Enantiomeric excess

 Compounds that are neither racemic nor enantiomerically pure are usually called enantiomerically enriched. Chemists have two ways of referring to the ratio of enantiomers in an enantiomerically enriched sample. The fi rst is the simple one we have just used: e.r. or enantiomeric ratio, expressed as two numbers adding to 100. More common, however, is to express this ratio as an enantiomeric excess. Enantiomeric excess (or ee) is defined as the excess of one enantiomer over the other, expressed as a percentage of the whole. So a 94:6 mixture of enantiomers consists of one enantiomer in 88% excess over the other, and we call it an enantiomerically enriched mixture with 88% ee. Why not just say that we have 94% of one enantiomer? Enantiomers are not like other isomers because they are simply mirror images. The 6% of the minor enantiomer can be paired with 6% of the major isomer to form a race mic mixture amounting to 12% of the total. The mixture contains 12% racemate and 88% of one enantiomer, hence 88% ee.

We will see shortly how we can make further use of the chiral auxiliary to increase the ee of the reaction products. But first, we should consider how to measure ee. One way is simply to measure the angle through which the sample rotates plane-polarized light. The angle of rotation is approximately proportional to the enantiomeric excess of the sample (see box). The problem with this method is that to measure an actual value for ee you need to know what rotation a sample of 100% ee gives, and that is not always possible. Also, polarimeter measure ments are notoriously unreliable—they depend on temperature, solvent, and concentration, and are subject to massive error due to small amounts of highly optically active impurities.

Chemists now usually use chromatography, or occasionally spectroscopy, to quantify ratios of enantiomers. You may think that this should be impossible—since enantiomers are chemically identical and have identical NMR spectra, how can chromatography or spectroscopy tell them apart? Well, again, they are identical unless they are in a chiral environment. We introduced HPLC on a chiral stationary phase as a way of separating enantiomers preparatively in Chapter 14. The same method can be used analytically—less than a milligram of chiral compound can be passed down a narrow column containing silica modifi ed which a chiral additive. One enantiomer passes through the silica faster than the other; the two enantiomers are separated and the quantity of each can be measured (usually by UV absorption or by refractive index changes) and an ee derived. Gas chromatography can be used in the same way—the columns are packed with a chiral stationary phase such as the isoleucine derivative shown in the margin. Distinguishing enantiomers spectroscopically relies again on putting them into a chiral environment. One way of doing this, if the compound is, say, an alcohol or an amine, is to make a derivative (an ester or an amide) with an enantiomerically pure and racemization proof acyl chloride. The one most commonly used is known as Mosher’s acyl chloride, after its inventor Harry Mosher, although there are many others. The two enantiomers of the alcohol or amine now become diastereoisomeric esters, and give different sets of peaks in the NMR spectrum—the integrals can be used to determine ee and, although the 1H NMR of such a mixture of diastereoisomers may become quite cluttered because it is a mixture, the presence of the CF3 group means that the ratio can alternatively be measured by integrating the two singlets in the otherwise featureless plain of the 19F NMR spectrum.

Another powerful method of discriminating between enantiomers is to add an enantiomerically pure compound to the NMR sample that simply forms a complex with the compound under investigation. The complexes formed from the two opposite enantiomers are diastereo isomeric, and therefore have different chemical shifts and, by integrating the NMR signals, the ratio of enantiomers can be determined. Among the most commonly used is this alcohol, 2,2,2-trifl uoro-1-(9-anthryl)ethanol, or TFAE, which can both hydrogen-bond to and form  π-stacked complexes with a range of functionalized compounds, and often splits NMR signals due to enantiomeric compounds very cleanly. Time to go back to chiral auxiliaries. We pointed out that, although we want to get maxi mum levels of stereoselectivity in our chiral-auxiliary-controlled reaction, we may still have a small percentage of a minor diastereoisomer, which, once we have removed our chiral aux iliary, will compromise the ee of our fi nal product. It is at this point that we can use a trick that essentially employs the chiral auxiliary in a secondary role as a resolving agent. Provided the products are crystalline, it will usually be possible to recrystallize our 94:6 mixture of diastereoisomers to give essentially a single diastereoisomer, rather like carrying out a resolution with an enormous head start. Once this has been done, the chiral auxiliary can be removed and the product may be very close to 100% ee. Of course, the recrystallization sacrifices a few percentage points of yield, but these are invariably much less valuable than the few percentage points of ee gained! Here is an example from the work of Evans himself. During his syn thesis of the complex antibiotic X-206 he needed large quantities of the small molecule below. He decided to make it by a chiral-auxiliary-controlled allylation, followed by reduction to give the alcohol. The auxiliary needed is the one derived from norephedrine, and the reaction of the enolate with allyl iodide gives a 98:2 mixture of diastereoisomers. However, recrystalliza tion converts this into an 83% yield of a single diastereoisomer in >99% purity, giving mate rial of essentially 100% ee after removal of the auxiliary.

This is one big bonus of using a chiral auxiliary—it’s much easier to purify diastereoisomers than enantiomers and a chiral auxiliary-controlled reaction necessarily produces diastereo isomeric products. Both these examples of auxiliary-controlled alkylation make use of LiAlH4 reduction to the alcohol in the step which removes the auxiliary. You saw attack with an alkoxide above, and several other alternative methods are possible as well, summarized below. DIBAL (i-Bu2AlH) reduces the product to an aldehyde, while converting the product to a Weinreb amide makes formation of a ketone possible.

Simple hydrolysis under acid or basic conditions risks epimerizing the newly created chiral centre, and a good solution is to use the less basic, more nucleophilic hydroperoxide anion. This was the approach taken by chemists making this component of a collagenase inhibitor. Notice that this auxiliary is a variant based on L-phenylalanine.

These various ways of removing auxiliaries illustrate the ways in which it is possible to make a virtue out of one of their big disadvantages: chiral auxiliaries must fi rst be attached to the compound under construction, and after they have done their job they must be removed. The best auxiliaries can be recycled, but even then there are still at least two ‘unproductive’ steps in the synthesis.

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علماء يكتشفون أن نقص عنصر غذائي "شائع" قد يسبب الزهايمر

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المزيد

مواضيع ذات صلة

Catalytic asymmetric reduction of ketones

Chiral reagents

Alkylation of enolates

Resolution can be used to separate enantiomers

Nature is asymmetric

Palladium catalysis in the total synthesis of a natural alkaloid

Alcohols and amines as intramolecular nucleophiles

Oxypalladation and the Wacker oxidation

Alkenes coordinated to palladium (II) are attacked by nucleophiles

Palladium-catalysed amination of aromatic rings

Intramolecular alkylations make rings

Vinyl epoxides provide their own alkoxide base