Total Syntheses of (+)-1893B and Its Three Diastereomers and Evaluation of Their Biological Activities

Abstract

The total syntheses of natural (ϩ)-1893B (2) and three other diastereomers 14, 18, and 21 were accomplished. Starting from the sequential metathesis product 5 prepared in turn from a 7-oxanorbornene derivative (ϩ)-4, 2 was synthesized by means of an epoxyring opening of 9a with trimethylsilylacetylide followed by Wacker-type oxidation of the resulting alkyne 10 for the construction of the g-lactone moiety. By applying the same synthetic sequence, three additional diastereomers of 2, 14, 18, and 21 were also synthesized. The biological activities of previously synthesized 1893A (1), 1893B (2), and the diastereomers of 1893B 14, 18, and 21 were investigated. Introduction1893A (1) and 1893B (2) were isolated in 2003 during the course of antitumor natural products searching from a marine endophytic fungus designated as No. 1893, which exists in mangroves (Fig. 1) [1]. Lin and Chen reported that the extract mixture of No. 1893 appeared to exhibit cytotoxic and insecticidal activities. However, the biological activity of the pure metabolites 1 and 2 has not reported. The structure of 1 was elucidated by extensive spectroscopic studies and finally determined by X-ray crystallographic analysis. As structurally related natural product, (ϩ)-mycoepoxydiene (3) was isolated in 1999 [2,3]. We already reported the total syntheses of 1 and 3, which were characterized by a sequential ringopening/cross/ring-closing metathesis strategy [4,5]. Although the stereostructures of 1 and 3 were confirmed by our synthetic studies, the stereochemistry of 2 was not unambiguously established at that time. Later, we were concerned with the stereochemically defined total synthesis of 2 through the total syntheses of all four possible stereoisomers regarding the vicinal diol moiety in 2. The first total synthesis of natural (ϩ)-2 was reported as a preliminary communication [6]. Herein, we describe in detail the total syntheses of 2 and three additional diastereomers. The evaluation of their biological activities is also presented. Results and DiscussionAccording to our previous report [5], we converted the enantioenriched 7-oxanorbornene derivative (ϩ)-4 (Ͼ95% ee) into the cyclooctadiene 5 through a one-pot ring-expansion metathesis strategy (Scheme 1). The