Stereoisomers

Stereoisomers include cis and trans isomers, chiral isomers, compounds with different conformations of chelate rings, and other isomers that differ only in the geometry of attachment to the metal ion. As mentioned at the beginning of this chapter, study of stereoisomers provided much of the experimental evidence used by Werner to develop and defend his coordination theory. Similar study of new compounds is useful in establishing structures and reactions, even though development of experimental methods such as automated X-ray diffraction can shorten the process considerably. 

In this chapter we describe the unified generation of stereoisomers including conform-ers of a molecular structure [102,103,105]. This method has the potential to generate stereoisomers that cannot be described in terms of stereocenters, stereogenic double bonds or single bond rotations. Fundamentals such as the concept of a (partial) orientation function are discussed, and mathematical tools such as Radon partitions and binary Grassmann-Plucker relations are used to construct tests for abstract orientation functions. Some simple examples are treated in detail. 

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Understanding the three-dimensional properties of organic molecules is an essential part of organic chemistry. The experiments in this chapter are designed to provide an introduction to stereoisomers. Such isomers have molecular skeletons that are identical, but they differ in the three-dimensional orientation of their atoms in space. The two broad subclasses of stereoisomers that are of importance in organic chemistry are conformational isomers and configurational isomers. 

Conformational isomers, as illustrated by the two Newman projections 1 and 2 for 1,2-dibromoethane, are stereoisomers that are interconverted by rotation 

Enantiomers have identical physical and chemical properties in an achiral environment. Their differential effect on plane-polarized light, however, is an important exception to this general rule Enantiomers rotate the plane of such light an equal number of degrees but in opposite directions. For this reason they are sometimes called optical isomers and are said to possess optical activity. Under most circumstances, the chiral compounds that you will prepare or use in the laboratory will be 50 50 mixtures of the two enantiomers, a composition referred to as the racemate or the racemic mixture. An equimolar mixture of 3 and 4 would thus be called a race-mate and would produce no net rotation of plane-polarized light. 

Frequently the source of chirality in an organic molecule is the presence of a center of chirality, also called a stereocenter, which is usually a carbon atom bearing four different substituents. This is the case for the atom marked with an asterisk in 3 and 4. The substituents are a hydrogen atom, an isopropenyl group, and two methylene groups. The methylene groups are distinct from each other because one of them is bound to a carbon atom of a carbon-carbon double bond, and the other to a carbon atom doubly bound to oxygen. 

If you understand observed rotation, you won t have any trouble with specific rotation should it come up in a passage on the MGAT. 

For a given molecular formula there is often more than one way of joining the atoms together, whilst still satisfying the rules of valency. Such variants are called structural isomers or constitutional isomers - compounds with the same molecular formula but with a different arrangement of atoms. A simple example is provided by C4H10, which can be accommodated either by the straight-chained butane, or by the branched-chain isobutane (2-methylpropane). 

Isomers are compounds that have the same formula as the parent, but different molecular orientation. Because of potential differences in therapeutic 

Need to determine whether the achiral method is specific for diastereomers or geometric MUST 

For drug product applications, sample matrix is an important component of the KPSS. Typically, a MUST representative placebo, placebo blend, or excipient soup is included in the KPSS for each formulation. 

Antioxidants, flavours, and preservatives are commonly monitored for during stability. MUST 

Isolated samples of these compounds are recommended for inclusion in the method development sample set, where applicable. 

By now you are well aware that molecules are three-dimensional objects. This chapter explores some of the more subtle, but extremely critical, consequences of this fact. If you have not done so yet, don t wait any longer to obtain a set of models to aid you in visualizing the structures described in this chapter. For many students, the isomeric relationships discussed here are the most difficult ones encountered in organic chemistry, and they are important later on in descriptions of several types of compounds and reactions. The implications for biological chemistry are especially significant. 

The key definitions what makes an object different from its mirror image. 

Further elaboration, including the introduction of several new terms describing relationships between more complex molecules. Moves toward biological systems. 

In this chapter you will be introduced to many new terms. Follow their definitions along with the structures given as examples. The first new term is the chapter title stereoisomer. In brief, stereoisomers are molecules 

What makes a molecule chiral The most common of several types of structural features that can make a molecule chiral is the presence of a carbon atom attached to four different atoms or groups (an asymmetric carbon atom, an example of what is called a stereocenter). At this point it is worthwhile to dust off your set of models and start manufacturing chiral molecules. Prove to yourself that the model of the mirror image of one cannot be superimposed on the original. This is the first step toward developing the ability to visualize this relationship clearly. 

Sometimes the different order of arrangements of atoms results in different functional These may also be referred to as 

In stereoisomers the atoms are linked together in the same atom-to-atom order, but their arrangements in space are different. 

Geometric isomers (or cis-mms isomers) differ only in the spatial orientation of groups about a plane or direction. Two geometric isomers have the same molecular formula, the same functional groups, the same base chain or ring, and the same order of attachment of atoms they differ in orientation either (1) around a double bond or (2) across the ring in a cyclic compound. 

