Configuration:

These compounds are assigned in Chemistry 3719 at YSU and require careful analysis of the priority schemes at each chiral centre in order to come up with correct absolute configurations. The priority schemes are developed from the detailed rules published by IUPAC.


Topamax



Topamax is used to treat epilepsy and migraine and is a sugar-like molecule with 4 chiral centres. The configuration of each is assigned as follows:

1. Hydrogen is the lowest substituent, and although it is not visible, it is a wedge. Oxygen takes priority at this centre (highest atomic number) and it is a dash. The two carbons directly attached both are attached to oxygens, but the one takes precedence over the other because it also has a carbon as opposed to two hydrogens in the following scheme: O = 1 ; C (O, C, H) = 2 ; C (O, H, H) = 3 ; H = 4. This chiral centre is therefore R.
2. Again, hydrogen is the lowest priority substituent and a wedge while the top priority oxygen is a dash. The other two carbons must now be compared until it can be determined which is higher priority. This results in the following scheme: O = 1 ; C (O, C, H) – C (O, C, H) = 2 ; C (O, C, H) – C (C, H, H) = 3 ; H = 4. This chiral centre is therefore R.
3. The hydrogen is a dash so "reverse order" is not needed. The wedge oxygen is the main substituent, while the two carbons need to be compared. This results in the following scheme: O = 1 C (O, C, H) – C (O, C, H) = 2 C (O, C, H) – C (C, H, H) = 3 H = 4. This chiral centre is therefore S.
4. Three of the substituents of this chiral centre have O directly attached. The highest priority is the dashed oxygen because attached further out is Sulfur. The other two oxygens attached much be compared to determine which takes precedence. The O with isopropyl will be a higher priority because it has more carbons than the other. The other oxygen has a carbon with two hydrogens attached as follows: O – S = 1 ; O – C (O, C, C) = 2 ; O – (C, H, H) = 3 ; H = 4. This chiral centre is therefore S.


Zocor



Zocor is used to lower levels of fatty materials such as LDL cholesterol and triglycerides and is a steroid-like molecule with 7 chiral centres. The configuration of each is assigned as follows:

1. The primary substituent is the oxygen that is directly attached. The fact that it is a wedge means the order doesn't need to be reversed. The two carbon substituents need to be compared to decide which has a higher priority.: O = 1 ; C (C, H, H) – C (O, O, C) = 2 ; C (C, H, H) – C (O, C, H) = 3 ; H = 4. This chiral centre is therefore R.
2. The unseen hydrogen is the lowest priority; its wedge orientation means that the order needs to be reversed. The oxygen takes priority here, while the other carbons need to be compared to each other. This results in the following scheme: O = 1 ; C (C, H, H) – C (O, C, C) = 2 ; C (C, H, H) – C (C, H, H) = 3 ; H = 4. This chiral centre is therefore R.
3. Three of the substituents of this chiral centre contain carbons, therefore they must be compared between each other. The lowest priority hydrogen is a dash, therefore no reverse order required: O = 1 C (C, C, H) – C (O, C, H) = 2 C (C, C, H) – C (C, C, H) = 3 H = 4. This chiral centre is therefore S.
4. Again, three substituents have carbons directly attached and need to be compared. The lowest priority hydrogen is a dash; no reverse order required and the scheme is as follows: C (C, C, H) – C (C, C, H) – C (O, C, H) = 1 ; C (C, C, H) – C (C, C, H) – C (C, C, C) = 2 ; C (H, H, H) = 3 ; H = 4. This chiral centre is therefore S.
5. This is another case of three carbons that are directly attached that need to be compared. The hydrogen is a wedge; the order needs reversed, and the scheme is as follows: C (C, C, H) = 1 ; C (C, H, H) = 2 ; C (H, H, H) = 3 ; H = 4. This chiral centre is therefore R.
6. The oxygen directly attached takes precedence, however it is a dash. This means the order will need to be reversed. The two carbon substituents must be compared as follows: O = 1 ; C (C, C, H) = 2 ; C (C, H, H) = 3 ; H = 4. This chiral center is therefore S.
7. The H shown as a wedge means that the other three groups are pointing down and the rotation will have to be reversed. The three carbon substituents are ranked as follows: C (O, C, H) = 1 ; C (C, C, C) = 2 ; C (C, C, H) = 3 ; H = 4. This chiral centre is therefore R.


