Other Racemization Methods

In this section we discuss some DKRs in which racemization occurs spontaneously during the enzymatic resolution and without further addition of any reagent. 

Faber and coworkers have reported a DKR of mandelic acid by using a lipase-catalyzed O-acylation followed by a racemization catalyzed by mandelate racemase. However, these two transformations do not take place simultaneously in the same pot. When the sequence was repeated four times, (S)-O-acetylmandelic acid was obtained in 80% isolated yield and 98% ee [57]. 

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This reagent was treated iu situ with pentanal to give the anti-addition product in 59% yield. In principle, this method can be modified using the methods discussed in Section 1.3.3.3.2.1. to provide other racemic ( )- -alkoxy-2-butenylboronates. 

In this chapter, DKRs will be categorized according to the racemization method employed, as being catalyzed by (i) a metal, (ii) a base, (hi) an acid, (iv) an aldehyde, or (v) an enzyme. Also racemizations that take place through continuous cleavage/ formation of the substrate, or through 5 2 displacement, among other methods, will be discussed. In most cases, the racemization method of choice depends on the structure of the substrate. In all cases, the KR is catalyzed by an enzyme. 

CD and ORD measurements are a useful tool in studying configuration and conformation. The configuration of optically active 4,4 -dicarboxy-2,2, 5,5 -tetramethyl-3,3 -biselenienyl (1, X = Se) relative to its thiophene analog (1, X = S), was determined by reducing both to the corresponding 4,4 -dihydroxymethyl derivatives (2), which could be related to each other by the quasi-racemate method and by circular dichroism studies.15 Compounds 1 have also been related to 3,3, 6,6 -tetramethyl-2,2 -diphenic acid (3), and it was found that the levorotatory form of 1 (X = Se, S) and the dextrorotatory form of 3 have the -configuration.16... 

In addition to other methods, the quasi-racemate method was used (98) to determine the absolute configuration of iV-tosyl methyl-p-tolylsufimide 91. 

Racemic diquinane enone rac-6 was prepared by Piers and Orellana starting from cyclopentenone (Scheme 6) [11]. After the preparation of the heterocuprate from stannane 20, conjugate addition to cyclopentenone in the presence of BF3 Et20 provided carbonyl compound 21. It was expected that conversion of 21 by intramolecular alkylation and subsequent hydrogenation should provide the desired endo-substituted diquinane rac-13. While other hydrogenation methods proved to be rather unselective, reduction in the presence of Wilkinson s catalyst finally resulted in the formation of rac-13 with good facial diastereoselectivity [11]. 

The trends among the parameters studied by the UNCA racemization assay have been borne out when other activation methods are used. By a modification of chiral HPLC procedure below, the assay can be used to study any method of activation (for example, uronium or phosphonium methods), keeping in mind that the activation must be rapid and that epimerization by multiple mechanisms becomes possible. These findings also hold for solid-phase synthesis reactions. 

Racemic colchiceine was obtained by Corrodi and Hardegger by a base-catalyzed equilibration of the Schiff base obtained by reacting deacetyl-colchiceine with benzaldehyde (34). Aldimine-ketimine isomerization was found to be the mechanism by which the racemization had occurred (35). The optical resolution of deacetylcolchiceine was accomplished with cam-phorsulfonic acids, affording, after O-methylation with diazomethane, separation of the enolate isomers and after N-acetylation, unnatural (+)-and natural (-)- colchicine (Fig. 1). Racemization of colchicine in refluxing acetic anhydride followed by mild hydrolysis of the intermediate triacetate represents a much improved method of preparing ( )-colchicine (36). The Blade-Font procedure was later extended to the preparation of ( )-3-demethylcolchicine and other racemic analogs (5). 

If one enantiomer obtained by resolution is the desired one, the other recovered from the mother liquor of the resolution should be racemized to use for the next resolution. In general, whether the racemization method for unwanted enantiomer is known or not will be key to producing optically active compounds on an industrial scale. In most cases, optical resolution and racemization are non-divisable for the realization of a practical and economical process. For instance, nickel chloride complex of DL-a-amino-e-caprolactam has been successfully resolved. The complex, dissolved in ethanol, was heated and inoculated with enantiopure complex, then racemization and crystallization of the complex occurred at the same time. As a result,... 

