File Name: stereochemistry problems and solutions .zip
- 4.E: Solutions to Stereochemistry, Conformation, and Configuration Problems
- Solutions to exercises
- Chirality and Stereochemistry Practice Quiz
The molecules in this problem are isomers because they each have unique configurations and do not share the same funcitonal groups at the same carbon positions.
Both compounds are 4-ethylmethylhexane. Therefore, they are identical compounds. The first compound is 2,3,5-trimethylheptane, and the second is 3-ethyl-2,5-dimethylhexane.
4.E: Solutions to Stereochemistry, Conformation, and Configuration Problems
Although they have the same chemical structure, most isomers of chiral drugs exhibit marked differences in biological activities such as pharmacology, toxicology, pharmacokinetics, metabolism etc. Some mechanisms of these properties are also explained. Therefore, it is important to promote the chiral separation and analysis of racemic drugs in pharmaceutical industry as well as in clinic in order to eliminate the unwanted isomer from the preparation and to find an optimal treatment and a right therapeutic control for the patient.
In this article, we review the nomenclature, pharmacology, toxicology, pharmacokinetics, metabolism etc of some usual chiral drugs as well as their mechanisms. Different techniques used for the chiral separation in pharmaceutical industry as well as in clinical analyses are also examined. Chiral chemistry was discovered by Louis Pasteur, a French chemist and biologist, when he separated by hand for the first time, in , the two isomers of sodium ammonium tartrate 1 , 2.
However, it needed about a century later to find that the phenomenon of chirality plays a key role not only in the life of plants and animals but also in pharmaceutical, agricultural and other chemical industries. All proteins, enzymes, amino acids, carbohydrates, nucleosides and a number of alkaloids and hormones are chiral compounds.
In contrast to chiral artificial products, all natural compounds are under single enantiomeric form, for example, all natural amino acids are l-isomer levorotatory as well as all natural sugars carbohydrates are d-isomer dextrorotatory. Although they have the same chemical structure, most enantiomers of racemic drugs exhibit marked differences in biological activities such as pharmacology, toxicology, pharmacokinetics, metabolism etc.
The mechanisms of chiral drugs with biological environment are now explained. Chirality is now a top-class subject for academic research as well as for pharmaceutical development. Accounting for the important role of chiral separation, the Nobel Prize in Chemistry has been awarded to three scientists: Dr.
William S. Knowles and Pr. Ryori Nyori in Japan, for their development of asymmetric synthesis using chiral catalysts in the production of single enantiomer drugs or chemicals 6 , 7. Thanks to a wide range of new technologies for chiral separation, US Food and Drug Administration FDA recently recommends the assessments of each enantiomer activity for racemic drugs in body and promotes the development of new chiral drugs as single enantiomers 7.
In this article, we review the nomenclature of chiral compounds, the biological activities such as pharmacology, toxicology, pharmacokinetics, metabolism etc of some usual racemic drugs in therapeutics as well as their mechanisms.
The terminology used to describe different stereochemical properties is resumed as following 8 - Chirality also sometimes called stereoisomerism or enantiomerism or dissymmetry is a property of an object which is non-superimposable with its mirror image. When a molecule cannot be superimposed on its mirror image, this molecule and its image are called chiral.
It is like left and right hands. The two non-superimposable mirror-image forms of chiral molecules are called enantiomers. Enantiomers are most commonly formed when a carbon atom contains four different substituents asymmetric carbon atom or stereogenic carbon or also called chiral center. A chiral molecule is a molecule having at least one asymmetric carbon.
Carbon is not the only atom that can act as an asymmetric center. Sulfur, phosphorus and nitrogen can sometimes form chiral molecules such as omeprazole, cyclophosphamide and methaqualone, respectively.
Chiral molecules exhibit optical activity, so enantiomers are also sometimes called optical isomers. Optical isomers or enantiomers are molecules having the same chemical formula, the same physical and chemical properties, but differing in their optical activity and their spatial arrangement. Enantiomers are now determined by their spatial arrangement 3 dimensions of substituents groups around a chiral center asymmetric carbon in the molecule.
This configuration follows the Cahn-Ingold-Prelog CIP convention 11 which is used to assign priorities to substituent groups. This system is based on a set of rules for ordering the substituents attached to the asymmetric atom by using sequence rules to assign priorities.
First, draw a picture so that the atom with lowest priority, for example H, seems below the plane of the picture Fig. If the counting goes in a clockwise direction, the configuration is designated as R rectus or right ; otherwise in a counter clockwise direction, it is S sinister or left. A racemate is designated as R,S. The optical activity of an enantiomer is determined by a polarimeter or by optical rotary dispersion and circular dichroism.
Diastereomers are any molecules which have two or more chiral centers. A diastereomer with two chiral carbon has four isomers. Unlike enantiomers, the physical and chemical properties of diastereomers can differ and consequently, their chemical characterization is easy and their biological activities are often different. This is the basis for derivatization of enantiomers to form diastereomers in chiral separation and also for the explanation of enantiomer activities with their chiral receptors in the body.
