Stereoselective synthesis of pentaseter analogs of didemnaketal A and B

ORGN 657

Xiaodong Fan, xfan@atherogenics.com, Medicinal Chemistry, AtheroGenics, Inc, 8995 Westside Parkway, Alpharetta, GA 30004 and Daniel H. Rich, dhrich@wisc.edu, School of Pharmacy & Department of Chemistry, University of Wisconsin-Madison, 7109 Rennebohm Hall, 777 Highland Ave, Madison, WI 53705.
The Didemnaketal A and B (1a,b) inhibit HIV protease with IC50s of 2 mM and 10 mM, respectively, and are early examples of HIV protease inhibitors that lack nitrogen. In the course of determining the key portion of these compounds that inhibits the protease, we have identified that the pentaester subunit (C1 to C11) interact with the HIV-1 protease (see, Fan, X., et al, J. Am. Chem. Soc. 1998, 120, 8893). We then developed an efficient stereoselective synthesis toward the analogs 2. Synthetic efforts toward the all eight diastereomers of analogs 2 will be presented.