Efficient synthesis of achiral seco-hydroxy-cyclopropylbenz[e]indolone (CBI) and seco-amino-CBI analogs of the duocarmycins

ORGN 446

Atsushi Sato1, Adrienne Scott1, Toni Brown2, and Moses Lee, lee@hope.edu2. (1) Chemistry, Furman University, 3300 Poinsett Hwy, Greenville, SC 29613, (2) Department of Chemistry, Hope College, Natural Sciences Division, 35E. 12th. Street, Holland, MI 49422
(+)-CC-1065 and (+)-duocarmycins are natural products that exhibit potent anticancer activity. They derive their biological activity through covalent bonding with adenine-N3 in the minor groove of AT-rich sequences of DNA. Our group has recently developed a novel class of duocarmycin analogs that are devoid of a chiral center. The achiral seco-hydroxycyclopropylbenzoindoline (seco-hydroxy-CBI) analogs and its amino-counterparts (seco-amino-CBI) were designed, and they were found to exhibit potent anticancer activity in xenograft studies. The synthetic strategies for the preparation of these achiral compounds were long and the yields were modest. In this presentation, we will report significant improvements to the synthesis of these compounds. In the case for seco-hydroxy-CBI, a different strategy involving an Emmons-Horner reaction was developed.
 

Total Synthesis of Complex Molecules
8:00 AM-12:00 PM, Wednesday, 29 March 2006 Georgia World Congress Center -- C301, Oral

Division of Organic Chemistry

The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006