Diastereomers, enantiomers and geometric isomers form a family called stereoisomers that are molecules having the same chemical formulas but differing only with respect to the spatial arrangement. Eutomer refers to bioactive enantiomer or enantiomer having higher pharmacological activity. Its opposite is called distomer. Epimers are two diastereoisomers having a different configuration at only one chiral centre.
Enantioselectivity is a property of a process whereby one enantiomer is expressed exclusively or predominantly over the other. In pharmacological terms, that means a biological structure enzyme, antibody or receptor which exhibits affinity towards one enantiomer over the other. Enantioselective assay is an analytical method capable of separating and quantifying enantiomers. In a stereoselective synthesis, one of a set of isomers is predominantly or exclusively formed whereas in a stereospecific synthesis, one isomer leads to one product while another isomer leads to the opposite product.
Homochirality is the biological chirality in which all biologic compounds have the same chirality such as all amino acids are levorotary isomers. Chiral switch is a procedure used to transform an old racemic drug into its single active enantiomer.
This new enantiomeric drug developed by a pharmaceutical manufacturer will receive additional patent protection and a new generic name. The body with its numerous homochiral compounds being amazingly chiral selector, will interact with each racemic drug differently and metabolize each enantiomer by a separate pathway to generate different pharmacological activity.
Thus, one isomer may produce the desired therapeutic activities, while the other may be inactive or, in worst cases, produce undesired or toxic effects 9 , 12 , 13 , 15 , 25 , In pharmacology area, only racemic drugs will be examined and their activity can be divided into three main groups. The majority of racemic pharmaceuticals have one major bioactive enantiomer called eutomer , the other is inactive or less active distomer or toxic or can exert other desired or undesired pharmacological properties.
The second category is intended to drugs where the two enantiomers are equally active and have the same pharmacodynamics. The last one is racemic drugs having only one eutomer, but the distomer could be transformed in body into its bioactive antipode by chiral inversion 12 - In this group, there are a number of cardiovascular drugs, agents widely used for the treatment of hypertension, heart failure, arrhythmias, and other diseases.
However, it has been demonstrated that d,l- and d-propranolol can inhibit the conversion of thyroxin T4 to triiodothyronin T3 , contrary to its l-form 19 - It is to know that for a racemic drug, each enantiomer possesses its own pharmacological activities that can be null, similar, different or opposite. Many calcium channel antagonists are used under racemic form such as verapamil, nicardipine, nimodipine, nisoldipine, felodipine, mandipine etc, except diltiazem is a diastereoisomer with two pairs of enantiomers.
On the other hand, verapamil has another possible application in cancer chemotherapy as a modifier of multidrug resistance. Unfortunately, for this purpose, verapamil must be used at high concentrations leading to high cardiotoxicity. Therefore, the R-enantiomer would be preferable as a modifier of multidrug resistance in cancer chemotherapy, while the S-enantiomer or the racemate would be preferable as a calcium channel blocker for cardiovascular therapy All ACE inhibitors such as captopril, benazepril, enalapril, idapril are chiral compounds under diastereoisomeric form and most of them are marketed as single isomer.
Valsartan, an angiotensin II receptor antagonist, is used as a single S-enantiomer and the activity of the R-enantiomer is clearly lower than the S-enantiomer They are longtime marketed as racemate. The Food and Drug Administration recently approved a chiral switch drug, levalbuterol the pure l-isomer of albuterol as a preservative-free nebulizer solution.
However, some clinical studies recently reported that it is neither safer nor more effective than a same dose of racemic albuterol. In contrast, levalbuterol may cost as much as 5 times more than its racemate 26 - In neurology and psychiatry, many pharmaceuticals used are chiral compounds and most of them are marketed as racemates. Hypnotics such as hexobarbital, secobarbital, mephobarbital, pentobarbital, thiopental, thiohexital are racemic compounds and overall, only l-isomer is hypnotic or sedative, the other is either inactive or excitative.
Ketamine is an intravenous anesthetic. Isoflurane is an inhalational general anesthetic widely used in surgical operations as a racemic mixture of its two optical isomers. Methadone is a chiral synthetic compound used in therapy under racemic mixture. The list of racemic drugs with one eutomer is long.
It includes anticonvulsants such as mephenytoine, ethosuximide; antiarrhythmics and local anesthetics such as propafenone, disopyramide, prilocaine, tocainide; antibiotics such as ofloxacin, moxalactam; anticoagulants such as warfarine, acenocoumarol; antihistaminics such as terfenadine, loratadine; antihyperlipidemic such as atorvastatin; psychostimulants such as amphetamine, metamphetamine; proton pump inhibitors such as omeprazole, pantoprazole, lansoprazole, etc 15 , 31 - Some of these racemates recently undergo chiral switch to single enantiomer such as levofloxacin from ofloxacin , levalbuterol from albuterol , escitazolam from citalopram , esomeprazole from omeprazole , dexketoprophen from ketoprophen , dexmethylphenidate from methylphenidate , etc.
