Enantiomeric purity, control

If we consider natural synthetic processes, enzymes are seen to exert complete control over the enantiomeric purity of biomolecules (see Figure 8.2). They are able to achieve this because they are made of single enantiomers of amino adds. The resulting enantiomer of the enzymes functions as a template for the synthesis of only one enantiomer of the product Moreover, the interaction of an enzyme with the two enantiomers of a given substrate molecule will be different. Biologically important molecules often show effective activity as one enantiomer, the other is at best ineffective or at worst detrimental. 

This idea is elegant for its simplicity and also for its usefulness. While often in phenomenological theories of materials, control of parameters with molecular structure would provide useful properties, but the parameters are not related in any obvious way to controllable molecular structural features. Meyer s idea, however, is just the opposite. Chemists have the ability to control enantiomeric purity and thus can easily create an LC phase lacking reflection symmetry. In the case of the SmC, the macroscopic polar symmetry of this fluid phase can lead to a macroscopic electric dipole, and such a dipole was indeed detected by Meyer and his collaborators in a SmC material, as reported in 1975.2... 

Efficient methods of enantioseparation are always required to control the enantiomeric purity, or to separate the target molecule or one of its chemical precursors (obtained from conventional synthetic procedures), or for monitoring the completion of enantioselective reaction process (since the production of single enantiomer is a real difficult task). 

This presentation covers some aspects of stereochemistry of the drags that are marketed and administered as racemic mixtures with an emphasis on status of analytical chemistry methods for enantioseparation and control of enantiomeric purity. There is also a brief discussion on related historical knowledge. 

If an enantiomer is chemically pure it is possible to determine its degree of enantiomeric purity by measuring its optical rotation relative to a standard value, e.g if an enantiomeric mixture contains 1% of enantiomer A and 99% of enantiomer B [a] will be reduced by 2% compared to the value for optically pure B. Examples of the measurement of optical rotation as a quality control check are found in the BP monographs for Timolol maleate, Tobramycin and Phenylephrine Hydrochloride. 

Many syntheses of chiral allenes of high enantiomeric purity start from chiral precursors, notably propynyl compounds, with the central chirality being converted into allene axial chirality by a mechanism-controlled reaction. 

One of the most versatile methodologies of EPC synthesis of allenes is the chirality transfer reaction which involves highly stereoselective, mechanism-controlled, metal-mediated propyn-yl-allenyl transpositions. Of these, the organocopper(l)-mediated reactions are especially useful and provide a relatively straightforward route to a broad variety of allenes of high enantiomeric purity. 

The reaction with N-Boc-pyrrolidine may be taken a step further by inducing a double C-H insertion sequence [27]. This results in the formation of the elaborate C2-symmetric amine 35 as a single diastereomer with control of stereochemistry at four stereogenic centers. The enantiomeric purity of 35 is higher than that obtained for the single C-H insertion products, presumably because kinetic resolution is occurring in the second C-H insertion step. 

Asymmetric conjugate addition of a-substituted-oc-cyanoacetates 77 to acetylenic esters under phase-transfer conditions is somewhat of a challenge, because of the difficulty encountered in controlling the stereochemistry of the product. In addition, despite numerous examples of the conjugate additions to alkenoic esters, no successful asymmetric conjugate additions to acetylenic esters have been reported to date. In this context, Maruoka and coworkers recently developed a new morpholine-derived phase-transfer catalyst (S)-76 and applied it to the asymmetric conjugate additions of a-alkyl-a-cyanoacetates 77 to acetylenic esters, as indicated in Table 5.11 [40], In this asymmetric transformation, an all-carbon quaternary stereocenter can be constructed with a high enantiomeric purity. 

Further improvements in the stereocontrol were achieved by changing the substitution pattern of the succinic anhydride 2-phenyl succinic anhydride (roc)-36 gave the best control giving the monosubstituted succinic ester (f )-37 and (S)-38 in 95% ee and 85% ee respectively (Scheme 9). Simple chemoselective reduction gave the corresponding y-lactones (R)-39 and (S)-40 in similar enantiomeric purity. 

---