Chiral alcohol preparation

Chiral Alcohols and Lactones. HLAT) has been widely used for stereoselective oxidations of a variety of prochiral diols to lactones on a preparative scale. In most cases pro-(3) hydroxyl is oxidized irrespective of the substituents. The method is apphcable among others to tit-1,2-bis(hydroxymethyl) derivatives of cyclopropane, cyclobutane, cyclohexane, and cyclohexene. Resulting y-lactones are isolated in 68—90% yields and of 100% (164,165). 

The sesquiterpenoid hydrocarbons (5)-a-curcumene (59) and (5)-xanthorrhizol (60) were prepared by asymmetric conjugate addition of the appropriate aryllithium reagent to unsaturated oxazoline 56 to afford alcohols 57 (66% yield, 96% ee) and 58 (57% yield, 96% ee) upon hydrolysis and reduction. The chiral alcohols were subsequently converted to the desired natural products. ... 

Chiral alcohols have also been used in an asymmetric synthesis of sulphoxides based on halogenation of sulphides. Johnson and coworkers have found319 that the reaction of benzyl p-tolyl sulphide with JV-chlorobenzotriazole (NCBT) followed by addition of (—) menthol and silver tetrafluoroborate afforded diastereoisomeric menthoxysulphonium salts 267 which, upon recrystallization and hydrolysis, gave benzyl p-tolyl sulphoxide with 87% optical purity (equation 145). More recently, Oae and coworkers reported320 that optically active diaryl sulphoxides (e.e. up to 20%) were formed either by hydrolysis or thermolysis of the corresponding diaryl menthoxysulphonium salts prepared in situ from diaryl sulphides using ( —) menthol and t-butyl hypochlorite. 

The reaction of alkenylcarbene complexes and imines in the presence of a Lewis acid generates pyrroline derivatives as a result of a [3C+2S] cyclisation process [76]. This reaction has been extended to an asymmetric version by the use of chiral alkenylcarbene complexes derived from several chiral alcohols. However, the best results are found when (-)-8-phenylmenthol-derived complexes are used and catalytic amounts of Sn(OTf)2 are added to the reaction. In these conditions high levels of trans/cis selectivity are achieved and the hydrolysis of the major tram diastereoisomers allows the preparation of optically pure 2,5-disubstituted-3-pyrrolidinone derivatives (Scheme 29). 

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 usefulness of the carbonyl reductase from Candida magnoliae as an enzyme catalyst in the synthesis of chiral alcohol intermediates has been demonstrated by carrying out the reduction of several ketones on a preparative scale [56]. The isolated yields and enantiomeric excess of the product alcohols are summarized in Table 7.1, from which it can be seen that these chiral alcohols were obtained in essentially optically pure forms in excellent yields. These chiral alcohols are important intermediates in the synthesis of pharmaceuticals and agrichemicals. For example, optically active 2-hydroxy-3-methylbutyrate is an important chiral synthon... 

In summary, ketoreductases have emerged as valuable catalysts for asymmetric ketone reductions and are preparing to enter the mainstream of synthetic chemistry of chiral alcohols. These biocatalysts are used in three forms wild-type whole-cell microorganism, recombinant... 

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. 

Asymmetric hydrogenation of ketones is one of the most efficient methods for making chiral alcohols. Ru-BINAP catalysts are highly effective in the asymmetric hydrogenation of functionalized ketones,54,55 and this may be used in the industrial production of synthetic intermediates for some important antibiotics. The preparation of statine 65 (from 63b R = i-Bu) and its analog is one example (Scheme 6-28).56 Table 6-6 shows the results when asymmetric hydrogenation of 63 catalyzed by RuBr2[(R)-BINAP] yields threo-64 as the major product. 

This new hydrogenation procedure is clean, mild, and effective. It offers a very practical method for chiral alcohol synthesis. Isolated Ru complexes are fairly air and moisture stable and can be stored in an ordinary vial for quite a long time. Compared with the catalysts prepared in situ, the reaction rates in the asymmetric hydrogenations catalyzed by 70 are higher by two orders of magnitude. 

The mechanism of this one-pot reaction is proposed to be as follows (Figure 4.3) firstly, a chiral alkoxide ethylzinc is prepared from diethylzinc and the chiral alcohol with the evolution of a gas, which is probably ethane (I). The chiral ethylperoxyzinc alkoxide is formed by insertion of oxygen into the carbon zinc... 

The above three examples involved reactions where the electron transfer takes place from the metal to the organic substrate. The reverse scenario can also be used in radical reactions via oxidative generation of cationic radical species, which can undergo coupling reactions. Kurihara et al. have used chiral ox-ovanadium species as a one-electron transfer oxidant to silylenol ethers in a hetero-coupling process [165]. Treatment of 246 with a catalyst prepared in situ from VOCI3/chiral alcohol/MS 4 A followed by addition of 247 provided the coupling product 248 (Scheme 63). 8-Phenyl menthol 251 was found to be... 

As the integrity of chiral alcohols are retained in the phase-transfer catalysed O-alkylation, the procedure is valuable for the synthesis of chiral ethers under mild conditions as, for example, in the preparation of alkoxyallenes via the initial formation of chiral propargyl ethers [8]. It has been proposed that a combination of 18-crown-6 and tetra-n-butylammonium iodide provide the best conditions for the O-benzylation of diethyl tartrate with 99% retention of optical purity [9]. 

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. 

The chiral reagent prepared in situ from ( + )-a-pinene and 9-borabicyclo-[3.3.1]nonane reduced benzaldehyde-7- 7 to benzyl-/- 7 alcohol in 81.6% yield and 90% enantiomeric excess [709]. 

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). 

For preparative-type resolutions (chromatography or other separation techniques) it is of vital importance that the derivatives can be cleaved smoothly to avoid chemical and optical losses. In addition, it would be advantageous to recover the CDA (see Section 3.2.1.2.). The Noe lactol (Tabic 1, entry 55) fulfills such criteria almost perfectly during the course of reaction with chiral alcohols to form diastereomeric acetals220. 

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