Medicinal Chemistry

6. Additions to carbon–carbon multiple bonds


7. Additions to carbon–heteroatom multiple bonds


8. Elimination reactions


9. Rearrangements


10. Oxidations and reductions

These ten reactions provide the capacity to construct a molecular framework and then
to position functional groups precisely on this framework. Accordingly, these ten reac-
tions permit two fundamental construction activities:

1. Creation of C-C/C=C/C-H bonds (for the purpose of building a structural framework)


2. Creation of functional groups (to give functionality to the framework)

Appendix 3.1 at the end of this chapter lists 100 fundamental reactions used by syn-
thetic medicinal chemists to create C-C bonds and functional groups during drug mol-
ecule preparation. Detailed discussion and mechanisms for these reactions are not
provided, but are available in many textbooks of basic or advanced organic chemistry.

3.3.1 Synthon Approach to Drug Molecule Synthesis

To use these 100 reactions (and additional ones) for the purposes of drug molecule syn-
thesis requires an organized and systematic approach. The synthesis of a complicated
drug molecule from simple starting materials must be approached in a rigorous and sys-
tematic fashion. The synthon approach provides such a scheme. This approach is based
upon the notion that it is easier to work backwards from the target molecule (i.e., the
drug to be synthesized) to the starting materials. This backwards-thinking process is
referred to as retrosynthetic analysis. In retrosynthetic analysis, a procedure known as
disconnectionis used to dissect a molecule into progressively smaller and smaller frag-
ments until readily available starting materials are obtained. A disconnection involves
breaking a bond to a carbon atom. The fragments that result from this disconnection are
referred to as synthons. Typically, a bond is broken and the electron pair is assigned to
one of the fragments, resulting in a positively charged synthon and a negatively charged
synthon. The next task is to find readily available starting materials that can actually be
used as sources of these synthons. These available materials that are equivalent to a syn-
thon are referred to as synthetic equivalents, and are generally commercially available
compounds that represent the nucleophile and the electrophile that must react.
Sometimes, prior to a disconnection, one functional group is converted to another “syn-
thetically equal” functional group through the process of a functional group intercon-
version(FGI). This FGI may produce a molecule which is easier to disconnect and thus
easier to synthesize.
Figure 3.3 shows a simple example of a retrosynthetic synthesis of cyclohexanol.
Cyclohexanol may be disconnected to a hydride ion and a hydroxycarbocation (the syn-
thons). Sodium borohydride and cyclohexanone are the synthetic equivalents of these
two synthons. Thus, reacting cyclohexanone with NaBH 4 will produce cyclohexanol.
It is apparent that this system of disconnections can be applied to molecules of sig-
nificant complexity to deduce a synthetic route.

DESIGNING DRUG MOLECULES TO FIT RECEPTORS 129