Generating diverse skeletons of small molecules combinatorially.
Lack of efficient access to collections of synthetic compounds that have skeletal diversity is a key bottleneck in the small-molecule discovery process. We report a synthesis strategy that involves transforming substrates with different appendages that pre-encode skeletal information, named sigma elements, into products that have different skeletons with the use of common reaction conditions. With this approach, split-pool synthesis can be used to pre-encode skeletal diversity combinatorially and thereby generate such small molecules very efficiently. A split-pool synthesis of more than 1000 compounds produced overlapping, combinatorial matrices of molecular skeletons and appended building blocks in both enantiomeric and diastereomeric forms.
Burke
Martin D
MD
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Institute of Chemistry and Cell Biology, Harvard University, Cambridge, MA 02138, USA.
Berger
Eric M
EM
Schreiber
Stuart L
SL
D000107:Acetylation; D001557:Benzenesulfonates / Q000737:chemistry; D001974:Bromosuccinimide / Q000737:chemistry; D002625:Chemistry, Organic / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D005663:Furans / Q000737:chemistry*; D006900:Hydroxylation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013237:Stereoisomerism
D001557:Benzenesulfonates; D005663:Furans; D001974:Bromosuccinimide; C029501:4-toluenesulfonic acid