1. Potential For Naphthylisoquinoline Alkaloids Synthesis Via
Thiolate Demethylation and Benzylation
Eunice Hernandez, Chemical Engineering
Mentor: James Fennewald, PI: Dr. Bruce Lipshutz
Department of Chemistry and Biochemistry
Abstract
2. Benzylation
Methods
1)Bringmann, Gerhard, Barbara Hertlein-Amslinger, Inga Kajahn, Michael Dreyer, Reto Brun, Heidrun Moll,
August Stich, Karine Ndjoko Ioset, Werner Schmitz, and Luu Hoang Ngoc. "Phenolic Analogs of the N,C-
coupled Naphthylisoquinoline Alkaloid Ancistrocladinium A, from Ancistrocladus Cochinchinensis
(Ancistrocladaceae), with Improved Antiprotozoal Activities." Phytochemistry 72.1 (2011): 89-93. Print
2) Anh, Nguyen Hoang, Andrea Porzel, Helmut Ripperger, Gerhard Bringmann, Manuela Schäffer, Ralf God,
Tran Van Sung, and Günter Adam. "Naphthylisoquinoline Alkaloids from Ancistrocladus Cochinchinensis."
Phytochemistry 45.6 (1997): 1287-291. Print.
3) Tang, Chun Ping, Yi Ping Yang, Yi Zhong, Qiong-Xing Zhong, Hou-Ming Wu, and Yang Ye. "Four New
Naphthylisoquinoline Alkaloids from Ancistrocladus Tectorius." 63.10 (2000): 1384-387. Print.
4)Substituted Isoindoles as Bace Inhibitors. Astrazeneca AB, assignee. Patent WO2012/90219 A2. 2007.
Print.
The naphthylisoquinoline family of natural products exhibit antifungal, antimalarial, and antiviral activities,2 while 140 naphthylisoquinoline alkaloids have been
identified, only a select few have been isolated from Ancistrocladus cochinchinensis.1 This plant has been used in folk medicine as a diuretic, antifebrile, and
antiphlogistic, indicating that these alkaloids are promising candidates for medicinal applications. The pharmaceutical industry is always seeking a wider selection of
treatments for specific malarial and viral infections.3 A convergent synthesis of 4’-O demethylhamatine will facilitate the preparation of naturally occurring
napthylisoquinoline alkaloids, and synthetic derivatives for medicinal screening. The preliminary step in the total synthesis begins with the mono demethylation of 1-
chloro-3, 5-dimethoxybenzene. Demethylation provides the precursor needed for the secondary step, benzylation. Though several approaches to the mono-
demethylation of bismethoxy-benzenes have been reported, the conditions often lead to bis-demethylated products. The focus of this work is to evaluate these known
strategies and determine the optimum conditions for preparation of the key intermediate, 3-chloro-5-methoxyphenol.
1. Demethylation
Entry Thiolate Base %Yield
1. i-PrSNa N/A 21%
2. EtSNa K2CO3 No RxN
3. EtSNa N/A No RxN
4. MeSNa K2CO3 No RxN
5. MeSNa N/A 78%
by NMR
Conclusion
Discussion
References
Acknowledgments
A special thanks to James Fennewald, for his contribution and guidance this summer.
All the graduate students in the Lipshutz group for their assistance in this research
project because no question was ever a incorrect question. In addition, our super
mentor Sam Helmy was tremendously helpful this summer, his door was always open
for any questions.
This project was partially supported by the LSAMP program of the National Science
Foundation under Award no. DMR-1102531 and by the MRSEC Program of the National
Science Foundation under Award No. DMR- 1121053
The methodology screening demonstrated distinct behaviors whose
results varied for each reaction. Each reaction utilized one of three
thiolates; 1) sodium ethylthiolate; 2) sodium methylthiolate; and 3)
sodium iso-propylthiolate. Potassium carbonate was added to ensure no
any thiol present is converted to the thiolate in-situ. The added base
revealed no conversion of the starting material, 1-chloro-3, 5
dimethoxybenzene, to product, as shown in entries 2 and 4. Entry1,
sodium iso-propylthiolate, proved to form the expected product with an
isolated yield of 21%. Entry 5 utilized a literature procedure using
sodium methylthiolate4 with a 78% yield by NMR. Sodium
methylthiolate proved to be the most successful because of its lack of
steric hindrance in comparison to the ethyl and isopropyl substituted
thiolates. The benzylation reaction obtained a product yield of 11%, a
challenge in separation of the two products led to the loss of the final
product, 1-(benzyloxy)-3-chloro-5-methoxybenzene.
Demethylation and benzylation were the primary focus this summer. Of
the three different thiolates tested, sodium methylthiolate (Entry 5)
proved to be most effective candidate for demethylation. Reaction
conditions are currently still being examined to maximize product yield.
In addition, the benzylation reaction is also currently being investigated
and undergoing different test that will ensure maximum product yield.
Demethylation and benzylation are key steps to ensure a successful
synthesis of naturally occurring naphthylisoquinoline alkaloids.