Optically pure compounds, production

J. T. F. Keurentjes, F. J. M. Voermans, Membrane separations in the production of optically pure compounds in Chirality and Industry II. Developments in the Manufacture and applications of optically active compounds, A. N. Collins, G. N. Sheldrake, J. Crosby (Eds.), John Wiley Sons, New York (1997) Chapter 8. 

Numbers of asymmetric phase transfer catalysis can now be accomplished efficiently to give a variety of chiral non-racemic products with high enantiomeric excesses. Thus, asymmetric phase transfer catalysis has grown up into practical level in numbers of reactions and some optically pure compounds can be effectively produced on large scale by use of chiral phase transfer catalysts. 

From the point of view of efficiency and application to the industrial production of optically pure compounds the chiral catalyst procedure is the methodology of choice. In this context. Sharpless asymmetric epoxidation and dihydroxylation, Noyori-Takaya s second generation asymmetric hydrogenations and Jacobsen s epoxidation [3] have had a tremendous impact in the last few years and they constitute the basis of the newly spawned "chirotechnology" firms, as well as of the pharmaceutical, fine chemical and agriculture industries. 

Substituted acrylates (which reseitible the enamide substrates employed 1n asymmetric hydrogenation) may be deracemized by reduction with an optically active catalyst, especially DIPAMPRh . Selectivity ratios of 12 1 to 22 1 have been obtained for a variety of reactants with compounds of reasonable volatility, separation of starting material and product may be effected by preparative GLC. Recovered starting material can then be reduced with an achiral catalyst to give the optically pure anti product. Examples of kinetic resolutions by this method are given in Table II. More recently very successful kinetic resolutions of allylic alcohols have been carried out with Ru(BINAP) catalysts. 

In the case of diastereomeric mixtures of chiral hydroperoxides, standard chromatography on achiral phase can be employed to separate the diastereomers. As one example for the preparation of optically pure hydroperoxides via this method, the ex-chiral pool synthesis of the pinane hydroperoxides 11 is presented by Hamann and coworkers . From (15 )-cw-pinane [(15 )-cw-10], two optically active pinane-2-hydroperoxides cA-lla and trans-llb were obtained by autoxidation according to Scheme 17. Autoxidation of (IR)-c -pinane [(17 )-cw-10] led to the formation of the two enantiomers ent-lla and ent-llh. The ratio of cis to trans products was 4/1. The diastereomers could be separated by flash chromatography to give optically pure compounds. 

The procedure of enriching the (S) —(+)-enantiomer to 100% enantiomeric excess by the previously described crystallization method 1s tedious.4 It provides optically pure ethyl (S)-(+)-3-(3, 5 -dlnltro-benzoyloxy)butanoate of [ ]q5 +26.3° (chloroform, a 2), which after cleavage gives enantiomerically pure ( )-(+)-ethyl 3-hydroxybutanoate of [< ](j5 + 43.5° (chloroform, a 1.0). This optically pure compound has recently become commercially available from Fluka AG, CH-9470 Buchs (Switzerland), but it is very expensive. After submission and checking of this procedure, it was shown that the ee of the product can be increased to >95% by working under aerobic conditions and by adding the ketoester more slowly. 

The application of enzymes is now well documented. They are used in organic chemistry - mainly for the production of optically pure compounds - synthesis of detergents and emulsifiers, lipid modification, laundry formulations, food and beverage production etc. [1 - 6]. Due to their high chemo-, regio- and stereoselectivity, activity at ambient temperatures and pH, biocatalysts are often superior to chemical ones and this might explain that a considerable number of industrial bioprocesses have been established in recent years [2,7]. 

Mixtures of enantiomers rather than optically pure compounds can be rationalized by different assumptions (a) one enzyme with low enan-tioselectivity catalyzes the biogenetical process, (b) at least two enzymes with different enantioselectivities compete in the reaction, and (c) different pathways eventually leading to the same final products, however with opposite configurations, are involved. By addition of chemically synthesized precursors we aimed to trace some of the biogenetical routes involved in the biogenesis of chiral pineapple volatiles. 

The major product 105 was subjected to reactions with several nucleophiles to afford the corresponding optically pure compounds in high yield. Thus, the first highly selective nonenzymatic chiral induction was achieved using 3-methylglutaric acid. 

The chiral oxathianes have been broadly used for the synthesis of a number of natural products. Through these applications, these chiral auxiliaries have been shown to provide a viable proc ure for the synthesis of optically pure compounds. ... 

In the enantio-differentiating hydrogenation of substrates that meet with the "Stereochemical Model", certain types of substrates give almost prefect e.d.a. s. but all others give around a 75 to 90% e.d.a. This section briefly deals with a supplementary procedure, which allows for the imperfect nature of MNi and provides optically pure compounds from the reaction products. 

The thalidomide tragedy, described in chapter 7, started to focus the pharmaceutical industry on synthesis of single enantiomers rather than racemic mixtures. Even if there are no antagonistic or undesirable side effects from the other enantiomer, a racemic mixture may waste 50 percent of the mass of a drug. Optically pure compounds such as vitamin B]2, morphine, and L-dopa are available naturally. In some cases (e.g., vitamin B12), the natural source is really the only practical source. For simpler compounds like L-dopa, chemical synthesis is very practical but resolution of enantiomers may double the production cost. 

Production of enantiomerically pure substances has gained importance, which is far beyond academic interest. The industrial production of large amounts of optically pure compounds today is possible, even if the costs for the comparably laborious procedures may be considerable. 

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