Racemic alcohol preparation

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). 

The acid esters of 1,2-dicarboxylic acids are conveniently prepared by heating the corresponding cyclic anhydride with one molar proportion of the alcohol (see the preparation of alkyl hydrogen phthalates from phthalic anhydride and their use in the resolution of racemic alcohols, Section 5.19). 

The Pasteur method can also be applied to the resolution of neutral racemates, if these can be first converted into an acidic or basic derivative from which eventually a mixture of crystalline diastereoisomeric salts may be prepared by appropriate neutralisation. Thus, a racemic alcohol (e.g. ( )-octan-2-ol, Expt 5.220) may be converted into the corresponding racemic hydrogen phthalate ester by heating with phthalic anhydride, and the ester is then resolved by the Pasteur procedure using an optically active base. The resulting optically active hydrogen phthalate ester is then carefully hydrolysed with aqueous sodium hydroxide to regenerate one of the optically active forms of the alcohol. 

Actually, coordination complexes of different metal salts of DBTA with hydroxycarboxylic acid esters, hydroxycarboxylic acids and alcohols as well as host-guest complexes of DBTA with chiral phosphine oxides and racemic alcohols can be prepared and used for separation of optical isomers. In the next subchapters theoretical and practical aspects of these recent resolution processes are summarised. 

To demonstrate the synthetic application of this methodology, the authors subsequently demonstrated its use for the preparative kinetic resolutions of a series of 2° alcohols, Table 24, whereby 20 ml solutions of each racemic alcohol were passed through the bioreactor (3.3 h) and found to afford analogous results to those obtained during the initial optimization experiments. The authors successfully demonstrated the use of immobilized and lyophilized enzymes within a continuous flow reactor, presenting a synthetically viable approach to the kinetic resolution of racemic alcohols. 

A very useful intermediate for the attachment of further functionalities to Cgo is obtained by reaction of the fullerene with 2-[(trimethylsilyl)oxy]buta-1,3-diene, followed by hydrolysis of the resulting silyl enol ether under formation of a fullerene-fused cyclohexanone (214) which is reduced to the racemic alcohol ( )-215 (Scheme 1.18).374 Because of their great synthetic potential, silyloxy-substituted dienes, such as Danishefsky diene type systems,375-377 have been widely used in the preparation of fullerene derivatives, mostly in the form of stereoisomeric mixtures.378-383... 

Lipase B from Candida antarctica (CALB) has been shown to be an excellent enantioselective biocatalyst for the stereo-selective acylation of racemic alcohols [14, 15]. The most often used commercial preparation of CALB is Novozym 435, where the enzyme is immobilized on a macroporous acrylic resin and the matrix presents about 90% of the total mass. 

Enzymatic Resolution Approach (eq 2) Ketone (R)-l can also be obtained by enzymatic resolution of racemic acetate ( )-2, which is prepared by reduction and acetylation of racemic ( )-l (prepared according to the direct synthesis approach). Oxidation of the resulting (R)-alcohol affords (R)-l in high enan-tioselectivity (> 99% ee). This method has been employed for large-scale synthesis of (R)-l. 

Preparative Uses of MTPA Derivatives. Resolution of racemic compounds on a preparative scale is always a challenging endeavor. Conversion of the enantiomeric mixture into a mixture of diastereomers, each with unique physical properties, makes it possible to separate the components by a variety of physical methods, such as fractional recrystallization, distillation, or chromatography. One of the earliest uses of MTPA was the resolution of racemic alcohols via the separation of diastereomeric MTPA esters by preparative gas-liquid chromatography, followed by alcohol regeneration with Lithium Aluminum Hydride (eq 2). More frequently, diastereomeric MTPA esters have been separated by high performance liquid chromatography (HPLC), followed by al-... 

Utilization of enzymes in organic synthesis to prepare chiral compounds of synthetic value is well documented.For instance, porcine pancreatic hpase (PPL, E.C. 3.1.1.3.) which is an inexpensive commercially available enzyme, specifically catalyzes the hydrolysis of esters of racemic alcohols and wc50-diols. Thus, on a preparative scale (0.25 mol) dimethyl 2-methyl-butanedioate, on treatment with PPL in buffered water at pH 7.2, underwent regio- and en-antioselective hydrolysis. Extraction with diethyl ether gave the unhydrolyzed dimethyl (/ )-2-methylbutanedioate (93%), while acidification of the aqueous phase provided the (5)-half ester,which on esterification with methanol (acidified by thionyl chloride) gave the dimethyl (5 )-2-methylbutanedioate (76%). 

The MaNP acid method has been successfully applied to various racemic alcohols listed in Table 9.3 for preparation of enantiopure secondary alcohols and the simultaneous determination of their absolute configurations. If the separation factor a is as large as in the case of l-octyn-3-ol 56 (entry 2 in Table 9.3, a. = 1.88), a large-scale HPLC separation of diastereomeric MaNP esters is feasible. For example, in the case of esters 64a and 64b derived from alcohol 56, ca. 0.85-1.0 g of the mixture was separable in one run by the HPLC (hexane/EtOAc = 20 1) using a silica gel glass column (22 x 300 mm) (Figs. 9.19 and 9.20). 

The HPLC separation data of diastereomeric esters prepared from other racemic alcohols 24, 36, 38, 39, and 57-63 with MaNP acid (.S)-(+)-3 are listed in Table 9.3. It should be emphasized that for most alcohols, their diastereomeric MaNP esters are clearly separated with a values of 1.10-1.88. Phenylacetylene alcohol 57 was separable as the MaNP esters 65a/65b (a = 1.30, entry 3). Substituted cyclohexanols 58 and 59 were also effectively separated as MaNP esters (entries 4 and 5). Especially, the a value of trans-2-isopropylcyclohexanol MaNP esters 66a/66b is as large as 1.88, which is comparable to that of fhe menthol case. On the ofher hand, in the case of trans-2-methylcyclohexanol MaNP esters 67a/67b, the a value is relatively small, a = 1.21. These results indicate that the combination of a longer and larger alkyl group on one side and a smaller alkyl group on fhe ofher side leads to better separation of two diastereomers, as seen in 2-hexadecanol esters 54a/54b (see Fig. 9.15) and tro s-2-isopropylcyclohexanol MaNP esters 66a/66b. 

