Biomedical Engineering Reference
In-Depth Information
DOMINO REACTIONS IN
LIBRARY SYNTHESIS
MATTHEW G. LAPORTE, JOHN R. GOODELL, SAMMI TSEGAY, AND
PETER WIPF
5.1
INTRODUCTION
Domino reactions have been defined by Tietze et al. as “sequences in which a bond
formation (or a bond-breaking process) is combined with the formation of a new
functionality” [1]. In the purest version of a domino sequence, the functionalities
would be prearranged for further transformations without the need for subsequent
reagents, catalysts, or altered conditions. There are many elegant examples in total
synthesis that satisfy these stipulations [2]. The arrival of diversity-oriented synthesis
(DOS) is providing a powerful further incentive for the invention of new domino
reactions. Concise new reaction methodologies leading to the rapid synthesis of
novel chemotypes are the most effective source of structurally and stereochemically
diverse libraries for biological screening. The use of domino processes can offer
several benefits (financial, atom efficiency, environmental) compared to multistep
syntheses containing discrete workups and product isolations [1].
In this chapter we utilize the domino reaction classification system put forth by
Tietze et al. [1]. A modified interpretation of this definition also allows for the inclu-
sion of consecutive conversion(s) without the necessity for isolation of intermediates
in the sequence [3]. The examples selected are categorized transformation-dependent
as either cationic, anionic, pericyclic, oxidative-reductive, transitionmetal-mediated,
or radical reactions. A total of 14 case studies are described, with the largest group
using the powerful Diels-Alder cycloaddition process.