Amoxicillin



Amoxicillin is used to treat various bacterial infections and is one of many beta-lactam antibiotics that are based on the general chiral penicillin platform. Amoxicillin has 4 chiral centres, and the configuration of each is assigned as follows:
1. Nitrogen, the highest priority, is a wedge, so no reverse order is needed. Directly attached are two carbons and an unseen hydrogen, which is a dash. Comparing the substituents: N = 1 ; C (O, O, C) = 2 ; C (C, C, C) = 3 ; H = 4. This chiral centre is therefore R.
2. Nitrogen, the highest priority, is a dash, so the order needs to ultimately be reversed. Directly attached are two carbons and a hydrogen, which is a wedge. Comparing the substituents:

N = 1 ; C (S, N, H) = 2 ; C (O, O, N) = 3 ; H = 4. This chiral centre is therefore R.
3. The hydrogen here is a wedge so "reverse order" is needed. The sulfur is the main substituent, while the nitrogen beats the carbon. This results in the following scheme: S = 1 N = 2 C = 3 H = 4. This chiral centre is therefore R.
4. Nitrogen, the highest priority, is in the plane. The unseen hydrogen substituent is a dash because the carboxylic acid is shown to be a wedge, so the order does not need to be reversed. Directly attached to the chiral centre are two carbons and a hydrogen. Comparing the substituents: N = 1 ; C (S, C, C) = 2 ; C (O, O, O) = 3 ; H = 4. This chiral centre is therefore S.


Flonase



Flonase is a steroid-like synthetic molecule that is used to treat allergies and perennial nonallergic rhinitis. The compound has 9 chiral centres, and the configuration of each is assigned as follows:
1. Oxygen, the highest priority, is shown to be a dash, so the rotation order needs to be reversed. Also directly attached are three carbons, so comparing the substituents: O = 1 ; C (S, O, O) = 2 ; C (C, C, C) = 3 ; C (C, C, H) = 4. This chiral centre is therefore R.
2. This chiral centre has four carbons directly attached. The lowest priority, C (H, H, H), is shown to be a wedge, so the order needs to be reversed. Comparing the substituents: C (O, C, C) = 1 ; C (C, C, H) = 2 ; C (C, H, H) = 3 ; C (H, H, H) = 4. This chiral centre is therefore S.
3. The lowest priority, H, is a wedge, so the order will ultimately need to be reversed. Directly attached are also three carbons, so comparing the substituents: C (O, C, C) = 1 ; C (C, C, H) = 2 ; C (C, H, H) = 3 ; H = 4. This chiral centre is therefore R.
4. The lowest priority H is shown to be a dash, so the order does not need to be reversed. Directly attached to this chiral center are three carbons and that hydrogen. The substituents would be ranked as follows: C (C, C, C) = 1 ; C (C, C, H) = 2 ; C (C, H, H) = 3 ; H = 4. This chiral centre is therefore S.
5. The lowest priority, H, is shown to be wedge, so the order needs to be reversed. Directly attached to this chiral center are three carbons and that hydrogen. Comparing the substituents: C (C, C, F) = 1 ; C (C, C, H) = 2 ; C (C, H, H) = 3 ; H = 4. This chiral centre is therefore S.
6. Fluorine, the highest priority, is shown to be a dash, so the order needs to be reversed. Directly attached are also two carbons and an unseen hydrogen, which is a wedge. Ranking the substituents: F = 1 ; C (C, C, C) = 2 ; C (C, H, H) = 3 ; H = 4. This chiral centre is therefore S.
7. The lowest priority, C (H, H, H), is shown to be a wedge, so the order needs to be reversed. Directly attached to this chiral center overall are four carbons. Comparing the substituents: C (F, C, C) = 1 ; C (C, C, C) = 2 ; C (C, C, H) = 3 ; C (H, H, H) = 4. This chiral centre is therefore S.
8. The lowest priority group, C (C, C, H), is coming out of the plane so the order needs to be switched. Directly attached to this chiral center are three other carbons, which are ranked as follows: F = 1 ; C (O, C, H) = 2 ; C (C, C, C) = 3 ; C (C, C, H) = 4. This chiral centre is therefore S.
9. Oxygen, the highest priority, is shown to be a wedge, so the attached H will be a dash and the order does not need to be reversed. Directly attached are also two carbons and the substituents are ranked as follows: O = 1 ; C (F, C, C) = 2 ; C (C, H, H) = 3 ; H = 4. This chiral centre is therefore S.


