Diversity-oriented synthesis of biaryl-containing medium rings using a one bead/one stock solution platform.
Diversity-oriented synthesis of structurally complex and diverse small molecules can be used as the first step in a process to explore cellular and organismal pathways. The success of this process is likely going to be dependent on advances in the synthesis of small molecules having natural product-like structures in an efficient and stereoselective manner. The development, scope, and mechanism of the oxidation of organocuprates was investigated and exploited in the atropdiastereoselective synthesis of biaryl-containing medium rings (9-, 10-, and 11-membered rings). The methodology was performed on high-capacity, large polystyrene beads by metalating aryl bromides with i-PrBu(2)MgLi, followed by transmetalating with CuCN x 2LiBr and then oxidizing with 1,3-dinitrobenzene, and was used in a diversity-oriented synthesis of biaryl-containing medium rings (library total theoretical maximum 1412 members). The high capacity beads were arrayed into 384-well plates and, using a process optimized during the development of a one bead/one stock solution technology platform, converted into arrays of stock solutions, with each stock solution containing largely one compound. These stock solutions were used in numerous phenotypic and protein-binding assays. The process described outlines a pathway that we feel will contribute to a comprehensive and systematic chemical approach to exploring biology (chemical genetics).
Spring
David R
DR
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Institute of Chemistry and Cell Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Krishnan
Shyam
S
Blackwell
Helen E
HE
Schreiber
Stuart L
SL
D000818:Animals; D017360:Arabidopsis / Q000187:drug effects; D018360:Crystallography, X-Ray; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis* / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D015027:Zebrafish / Q000196:embryology
D011084:Polycyclic Aromatic Hydrocarbons; D011083:Polycyclic Compounds