Reference 1: Appendino, G.; Tron, G. C.; Cravotto, G.; Palmisano, G.; Annunziata, R.; Baj, G.; Surico, N. Eur. J. Org. Chem. 1999, 12, 3413-3420.

Synthesis of Modified Ingenol Esters

This research paper is concerned with the synthesis of ingenol derivatives. Ingenol has shown has shown capabilities to inhibit protein kinase C (PKC) which is a target of tumor-promoting ester. The paper addressed the possibility of replacing the 20-ester linkage of ingenol 3,20-dibenzoate, which was the first ingenol derivative in which anticancer activity was shown. The research group developed a way to prepare C-20 modified analogues of ingenols by manipulating the polyhydroxylated4 lower region of ingenol. This finding is significant as this synthesis can give a way to look at cytotoxicity and tumor-promoting activities of PKC related molecules. This research paper observes vinylogous retro-pinacol process in order to attach the methoxide group onto the C-2 (as noted in the diagram below). Our paper used their acidic degradation of ingenol in order to synthesize 18 from 17. Instead of attacking C-2 in the molecule, our original paper uses this synthesis to explain the reverse reaction to get a derivative of ingenol.

Reference 2: Cha, J. K.; Epstein, O. L. Tetrahedron 2006, 62, 1329-1343.

Synthetic approaches to ingenol

This group was interested in ingenol and similar compounds as biological activities of molecules similar to ingenol have not been widely studied, but isolations and derivatives from the ingenol have indicated wide functions from tumor promoting agents to anti-HIV activity. This research group synthesized phorbol, which is also an isolated product from a plant and is similar to ingenol, based on the intermediate provided by Wender, and also reviewed a number of synthesis methods for ingenol. The synthesis of ingenol is difficult due to the highly strained topography of related compounds, and thus the paper saw that there were many maneuvers that were used to stereoselectively add the substituents. The challenges of synthesizing phorbol came from the high degree of oxygenation and the double bonds, and the paper states that future studies should be done on this topic. The paper cited the original citation for the percent yield provided by vinylogous retro-pinacol rearrangement of the ingenol with aqueous HClO4.

Reference 3: Liang, X.; Grue-Sorensen, G.; Mansson, K.; Vedso, P.; Anke, S.; Stahlhut, M.; Bertelsen, M.; Engell, K. M.; Hogberg, T. Bioorg. Med. Chem. Lett. 2013, 23, 5624-5629.

Syntheses, biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer

In this paper, the cool paper was used to “inspire” the synthesis of the fluoro-analogue, which is used in the synthese of ingenol mebutate. Because of the information provided by reference 1, Liang et al. were able to perform a selective acetylation of the primary alcohol to create molecule 12. From 12, they performed a treatment of diethylaminosulfur trifluoride and acetyl group removal to create molecule 13. Also, during this experiment, a 20-O methyl ether of ingenol mebutate was created which did not have any “oxidative bursts and cytonkine release activity”. Using this first reference paper they were able to confirm that free 20-OHs are capable of engaging in hydrogen bonding.

Reference 4: Vasas, A.; Rédei, D.; Csupor, D.; Molnár, J.; Hohmann, J. Eur. J. Org. Chem. 2012, 2012, 5115-5130.

Diterpenes from European Euphorbia Species Serving as Prototypes for Natural-Product-Based Drug Discovery

Plants of the Euphorbiaceae family are of interest to scientists in search of natural products to produce drugs. Specifically, diterpenes offer a wide range of biological activities and various structural forms which make it the target of many scientists looking to synthesize natural drugs. Additionally, ingenol 3-angelate, a natural product of this form, has been approved by the FDA for the treatment of actinic keratosis and now serves as a prototype for natural product-based drug discovery.