Stereocenters enantiomers

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. 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Imagine that the two brothers are twins. They are identical in every way except one. One of them has a mole on his right cheek, and the other has a mole on his left cheek. This allows you to distinguish them from each other. They are mirror images of each other, but they don t look exactly the same (one cannot be superimposed on top of the other). It is very important to be able to see the relationship between different compounds. It is important to be able to draw enantiomers. Later in the course, you will see reactions where a stereocenter is created and both enantiomers are formed. To predict the products, you must be able to draw both enantiomers. In this section, we will see how to draw enantiomers. 

The simplest way to draw an enantiomer is to redraw the carbon skeleton, but invert all stereocenters. In other words, change all dashes into wedges and change all wedges into dashes. Eor example,... 

The compound above has a stereocenter (what is the configuration ). If we wanted to draw the enantiomer, we would redraw the compound, but we would turn the wedge into a dash ... 

This is a pretty simple procedure for drawing enantiomers. It works for compounds with many stereocenters just as easily. For example,... 

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 ... 

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). 

If you are given two stereoisomers, you should be able to determine whether they are enantiomers or diastereomers. All you need to look at are the stereocenters. They must all be of different configuration for the compounds to be enantiomers. 

Answer There are two stereocenters in each compound. The configurations are different for both stereocenters, so these compounds are enantiomers. In fact, if you... 

The analogy goes like this when yon have a lot of stereocenters in a com-ponnd, there will be many stereoisomers (brothers and sisters). Bnt, they will be paired up into sets of enantiomers (twins). Any one molecule will have many, many diastereomers (brothers and sisters), bnt it will have only one enantiomer (its mirror image twin). For example, consider the following compound ... 

This componnd has hve stereocenters, so it will have many diastereomers (compounds where only some of the wedges have been inverted). There are many, many possible componnds that fit that description, so this compound will have many brothers and sisters. Bnt this compound will only have one twin—only one enantiomer (there is only one mirror image of the componnd above) ... 

Now we can understand why we cannot draw a Fischer projection sideways. If we did, we would be inverting the stereocenter. To draw the enantiomer of a Fischer projection, do not turn the drawing sideways. Instead, you should use the second method we saw for drawing enantiomers (place the mirror on the side of the compound and draw the reflection). Recall that this was the method that we used for drawings where wedges and dashes were implied but not shown. Fischer projections are another example of drawings that fit this criterion ... 

EXERCISE 7.75 Determine the configuration of the stereocenter below. Then draw the enantiomer. 

PROBLEMS For each compound below, determine the configuration of every stereocenter. Then draw the enantiomer of each compound below (the COOH group is a carboxylic acid group). 

You will never be expected to look at a compound that you have never seen and then predict in which direction it will rotate plane-polarized light (nnless you know how the enantiomer rotates plane-polarized light, becanse enantiomers have opposite effects). Bnt yon will be expected to assign confignrations (R and S) for stereocenters in componnds that you have never seen. 

Each stereocenter has two possibilities (R or S). Since there are two stereocenters, we will have four total possibilitites SR, RS, RR, and SS. These four compounds represent two sets of enantiomers ... 

In cases like this, the stereochemistry is still irrelevant (as long as the compound does not possess any other stereocenters). Why With only one stereocenter, there will only be two possible products (not four). These two products will represent a pair of enantiomers (one will be R and the other will be S). You will get both of these products whether the reaction proceeds through a syn addition or through an anti addition. If the reaction is a syn addition, the OH group can come from above the plane or from below the plane of the double bond, giving both possible products. Similarly, if the reaction is an anti addition, the OH group can come from above the plane or from below the plane of the donble bond, giving both possible products. Either way, we get the two possible products. 

Next, we look at the stereochemistry. We are creating two new stereocenters in this case, which means that we could potentially create four products here, but we won t get all four. The reaction is a syn addition, so we will only get the pair of enantiomers that would come from a syn addition. To draw this pair of enantiomers, we do not have to rotate the alkene, as we have done in previous examples. In this example, it is simple enough to draw the products without rotating the alkene (sometimes, it will be simpler to do it this way) ... 

In the example above, we are creating two new stereocenters. So, theoretically, we could imagine four possible products (two pairs of enantiomers) ... 

In any reaction, the mechanism should explain not only the regiochemistry, but the stereochemistry as well. In this particular reaction (addition of H—X across alkenes), the stereochemistry is generally not relevant. Recall from the previous section that we need to consider stereochemistry (syn vs. anti) only in cases where the reaction generates two new stereocenters. If only one stereocenter is formed, then we expect a pair of enantiomers (racemic mixture), regardless of whether the reaction was anti or syn. You will probably not see an example where two new stereocenters are formed, because the stereochemical outcome in such a case is complex and is beyond the scope of our conversation. 

Answer HBr indicates that we will be adding H and Br across the double bond. The presence of peroxides indicates that the regiochemistry will be anti-Markovnikov. To determine whether stereochemistry is relevant in this particular case, we need to look at whether we are creating two new stereocenters. When we place the Br on the less substituted carbon (and the H on the more substituted carbon), we will only be creating one new stereocenter. With only one stereocenter, there are not four possible stereoisomers but just two possible products (a pair of enantiomers). And we will get this pair of enantiomers regardless of whether the reaction was syn or anti ... 

Answer (a) These reagents will accomplish an anti-Markovnikov addition of OH and H. The stereochemical outcome will be a syn addition. But we must first decide whether stereochemistry will even be a relevant factor in how we draw our products. To do that, remember that we must ask if we are creating two new stereocenters in this reaction. In this example, we are creating two new stereocenters. So, stereochemistry is relevant. With two stereocenters, there theoretically could be four possible products, but we will only get two of them we will only get the pair of enantiomers that come from a syn addition, hi order to get it right, let s redraw the alkene (as we have done many times earlier), and add OH and H like this ... 

Answer (a) We are adding Br and Br, so the regiochemistry is irrelevant. But what about the stereochemistry We look to see whether we are creating two new stereocenters. In this case, we are. So, the stereochemistry is relevant. We have explored the mechanism and justified why the reaction must be an anti addition. So, we must draw the pair of enantiomers that we would get from an anti addition. To do this properly, it will be helpful to redraw the alkene, as we have done many times before ... 

Answer (a) We are adding OH and OH, and therefore, regiochemistry will be irrelevant. What abont stereochemistry In this case, we are creating two new stereocenters, so we mnst carefully consider the stereochemistry of this reaction in order to draw the correct pair of enantiomers. This two-step synthesis gives an anti addition of OH and OH. Therefore,... 

Answer In this reaction, we are adding two OH groups, so we don t need to think about regiochemistry. As always, stereochemistry will only be relevant if we are forming two new stereocenters. In this example, we are creating two new stereocenters, and therefore, we must be careful to draw only the pair of enantiomers that represent the products of a syn addition ... 

Figure 5.5 A demonstration of chirality of a generalized molecule containing one tetrahedral stereocenter, (a) The four different groups around the carbon atom in III and IV are arbitrary, (b) III is rotated and placed in front of a mirror. Ill and IV are found to be related as an object and its mirror image, (c) III and IV are not superposable therefore, the molecules that they represent are chiral and are enantiomers.

Because of the tetrahedral stereocenter of the amino acid, three-point binding can occur with proper alignment for only one of the two enantiomers. 

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

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