Über die Autorin bzw. den Autor

Dr Vittorio Caprio, Lecturer in Organic and Medicinal Chemistry in the Department of Chemistry, University of Auckland, New Zealand. His research interests lie in the application of synthetic organic methods to the synthesis of bioactive natural products of diverse structure. A central aim is the efficient and elegant syntheses of target core structures in a stereocontrolled manner using nature as the source of chirality. The ultimate goal is to use natural medicines as the basis for designing and synthesizing drugs of greater therapeutic value.

Professor Jonathan MJ Williams (author of the first edition), Department of Chemistry, University of Bath, UK. Research involves with the use of transition metals for the synthesis of useful organic molecules. In particular, we have been developing reactions using 'borrowing hydrogen.' In this chemistry, ruthenium or iridium catalysts temporarily remove hydrogen to give an aldehyde.  This aldehyde then reacts to give an alkene (or imine) and the hydrogen is then returned to give a C-C or C-N bond. These procedures allow alcohols to be used as alkylating agents in place of more conventional, but often toxic/mutagenic alkyl halides.

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Catalysis in Asymmetric Synthesis

John Wiley & Sons

Chapter One

There are several ways of producing compounds as single enantiomers. The resolution of a mixture of enantiomers can often be the cheapest, most practical way of obtaining enantiomerically pure material. The conversion of a cheap enantiomerically pure starting material into another derivative represents another useful technique in some cases.

However, asymmetric synthesis can provide a more general approach to the preparation of enantiomerically enriched compounds. Asymmetric synthesis is limited by the range and scope of available methodology. Fortunately, with so much research in the area, there are many methods now available, with further asymmetric reactions being developed each year. There may still be cases where asymmetric synthesis doesn't provide the best method for the preparation of a particular enantiomerically pure compound, but it certainly allows for the preparation of a more diverse range of structures.

Asymmetric catalysis is an especially appealing aspect of asymmetric synthesis. Small amounts of a catalyst (frequently less than 1 mol%) can be used to control the stereochemistry of the bulk reaction. The use of a catalyst often makes the isolation of a product easier, since there is less unwanted material to remove at the end of a reaction.

1.1 Reactions Amenable to Asymmetric Catalysis

From a synthetic viewpoint, the individual chapter titles in the book give a fair impression of the scope of synthetic processes involved. The types of reaction amenable to asymmetric catalysis can also be considered from a more stereochemical viewpoint.

Most reactions involving asymmetric catalysis are based around the conversion of a planar [sp.sup.2] carbon atom into a tetrahedral [sp.sup.3] carbon atom. This category of reactions includes asymmetric hydrogenation of alkenes and ketones, as well as the addition of other reagents to these groups as identified in Figure 1.1.

Substrates containing enantiotopic groups can be converted into enantiomerically enriched compounds using asymmetric catalysis with representative examples outlined in Figure 1.2. These reactions break the symmetry (e.g. meso or achiral) of the starting material.

Asymmetric catalysis may also be achieved by the kinetic resolution of racemic substrates, where one enantiomer of starting material is selectively converted into product, leaving the other enantiomer unreacted. In some instances, both enantiomers of a starting material are converted into the same enantiomer of product, i.e. dynamic kinetic resolution. Most reactions fit into one of the categories identified in Figures 1.1-1.3, even if the exact structure is not represented.

1.2 Assignment of (R) and (S) Stereochemical Descriptors

The Cahn-Ingold-Prelog (CIP) system for describing the stereochemistry of chiral molecules is universally accepted. Simple molecules containing one chiral centre are described as (R) (from Latin: rectus) or (S) (from Latin: sinister). A short account of how to distinguish between (R) and (S) follows, although more detailed information is available elsewhere. For a tetrahedral carbon-based chiral centre, the priority of the four attached groups must be determined according to the sequence rules. The two enantiomers in Figure 1.4 have groups attached where a>b>c>d.

The structure must be viewed from the side opposite the lowest priority group. In these cases, the group d must therefore point away from us. If the priority of the remaining groups a- b-c is in an anticlockwise sense, the stereochemical descriptor is (S). When the a-b-c sequence is clockwise, the stereochemical descriptor is (R).

Of course, for real molecules, we need to be able to decide which groups have priority over other groups. In general, the most important sequence rule is that groups of higher atomic number precede groups of lower atomic number. Hence, the molecule (1.01) has the (R)-configuration.

However, not all molecules are so simple! The groups may need to be considered in more detail, when the first atoms attached to the chiral centre have the same priority.

In the case of molecule (1.02) we can quickly identify the lowest priority group, the H atom. However, the three remaining groups each contain a carbon attached to the chiral centre. We have to consider the next "sphere" of atoms. In the second sphere, the Cl atom takes priority over the O, which takes priority over the H. The compound therefore has the (S)-configuration.

For functional groups which contain multiple bonds, 'phantom' atoms are incorporated, making it easier to assign priorities. The 'phantom' atoms are not attached to any further groups. Some examples of expanded functional groups are identified in Figure 1.5.

The expansion of functional groups allows us to apply the sequence rules to more complex structures, (1.03-1.08). A few comments may be helpful for some of these assignments. In structure (1.04), the -C[H.sub.2]Cl group takes priority over the C[F.sub.3] group. The chloride takes precedence over the fluoride, even though there is only one chloride, because the fluorides are not added together. In the phosphine (1.07), the lone pair of electrons is considered to have the lowest priority (lower than any atom). In structure (1.08), the -C[H.sub.2]Cl group takes priority over the -C[H.sub.2]C[H.sub.2]I group. This is because the Cl atom comes in the second sphere, whereas the I atom does not appear until the third sphere.

Another aspect of the (R,S)-nomenclature involves assigning structures which possess axial chirality or planar chirality. Because of the number of ligands which possess axial chirality (BINOL, BINAP and related ligands), the assignment of (R) and (S) to these structures is briefly considered. An additional sequence rule is helpful here: the nearer end of an axis (or plane) precedes the further end. For the axially chiral molecule, BINOL (1.09), a simple way to assign stereochemistry is by looking down the chiral axis. The nearer groups take priority over the further groups, and hence the assignment of sequence is as shown in Figure 1.6. Again, clockwise corresponds to the (R)-configuration, and anticlockwise corresponds to the (S)-configuration. This is like a helix spiralling away from the viewpoint. The assignment will be made by looking along the chiral axis from the other end.

Axial chirality can also be assigned using (M,P)-nomenclature (see reference 2). For axial chirality, (R) is equivalent to (M), and (S) is equivalent to (P).

(Continues...)

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