Racemisation

Accordiug to Norkina c( the specific rotation varies with ti e solvent and racemisation is apt to occur during extraction. Values much lower than — 81° have been given by Smith.The salts are dextrorotatory. 

Atropa Belladonna Linn. Leaves, 0-4 roots, 0-5 seeds, 0-8 whole plant, 0-2 to 1-0 h5mscyamine with some hyoscine atropine has been found but may have resulted from racemisation during extraction apoatropine and possibly belladonnine (Kreitmair Atropa bcetica. Leaves, 0-82-1-06 roots, 0-94 fruit, 1-09 hyoscyamine and atropine. 

The alkaloid can usually be obtained from the mother liquors of hyoscyamine, but Datura Metel, in which hyoscine is the chief constituent, was the better primary source but may now prove less valuable than selected Duboisia spp. (p. 66). A process of manufacture has been described by Chemnitius, and a method for the recovery of 1-hyoscine from racemised base by Schukina et al. A method for its estimation in presence of opium alkaloids has been devised bj Wallen and Callback. 

Hyoscine, like hyoscyamine, is readily racemised by dilute alkalis, and... 

When warmed with barium hydroxide, dilute alkalis or acids, hyoscin is hydrolysed, yielding tropic acid and a new base, CgHjsOjN, oscine o scopoline. Depending on the conditions of experiment, the tropic aci obtained may be either the pure Z-form or the partially racemised acid but the oscine obtained is invariably inactive. 

Poroidine, C42H2i02N. The synthetic product was isolated as the hydrobromide, colourless plates, m.p. 224-5°. A mixture (10 parts) of this with synthetic isoporoidine hydro bromide (1 part) had m.p. 220° which was not depressed by addition of the hydro bromide of either natural or racemised base Z. The other salts prepared included oxalate, m.p. 301-2°, picrate, m.p. 172° and methiodide, m.p. 289°. 

It is considered that in these new forms racemisation or reversible inversion has occurred at the centre of asymmetry in the phthalide group, and that the centre of asymmetry in the isoquinoline nucleus is unaffected. The melting-point, 176°, of each new isomeride is depressed by addition of the corresponding a-narcotine and the specific rotation of l-j3-narcotine, W548 is 101° (CHCI3) or — 59-2° (N. HCl), that of i-a-narcotine, under the same conditions being — 246° and -f 50-4° respectively. 

The data given in the table for corynanthine are due to Foumeau and Fiore. Raymond-Hamet later found that corynanthine on alkaline hydrolysis gave a dextrorotatory acid, which Scholz confirmed and identified its methyl ester as yohimbine and suggested that corynanthine is a stereoisomeride of yohimbine. Fourneau and Benoit have confirmed that corynanthine on acid hydrolysis gives 1-corynanthic acid (m.p. 284°, [a]i) — 85-9° pyridine), but on alkaline hydrolysis, even in the cold, some racemisation occurs and the resulting acid is of low lasvo-rotation. They also point out that both yohimbine and corynanthine yield yohimbone on dehydrogenation cf., p. 504) and are probably stereoiso-merides. 

These urethanes and the amino-compounds described above do not isomerise or racemise like the lysergic acids and the ergot alkaloids, which is taken to indicate that the carboxyl group at C is an important factor in this reaction. 

Attempts to prepare the active limonenes were unsuccessful, as during the reactions, even when the various acids and the terpiheol were separated into their active components, racemisation takes plac during the dehydration and the most active product obtained had a rotation of — 5°, so that it consisted essentially of dipentene, with a very small amount of laevo-limonene. 

Process economics dictate the recycling of the unwanted isomer. Path A in Figure A8.2 illustrates that racemisation of the D-N-benzylidene amino add amide is fadle and can be carried out under very mild reaction conditions. After removal of die benzaldehyde die D,L-amino add amide can be recyded 100% conversion to the L-amino add is theoretically possible. Another method for racemisation and recycling of the L-amino add (path B, Figure A8.2) comprises the conversion of the L-amino add into die ester in the presence of concentrated add, followed by addition of ammonia, resulting in the formation of the amide. Addition of benzaldehyde and racemisation by OH- (pH =13) gives the D,L-amino add amide. In this way 100% conversion to die D-amino add is possible. 

