Article Cite This: J. Org. Chem. 2018, 83, 8003−8010
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Palladium(II)-Catalyzed Reaction of Lawsones and Propargyl Carbonates: Construction of 2,3-Furanonaphthoquinones and Evaluation 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*,†,‡
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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, United States S 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 conditions. 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.
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INTRODUCTION Natural products have been a fundamental source for 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), and 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 remains an open question. Previously, the indoleamine 2,3-dioxygenase 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, a 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 the particular nature of inhibiting IDO1 deserves a deeper © 2018 American Chemical Society
Figure 1. (A) Reported quinones as potent IDO1 inhibitors. (B) FNQ derivative 1a was found to be a potential IDO1 inhibitor by our group (hIDO1 inhibitory IC50 = 1.01 ± 0.05 μM).
investigation, but the present synthesis research toward the FNQ skeleton is limited. Though two groups have reported the synthesis of 1a,6 both of these methods had several disadvantages (Figure 2). The first method (reported by Received: April 8, 2018 Published: June 8, 2018 8003
DOI: 10.1021/acs.joc.8b00872 J. Org. Chem. 2018, 83, 8003−8010
Article
The Journal of Organic Chemistry
The Claisen rearrangement has offered an effective approach for the synthesis of complex molecules as a powerful C−C bond-forming reaction after being first reported a century ago.13 In addition, propargyl carbonate derivatives are observed to be more active and sensitive with the presence of transition-metal catalyst and often serve as good substrates in a wide range of molecule construction.14 Therefore, with current protocols in hand and on the basis of prior work by our group,15 we tried to develop a one-pot Pd-catalyzed reaction utilizing propargyl carbonates through a Claisen rearrangement to establish FNQ derivatives and subsequently investigate the bioactivity of inhibiting IDO1.
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RESULTS AND DISCUSSION Initially, we investigated if 2-hydroxy-1,4-naphthoquinone (2) could be successfully converted to desired product (1a) when treated with tert-butyl-(2-methylbut-3-yn-2-yl) carbonate (3) in the presence of Pd(OAc)2, the oxidant Cu(OAc)2, and 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 conditions, the effect of temperature was first investigated. The yield was barely improved by raising the temperature (entries 2 and 3), and 25 °C is appropriate for 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 because of its good solubility under this condition (entries 4−7). Our attention was then paid to evaluate the effect of solvent, and the results emphasized the importance of solvent in these reactions (entries 8−10). When DMF was employed as a solvent, a significant increase of yield at 81% was observed.
Figure 2. Reported reactions of FNQs and our proposal.
Perez et al.6a) needs to be stirred under nitrogen for 24 h using Cs2CO3, CsI, and CuI as mediate. The 58.4% yield was quite general. The second method (reported by da Silva Emery et al.6b) employs CuI as catalyst, which still required a rigorous condition of refluxing for 24 h. In addition, both of these methods could be obtained only at a small scale (milligram level) and could not be applied for synthesizing the derivatives of 1a during our study for searching for a large substrate scope as IDO1 inhibitors. Because the present methods are imperfect and unsatisfactory for further investigation of FNQs as efficient IDO1 inhibitors, development of a facile, versatile, and mild approach is urgently needed. Table 1. Reaction Optimizationa
entry
catalyst
oxidant
base
solvent
temp (°C)
yieldb
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2 Pd2(dba)3 Pd(TFA)2 Pd(OAc)2 (5 mol %) Pd(OAc)2 Pd(OAc)2
Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Ag2O CuI K2S2O8 − Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2d Cu(OAc)2e
NaOAc NaOAc NaOAc Et3N NaOH K2CO3 − Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N
THF THF THF THF THF THF THF CH2Cl2 CH3CN DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF
25 40 55 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25
61 62 60 66 trace 11 NR 39 76 81 NR 37 NR NR trace trace trace 75c 61 49
a
Reaction conditions: 2a (1.0 mmol), 3a (5.0 mmol, 5.0 equiv), Pd catalyst (10.0 mol %), oxidant (2.0 equiv), and base (2.0 equiv) in solvent (15 mL) for 1 h under air. bIsolated yield. c3 h; NR = no reaction. d1.0 equiv. eCatalytic amount of 0.1 equiv. 8004
DOI: 10.1021/acs.joc.8b00872 J. Org. Chem. 2018, 83, 8003−8010
Article
The Journal of Organic Chemistry
Scheme 2. Substrate Scope of Propargyl Carbonatesa,b
When the reaction was run in the presence of other oxidants instead of Cu(OAc)2, no product and reduced yields of
