b School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China;
c Pharmacy, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China;
d State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Flavones are a class of natural products widely distributed in different plants with a wide range of biological activities [1, 2, 3, 4]. The different substituents on the basic skeleton contributed to their different biological activities (Fig. 1). The most common substituent on the skeleton is hydroxyl or alkoxy groups. In some flavones, the benzyl group is directly connected to the skeleton,such as compounds a-h (Fig. 1) [5, 6, 7, 8]. These types of compounds are rare in nature,while some of which have interesting biological activities,e.g.,compound h exhibited multidrug resistance reversal effects on the human tumor cell lines . The introduction of a benzyl group to the flavone backbone of luteolin (compounds 8 and 9 in Fig. 1) was found previously by us to significantly increase its activity to bind with Bcl-2 protein and induce apoptosis of tumor cells . Therefore,the benzyl-substituted flavone compounds are a structural type worthy of further study.
The rearrangement reaction of benzyl groups can be observed in the debenzylation of aryl benzyl ethers,and the related reactions observed in previous reports are mainly involving simple aromatic compounds and aromatic amino compounds [10, 11]. Recently,this reaction was successfully used by the Seoane group and us to totally synthesize benzyl-substituted flavone compounds and benzyl-substituted flavanone compounds [9, 12]. Compared to the methods used previously [13, 14, 15, 16],the method using this rearrangement reaction offers simple protocols and high yields.
In this paper,the total synthesis of benzyl-substituted flavone derivatives via the acidic rearrangement of benzyl groups in flavone benzyl ethers was reported. Complicated regioselectivity during the rearrangement of benzyl groups was observed. Then the factors that determine the regioselectivity of benzyl groups during this reaction were discussed.2. Experimental
Using luteolin as an example,a benzyl group was tried to be introduced to the flavone ring B and ring A. The method of the oxidative cyclization of 2'-hydroxychalcone was selected to build the flavone skeleton [1, 17]. The method with trifluoroacetic acid or methylsulfonic acid under heat-refluxing conditions of the rearrangement reaction of the benzyl group was selected [12, 18, 19, 20]. However,this method required a long reaction time—at least 48 h. Thus,we applied microwaves and found that it significantly shortened the reaction time to less than 30 min. The detailed synthetic route is shown in Scheme 1. Detail materials and methods and the spectra of the products were listed in Supporting information.
|Scheme 1.Synthetic route I and II of benzyl-substituted flavone compounds. Reagents and conditions: a: DMS, K2CO3, acetone, r.t.; b: benzyl chloride, K2CO3, DMF, reflux; c: 50% KOH, CH3OH, r.t.; d: I2, pyridine, reflux; e: MSA, CHCl3, microwave; f: BBr3, DCM, r.t.|
First,to introduce the benzyl group to ring B of luteolin (Scheme 1,Route I),flavone benzyl ethers that benzylate the hydroxyl group on the B ring were needed. Intermediate 10 were synthesized by the known procedure [21, 22]. In the presence of iodine/pyridine,the intermediate 10 underwent cyclization to give a flavone benzyl ether compound 1 with 72% yield,in which the hydroxyl groups on the B ring were benzylated. Using microwave, the intermediate 1 underwent a rearrangement reaction in the presence of methylsulfonic acid. This reaction yielded rearrangement products and debenzylated product 6. Notably,the reaction produced two rearrangement products. Through structural characterization, the benzyl group was found to rearrange to the ortho position of the original benzyloxy group (position 5' of compound 1) to give a benzylated product 3. Furthermore,it also rearranged to the meta position (position 6' of compound 1) to yield the benzylated product 4. In addition,the proportions of the two products were equivalent,and the yields were 34% and 30%, respectively. Finally,intermediates 3 and 4 underwent demethylation via boron tribromide to obtain the target compounds 3'- benzyl luteolin 8 and 2'-benzyl luteolin 9 with 34% and 30% yields. Although the yield of the single reaction via this route was not high, the intermediate 6 could be re-used to improve the overall yield of the multiple reactions.
