A synthesis strategy yielding skeletally diverse small molecules combinatorially.
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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. |
Year of Publication | 2004
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Journal | J Am Chem Soc
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Volume | 126
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Issue | 43
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Pages | 14095-104
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Date Published | 2004 Nov 03
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ISSN | 0002-7863
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DOI | 10.1021/ja0457415
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PubMed ID | 15506774
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