Many other deracemizahon methods based on a two-enzyme system or in the successive enzymatic resolution/base-catalyzed racemization have been reported. They are often regarded as having a reduced environmental impact, not requiring a transition metal catalyst in the racemization step [4]. 

A relatively common use of optical rotation is as an identity test for a racemate with specification limits that are symmetrical around zero. Such a specification has Little if any regulatory significance. Its validation necessarily depends upon knowledge of the specific rotation and thus requires the resolution of the racemate on a laboratory scale. Furthermore, even with such supporting data, the method is dependent upon the accuracy of the sample preparation, since a solvent blank would also show a rotation of zero. Other analytical methods are far more appropriate for the stereochemically specific identification of racemates. 

Separations of [njhelicene racemates have also been attempted using n-acids, such as 2-(2,4,5,7)-tetranitrofluorenylidene-9-aminooxypropionic acid (TAPA, 112, see above) its butyric acid analogue TAB A 113 and binaphthyl-2,2-diyl-hydrogenphosphate (BPA, 115 Other employed methods were inclusion chromatography on triacetyl cellulose or helical polymers like (-l-)-poly(triphenyl-methyl-methacrylate [(-l-)-PTrMA, 776]... 

One other important method of preparation had been used by two groups of workers it involved the direct oxidation of the crotonic acids by means of barium permanganate. Fittig and Kochs obtained by this process an anhydrous, crystalline, racemic dihydroxybutanoic acid (IVab) of m.p. 74-75° from crotonic acid, and a liquid dihydroxybutanoic acid (Illab) from isocrotonic acid. In 1904, Morrell and Hanson resolved the jS-methylglyceric acid (Illab) of Fittig and Kochs with quinidine and... 

An example of the construction of a 1,2-diketone from a 1,2-diol comes from the total synthesis of ( )-cephalotaxine (54) where the Corey-Kim conditions were used to convert diol 52 to diketone 53 in 89% yield while other oxidation methods were reported to have failed to affect this conversion.15 The more accessible ketone was then converted to the enol ether and LAH reduction afforded the racemic natural product 54. 

Racemic pterocarpin was synthesised (ref. 108) and later by other improved methods (ref. 109, 110). In the first of these latter methods (ref. 109) 2-benzyloxy-4,5-methylenedioxyphenylacetaldehyde was converted with pyrrolidine to an enamine which underwent reaction with 2-acetoxy-4-methoxybenzoyl chloride. Cyclisation led to an isoflavone acidic treatment of which followed by borohydride reduction and ring closure effected formation of the required pterocarpin as depicted in Scheme 31. 

The use of two types of liquid membranes is described in [302] liquid emulsion membranes (LEMs), and supported liquid membranes (SLMs), where isoparaffin or kerosene and their mixtures were used as organic phases. A surfactant of the type of Span 80 served as emulsifier. LEMs are used, for example, for selective separation of L-phenylalanine from a racemic mixture of L-leucine biosynthesis as well as conversion of penicillins to 6-APA (6-aminopenicillanic acid). SLMs have a higher stability. A number of their commercial applications have been studied, e.g. in separation of penicillin from fermentation broth, as well as in the recovery of citric acid, lactic acid and some aminoacids. Compared with other separation methods (ultrafiltration, ultracentrifugation and ion exchange), LEMs and SLMs are advantageous in the separation of stereospecific isomers in racemic mixtures. 

In tests devised to determine the amount of racemization to be expected in peptide syntheses in which the carboxyl component is a di-or higher peptide, this method ranks below the racemization-resistant azide procedure but above almost all other standard methods. Using a very sensitive and accurate isotope dilution assay, 1 % racemization was observed in the formation of the Anderson test peptide (Z-Gly-Phe-Gly-OEt) and 7% racemization was observed in the formation of the Young test peptide (Bz-Lou-Gly-OEt) under optimized conditions. (The Young test was designed to exaggerate racemization problems, thus permitting more accurate studies of the effects of reaction condition variations.)... 

A significant feature of the azide coupling method is that it has a minimal tendency to lead to racemization. Although minor amounts of racemization have been detected in certain systems, other coupling methods usually lead to more extensive racemization under comparable conditions. ... 

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