THE BASICS OF DIVERSITY-ORIENTED SYNTHESIS - Diversity-Oriented Synthesis - page 14

blocks through the well-established and powerful process of retrosynthetic analysis.
In complex molecule synthesis, retrosynthetic analysis breaks a molecule down into
simple precursors or building blocks, which are then combined in a “convergent”
fashion.
In DOS an ideal stategy involves “divergent” synthesis, where a small number
of compounds are transformed into many distinct structures. It is not possible then
to apply retrosynthetic analysis directly to DOS pathways, so the synthetic analysis
must be carried out in the forward direction [1,2]. This means that starting materials
and intermediates must be chosen with a view to diverse reactivity at a later point in
the synthetic sequence. Generally, DOS pathways make use of complexity-generating
reactions to quickly build up molecular scaffolds and product-substrate relationships
in which the product of one reaction is the substrate for the next. Figure 1.1 represents
the synthetic strategies used in, and the chemical space coverage achieved by, TOS,
focused library synthesis, and DOS.
1.5 MOLECULAR DIVERSITY
The absolute assessment of the degree of molecular diversity within a given set of
compounds is not straightforward, although a number of possible methods do exist
(see below). Any synthesis involving the production of more than one molecule,
such as focused library synthesis, must contain some degree of diversity between
the products, as the compounds produced are not identical, and therefore the term
DOS can be used with some legitimacy to describe focused library synthesis. It
has been emphasized, however, that this is not really in the “spirit” of DOS, where
the aim should be to incorporate, as efficiently as possible, the maximum degree of
structural diversity for a given synthetic sequence [19,30]. Ideally, this should involve
incorporation of the four types of molecular diversity that are frequently identified in
the literature [2,5,19,30,31]:
1. Appendage or building block diversity : variation resulting from the choice of
starting materials or “building blocks” used, usually resulting in the variation of
R-groups around a single scaffold. (This is the approach used most frequently,
almost by definition, in combinatorial libraries.)
2. Functional group diversity : variation of the functional groups present in a
molecule generally, and also at specific sites within the gross structure. This
gives the potential for interactions with different polar, apolar, or charged groups
present in biological macromolecules.
3. Stereochemical diversity : variation in the orientation of functional groups and
potential macromolecule-interacting elements. This is clearly very important,
as nature is a three-dimensional environment.
4. Scaffold or skeletal diversity : variation in the overall molecular framework,
typically considered to be variation in ring structures and other rigidifying
elements, resulting in molecules with distinct scaffolds and, consequently,
distinct molecular shapes.