Studies towards the synthesis of the Grb2-SH2 domain antagonist 8-O-methylsclerotiorinamine

ORGN 861

Daniel M. Bruggemeyer, bruggs@bu.edu1, Jianglong Zhu, zjl@bu.edu1, Andrew R. Germain, germain@bu.edu1, Cédric Genet, cedricgenet@yahoo.fr2, Peter O'Brien, paob1@york.ac.uk2, and John A. Porco Jr., porco@bu.edu1. (1) Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 24 Cummington Street, Boston, MA 02215, (2) Department of Chemistry, University of York, Heslington, York, YO10 5DD, United Kingdom
The development of Grb2-SH2 domain binding antagonists has important implications in the treatment of various diseases, including human cancers. As a result of screening the fermentation broth of Penicillium multicolor, 8-O-methylsclerotiorinamine (Figure 1) was found to significantly inhibit binding between the Grb2-SH2 domain and [3H]-phosphopeptide derived from Shc as well as inhibit the Grb2-Shc interactions in cell-based experiments. Herein, we report our approach towards the synthesis of 8-O-methylsclerotiorinamine featuring copper-mediated enantioselective oxidative dearomatization as a key step.

 

Total Synthesis of Complex Molecules
8:00 AM-12:00 PM, Thursday, 14 September 2006 Moscone Center -- Room 134, Oral

Division of Organic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006