Scientific Publications

A synthesis strategy yielding skeletally diverse small molecules combinatorially.

Publication TypeJournal Article
AuthorsBurke, MD, Berger EM, and Schreiber SL
AbstractThe efficient synthesis of small molecules having many molecular skeletons is an unsolved problem in diversity-oriented synthesis (DOS). We describe the development and application of a synthesis strategy that uses common reaction conditions to transform a collection of similar substrates into a collection of products having distinct molecular skeletons. The substrates have different appendages that pre-encode skeletal information, called sigma-elements. This approach is analogous to the natural process of protein folding in which different primary sequences of amino acids are transformed into macromolecules having distinct three-dimensional structures under common folding conditions. Like sigma-elements, the amino acid sequences pre-encode structural information. An advantage of using folding processes to generate skeletal diversity in DOS is that skeletal information can be pre-encoded into substrates in a combinatorial fashion, similar to the way protein structural information is pre-encoded combinatorially in polypeptide sequences, thus making it possible to generate skeletal diversity in an efficient manner. This efficiency was realized in the context of a fully encoded, split-pool synthesis of approximately 1260 compounds potentially representing all possible combinations of building block, stereochemical, and skeletal diversity elements.
Year of Publication2004
JournalJournal of the American Chemical Society
Volume126
Issue43
Pages14095-104
Date Published (YYYY/MM/DD)2004/11/03
ISSN Number0002-7863
DOI10.1021/ja0457415
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/15506774?dopt=Abstract