Exploiting the Facile Release of Trifluoroacetate for the α-Methylenation of the Sterically Hindered Carbonyl Groups on (+)-Sclareolide and (−)-Eburnamonine

Abstract

An efficient method for the α-methylenation of carbonyl groups is reported, and this transformation is accomplished by a facile elimination of trifluoroacetate during the formation of the olefin. This method represents an improvement beyond existing protocol in cases of steric hindrance, and we have demonstrated the utility of the process across a series of ketones, lactams, and lactones. Additionally, we have applied this method to produce semisynthetic derivatives of the natural products (+)-sclareolide and (-)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is also provided from a time course of (19)F NMR. Biological evaluation of the natural-product-derived enones led to the identification of a derivative of (-)-eburnamonine with significant cytotoxicity (LC(50) = 14.12 μM) in drug-resistant MDA-MB-231 breast cancer cells.

15‐Methylene‐Eburnamonine Kills Leukemic Stem Cells and Reduces Engraftment in a Humanized Bone Marrow Xenograft Mouse Model of Leukemia

“…20 Subsequent studies showed that this functional group is not only required for activity but also susceptible to conjugation by reactive thiols. 21 In a similar fashion, this functional group imparts biological activity to another natural product, parthenolide ( 4 ), and this compound has been shown to eliminate LSCs by increasing intracellular reactive oxygen species (ROS) 8 and depleting intracellular glutathione levels.…”

“…19 Recently, we designed and synthesized (−)-15-methylene-eburnamonine ( 3 ) to impart antiproliferative activity through structural modification. 20 Specifically, the analogue 3 displays a critical enone group, 21 and this functional group imparts cytotoxic properties similar to other enone-bearing natural products, such as parthenolide ( 4 ) 22 and andrographolide ( 5 ). 23 Additionally, 3 was shown to exert antiproliferative activity against human multiple myeloma, breast, and prostate cancer cell lines in vitro.…”

Cleaving Carbon-Carbon Bonds by the Release of Trifluoroacetate to Remodel Molecules and Assemble Fluorinated Structures

“…Recent developments in the release of trifluoroacetate present an additional protocol to break C-C bonds and generate reactive intermediates for synthesis. 3,18,20 Generally, it displays a high tolerance for organic functional groups as well as sensitive substrates. The future possibilities for expanding the role of trifluoroacetate release in synthesis will lie in the incorporation of transition metals and identifying additional substrates, fluorinated and nonfluorinated, that participate in this process.…”

“…20 Specifically α-methylenation was accomplished through a detrifluoroacetylative olefination that is fully compatible with ketones, lactones, and lactams (Scheme 8). This strategy was especially useful when existing olefination reactions fail due to the presence of proximal steric congestion.…”

Synthesis of 15-methylene-eburnamonine from (+)-vincamine, evaluation of anticancer activity, and investigation of mechanism of action by quantitative NMR

“…5 In 2011, Colby and co-workers synthesized 15-methylene-eburnamonine ( 4 ) by using an α-methylenation strategy that is promoted by the release of trifluoroacetate (Scheme 1). 19 Analogue 4 displays antiproliferative activity in HL-60 (human leukemia) and cytotoxicity in MDA-MB-231 (breast cancer) cells (LC 50 = 14.1 μM); however, the parent natural product 2 is nearly inactive in both cell lines. Even though the conversion of eburnamonine 2 into 15-methylene-eburnamonine 4 was accomplished in two steps, the yield was quite low (i.e., 28%).…”