A synthesis strategy yielding skeletally diverse small molecules combinatorially.
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.
Burke
Martin D
MD
Broad Institute of Harvard and MIT, Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Berger
Eric M
EM
Schreiber
Stuart L
SL
D002625:Chemistry, Organic / Q000379:methods*; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D005663:Furans / Q000737:chemistry*
D005663:Furans