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Palladium(II)-Catalyzed Reaction of Lawsones and Propargyl Carbonates: Construction of 2,3-Furanonaphthoquinones and Evaluated as Potential Indoleamine 2,3-Dioxygenase Inhibitors Xi Feng, Xiaqiu Qiu, Huidan Huang, Jubo Wang, Xi Xu, Pengfei Xu, Ruijia Ge, Xiaojin Liu, Zhiyu Li, and Jinlei Bian J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00872 • Publication Date (Web): 08 Jun 2018 Downloaded from http://pubs.acs.org on June 8, 2018
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The Journal of Organic Chemistry
Palladium(II)-Catalyzed Reaction of Lawsones and Propargyl Carbonates: Construction of 2,3-Furanonaphthoquinones and Evaluated as Potential Indoleamine 2,3-Dioxygenase Inhibitors Xi Feng,†,‡ Xiaqiu Qiu,†,‡ Huidan Huang,║ Jubo Wang,†,‡ Xi Xu,†,‡ Pengfei Xu,†,‡ Ruijia Ge,§ Xiaojin Liu,‡ Zhiyu Li,*,†,‡ and Jinlei Bian*,†,‡ †
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China ‡
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
║
Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 210009, China
§
The Madeira School, 8328 Georgetown Pike McLean, Virginia 221022 Supporting information
ABSTRACT: An efficient reaction utilizing propargyl carbonates through Claisen rearrangement to synthesize furanonaphthoquinones is described. The remarkable transformation exhibits excellent functional group tolerance, affording the target furanonaphthoquinones in moderate to good yields (41-85%) under mild reaction condition. Scaled up preparation of the model product can make this reaction a method of choice for synthesis of furanonaphthoquinone derivatives. The resulting furanonaphthoquinones were evaluated as potential indoleamine 2,3-dioxygenase inhibitors in vitro.
INTRODUCTION
Natural products have been a fundamental source in discovering novel scaffolds as lead compounds in pharmaceutical research. Quinone chromophores are important structure units that can be found in many active natural ingredients, which can undergo many important biological transformations and received significant attention for decades.1 A series of quinone derivatives based on unique conjugated cyclic dione structures have been uncovered and investigated including benzoquinones, naphthoquinones(NQs), anthraquinones. Favorable biological activities of these natural quinone products are widely employed in many fields.2, 3 Though quinones, naphthoquinones especially, are certified to be capable of possessing antitumor efficacy,3 the exact mode of action still remain an open question. Previously, the indoleamine 2,3dioxygenase 1 (IDO1) has been identified as a potential biological target for several quinone derivatives (Figure 1). IDO1 has been developed as an efficient and attractive target in cancer immunotherapy and showed potential druggability in recent years.4 Inhibitors of IDO1 have potential as anticancer drugs and the first compound in this class is now entering the clinic.4, 5 Furanonaphthoquinones (FNQs) belong to a class of naphthoquinone derivatives, and in our preliminary study, an FNQ derivative 1a was found to be a potential IDO1 inhibitor (IC50= 1.01 ± 0.05 μM, equally potent with the inhibitors listed in Figure 1) as a result of screening natural products as IDO1 inhibitors. The obtained FNQ derivative 1a with particular nature of inhibiting IDO1 deserves a
deeper investigation but the present synthesis research toward FNQ skeleton is limited. Though two groups have reported the synthesis of 1a,6 both of these methods existed several disadvantages (Figure 2). The first method (reported by Perez6a) needs stirred under nitrogen for 24 hours using Cs2CO3, CsI and CuI as mediate. The 58.4% yield was quite general. The second method (reported by Emery6b) employs CuI as catalyst which still required a rigorous condition of refluxing for 24 h. In addition, both of these methods could only be obtained at a small scale (milligram level) and could not be applied for synthesizing the derivatives of 1a during our study for searching a large substrate scope as IDO1 inhibitors. Due to the present methods are imperfect and unsatisfied for further investigation of FNQs as efficient IDO1 inhibitors, a facile, versatile and mild approach is urgent to be developed.
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Figure 1. (A) Reported quinones as potent IDO1 inhibitors. (B) an FNQ derivative 1a was found to be a potential IDO1 inhibitor by our group (hIDO1 inhibitory IC50 = 1.01 ± 0.05 μM).
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Initially, we investigated that 2-hydroxy-1,4naphthoquinone (2) could be successfully converted to desired product (1a) when treated with tert-butyl-(2methylbut-3-yn-2-yl) carbonate (3) in the presence of Pd(OAc)2, the oxidant Cu(OAc)2, the base NaOAc in THF at room temperature for 1 h with a tolerable yield of 61% (Table 1, entry 1). To optimize the reaction condition, the effect of temperature was first investigated. The yield was barely improved by raising the temperature (entries 2-3) and 25 oC is appropriate to carry this reaction. We then focused on investigating the effect of base, and triethylamine was found to be the best one for the reaction among the tested bases (entries 4-7), probably due to its good solubility under this condition (entries 4-7). Our attention was then paid to evaluate the effect of solvent, the results emphasized the importance of solvent in these reactions (entries 8-10). When employing DMF as solvent, a significant increase of yield at 81% was observed. When the reaction was run in the presence of other oxidants instead of Cu(OAc)2, no product and reduced yields of
