STRUCTURE OF THE TARGET MOLECULE

The term diastereoisomeric refers to those molecules having the same structure (functional groups and skeletal arrangement) but which are not mirror image 

Whereas enantiomers (e.g. 4a and 4b) have indentical chemical and physical properties (except their effect on plane polarised light), diastereoisomers (e.g. 4a, or 4b and 4c) frequently differ in their chemical properties, and have different physical properties. 

One simple practical method of assessing the possibility of the existence of non-superimposable mirror images, particularly with complex structures, is to construct models of the two molecules. The property of chirality may alternatively be described in terms of the symmetry elements of the molecule. If there is a lack of all elements of symmetry (i.e. a simple axis, a centre, a plane, or an n-fold alternating axis) the chiral molecule is asymmetric, and will possess two non-superimposable mirror image structures (e.g. 2a and 2b). If, however, the molecule possesses a simple axis of symmetry (usually a C2 axis) but no other symmetry elements, the chiral molecule is dissymmetric. Thus 4a and 4b are dissymmetric and the simple C2 axis of symmetry, of for example 4a, is shown below. If the molecule possesses a centre of symmetry (C,) or a plane of symmetry ( r), or an n-fold alternating axis of symmetry (S ), the mirror images of the molecule are superimposable and the molecule is optically inactive. These latter three symmetry elements are illustrated in the case of the molecule 4c. 

Optical activity was first observed with organic compounds having one or more chiral carbon atoms (or centres) (i.e. a carbon substituted with four different groups). In the structures (1) to (17) the chiral carbons are specified with an asterisk. Subsequently compounds having chiral centres at suitably substituted heteroatoms (e.g. silicon, germanium, nitrogen, phosphorus, arsenic, sulphur, etc.) were also synthesised. Molecular dissymmetry, and hence chirality, also 

The convention has over the last three decades proved to be adaptable, versatile and universal.9 It should be pointed out, however, that with amino acids (Section 5.14.4, p. 746), and hence in peptide and protein chemistry, and with carbohydrates (Section 5.10), the d/l convention is still the more convenient, mainly because it is used specifically to designate generic relationships between an enormous number of compounds of closely related structure. 

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As an example, let s analyse the synthesis of y-lactones (e.g. TM 334) and see how we may choose one of a number of strategies depending on the structure of the target molecule. We ll consider in turn each of the three C-C bond disconnections. The one with the most appeal is probably b complete the analysis for this approach. 

In the direct associative approach, which is applied in the case of relatively simple molecules, the chemist directly recognises within the structure of the target molecule a number of readily available structural subunits which can be properly joined, by using standard reactions with which he is very familiar. For instance, it is easy to see that structure 1 can be obtained by bringing together, the fragments a, b and c, in a Mannich condensation ... 

In the first place, the structure of the target molecule is submitted to a rational analysis in order to perceive the most significant structural features, and it may be useful to use different types of molecular models at this point. It should be remembered that a molecular structure has "thousand faces" and finding the most convenient perspective may greatly simplifly the synthetic problem. The synthesis of opium alkaloids, for instance, is much simplified if one realises that they are, in fact, derivatives of benzyltetrahydroisoquinoline (18) (see Scheme 3.8). This was indeed the inspired intuition of Sir Robert Robinson which led to the structural elucidation of morphine (19) and to a first sketch of the biogenetic pathway [22], and later on to the biomimetic synthesis of thebaine 20 [23] [24]. 

The recognition of symmetry -either real or potential- in the structure of the target molecule may be of paramount importance not only in the simplification step. 

The choice of the radionuclide and the position of the labelling are generally determined by the chemical structure of the target molecule to label and the ease of introduction of the radionuclide from a chemical point of view. The physical half-life of the radionuclide should however match the timescale of the studied process. For example, in repeated blood flow measurements, oxygen-15 in the form of p Ojwater is ideal, while carbon-11 and especially fluorine-18 are preferable in the study of slower processes. 

Disulfide connectivities of a partially reduced and alkylated peptide can be identified by the pairwise recognition of the specifically derivatized PTH-Cys on sequencing/46 PTH-Cys(Cam) and PTH-Cys(CM) are reported to elute on the ABI sequencer with PTH-Glu and PTH-Ser, respectively/46 and PTH-Cys(NEM) after PTH-Pro. 49 Therefore, it is important to know the primary structure of the target molecule in advance and to focus on the determination of its disulfide arrangement during sequence analysis in order to avoid mis-assignment of the amino adds at the cycles of the modified cysteine residues. 

StractuiE-fimction analysis of other drugs performances indicated the structure of the target molecule (oxamniquine). 

By examining the structure of the target molecule, compound C, we see that the bond indicated in the following structure joins two fragments that are related to the given starting materials A and B ... 

Sometimes the natural products that are needed are immediately obvious from the structure of the target molecule. An apparently trivial example is the artificial sweetener aspartame (marketed as Nutrasweet), which is a dipeptide. Clearly, an asymmetric synthesis of this compound will start with the two members of the chiral pool, the constituent (natural) (S)-amino acids, aspartic acid and phenylalanine. In fact, because phenylalanine is relatively expensive for an amino acid, significant quantities of aspartame derive from synthetic (S)-phenylalanine made by one of the methods discussed later in the chapter. 

In much the same way, if the structure contains heteroatoms that are not a part of the heteroaromatic system, it makes sense to start the analysis by rupturing a carbon-heteroatom bond as the reverse reaction represents, essentially, a trivial transformation of functional groups. The presence of small ring fragments such as cyclopropane or epoxide rings in the structure of the target molecule almost automatically dictates the retrosynthetic scission of these moieties in the initial steps of retrosynthetical analysis, as both these groups can be easily introduced with the help of very reliable methods. 

This cycloaddition works best with substituted oxyallyl cations, like the one from the dibromo-ketone 93 which reacts with the morphol ine enamine of cyclohexanone 95 to give the cyclopentenone 96 in excellent yield.24 You should mark the difference in structure between the Nazarov products, e.g. 70, formed in an electrocyclic reaction, and these cycloadducts, e.g. 96. Each strategy has its part to play and must be chosen according to the structure of the target molecule. 

Up to this point, we have discussed the situation of the three-dimensional structure of the target molecule being known or computable. The next few seaions deal with the more common situation, namely that where such infer-... 

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