Silicon-Tethered Intramolecular [5+2] Oxidopyrylium-Based Cycloaddition and Reductive Cleavage of Ether Bridge: Synthetic Studies Toward Arteminolides

Abstract

Arteminolides A-D (1-4), natural triterpene lactones, were isolated from the leaves of Artemisia sylvatica Maxim and have been reported to be strong inhibitiors of farnesyltrnasferase (FTase) targeting members of the Ras superfamily of small GTP-binding proteins critical to cell cycle progression. Thus, arteminolides have displayed the tumor cell growth inhibition in a dose-dependent manner. In addition, arteminolide A (1) exhibited selective inhibition of recombinant rat FTase with no significant inhibition of rat squalene synthase or geranylgeranyltransferase (GGTase), and arteminolide C (3) blocked in vivo growth of human colon and lung tumor xenograft without the loss of body weight in nude mice. As well as the biological profile their structural complexity with the rigid ring skeleton could facilitate the study on the structure-activity relationships (SARs) with three dimensional information, which can direct new FTase inhibitor with high therapeutic value. Despite their favorable biological profile and intriguing structural complexity the success in the synthesis of arteminolides has not been reported since their first isolation in 1998. Due to identification of dehydromatricarin A (5) and arglabin diene (6), the biogenic synthesis of arteminolides are believed to be accomplished via Diels-Alder reaction between the two precursors (Scheme 1). Since the most logical precursors for the total synthesis of these natural products are the two biogenic precursors, we envisioned a common intermediate 9 which could offer the two precursors, 5 and 6, via Pauson-Khand reactions of 7 and 8, respectively. The intermediate 9 contains the silicon which could serve as surrogates for both hydroxyl group and hydrogen corresponding to C8-OH of 5 and C8'-H of 6, respectively, and was expected to be obtained through intramolecular [5+2] dipolar cycloaddition reaction of oxidopyrylium ylide. The silyl group would be stable under various reaction conditions and readily converted to the hydroxyl with the retention of the configuration. We previously found that base-mediated cleavage of the ether bridge in 7' (R = H, R' = PMB) afforded 11 in low yield (32%). In addition, attempts to oxidize alcohol 11 into ketone 12 under various reaction conditions for introduction of the exo methylene and methyl group at C10 and C10', respectively, resulted in ketone 12 with unacceptable low yields and, unexpectedly, TPAP oxidation produced a 1:1 mixture of ketone 12 and initial ether bridged 7'. These unfavorable results directed our efforts to prepare intermediate 13 possessing iodomethyl group which could allow to cleave the ether bridge using reductive deiodination, resulting in exo methylene (Scheme 2). The synthesis of 13 commenced with aldehyde 15 which was prepared by selective mono-silylation of 1,3-propanediol, followed by Swern oxidation. Coupling of 15 with lithiated furan 16 produced furanyl alcohol 17 in 60% yield, which was then converted to vinylsilyl ether 18 having necess-