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Journal of the American Chemical Society DOI:10.1021/ja0457415

A synthesis strategy yielding skeletally diverse small molecules combinatorially.

Publication TypeJournal Article
Year of Publication2004
AuthorsBurke, MD, Berger, EM, Schreiber, SL
JournalJournal of the American Chemical Society
Volume126
Issue43
Pages14095-104
Date Published2004/11/03
ISSN0002-7863
Abstract

The 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.

URLhttp://dx.doi.org/10.1021/ja0457415
DOI10.1021/ja0457415
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/15506774?dopt=Abstract