Biomedical Engineering Reference
In-Depth Information
CYCLOADDITION REACTIONS IN
DIVERSITY-ORIENTED SYNTHESIS
GIOVANNI MUNCIPINTO
3.1
INTRODUCTION
Cycloaddition reactions are fundamental processes in organic chemistry, as they are
among the most powerful methodologies that can be used to provide rapid access to
natural and unnatural compounds of medicinal interest. Their ability to provide cyclic
and heterocyclic compounds with a high degree of structural complexity and skeletal
and stereochemical diversity have made cycloaddition reactions some of the most use-
ful and widely utilized reactions in diversity-oriented synthesis (DOS) [1]. Large and
unexploited regions of chemical space need to be addressed to increase the chances
of succeeding in drug discovery and to take advantage of the extraordinary insights
made by genomics in understanding the biological causes underlying human diseases
[2]. Recently, there has been a growing consensus that the crucial factor for drug dis-
covery success is not library size but a library's structural diversity [3]. DOS aims to
generate such structural diversity in an efficient manner. It is therefore not surprising
that most papers in the early days of DOS reported cycloaddition reactions as tools to
access structurally complex and diverse polyheterocyclic systems, frameworks that
are also present in biologically relevant natural products. Diels-Alder and 1,3-dipolar
cycloaddition reactions represent the ideal reactions for this purpose. In fact, a large
number of DOS publications report them as pairing reactions of strategically placed
appendages in building blocks. In the build/couple/pair strategy [4], cycloaddition
reactions have been used both as diversity-generating reactions (same
diverse) and
 
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