A synthesis strategy yielding skeletally diverse small molecules combinatorially

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

Research output: Contribution to journalArticlepeer-review


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 σ-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 σ-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 ∼1260 compounds potentially representing all possible combinations of building block, stereochemical, and skeletal diversity elements.

Original languageEnglish (US)
Pages (from-to)14095-14104
Number of pages10
JournalJournal of the American Chemical Society
Issue number43
StatePublished - Nov 3 2004
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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