Chiral alcohol racemization

Alcohol dehydrogenase-catalyzed reduction of ketones is a convenient method for the production of chiral alcohols. HLAD, the most thoroughly studied enzyme, has a broad substrate specificity and accommodates a variety of substrates (Table 11). It efficiendy reduces all simple four- to nine-membered cycHc ketones and also symmetrical and racemic cis- and trans-decalindiones (167). Asymmetric reduction of aUphatic acycHc ketones (C-4—C-10) (103,104) can be efficiendy achieved by alcohol dehydrogenase isolated from Thermoanaerohium hrockii (TBADH) (168). The enzyme is remarkably stable at temperatures up to 85°C and exhibits high tolerance toward organic solvents. Alcohol dehydrogenases from horse Hver and T. hrockii... 

With this epoxidation procedure it is possible to convert the achiral starting material—i.e. the allylic alcohol—with the aim of a chiral reagent, into a chiral, non-racemic product in many cases an enantiomerically highly-enriched product is obtained. The desired enantiomer of the product epoxy alcohol can be obtained by using either the (-1-)- or (-)- enantiomer of diethyl tartrate as chiral auxiliary ... 

Most of the reactions applied to amines can also be transferred to alcohols (Eig. 7-5). One large group of chiral alcohols are the (i-adrenoreceptor blockers, for which a variety of derivatization agents was developed. One highly versatile reagent for the separation of (i-blockers is A-[(2-isothiocyanato)cyclohexyl]3,5-dinitrobenzoyl-amide (DDITC) [11]. Alternatively, unichiral drugs such as (3-blockers or (S)-naproxen [12] may be used in a reciprocal approach to derivatize racemic amine compounds. 

Most of the biochemical reactions that take place in the body, as well as many organic reactions in the laboratory, yield products with chirality centers. Fo example, acid-catalyzed addition of H2O to 1-butene in the laboratory yield 2-butanol, a chiral alcohol. What is the stereochemistry of this chiral product If a single enantiomer is formed, is it R or 5 If a mixture of enantiomers i formed, how much of each In fact, the 2-butanol produced is a racemic mix ture of R and S enantiomers. Let s see why. 

Modena and colleagues47 have developed use of some chiral, non-racemic terpene alcohols as directing groups for highly diastereoselective m-chloroperbenzoic oxidation of sulfides into sulfoxides. Specifically the isobornyl vinylic sulfides 8 undergo hydroxyl-directed oxidation to give a 9 1 ratio of diastereomeric sulfoxides (equation 11). 

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

The first reductive kinetic resolution of racemic sulphoxides was reported by Balenovic and Bregant. They found that L-cysteine reacted with racemic sulphoxides to produce a mixture of L-cystine, sulphide and non-reduced optically active starting sulphoxide (equation 147). Mikojajczyk and Para reported that the reaction of optically active phosphonothioic acid 268 with racemic sulphoxides used in a 1 2 ratio gave the non-reduced optically active sulphoxides, however, with a low optical purity (equation 148). It is interesting to note that a clear relationship was found between the chirality of the reducing P-thioacid 268 and the recovered sulphoxide. Partial asymmetric reduction of racemic sulphoxides also occurs when a complex of LiAlH with chiral alcohols , as well as a mixture of formamidine sulphinic acid with chiral amines, are used as chiral reducing systems. ... 

Arguably the most challenging aspect for the preparation of 1 was construction of the unsymmetrically substituted sec-sec chiral bis(trifluoromethyl)benzylic ether functionality with careful control of the relative and absolute stereochemistry [21], The original chemistry route to ether intermediate 18 involved an unselective etherification of chiral alcohol 10 with racemic imidate 17 and separation of a nearly 1 1 mixture of diastereomers, as shown in Scheme 7.3. Carbon-oxygen single bond forming reactions leading directly to chiral acyclic sec-sec ethers are particularly rare since known reactions are typically nonstereospecific. While notable exceptions have surfaced [22], each method provides ethers with particular substitution patterns which are not broadly applicable. 

The use of a chiral alcohol to prepare diastereomeric alkoxystannanes from racemic triorganostannyl halides, then displacement with a Grignard reagent, constitutes a general route to nonracemic tetraorganostannanes. Chinconine has proven particularly effective as the chiral alcohol (equation 7)19. 