Second,a benzyl group was tried to be introduced to the ring A of luteolin (Scheme 1,Route II). Similarly,flavone benzyl ethers,in which the hydroxyl groups on the A ring was benzylated,were obtained. In the preliminary study,the cyclization reaction in the presence of iodine/pyridine was found to generate a byproduct that was demethylated at position 5 of the flavone backbone. In addition,it will gradually become the main product with an increasing amount of iodine and a prolonged reaction time. This side reaction was used to design the following synthetic route. Intermediate 11 were synthesized by the known procedure [21, 22]. In the presence of iodine/pyridine,the cyclization of intermediate 11 and demethylation yielded flavone compound 7 with a hydroxy group at position 5 of ring A with 73% yield. In the presence of benzyl chloride,intermediate 7 gave the flavone benzyl ether compound 2,in which the hydroxyl groups on the A ring is benzylated. Intermediate 2 underwent a rearrangement reaction under microwave conditions in the presence of methylsulfonic acid to yield rearrangement products and debenzylated product 7, similar to the reaction above. Surprisingly,the benzyl group in the reaction was not rearranged to the position ortho of the original benzyloxy group of ring A (position 6 of compound 2). The structural characterization confirmed that the benzyl group was rearranged to the position 6' of compound 2 and yielded a benzylated product 5. The yield of all of the rearrangement products declined (26%) versus compound 1 (64%). Finally,the demethylation of intermediate 5 yielded the same target compound 2'-benzyl luteolin 9 in the presence of boron tribromide. Similarly,the cyclic utilization of intermediate 7 could enhance the overall yield through multiple reactions down this route.3. Results and discussion
From the total synthesis of benzyl-substituted flavone derivatives, complicated regioselectivity during the rearrangement of the benzyl group in flavone benzyl ether compounds was observed. The benzyl group could be rearranged not only to the position ortho of the original benzyloxy group,but also to the meta position (the benzyl group of compound 1 rearranged from the 4' to the 5' and 6' positions). Rearrangement to the flavone B ring from the flavone A ring is also possible (the benzyl group of compound 2 rearranged from position 5 to position 6'). This is different from the regioselectivities previously reported for simple aromatic compounds and flavanone compounds,in which the rearrangement of a benzyl group mainly occurred on the ortho and para positions, and ortho rearrangement dominated [10, 12]. This may be because previous systems were relatively simple,and the flavone compound system with four substituted groups used here is relatively complicated. This gives a relatively complicated regioselectivity during the rearrangement of the benzyl group.
A reaction mechanism for the acidic rearrangement of the benzyl group in aromatic benzyl ether compounds was proposed by some researchers,based the observation of the intermolecular benzylated product [10, 12]. According to this reaction mechanism (Scheme 2),the flavone benzyl ethers were first protonated under the conditions of methylsulfonic acid (MSA) to form free debenzylated flavones and benzyl cation. Benzyl cations could electrophilic attack the aromatic ring to form the corresponding rearrangement products. This intermolecular reaction mechanism was further confirmed by a cross reaction by using two different substrates in which the flavone moieties and the benzyl groups are different. The crossed rearrangement product was isolated and detected from the reaction mixture by LS-HRMS (see the Supporting information).
|Scheme 2.Possible mechanism for the acidic rearrangement of benzyl group in flavone benzyl ethers.|
Based on this reaction mechanism,the regioselectivity of the benzyl rearrangement of compounds 1 and 2 should be related to the steric hindrance at different positions of corresponding debenzylated flavone compounds (i.e.,compounds 6 and 7). The position with a high steric hindrance is not favorable for the formation of rearrangement products. This explained nicely why compounds 1 and 2 could only yield the benzyl rearrangement products at position 6' or 5'. If the benzyl group was rearranged to the position 2',3,6 and 8 of compound 1 or compound 2,the substitution pattern containing five adjacent substituents was formed which is high sterically demanding.
However,the reaction of compound 2 only yielded the benzyl rearrangement products at position 6'. A reasonable explanation was that the ease of the electrophilic substitution reactions that involved benzyl cations also played an important role in determining the regioselectivity. The frontier orbital theory can be used to predict the reactivity of electrophilic substitution at different sites on aromatic rings . The method proposed by Lu et al. was used [24, 25, 26],based on Gaussian 09  with HF/6-31G* and B3LYP/6-31G* as the basis set and Multiwfn 3.3.4—a multifunctional program for wavefunction analysis . The HOMO orbital diagrams obtained from the calculations of flavone compounds 6 and 7 are shown in Fig. 2,and the detailed atomic contributions to HOMO of position 6' and 5' are listed in Table 1. According to the results,the position 5' carbon of compound 7 showed very low contributions to HOMO. This explained why no benzyl rearrangement product at position 5' was obtained from the reaction of compound 2.
In summary,the total synthesis of luteolin derivatives with a benzyl group introduced on positions 5' and 6' of ring B via the acidic rearrangement of benzyl groups in flavone benzyl ethers was reported. The complicated regioselectivity of the rearrangement of benzyl group in this reaction was observed. Furthermore, the regioselectivity of this reaction was proposed to be determined by steric hindrance as well as the ease of electrophilic substitution reaction for benzyl cations at different positions of corresponding debenzylated flavone compounds. This result could help predict the regioselectivity of the acidic rearrangement of benzyl group in flavone benzyl ethers,and design specific benzyl-substituted flavone compounds.Acknowledgments
The work was supported by the National Natural Science Foundation of China (Nos. 21172260 and 30901859),Shanghai Natural Science Foundation (No. 09ZR1438800) and “Chen Guang” project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (12CG42).Appendix A. Supplementary data
Supplementary data associated with this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2015.03.035.
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