Compounds with Two Chiral Centres

The symbols (2RS,3RS) and (2RS,3SR) can also be used for the racemic diastereoisomers of compounds with two chiral centres though CAS does not use this system. Where the absolute configuration appears to be unknown, asterisked symbols, e.g. (2R, 3R ) may be used. 

Graphical representation of stereoisomers of 3-bromo-2-chlorobutanoic acid 

CAS now registers and names substances with partially defined stereochemistry. Previously, partial stereochemistry was generally ignored. The presence of unknown chiral centers is indicated by the addition of the term [partial]- to the end of the normal stereochemical descriptor. When the reference ring or chain has incompletely defined chiral atoms/bonds, the format cites the stereochemistry using R and S terms with their nomenclature locants for all known centers. If this method is used to describe a substance for which only relative stereochemistry is known, rel is added to the stereochemical descriptor. Any stereochemical descriptor marked as rel always cites the first centre as R-. 

Beilstein uses a number of additional stereochemical descriptors for specialised situations. Examples are (RS), R, S, and H. For full details, see the booklet Stereochemical Conventions in the Beilstein Handbook of Organic Chemistry, issued by the Beilstein Institute, and Section 7.6. 

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Dizocilpine is a chiral compound with two chirality centres. The methylated centre has the S configuration, whilst the other bridgehead atom is -configured. For clarification it is helpful to add hydrogen atoms or wedged bonds. Two other possible formulae for the structure are shown below, the last one of which, however, although frequently used is not recommended. 

Optically pure compounds with two chiral centres... 

So much for one chiral centre. The problems really begin when you come up against molecules which have two or more chiral centres With two chiral centres, we can construct four possible stereoisomers. These can be separated into two enantiomeric pairs (indistinguishable by NMR). But, (key sentence coming up) if we compare one member of each of these enantiomeric pairs, we will find that they may be distinguished from each other by NMR, because they are diastereoisomers. Diastereoisomers are stereoisomers which are not mirror images of each other - they are different compounds with distinct physical and chemical properties. See Figure 6.1 if this isn t clear. 

Stereoisomerism in compounds with two stereo centres diastereomers and meso structure In compounds whose stereoisomerism is due to tetrahedral stereocentres, the total number of stereoisomers will not exceed 2", where n is the number of tetrahedral stereocentres. For example, in 2,3,4-trihydroxybutanal, there are two chiral carbons. The chiral centres are at C-2 and C-3. Therefore, the maximum number of possible isomers will be 2 = 4. All four stereoisomers of 2,3,4-trihydroxybutanal (A-D) are optically active, and among them there are two enantiomeric pairs, A and B, and C and D, as shown in the structures below. 

Now if we draw syn-21, we would like it to mean only that enantiomer. But now comes the difficulty. How do we distinguish this diagram from the one we used for the racemic compound They both look the same. Sadly there is no easy answer to this and with two chiral centres it is ambiguous but for a start we can label the drawing (+)-.s vn-27 if racemic. Sound advice is to spell it out on your... 

These might be called derivatives since they are further removed from the stereochemical information than R or S. As such they are less useful since they need more decoding to get back to the actual structure. They are used for compounds with adjacent chiral centres. They are easy enough to understand - a compound with two R chiral centres (or one with two S chiral centres) is a Ik (Ik for like ) compound whereas a compound with one R and one S centre would be ul (ul for unlike ). Although this has the advantage of being unambigous, it does not convey a pictorial... 

Stractures of the various o-aldoses in the range C3-C6 are shown below. These compounds are multifunctional stmctures, having a carbonyl group and several hydroxyls, usually with two or more chiral centres. You will notice that we are comparing the stereochemistry in the different possible diastereoiso-mers for compounds containing several chiral centres (see Section 3.4.4). There is a corresponding series of enantiomeric L-sugars only a few of these are shown. 

The solution to the second problem is to start with two enantiomerically pure compounds derived from nature and that suggests adding an alkene between the two chiral centres 44 as that could be made by a Wittig reaction from, say, 45 and 46. 

Since this compound possesses a chirality centre at the sulfur atom, two enantiomers can exist which can be separated on a suitable chiral stationary phase (e.g. on silica gel modified with substituted 1,2,3,4-tetrahydrophen-anthren-4-amine). If it is not enantiopure, two peaks will be observed in the chromatogram. 

