Cyclophosphamide

molecules exist in either left or right handed spirals in the same way that a corkscrew, or spiral staircase, may be either left (4.17) or right (4.18) handed. Thus, chirality may arise as a result of helicity in a structure. While the above example has little significance in medicinal chemistry it is important to appreciate that a number of biologically important macromolecules exist as helical structures. For example the a-helix of proteins, composed

of L-a-amino acids, is right handed and the two polynucleotide strands of the DNA double helix wind around a common axis with a right-handed twist. In the case of these molecules not only are the individual building blocks, i.e. the amino acids and nucleotides chiral but the biopolymers themselves exhibit chirality.

4.2.1 Nomenclature and Designation of Stereoisomers

The classical method of distinguishing between a pair of optical isomers makes use of their unique property of rotation of the plane of plane polarised light. Those isomers which rotate light to the right being termed dextrorotatory, indicated by a (+)-sign

before the name of the compound while those which rotate light to the left are termed laevorotatory indicated by a (-)-sign. In the older literature the letters d- and l- are also used to indicate (+)- and (-)- enantiomers respectively. The use of these lower case letters gives rise to confusion with the upper case D and L designation for configuration and should be avoided. A racemic mixture, a 1:1 mixture of enantiomers, is indicated by a (±)-sign before the name of the compound. It is important to appreciate that this form of designation yields information concerning a physical property of the material but does not provide information concerning the three dimensional spatial arrangement, or absolute configuration, of the molecule. Also considerable care is required when using the direction of rotation as a stereochemical descriptor as both the magnitude and direction of rotation may vary with the conditions used to make the determination, e.g. temperature, solvent, analyte concentration etc. For example the antimicrobial agent chloramphenicol (4.19) contains two chiral centres and therefore four stereoisomeric forms are possible. The active isomer has the RR-absolute configuration (see p. 107 for convention), but this stereoisomer is dextrorotatory when the optical rotation is determined in ethanol and laevorotatory in ethyl acetate. Similarly the active S-enantiomers of the 2-arylpropionic acid (4.20) non-steroidal anti-inflammatory agents, e.g. ibuprofen (4.21), are dextrorotatory as the free acids but the corresponding sodium salts are laevorotatory.

Additional complications arise if the drug material is a mixture of two diastereoisomers, e.g the P-lactam antimicrobial agent moxalactam (latamoxef) is a mixture of two epimers which are both laevorotatory. Their designation, based on the configuration of the side chain chiral centre and optical rotation are (-)-(R)- and (-)-(S)-moxalactam (4.22). In this

case the designation of the material by optical rotation is meaningless and provides no information concerning the stereochemical composition of the material, i.e. single isomer or mixture.

Once the three dimensional structure of a stereoisomer has been determined, by for example X-ray crystallography, then the absolute configuration of a molecule may be indicated by the use of a prefix letter to the name of the compound. Two systems are currently used, the R/S or Sequence Rule nomenclature of Cahn, Ingold and Prelog and the older D/L system of Fischer and Rosanoff.

One of the major problems in organic chemistry is the representation of three dimensional structures on two dimensional sheets of paper, the relationships between stereoisomers can best be seen and understood by the use of molecular models. The Fischer projection, devised by the carbohydrate chemist Emil Fischer, is a common method for two dimensional representations of three dimensional structures. In Fischer projections the structure is drawn in a vertical rather than horizontal form with the lowest numbered carbon atom, in standard nomenclature terms, or the most highly oxidised end of the chain, drawn at the top. At each chiral centre along the main axis of the molecule the vertical bonds project back away from the reader while the horizontal bonds project up towards the reader. In the case of glyceraldehyde (2,3-dihydroxypropanal) the simplest carbohydrate, containing one chiral carbon atom the individual enantiomers are drawn thus (4.23):

The chiral carbon atom is regarded as being in the plane of the paper and those groups which are bonded horizontally, i.e. the H and OH project up towards the reader and those bonded vertically, i.e. the CHO and CH2OH project back away from the reader. Thus the above structures represent (4.24):

