Diastereomers

We have defined stereoisomers as isomers whose atoms are bonded together in the same order but differ in how the atoms are directed in space. We have also considered enantiomers (mirror-image isomers) in detail. All other stereoisomers are classified as diastereomers, which are defined as stereoisomers that are not mirror images. Most diastereomers are either geometric isomers or compounds containing two or more chirality centers (usually asymmetric carbons). 

We have already seen one class of diastereomers, the ds-trans isomers, or geometric isomers. For example, there are two isomers of 2-butene  

These stereoisomers are not mirror images of each other, so they are not enantiomers. They are diastereomers. 

5-11C Diastereomers of Molecules with Two or More Chirality Centers 

Apart from geometric isomers, most other compounds that show diastereomerism have two or more chirality centers, usually asymmetric carbon atoms. For example, 2-bromo-3-chlorobutane has two asymmetric carbon atoms, and it exists in two diastereomeric forms (shown next). Make molecular models of these two stereoisomers. 

We have also observed that three small chiral molecules, e.g., three propylene sulfides, can be accommodated inside the cylindrical capsule. The odd number of molecules inside has the ineluctable consequence that each capsule is chiral the constellational isomerism shown here involves diastereomers (Fig. 7.15) [38]. The assignments could be made using an optically pure propylene sulfide and the gradual addition of racemic material and at 60 % ee each isomer could be assigned. Put another way, it is possible to use encapsulation to determine enantiomeric excesses of small molecules inside, but there are many other ways to do this. 

In all of our examples so far, we have been comparing two compounds that are mirror images. For them to be mirror images, they need to have different configurations for every single stereocenter. Remember that our first method for drawing enantiomers was to switch all wedges with dashes. For the two compounds to be enantiomers, every stereocenter had to be inverted. But what happens if we have many stereocenters and we only invert some of them  

Let s start off with a simple case where we only have two stereocenters. Consider the two compounds below  

We can clearly see that they are not the same compound. In other words, they are nonsuperimposable. But, they are not mirror images of each other. The top stereocenter has the same configuration in both compounds. If they are not mirror images, then they are not enantiomers. So what is their relationship They are called di-astereomers. Diastereomers are any compounds that are nonsuperimposable stereoisomers that are not mirror images of each other. 

We use the term diastereomer very much like we used the term enantiomer (remember the brother analogy). One compound is called the diastereomer of the other, and you can have a group of diastereomers. When we were talking about enantiomers, we saw that they always come in pairs, never more than two. But diastereomers can form a much larger family. We can have 100 compounds that are all diastereomers of each other (if there are enough stereocenters to allow for that many permutations of the stereocenters). 

Thomson . OW Click Organic Interactive to use a web-based palette to draw stereoisomers. 

The four stereoisomers of 2-amino-3-hydroxybutanoic acid can be grouped into two pairs of enantiomers. The 2R,3R stereoisomer is the mirror image of 25,35, and the 2R,35 stereoisomer is the mirror image of 25,3R. But what is the relationship between any two molecules that are not mirror images What, for example, is the relationship between the 2R,3R isomer and the 2R,3S isomer They are stereoisomers, yet they aren t enantiomers. To describe such a relationship, we need a new term—diastereomer. 

Note carefully the difference between enantiomers and diastereomers. Enantiomers have opposite configurations at all chirality centers, whereas diastereomers have opposite configurations at some (one or more) chirality centers but the same configuration at others. A full description of the four stereoisomers of threonine is given in Table 9.2. Of the four, only the 2S,3R isomer, [o]D= -28.3, occurs naturally in plants and animals and is an essential human nutrient. This result is typical most biological molecules are chiral, and usually only one stereoisomer is found in nature. 

In the special case where two diastereomers differ at only one chirality center but are the same at all others, we say that the compounds are epimers. Cholestanol and coprostanol, for instance, are both found in human feces and 

One of the following molecules (a)-(d) is D-erythrose 4-phosphale, an intermediate in the Calvin photosynthetic cycle by which plants incorporate C02 into carbo- hydrates. If D-erythrose 4-phosphate has R stereochemistry at both chirality centers, which of the structures is it Which of the remaining three structures is the enantiomer of D-erythrose 4-phosphate, and which are diastereomers  

We have now seen many examples of compounds containing one tetrahedral stereogenic center. The situation is more complex for compounds with two stereogenic centers, because more stereoisomers are possible. Moreover, a molecule with two stereogenic centers may or may not be chiral. 

When n = 1, 2 = 2. With one stereogenic center there are always two stereoisomers and they are enantiomers. 

When n = 2, 2 = 4. With two stereogenic centers, the maximum number of stereoisomers is four, although sometimes there are fewer than four. 

ProblGtn 5.16 What is the maximum number of stereoisomers possible for a compound with (a) three stereogenic centers (b) eight stereogenic centers  

Let s illustrate a stepwise procedure for finding all possible stereoisomers using 2,3-dibromo-pentane. 

Molecules like lactic acid, alanine, and glyceraldehyde are relatively simple because each has only one chirality center and only two stereoisomers. The situation becomes more complex, however, with molecules that have] more than one chirality center. 

The four threonine stereoisomers can be grouped into two pairs of enantiomers. The 2R, 3Jt stereoisomer is the mirror image of 2S,3S, and the 212,33 stereoisomer is the mirror image of 2S,3R. But what is the relationship 

The four stereoisomers of 2-amino-3-hydroxybutanoic acid (threor ine). 

