Diversity-Oriented Synthesis of Biaryl-Containing Medium Rings Using a One Bead/One Stock Solution Platform

• Published in: Journal of the American Chemical Society 2002-02, Vol.124 (7), p.1354-1363
• Main Authors: Spring, David R, Krishnan, Shyam, Blackwell, Helen E, Schreiber, Stuart L
• Format: Article
• Language: English
• Subjects: Animals; Arabidopsis - drug effects; Chemistry; Crystallography, X-Ray; Exact sciences and technology; Organic chemistry; Polycyclic Aromatic Hydrocarbons - chemical synthesis; Polycyclic Aromatic Hydrocarbons - pharmacology; Polycyclic Compounds - chemical synthesis; Polycyclic Compounds - pharmacology; Zebrafish - embryology
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja017248o

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-PrBu2MgLi, followed by transmetalating with CuCN·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).