In the crossed aldol reaction between acetaldehyde and propiophenone, two chirality centres are created and consequently, four stereoisomers will be produced. Compounds A and B are enantiomers of each other and can be described with the stereo descriptor u. Similarly, C and D are enantiomers and are /-configured. Since both starting materials are achiral, without the use of a chiral base or chiral auxiliary, racemates will be produced. Likewise the choice of base, the addition of a Lewis acid and the reaction conditions used to form the enolate can control which diastereomer is preferentially formed. If the Z enolate is formed, the u product is the preferred product, whilst the E enolate yields predominately the / product. 

Reactions like these, in which stereoselectivity is the consequence of steric hindrance to bond rotation, are most well known among the biaryls, and derivatives of binaphthyl have provided chemists with a valuable range of chiral ligands [4-6]. But the biaryls are only a small subset of axially chiral compounds containing two trigonal centres linked by a rotationally restricted single bond. Many others are known, some with much greater barriers to rotation than Fuji s enol ether [7]. Yet until quite recently there were no reports of reactions in which nonbiaryl atropisomers were the source, conveyor, or product of asymmetric induction. 

RS)- and SR)- In a one-centre compound RS) means the racemate, equivalent to ( ). In a compound with two or more centres of chirality, RS and SR are used to define the relative configurations of the centres in racemic diastereomers, e.g., ( )-threitol = 2RS,3RS)-1,2,3,4-butanetetrol, erythritol = (2RS,3S / )-l,2,3,4-butanetetrol. Priority is given to RS)-for the lowest-numbered centre. (CAS uses R and 5 together with the ( )- identifier to show that a racemate is meant.)... 

The first intermediate produced by alkylation with the primary alkyl bromide (or the epoxide) has two chiral centres and will no doubt be formed as a mixture of diastereoisomers. But this doesn t matter as the enolate has to be reformed for the next alkylation and that destroys one of the chiral centres. We are back to a single compound again. 

Most of the compounds we shall be looking at in this chapter will be in racemic form. We are concerned only with the control of relative stereochemistry and not with the control of absolute stereochemistry. However, many of the reactions have been developed into asymmetric versions. It is certainly true that many of the reactions have been employed within asymmetric synthesis - that is, where the asymmetric part has come from elsewhere and this idea will be revisited in Chapter 30. If we are to concern ourselves simply with relative stereochemistry then, for there to be any stereochemical relationship, we must have at least two chiral centres. If there is no chirality in the starting materials this means that two chiral centres must form in one reaction and if there is only one new chiral centre that forms in the reaction then there must have been a chiral centre already in one of the starting materials. 

The obvious answer is as early as possible. The first chiral intermediate is 146 and that already has two chiral centres. The first intermediate with a useful functional group is 149 with its two alcohols. The chemists at what was then Glaxo (now GlaxoSmithKline) chose an ingenious resolution of the stable ketone 147. Because this is a strained ketone it forms a stable adduct with bisulfite and that could be resolved as a salt with our old friend 1-phenylethylamine 2. The bisulfite compound reverts to the ketone 147 on treatment with base and the resolution was complete. 

The activity ratio is Eu/Rac = 1 in this case both isomers are equipotent and no stereoselectivity is observed. This can be explained by the assumption that (1) the compounds act through a non-specific mechanism (2) the active compound and the receptor make only a two-point contact with the chiral centre (3) the chiral centre is not involved in the contact (is located in a silent region ). 

So tartaric acid can exist as two diastereoisomers, one with two enantiomers and the other achiral (a meso compound). It s worth noting that the formula stating that a compound with n stereogenic centres has 2 diastereoisomers has worked but not the formula that states there are 2 stereoisomers. In general, it s safer not to count up total stereoisomers but to work out first how many diastereoisomers there are, and then to decide whether or not each one is chiral, and therefore whether or not it has a pair of enantiomers. 

This structure has two chiral centres, so how will we know which diastereoisomer we have The answer was simple the stereochemistry has to be trans because Feist s acid is chiral it can be resolved (see later in this chapter) into two enantiomers. Now, the cis diacid would have a plane of symmetry, and so would be achiral—it would be a meso compound. The trans acid on the other hand is chiral. If you do not see this, try superimposing it on its mirror image— you will find that you cannot. In fact. Feist s acid has an axis of symmetry, and you will see shortly that axes of symmetry are compatible with chirality. 

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