However, the products are separated using ion-exchange columns and the starting material is a derivative rattier than a precursor of the racemic amino add, thus making the total process drcuitous since it involves several chemical steps in addition to die enzymatic resolution step. Furthermore, racemisation of the unwanted isomer is not easily accomplished. 

The flow diagram of the enzyme reactor for continuous production of the L-amino add is given in Figure A85. The acetyl amino add is continuously charged into the enzyme column through a filter and a heat exchanger. The effluent is concentrated and the L-amino add is crystallised. The acyl-D-amino add contained in the mother liquor is racemised by heating in a racemisation tank, and reused. 

Chemically synthesised D,L-hydantoins prepared from the corresponding aldehydes via die Bucherer Berg reaction are converted by the bacterial cells (Bacillus brevis), containing a D-spedfic hydantoinase, to a mixture of D-N-carbamoyl amino acid and L-hydantoin. The latter compound undergoes rapid and spontaneous racemisation under the conditions of the reaction, therefore, in principle 100% of the hydantoin is converted into the D-N-carbamoyl compound. The D-amino add is obtained after treatment of the D-N-carbamoyl compound with nitrous add. This process is operated on an industrial scale by the Japanese firm Kanegafuchi. 

Although this route seems quite elegant there are some disadvantages. From foe point of economic feasibility, it would be more attractive to start with a substrate that is a precursor of the optically pure a-disubstituted amino add. In foe method described, first foe D,L-amino add has to be prepared and protected. After foe enzymatic step deprotection is necessary to obtain foe D-amino add and the total process is circuitous. Furthermore, foe unwanted isomer cannot be racemised. 

The process uses cells of Rhodotorula minuta entrapped in polyurethane. These cells selectively hydrolyse the L-ester. The remaining D-menthyl succinate is then hydrolysed and the 15-menthol racemised via D-menthone and then recycled. We have represented this process in Figure 9.9. 

Kinetics and mechanisms of isomerisation and racemisation processes of six coordinate chelate complexes. N. Serpone and D. G. Bickley, Prog. Inorg. Chem., 1972,17,391-566 (359). 

As far as "racemization" is concerned, we checked further the optical stability of representative 2-bromoamides. Whereas (S)-2-bromopropananilide or the aprotic (S)-2-bromo-N-methylpropananilide are stable in ethanol or ethanolic triethylamine, slow racemisation was observed, at room temperature, for the latter compound (oil) and for both ones in ethanolic HCl (1-5 mol.). 

A direct conversion of the oxazoline (44) to the thiazoline (45) can be achieved by the thiolysis of the oxazoline (44) with H2S in methanol in the presence of triethylamine followed by cyclodehydration with Burgess reagent. This method is essentially free from racemisation and has been used in the transformation of peptide substrates <95TL6395>. 

The ability of enzymes to achieve the selective esterification of one enantiomer of an alcohol over the other has been exploited by coupling this process with the in situ metal-catalysed racemisation of the unreactive enantiomer. Marr and co-workers have used the rhodium and iridium NHC complexes 44 and 45 to racemise the unreacted enantiomer of substrate 7 [17]. In combination with a lipase enzyme (Novozyme 435), excellent enantioselectivities were obtained in the acetylation of alcohol 7 to give the ester product 43 (Scheme 11.11). A related dynamic kinetic resolution has been reported by Corberdn and Peris [18]. hi their chemistry, the aldehyde 46 is readily racemised and the iridium NHC catalyst 35 catalyses the reversible reduction of aldehyde 46 to give an alcohol which is acylated by an enzyme to give the ester 47 in reasonable enantiomeric excess. 

You and co-workers have demonstrated a further application of NHCs in the kinetic resolution of formyl p-lactams ( )-265 [103]. Upon treatment with a chiral NHC, the Breslow-type intermediate is formed, followed by ring-opening of the P-lactam moiety, with subsequent trapping of the acylazolium intermediate leading to the enantio-enriched succinimide product 266 and resolved formyl P-lactam (which is reduced to its alcohol 267). The authors note that when R" = H, the products undergo racemisation readily, and this is a possible explanation for the lower levels of enantioselectivity observed in the succinimide products 266 (Scheme 12.60). 

The technique of purification based on seeded crystallization of the desired isomer and simultaneous racemisation of the undesired isomer, termed crystallization induced asymmetric transformation , has been covered by Davey (1994) with the example of a chiral pesticide, paclobutrazol (P). 

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