ABSOLUTE STEREOCHEMISTRY AND TOTAL SYNTHETIC STUDIES OF PSOROSPERMIN, AN ANTITUMOR XANTHONE FROM PSOROSPERMUM FEBRIFUGUM (EPOXYROTENONE, X-RAY ANALYSIS, STEREOSELECTIVE SYNTHESIS)

DAVID KEI-KUNG HO, Purdue University

Abstract

Psorospermin, a novel xanthone from Psorospermum febrifugum (Guttiferae), showed antitumor activities in the 9KB cell culture and the P388 mouse leukemia systems. Also isolated from the same plant are closely-related bioactive xanthones, namely 3',4'-deoxypsorospermin, 3',4'-deoxypsorospermin-3',4'-diol, and 3',4'-deoxypsorospermin-4'-chloro-3'-ol. Therefore the purposes of our investigation were to assign the absolute stereochemistry of these compounds, design a stereoselective synthetic pathway leading to psorospermin, and study the structure-activity relationships in this series. By ORD and ('1)H-NMR studies which employed epoxyrotenones and epoxytubaic acids, the relative configuration of psorospermin and related xanthones were assigned. X-ray analysis of crystals of one of the diastereomeric epoxyrotenone and chemical correlations led to assignment of the absolute stereochemistry of psorospermin as 2'R,3'R, deoxypsorospermin as 2'R, the diol as 2'R,3'R, and the chlorohydrin as 2'R,3'S. By retrosynthetic analysis, it was proposed that the epoxydihydrofuran system of psorospermin may be constructed in a concerted fashion from a properly functionalized phenol. Thus, (+)-2'R,3'S-psorospermin methyl ether was chosen as the synthetic target to investigate this chemistry. The first key step was the ortho-Claisen rearrangement leading to the 4-allyl-substituted xanthone. The next crucial step was the Wittig reaction resulting in an E-allylic ester that was reduced to an E-allylic alcohol. Epoxidation and other transformation produced the functionalized phenol that was cyclized to give (+)-2'R,3'S-psorospermin methyl ether. Our structure-activity relationship study showed that an epoxide was essential to biological activity.

Degree

Ph.D.

Subject Area

Organic chemistry

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