Morphine



Morphine is an opioid analgesic, related structurally to codeine and herion, which is used to suppress pain in various scenarios. It has 5 chiral centres, the configuration of which are calculated as follows:


1. Hydrogen, the lowest priority, has to be a wedge, so reverse order is necessary. Directly attached are two carbons and the oxygen. The ranking would be as follows: O = 1 ; C (O, C, H) = 2 ; C (C, C, H) = 3 ; H = 4. This chiral centre is therefore S.
2. The lowest priority hydrogen will again be a wedge, so reverse order is necessary. Directly attached to the chiral centre are also two carbons and the oxygen. The substituents would be ranked: O = 1 ; C (O, C, H) = 2 ; C (C, C, C) = 3 ; H = 4. This chiral centre is therefore R.
3. The lowest priority group, C (C, H, H) is a wedge so "reverse order" is needed. The remaining carbon substituents would be ordered according to the following scheme: C (O, C, H) = 1 ; C (C, C, C) = 2 ; C (C, C, H) = 3 ; H = 4. This chiral centre is therefore S.
4. Hydrogen, the lowest priority group, is a wedge, so the order will need to be reversed. Also attached to the chiral centre are three carbons, which are ranked as follows: C (N, C, H) = 1 ; C (C, C, C) = 2 ; C (C, C, H) = 3 ; H = 4. This chiral centre is therefore R.
5. Although not shown, the hydrogen as the lowest priority group, is a dash so the order does not need to be reversed. Also attached to the chiral centre is a nitrogen and two carbons. The substituents would be organized thus: N = 1 ; C (C, C, H) = 2 ; C (C, H, H) = 3 ; H = 4. This chiral centre is therefore R.


Erythromycin



Erythromycin is a broad-spectrum macrolide antibiotic that is isolated from the actinomycete Saccharopolyspora erythraea and which has activity against various bacterial infections. The structure is comprised of a 14-membered ring macrocycle that is attached to the rare sugars L-cladinose and D-desosamine through glycosidic linkages. For brevity, the configurations of the 10 chiral centres in the macrocycle are described here while the (less ccomplicated) assignments for the sugars are provided in the picture to the left.
1. Hydrogen, the lowest priority, has to be a wedge, so reverse order is ultimately necessary. Also attached are two carbons and the oxygen. The substituents would be ranked like this: O = 1 ; C (O, C, H) = 2 ; C (C, C, H) = 3 ; H = 4. This chiral centre is therefore S.
2. The lowest priority group C (H, H, H) is already in the corrent orientation. Directly attached to the chiral centre is an oxygen and two other carbons. The substituents would be ranked: O = 1 ; C (O, C, H) – C (O, O, C) = 2 ; C (O, C, H) – C (C, C, H) = 3 ; C (H, H, H) = 4. This chiral centre is therefore S.
3. The lowest priority group, hydrogen, is a wedge so no switching is needed. The remaining substituents would be ordered according to the following scheme: O = 1 ; C (O, C, C) = 2 ; C (C, C, H) = 3 ; H = 4. This chiral centre is therefore R.
4. Hydrogen, the lowest priority group, is a dash, so it is in the correct orientation. Also attached to the chiral centre are three carbons, which are ranked as follows: C (O, O, C) = 1 ; C (O, C, H) = 2 ; C (H, H, H) = 3 ; H = 4. This chiral centre is therefore R.
5. The hydrogen as the lowest priority group is a wedge so the rotation order will need to be reversed. Also attached to the chiral centre are three carbons. The substituents would be organized like this: C (O, O, C) = 1 ; C (C, H, H) = 2 ; C (H, H, H) = 3 ; H = 4. This chiral centre is therefore R.
6. The hydrogen as the lowest priority group is a wedge so the rotation order will need to be reversed. Also attached to the chiral centre are three carbons. The substituents would be organized like this: O = 1 ; C (O, C, H) = 2 ; C (C, H, H) = 3 ; C (H, H, H) = 4. This chiral centre is therefore R.
7. The lowest priority group, hydrogen, has to be a wedge so the rotation scheme will need to be reversed. Attached to the chiral centre are an oxygen and two carbons so the priority scheme is worked out as follows: O = 1 ; C (O, C, C) = 2 ; C (C, C, H) = 3 ; H = 4. This chiral centre is therefore R.
8. Hydrogen, the lowest priority substituent, will be a wedge so the rotation scheme will need to be reversed. Also attached three carbons in the following priority order: C (O, C, H) - C (O, C, C) - C (O, C, H) = 1 ; C (O, C, H) - C (O, C, H) - C (C, C, H) = 2 ; C (H, H, H) = 3 ; H = 4. This chiral centre is therefore S.
9. Hydrogen is again the lowest priority substituent and it will be a wedge. This needs to be taken into account in the assignment. The oxgen and two carbons attached are ranked like this: O = 1 ; C (C, C, H) - C (O, O, O) = 2 ; C (C, C, H) - C (O, C, H) = 3 ; H = 4. This chiral centre is therefore S.
10. The lowest priority substituent, hydrogen, will be a dash and so orientated correctly. The three carbons attached are then ranked as follows: C (O, O, O) = 1 ; C (O, C, H) = 2 ; C (H, H, H) = 3 ; H = 4. This chiral centre is therefore R.




Department of Chemistry, Youngstown State University, 1 University Plaza Youngstown, Ohio 44555; Contact: 330-941-1553; pnorris@ysu.edu

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