Improved synthesis of the C17-C25 fragment of the anti-tumor natural product Psymberin/Irciniastatin A

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Jef K. De Brabander, jdebra@biochem.swmed.edu1, Benjamin Pham, da0pham@yahoo.com2, and Xin Jiang1. (1) Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, (2) Department of Chemistry, Union University, 1050 Union University Drive, Jackson, TN 38305
A concise, flexible synthetic avenue was developed for the preparation of compounds with the structures related to those proposed for the novel marine-derived differential cytotoxins Psymberin and Irciniastatin A. These are effective human cancer and murine cell growth inhibitors (GI50 from 0.001 to < 0.0001 µg/mL). Our efforts led to their complete stereochemical assignment and the conclusion that Psymberin and Irciniastatin A are identical compounds. The retrosynthetic analysis envisioned joining three fragments to create the target molecule. Model reactions predicted an overall yield of 8.9%. During the synthesis of fragment C17-C25, our group was unable to remove the protecting PMB groups. By changing the protecting groups to benzoyl, a more efficient synthesis of the C17-C25 fragment (23.75% yield) was obtained. This intermediate was then successfully used in the total synthesis of the Psymberin natural product.