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Light beam txxning directly out of the plane of the paper 

In the early 1880s, it was discovered that certain substances (for example, turpentine and other organic liquids, aqueous sugar solutions, quartz, and other minerals) 

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Carbon atom 1 in this formula is asymmetric and two stereoisomers therefore exist, depending on whether the OH group is written below (a) or above ( ) the plane of carbon atoms. Both forms crystallize either as the monohydrate or anhydrous. 

NOE-difFerence spectroscopy is particularly valuable for distinguishing stereoisomers, for it relies solely on intemuclear distances, and thus avoids any problems of ambiguity or absence associated with couplings. With smallish molecules, it is best carried out in the above 1D maimer, because 2 s are necessary for tire transmission of the NOE. The transmission process becomes more efficient with large molecules and is almost optimal for proteins. However, problems can occur with molecules of intemiediate size [3f]. A 2D version of the NOE-difference experiment exists, called NOESY. 

The earlier sections have only considered the way atoms are bonded to each other in a molecule (topology) and how this is translated into a computer-readable form. Chemists define this arrangement of the bonds as the constitution of a molecule. The example in Figure 2-39, Section 2.5.2.1, shows that molecules with a given empirical formula, e.g., C H O, can have several different structures, which are called isomers [lOOj. Isomeric structures can be divided into constitutional isomers and stereoisomers (see Figure 2-67). 

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. 

Figure 2-71. The ordered list of 24 priority sequences of the ligands A-D around a tetrahedral stereocenter, The permutations can be separated into two classes, according to the Cl P rules the R stereoisomer is on the right-hand side, and the S stereoisomer on the left.

Figure 2-74. Basic stages for describing a stereoisomer by a permutation descriptor. At the stereocenter, the molecule is separated into the skeleton and its ligands. Both are then numbered independently, with the indices of the skeleton in italics, the indices of the ligands in bold.

Figure 2-75. Determination of a permutation descriptor of a stereoisomer after reflection at the stereocenter...

Two steroids with the same constitution should be checked to see if they are stereoisomers (Eq. (10). 

However, the descriptors cannot be considered independently as there is no free rotation around the double bond, In order to take account of this rigidity, the descriptors of the two units have to be multiplied to fix a descriptor of the complete stereoisomer. 

Here we will illustrate the method using a single example. The aldol reaction between an enol boronate and an aldehyde can lead to four possible stereoisomers (Figure 11.32). Many of these reactions proceed with a high degree of diastereoselectivity (i.e. syn anti) and/or enantioselectivity (syn-l syn-Tl and anti-l anti-lT). Bernardi, Capelli, Gennari,... 

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

The Julia-Lythgoc olefination operates by addition of alkyl sulfone anions to carbonyl compounds and subsequent reductive deoxysulfonation (P. Kocienski, 1985). In comparison with the Wittig reaction, it has several advantages sulfones are often more readily available than phosphorus ylides, and it was often successful when the Wittig olefination failed. The elimination step yields exclusively or predominantly the more stable trans olefin stereoisomer. 

A highly successful route to stereoisomers of substituted 3-cyclohexene-l-carboxylates runs via Ireland-Claisen rearrangements of silyl enolates of oj-vinyl lactones. The rearrangement proceeds stereospeaifically through the only possible boat-like transition state, in which the connecting carbon atoms come close enough (S. Danishefsky, 1980 see also section 4.8.3, M. Nakatsuka, 1990). 

In the Sharpless epoxidation of divinylmethanols only one of four possible stereoisomers is selectively formed. In this special case the diastereotopic face selectivity of the Shaipless reagent may result in diastereomeric by-products rather than the enantiomeric one, e.g., for the L -(-(-)-DIPT-catalyzed epoxidation of (E)-a-(l-propenyl)cyclohexaneraethanol to [S(S)-, [R(S)-, [S(R)- and [R(R)-trans]-arate constants is 971 19 6 4 (see above S.L. Schreiber, 1987). This effect may strongly enhance the e.e. in addition to the kinetic resolution effect mentioned above, which finally reduces further the amount of the enantiomer formed. 

The 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde. 

The cyclization to form very congested quaternary carbon centers involving the intramolecular insertion of di-, tri-, and tetrasubstituted alkenes is particularly useful for natural products synthesis[l36-138], In the total synthesis of gelsemine, the cyclization of 166 has been carried out, in which very severe steric hindrance is e.xpected. Interestingly, one stereoisomer 167... 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

The Pd-catalyzed hydrogenolysis of vinyloxiranes with formate affords homoallyl alcohols, rather than allylic alcohols regioselectively. The reaction is stereospecific and proceeds by inversion of the stereochemistry of the C—O bond[394,395]. The stereochemistry of the products is controlled by the geometry of the alkene group in vinyloxiranes. The stereoselective formation of stereoisomers of the syn hydroxy group in 630 and the ami in 632 from the ( )-epoxide 629 and the (Z)-epoxide 631 respectively is an example. 

Allylic amines can be cleaved. Hydrogenolysis of allylic amines of different stereochemistry with NaBH CN was applied to the preparation of both dia-stereoisomers 655 and 657 of cyclopentenylglycine from the cyclic amines 654 and 656 of different stereochemistry[405]. 

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