Short synthesis of skeletally and stereochemically diverse small molecules by coupling petasis condensation reactions to cyclization reactions.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.Angewandte Chemie International Edition (Impact Factor: 13.73). 06/2006; 45(22):3635-8. DOI:10.1002/anie.200600497
- Chemical Reviews 04/2002; 102(3):813-34. · 41.30 Impact Factor
- Organic & Biomolecular Chemistry 02/2003; 1(2):215-36. · 3.57 Impact Factor
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ABSTRACT: Systematic and quantitative measurements of the roles of stereochemistry and skeleton-dependent conformational restriction were made using multidimensional screening. We first used diversity-oriented synthesis to synthesize the same number (122) of [10.4.0] bicyclic products (B) and their corresponding monocyclic precursors (M). We measured the ability of these compounds to modulate a broad swath of biology using 40 parallel cell-based assays. We analyzed the results using statistical methods that revealed illuminating relationships between stereochemistry, ring number, and assay outcomes. Conformational restriction by ring-closing metathesis increased the specificity of responses among active compounds and was the dominant factor in global activity patterns. Hierarchical clustering also revealed that stereochemistry was a second dominant factor; whereas the stereochemistry of macrocyclic appendages was a determinant for bicyclic compounds, the stereochemistry of the carbohydrates was a determinant for the monocyclic compounds of global activity patterns. These studies illustrate a quantitative method for measuring stereochemical and skeletal diversity of small molecules and their cellular consequences.Journal of the American Chemical Society 11/2004; 126(45):14740-5. · 10.68 Impact Factor
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