Biomedical Engineering Reference
In-Depth Information
TABLE 7.1 Factors Attributed to the Decision Process
Criteria
Solution Phase
Solid Phase
Reaction condition optimization
None or fast
Critical and tedious
Additional synthetic step
No
Anchoring and release
Excess of reagents
None or small
High
Limits on chemistry
No
Some
Analysis of intermediates
Simple
Requires release
Isolation of intermediates
Time consuming
Fast and simple
Integration/automation
Complex
Simple
Solvent removal
Evaporation
Washing (DMF, DMSO okay)
Compound loss due to handling
Some
None
Pooling of intermediates
No
Ye s
thus benefiting from the effort to develop their synthesis (c.f. page 220). In the follow-
ing pages we provide useful coordinates for those considering solid-phase chemistry
a valid alternative to solution-based synthetic strategies.
We used diversity classification as suggested by Burke and Schreiber and divided
our chapter into the following diversity sections: skeletons, stereochemistry, and
appendages [1]. Skeletal diversity involves the formation of several discrete scaffolds
and it was approached via either branching or folding processes (for more informa-
tion, see Section 7.2). Stereochemical diversity represents different three-dimensional
spatial arrangements of identical two-dimensional structures (different
S/R
orienta-
tion) and thus influences the behavior (e.g., binding, affinity) of a given compound.
Finally, appendage diversity is achieved by incorporation of various substructures
(e.g. heterocycles) on one core unit using several chemistries and building blocks.
The build/couple/pair (B/C/P) [2] approach to chemical diversity includes all three
categories mentioned above. In addition, chemical diversity can be achieved by a
scaffold hopping process.
This chapter is devoted to diversity-oriented solid-phase synthesis with the pri-
mary emphasis on skeletal diversity. Several syntheses that qualify for both skeletal
and stereochemical diversity are listed in the skeletal section; only a reference is
given in the stereochemical section. One particular scaffold decorated with a set of
various building blocks does not fulfill our criteria for diversity-oriented synthesis
(DOS), even though the combination of several building blocks undoubtedly increases
the diversity and thus induces an effect on the biological activity of the particular
heterocycle.
There are a limited number of realistic chemical reactions; however, the diver-
sity of compounds is practically unlimited. Thus, several reactions are recurrent
throughout this chapter, some of them bearing an inherent propensity to serve as
diversity creators. Among them, cycloadditions, including Diels-Alder reactions and
1,3-dipolar additions, and iminium chemistry with subsequent nucleophilic addition
are transformations that are used frequently.