The racemic alcohol was prepared by lithium aluminum hydride reduction of (R,S)-4. An abbreviated library of commercially available enzymes (entries 1-11 in Tab. 1) was used to screen the vinyl acetate acylation. Enzymes in entries 2, 3, 4, 8, and 11 catalyzed the acylation with a relatively fast rate (>20% conversion in... 

Inositol monophosphatase catalyses the hydrolysis of a range of phosphate esters of inositol, and in so doing, participates in brain cell chemistry and is believed to be the target for lithium therapy. In the search for inhibitors of the enzyme, phosphate derivatives from 6-0-(2 -hydroxyethyl)cyclohexane-l,2,4,6-tetraol have been prepared, the racemic epoxide (26) acting as a key intermediate. The conversion of (26) into the racemic 1-phosphate (29) via (27) and (28) employed the steps indicated in Scheme 1. Further, the racemic alcohol (27) was... 

The enzyme-catalyzed production of (R)-2-(2-aminobutyl)-3-chlorothio-phene ((R)-42) was a research project at Zeneca a few years ago [72]. Compound 42 was an intermediate in the preparation of adenosine derivatives and Scheme 13 outlines the relevant enzymatic step. Racemic alcohol rac-40 was treated with Rhizomucor miehei lipase immobilized on an ion-exchange resin (Lipozyme RM IM from Novozymes) in the presence of vinyl butyrate to yield the free (S)-alcohol 40 and the (R)-ester 41. Alcohol 40 was subsequently converted into the strategic intermediate 42, which found further use in the synthesis of antihypertension drugs. 

The asymmetric transfer hydrogenation of ketones is an effective way to prepare enan-tiopure alcohols." " We were attracted to this reaction as we anticipated that one could exploit the reversibility of the reaction to perform either for the enantioselective reduction or for the kinetic resolution of racemic alcohols via oxidation. This behaviour is reminiscent of alcohol dehydrogenases which can operate either as oxidases or reductases. ... 

Treatment of the enone (69) with an excess of the diene (70) in the presence of aluminium trichloride and 4,4-thiobis-(6-t-butyl-3-methylphenol) gave the tricyclic ketone (71) (40%) as the sole Diels-Alder product. Reduction then afforded the lactone (72) whose constitution and stereochemistry were established by X-ray analysis. Finally, demethylation gave the racemic alcohol (73) which differs from the quassin skeleton only in the stereochemistry at C-9. The Diels-Alder reaction also plays a key role in two other de novo syntheses. The ring A seco-derivative (75) has been prepared from the adduct (74), and the ring A nor-compound (77), a possible intermediate for the synthesis of quassimarin (78), has been obtained from the Diels-Alder product (76). ... 

The synthesis of enantioenriched acyl chloride 54 was originally conducted using a modification of procedures described by Villieras and coworkers for the preparation of racemic alcohol 55 (Scheme 12). Thus, the synthesis commenced with the preparation of racemic allylic alcohol 55 from 2,5-dimethoxytetrahydrofuran. The alcohol was resolved enzymatically, following procedures reported by Ogasawara, to provide enantioenriched alcohol (S)-55 in 50% yield and 99% ee. Protection of the alcohol with the sterically encumbered ferf-butyl dimethylsilyl group allowed a diastereoselective copper(I)-mediated conjugate addition of methyl magnesium bromide to... 

To clarify the effect of the trans-cis photoisomerization of the chiral azobenzene compounds on the change in HTP, the change in the hehcal pitches of Ch LCs containing nonchiral azobenzene compound, p-azo-7-dl (Fig. 10.7), which was derived with racemic alcohol, was examined. Ch LCs were prepared by adding R811 and chiral or nonchiral azobenzene compounds with the same structure, p-azo-7-dl or p-azo-7, in E44. In the case of the (R811/p-azo-7/E44) sample, the helical pitch was increased by the trans-cis photoisomerization of... 

Recently, many research groups have focused their efforts oti the development of stereoselective routes leading to optically pure aminophosphinic acids. With this aim, Yamagishi and co-workers recently devised a practical methodology for the preparation of optically pure A-protected 1,1-diethoxyethyl(aminomethyl) phosphinates (12) [39] and their participation in diastereoselective alkylation reactions [40] which were first studied several years ago by McCleery and Tuck [41] (Scheme 4). In particular, they managed to obtain on a gram-scale and 99 % enantiomeric excess (ee) compound 11, after addition of paraformaldehyde to l,l-diethoxyethyl-//-phosphinate (10) and subsequent lipase-catalyzed resolution of the resulting racemic alcohol. Conversion of 11 to substrate 12 in four steps afforded a valuable substrate suitable for lithium bis(trimethylsilyl)amide (LHMDS)-promoted alkylation performed in a diastereoselective fashion (dr = 10 1) (Scheme 4). 

As noted earlier in this chapter, the enantioselective hydrosilylation of olefins could be a useful method to prepare chiral, non-racemic alcohols. A.lthough the scope of highly enantioselective hydrosilylations is limited, high enantioselectivities have been obtained for the asymmetric hydrosilylation of alkenes and vinylarenes. A majority of the most selective chemistry has been conducted using a palladium catalyst containing an axially chiral monophosphine ligand. 

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