The structure of glyceraldehyde with the secondary hydroxyl group drawn on the right of the Fischer projection was designated as having the D configuration and that with the secondary hydroxyl on the left the L configuration. At the time this representation of structure was developed there were no methods for the determination of the three dimensional nature of molecules and the observed optical rotations of the two enantiomers were arbitrarily assigned as D-(+) and L-(-). At this time the letters d and 1 were used to indicate the direction of rotation rather than (+) and (-), and this combination of both upper and lower case letters to define both the physical property and the shape of the molecule, as pointed out above, continues to add to the confusion associated with the study of stereochemistry. It was not until the 1950s that it was possible to show that the optical rotation assignment in fact corresponded to the structures drawn which was highly fortuitous. Stereoisomers of compounds which can be related to D-glyceraldehyde by synthesis, are given the D-configuration, irrespective of the observed direction of rotation of polarised light and compounds related to L-glyceraldehyde are given the L-configuration. For example (+)-glucose (4.25), (-)-2-deoxyribose (4.26) and (-)-fructose (4.27) having the terminal configuration of (D)-(+)-glyceraldehyde, are assigned to the D-series. In the case of the amino acids the reference compounds used are D-(+)- and L-(-)-serine (4.28).

The use of this system presents a number of problems particularly if there is more than one chiral centre in the molecule. Thus the amino acid L-threonine (4.29) may be related to L-serine at carbon 2 and D-glyceraldehyde at carbon 3. In the case of the a-amino acids the a-carbon atom is used to define the stereochemistry and the majority of natural amino acids have the L-configuration at this centre. D-amino acids are however found in a number of peptide antibiotics, e.g. bacitracin, penicillins etc.

In an attempt to overcome the difficulties associated with the D/L system Cahn, Ingold and Prelog devised their Sequence Rule system. Using this method the substitutent atoms attached to a chiral centre are ranked in order of priority which is based on their atomic number. The higher the atomic number the greater the priority. If a decision on priority cannot be made on the basis of the atoms directly attached to the chiral centre then the atoms two bonds away are considered. This process is continued along a substituent until all the priorities have been assigned. The molecule under examination is then viewed from the side opposite to the group of lowest priority and if the priority sequence, highest to lowest, is to the right (i.e. clockwise) then the centre is of the R-absolute configuration (Latin rectus, right) and if to the left (i.e. anticlockwise) the S-absolute configuration (Latin sinister, left).

In the case of glyceraldehyde (4.23) the priority order of the groups is: HO-(highest), -CHO, -CH2OH, H (lowest). The aldehyde group has a higher priority than the primary alcohol as the aldehydic carbon atom is considered to be bonded to two oxygen atoms, one "real" and one "ghost" or "phantom" oxygen so that the carbon-oxygen double bond is taken into account. The application of these rules to the enantiomers of glyceraldehyde is illustrated below (4.23).

Thus D-(+)-glyceraldehyde has the ^-absolute configuration using the Cahn, Ingold, Prelog sequence rules and L-(-)-glyceraldehyde has the 5-absolute configuration.

The naturally occurring catecholamines, (-)-noradrenaline (4.30) and (-)-adrenaline (4.31) have been stereochemically related, by chemical degradation studies, to D-(-)-mandelic acid (4.32) and therefore these two compounds are assigned the D-configuration. In the case of noradrenaline (4.30) and adrenaline (4.31), and related chiral derivatives of phenylethylamine, the convention regarding the presentation of Fischer projections with the lowest numbered carbon atom at the top is not strictly applied. These agents are conventionally drawn "upside down" as Fischer projections as shown in the structures (4.30) and (4.31).

Redrawing the Fischer projections of (4.30) and (4.31) to a form suitable for assigning the configuration yields structure (4.33), and examination of the sequence indicates that the D-enantiomers of both catecholamines correspond to the R-absolute configuration.

One of the major problems with stereochemical nomenclature is the continued use of both the above systems for designation of absolute configuration and also the use of the physical descriptors (+) and (-). The potential problems associated with the use of the

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