Chemo- and Regioselective Functionalization of Nortrilobolide: Application for Semisynthesis of the Natural Product 2-Acetoxytrilobolide

Abstract

The difference in reactivity of the hexaoxygenated natural product thapsigargin (1) and the pentaoxygenated nortrilobolide (3) was compared in order to develop a chemo- and regioselective method for the conversion of nortrilobolide (3) into the natural product 2-acetoxytrilobolide (4). For the first time, a stereoselective synthesis of 2-acetoxytrilobolide (4) is described, which involves two key reactions: the first chemical step was a one-pot substitution-oxidation reaction of an allylic ester into its corresponding α,β-unsaturated ketone. The second process consisted of a stereoselective α'-acyloxylation of the key intermediate α,β-unsaturated ketone to afford its corresponding acetoxyketone, which was converted into 2-acetoxytrilobolide (4) in a few steps. This innovative approach would allow the synthesis of a broad library of novel and valuable penta- and hexaoxygenated guaianolides as potential anticancer agents.

Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8-O-(12-Aminododecanoyl)-8-O-Debutanoylthapsigargin

“…The key step of Tb transformation to 12ADT (7) is the insertion of an octanoyl moiety to the C-2 position of the Tb skeleton ( Figure 1A). This was achieved via ketone 1, in which H-2 is activated [26,27] (Scheme 1a). This reaction path involves the selective removal of the angeloyl moiety (Ang) from O-3 and subsequent oxidation of the formed alcohol.…”

“…This reaction path involves the selective removal of the angeloyl moiety (Ang) from O-3 and subsequent oxidation of the formed alcohol. A similar reaction was performed with nTb [26,27]. In situ oxidation of the intermediate alcohol prevents degradation of labile 3-O-desangelyl-Tb.…”

“…The NMR spectra of the product revealed that no further purification was needed. The acylation precursor Boc-N-12-aminododecanoic acid (7.1 g, 22.5 mmol) was obtained as a white solid at 97% yield (in [27], the yield was 93%). Figure S9B.…”

“…In terms of total synthesis, firstly, the number of steps in the published methods for the total synthesis of Tg preclude their use for commercial production, and, secondly, the total yields are rather poor [24,25]. Another option is to take advantage of the published procedure for converting nortrilobolide (nTb) into Tg [26,27]. Here, we describe a procedure for transforming Tb into the cytotoxin in the prodrug mipsagargin, 8-O-(12-aminododecanoyl)-8-O-debutanlyothapsigargin in gram scale.…”

Use of a temporary immersion bioreactor system for the sustainable production of thapsigargin in shoot cultures of Thapsia garganica

“…The combination of the treatment and the TIB cultivation can provide a sustainable and viable production of thapsigargin and nortrilobolide. Additionally, nortrilobolide can easily be converted into thapsigargin or other relevant drug precursors by a 3-step chemical synthesis [ 52 ].…”