A synthesis strategy for generating diverse skeletons of small molecules combinatorially

Abstract

Lack of efficient access to collections of synthetic compounds having skeletal diversity is a key bottleneck in the small-molecule discovery process. This thesis comprises the development and application of a potentially general synthesis strategy that involves transforming substrates having different appendages that pre-encode skeletal information, named σ-elements, into products having different skeletons using common reaction conditions. With this approach, split-pool synthesis can be used to pre-encode skeletal information combinatorially, and thereby generate small molecules having distinct skeletons efficiently. This was demonstrated with the split-pool synthesis of ∼1260 compounds representing overlapping, combinatorial matrices of molecular skeletons and appended building blocks in both enantiomeric and diastereomeric forms.*

*Please refer to dissertation for diagrams.