An enantioenriched propargylic phosphate was converted to a racemic allene under the foregoing reaction conditions (Eq. 9.152) [124]. It is proposed that the racemization pathway involves equilibration of the allenyl enantiomers via a propargylic intermediate (Scheme 9.37). Both the allenylpalladium precursor and the allenylsamarium reagent could racemize by this pathway. When a chiral alcohol was used as the proton source, the reaction gave rise to enantiomerically enriched allenes (Table 9.61) A samarium alcohol complex is thought to direct the protonolysis (Scheme 9.38). 

Chiral sulfinates are important intermediates that are widely applied in the synthesis of other classes of chiral organosulfur compounds and in their configurational correlations. Optically active sulfinates were first prepared in 1925 by Phillips (100) in two ways. The first consisted in the transesterification of racemic alkyl p-toluenesulfin-ates with chiral alcohols such as (-)-menthol and (-)-2-octanol yielding a mixture of two optically active sulfinates as shown in eq. [26]. The... 

Cathodic deprotection of tosylates of chiral alcohols was achieved without racemization by cleavage of the O—SO2 bond [351]. Optically active quaternary arsonium [352, 353] and phosphonium salts [354] are cathodically cleaved to tertiary arsines and phosphines respectively, with retention of the configuration. The first enantiomer enriched chiral phosphines have been prepared this way. 

Pahnans et al. prepared 5 by the reaction of [RuCl2(p-cymene)]2 and 2-phenyl-2-aminopropionamide in the presence of potassium carbonate. They used 5 in an iterative tandem catalysis for the synthesis of chiral oligoesters. The enzymatic ring opening of 6-methyl-e-caprolactone was combined with ruthenium-catalyzed alcohol racemization to produce optically active oligomers of 6-methyl-e-capro-lactone [23] (Scheme 1.17). 

Analogous to the reactions of chiral alcohols, enantiomerically pure amines can be prepared by (D)KR of the racemate via enzymatic acylation. In the case of alcohols the subsequent hydrolysis of the ester product to the enantiomerically pure alcohol is trivial and is generally not even mentioned. In contrast, the product of enzymatic acylation of an amine is an amide and hydrolysis of an amide is by no means trivial, often requiring forcing conditions. 

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 this case both enantiomers 3 and ent-3 react with Pd(0)/BPA with formation of the two diastereomeric 7c-allyl-Pd( II) complexes 25 and 26, respectively (Scheme 2.1.4.29). Only if the following conditions exist can the racemic substrate be completely converted to the chiral alcohol with high efficiency 1) the reactivity of the 7c-allyl-Pd(II) complexes 25 and 26 must be different 2) a fast diastereom-erization of 25 and 26 or racemization of 3 and/or ent-3 must take place 3) BPA must induce a high stereoselectivity 4) the substituents of the allylic substrate have to provide for a high regioselectivity [39]. 

Problem 16.42 Acid-catalyzed hydrolysis with H2 "0 of an ester of an optically active 3° alcohol, RCOOC R R"R", yields the partially racemic alcohol containing O, R R R C "OH. Similar hydrolyses of esters of 2° chiral alcohols, RCOOC HR R", produce no change in the optical activity of the alcohol, and "O is found in RC OjH. Explain these observations. ... 

The application of enzymatic acylation for the resolution of racemic alcohols in organic solvent has shown to be an effective method to rapidly synthesize chiral alcohols. The racemic alcohols are treated with the lipase and acylating agent one enantiomer remains unconverted whereas the second enantiomer is esterified and easily separated by distillation (Scheme 7.2). Vinyl acetate or isopropenyl acetate are typical acylating agents, as the generated vinyl alcohol tautomerizes rapidly... 

Kinetic resolutions, such as the ones discussed above, are limited to a 50% yield. Consequently, the undesired enantiomer needs to be recovered, racemized, and recycled, which makes the process more complex and leads to an increased solvent use. The obvious solution is to racemize the slow-reacting enantiomer in situ. With chiral alcohols, the racemization catalysts of choice are based on ruthenium (Figure 10.17). 

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