADH to (he carbonyl carbon atom of the ketone. It is generally agreed that this step proceeds with considerable stereoselectivity." Consequently, it is not surprising to find many reports of xenobiotic ketones that are i uced prefer-emi ly to a predominant stereoisomer. Often, ketone reduction yields dcohol metabolites that arc pharmacologically active. 

Reaction of phenylethanone with, for example, lithium aluminium hydride, gives a racemic mixture of enantiomeric alcohols... 

An advantage of this ester is that the diastereoisomer ratio can be measured in two ways (1) from the H NMR spectrum, e.g. by integration of the methoxy proton absorptions of 53 and 54 (2) by integration of the 19F absorptions of the CF3 groups of this pair of compounds. With the aid of esters 53 and 54 it is possible to determine the ratio of two enantiomeric alcohols in a mixture. However, assignment of absolute configuration to the alcohols can be problematic. 

Other carboxylic acids such as 55 have been used to make corresponding diastereoisomeric esters. The choice of aromatic substituent in 55 is made on the basis of the greater anisotropy of the three fused aromatic rings in 55 with respect to phenyl. It has recently been possible to assign configuration to a pair of enantiomeric alcohols directly from the H NMR spectra of their esters with 55. The discussion goes beyond the scope of this text, but for details the work of Fukushi et al. 1 Takahashi et a/.18 and Seco et al 9 should be consulted. 

Similarly, if the racemic mixture is composed of basic drugs, use is made of camphor-10-sulfonic acid, a natural product obtainable as an optically pure enantiomer. An example of the type of reactions involved is shown in Figure 4.13, where a pair of enantiomeric alcohols is resolved by reaction with phthalic anhydride and an optically pure base to form a pair of diastereoisomeric salts. Reactions of this type can be tedious to perform and, with the advent of HPLC with chiral stationary phases, are gradually being replaced. 

In this case, the reversible coordination of tin with aldehyde favors the closed transition state for Felkin-Anh addition in 339, whereas the jS-chelation model of 340 introduces destabilizing steric interactions owing to placement of the methyl substituent of the chiral allene. Transmetalations of chiral allenylstannanes with InBrs occur with net retention of allene geometry (Scheme 5.2.64). Thus, the starting (P)-286 can also be utilized for a stereoselective reaction with the corresponding (5 )-aldehyde (Scheme 5.2.72, bottom). The enantiomeric alcohol ent-337 is produced via the closed transition state... 

Combination of a nonracemic isocyanate and a l,3-disul)sliluted distannoxane has provided a new method for determination of the optical purity of chiral alcohols (Scheme 12.174) [316]. When a chiral alcohol was reacted with commercially available (l )-l-(l-naphthyl)efhyl isocyanate in the presence of 1,3-disubstituted distannoxane, formation of the desired carbamates occurred rapidly, with acid-labile functional groups such as ester, THP and /Miydroxyketone remaining intact. Subsequent HPLC analysis of the resulting carbamate revealed a pair of well-separated peaks of diastereomers derived from both enantiomeric alcohols. 

Both enantiomeric (R)- and (S)-oxazaborolidines are available so it is possible to obtain at will either enantiomeric alcohol. The selectivity depends upon the geometry of the complex formed by coordination of the carbonyl oxygen to the Lewis acidic heterocyclic boron atom, complex 3.72 being favored. The catalytic cycle is shown in Figure 3.25. 

The formation of the enantiomerically enriched or pure esters by reaction (14) was not a result of a dynamic process but a one-pot two-step procedure consisting of lipase-catalyzed resolution and a subsequent inversion of the slow reacting enantiomeric alcohol by Mitsunobu reaction. 

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