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Science 24 October 2003:
Vol. 302. no. 5645, pp. 613 - 618
DOI: 10.1126/science.1089946
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Reports

Generating Diverse Skeletons of Small Molecules Combinatorially

Martin D. Burke, Eric M. Berger, Stuart L. Schreiber*

Lack of efficient access to collections of synthetic compounds that have skeletal diversity is a key bottleneck in the small-molecule discovery process. We report a synthesis strategy that involves transforming substrates with different appendages that pre-encode skeletal information, named {sigma} elements, into products that have different skeletons with the use of common reaction conditions. With this approach, split-pool synthesis can be used to pre-encode skeletal diversity combinatorially and thereby generate such small molecules very efficiently. A split-pool synthesis of more than 1000 compounds produced overlapping, combinatorial matrices of molecular skeletons and appended building blocks in both enantiomeric and diastereomeric forms.

Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Institute of Chemistry and Cell Biology, Harvard University, Cambridge, MA 02138, USA.

* To whom correspondence should be addressed. E-mail: sls{at}slsiris.harvard.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)