TABLE 9,2 Relationships Among Four Stereoisomers of Threonine  

Up to now we have limited ourselves to compounds with a single chiral element, but we will now consider the case where several chiral elements are present in the same compound. If the latter has n distinct chiral elements there will be a maximum of n isomers that carry the name of diasteromer. We will see, however, that taking into account elements of inverse symmetry can reduce this number. 

Let us take the simplest example of a compound where two distinct chiral elements (the foot and the hand) are present. The four possible combinations (diasteromers) are therefore  

Possible combinations for an object possessing two stereogenic centres. 

Although the enantiomers of a compound have the same physical properties (except the sense of rotation of plane polarized light), this is not true for diastereomers, which have different properties and, apart from the chemical formula and the connectivity of their atoms, must be considered as different compounds. This is reflected in differing solubilities and melting or boiling points, which can be exploited in their separation. 

We have just considered the case where the two chiral elements are different. Now we will look at what happens when they are identical (two hands for example). There are four possible combinations  

Examples Orienting the lowest priority group in back 

Problem 5.16 Draw both enantiomers of clopidogrel (trade name Plavix), a drug given to prevent the formation of blood clots in persons who have a history of stroke or coronary artery disease. Plavix is sold as a single enantiomer with the S configuration. Which enantiomer is Plavix  

Draw a tetrahedral representation of (S)-pentan-2-ol (2-hydroxypentane). Problem 5.12 

Assign Rot S configuration to the chirality center in the following molecular model of the amino acid methionine (yellow = S)  

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If compounds have the same topology (constitution) but different topography (geometry), they are called stereoisomers. The configuration expresses the different positions of atoms around stereocenters, stereoaxes, and stereoplanes in 3D space, e.g., chiral structures (enantiomers, diastereomers, atropisomers, helicenes, etc.), or cisftrans (Z/E) configuration. If it is possible to interconvert stereoisomers by a rotation around a C-C single bond, they are called conformers. 

Diastereomers= stereoisomers which are not rnirror images usually have different physical properties... 

Sharpless Asymmetric Dihydroxylation (AD) - Ligand pair are really diastereomers ... 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Stereoisomer I is not a mirror image of III or IV so it is not an enantiomer of either one Stereoisomers that are not related as an object and its mirror image are called diastereomers diastereomers are stereoisomers that are not enantiomers Thus stereoisomer I is a diastereomer of III and a diastereomer of IV Similarly II is a diaste reomer of III and IV... 

Because diastereomers are not mirror images of each other they can have quite different physical and chemical properties For example the (2R 3R) stereoisomer of 3 ammo 2 butanol is a liquid but the (2R 3S) diastereomer is a crystalline solid... 

A good thing to remember is that the cis and trans isomers of a particular compound are diastereomers of each other... 

Turning to cyclic compounds we see that there are three not four stereoisomeric 1 2 dibromocyclopropanes Of these two are enantiomeric trans 1 2 dibromocyclo propanes The cis diastereomer is a meso form it has a plane of symmetry... 

Steroids are another class of natural products with multiple chirality centers One such compound is cholic acid which can be obtained from bile Its structural formula IS given m Figure 7 12 Cholic acid has 11 chirality centers and so a total (including cholic acid) of 2" or 2048 stereoisomers have this constitution Of these 2048 stereoiso mers how many are diastereomers of cholic acid s Remember Diastereomers are stereoisomers that are not enantiomers and any object can have only one mirror image Therefore of the 2048 stereoisomers one is cholic acid one is its enantiomer and the other 2046 are diastereomers of cholic acid Only a small fraction of these compounds are known and (+) cholic acid is the only one ever isolated from natural sources... 

A reaction that introduces a second chirality center into a starting material that already has one need not produce equal quantities of two possible diastereomers Con sider catalytic hydrogenation of 2 methyl(methylene)cyclohexane As you might expect both CIS and trans 1 2 dimethylcyclohexane are formed... 

The double bond m 2 methyl(methylene)cyclohexane is prochiral The two faces however are not enantiotopic as they were for the alkenes we discussed m Section 7 9 In those earlier examples when addition to the double bond created a new chirality cen ter attack at one face gave one enantiomer attack at the other gave the other enantiomer In the case of 2 methyl(methylene)cyclohexane which already has one chirality center attack at opposite faces of the double bond gives two products that are diastereomers of each other Prochiral faces of this type are called diastereotopic... 

Dissociate diastereomer to single enantiomer recover resolving agent... 

This method is widely used for the resolution of chiral amines and carboxylic acids Analogous methods based on the formation and separation of diastereomers have been developed for other functional groups the precise approach depends on the kind of chem ical reactivity associated with the functional groups present m the molecule... 

The CIS and trans isomers of 4 methylcyclohexanol are stereoisomers but they are not related as an ob ject and its mirror image they are diastereomers... 

Stereoisomers that are not enantiomers are classified as diastereomers Each enantiomer of erythro 3 bromo 2 butanol is a diastereomer of each enantiomer of threo 3 bromo 2 butanol... 

Section 7 14 Resolution is the separation of a racemic mixture into its enantiomers It IS normally carried out by converting the mixture of enantiomers to a mixture of diastereomers separating the diastereomers then regenerating the enantiomers... 

If they are stereoisomers are they enantiomers or diastereomers" (Molecular models may prove useful in this problem )... 

Streptirnidone is an antibiotic and has the structure shown How many diastereomers of streptimidone are possible" How many enantiomers" Using the E Z and R S descnptors specify all essential elements of stereochemistry of streptimidone... 

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