There are only some racemic drugs that could belong to this group such as cyclophosphamide antineoplastic , flecainide antiarrhythmic , fluoxetine antidepressant There are two kinds of drug chiral inversion: unidirectional and bidirectional inversion Unidirectional enzyme mediated inversion was previously described only with 2-arylpropionate nonsteroidal anti-inflammatory drugs NSAID , namely ibuprofen, ketoprofen, fenprofen, benoxaprophen, etc.
For this group, only S-enantiomer is active i. For example, S-ibuprofen is over fold more potent as an inhibitor of cyclooxygenase I than R -ibuprofen. In the body, only inactive R-enantiomer can undergo chiral inversion by hepatic enzymes into the active S-enantiomer and not vice-versa 9 , Bidirectional chiral inversion or racemization should be represented by 3-hydroxy-benzodiazepines oxazepam, lorazepam, temazepam and thalidomide in which R and S enantiomer can racemize in vitro by aqueous solution.
However, in vivo this phenomenon could occur with thalidomide, but not with hydroxyl-benzodiazepines because of the differences in substituents around their chiral carbon. Some authors 33 have found for the first time the difference in R- and S-oxazepam concentrations in treated rabbit serum.
They explained that the chiral inversion by tautomerization of oxazepam cannot occur in vivo because each enantiomer is transported by protein albumin with different affinity. The binding affinities of the enantiomers to albumin may inhibit the attack of hydroxyl ions water and thus retard the epimerization and racemization in vivo.
Therefore, R- and S-oxazepam concentrations can be found different in the serum of these treated rabbits. Thalidomide is a former racemic sedative withdrawn from the market in the s due to severe teratogenic effects phocomelia, amelia.
Single thalidomide enantiomers and its derivative, N-hydroxythalidomide, were also synthetized by asymmetric technique in order to study their individual biological and chemical activities 37 , It seems that a multitude of its pharmacological activities could be due not only to the mother molecule but also to its numerous chiral and achiral metabolites. Because of this in vivo interconversion of thalidomide, it is difficult to determine exactly the pharmacological effect of each enantiomer.
Since there are frequently large pharmacodynamic and pharmacokinetic differences between enantiomers, it is not surprising that enantiomers may result in stereoselective toxicity. In toxicology, the different toxic effects of chiral drugs can reside either in one enantiomer only or in both ones. The toxicological properties in a pair of enantiomers can be identical or entirely different.
They can reside in the pharmacologically active enantiomer or in the inactive one 9 , 12 , 15 , 25 , 32 , 40 , Some following drugs are marketed as single enantiomer solely because their toxicities reside almost in one of their two enantiomers.
Solutions to exercises
The key to mastering chirality and stereochemistry is through practice, practice, and more practice. But where do you get all those practice problems? Determine if the following molecules are optically active chiral or optically inactive achiral. Rank each set of substituents from high to low priority using Cahn-Ingold-Prelog ranking rules. Hint: Need help ranking? See Chirality video 2. Hint: Need a review on naming?
It seems that you're in Germany. We have a dedicated site for Germany. The late Edgar Heilbronner, one of the great physical and organic chemists of the 20th century, had a particularly effective lecture. He started it as follows: "You know pretty much everything I am going to say. So let us begin with the questions.
Chirality and Stereochemistry Practice Quiz
Orient the following so that the least priority 4 atom is paced behind, then assign stereochemistry R or S. Draw R bromobutanol. The stereo center is R. Determine the stereochemistry of the following molecule:. Which of the following are meso-compounds:.
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Review of “” by K.-H. Hellwich and C. D. Siebert.
- С какой стати такой параноик, как Танкадо, доверился столь ненадежному типу, как Хейл. Сьюзан понимала, что теперь это не имеет никакого значения. Нужно немедленно доложить обо всем Стратмору. Ирония ситуации заключалась в том, что партнер Танкадо находился здесь, прямо у них под носом. Ей в голову пришла и другая мысль - известно ли Хейлу, что Танкадо уже нет в живых.
ОНА ОТБРОСИТ АНБ НАЗАД НА ДЕСЯТИЛЕТИЯ. Сьюзан как во сне читала и перечитывала эти строки. Затем дрожащими руками открыла следующее сообщение. ТО: NDAKOTAARA. ANON. ORG FROM: ETDOSHISHA.
Стратмор вздрогнул и замотал головой: - Конечно. Убивать Танкадо не было необходимости. Честно говоря, я бы предпочел, чтобы он остался жив. Его смерть бросает на Цифровую крепость тень подозрения. Я хотел внести исправления тихо и спокойно. Изначальный план состоял в том, чтобы сделать это незаметно и позволить Танкадо продать пароль.
Он постучал. Послышался голос с сильным немецким акцентом: - Ja.