Synthesis of Chiral Chalcone Derivatives Catalyzed by the Chiral Cinchona Alkaloid Squaramide

An effective method has been developed for the preparation of novel chiral chalcone derivatives under mild conditions from the easily accessible starting materials nitromethane and chalcone derivatives 2. The corresponding products were obtained in moderate yields with excellent enantioselectivities (up to 99%).


Introduction
Chalcones are not only excellent scaffolds for synthetic manipulations but also possess multiple biological and medicinal properties as antioxidant [1], antibacterial [2][3][4], antifungal [5], anti-Alzheimer's disease [6], anticancer [7], antitumor [8], antimalarial [9], antiproliferative [10], anti-inflammatory [11], and anti-HIV-1 agents [12]. Research laboratories worldwide are focusing on the synthesis of different chalcone analogues for the development of novel and potent drugs [13]. Asymmetric catalysis has proven its potential in numerous demanding applications which have been OPEN ACCESS reported and developed for the direct asymmetric addition reactions of chalcones in the past. Lu et al. reported a highly diastereoselective and enantioselective conjugate addition of phthalide derivatives to chalcones, leading to the formation of chiral phthalides bearing vicinal quaternary and tertiary stereogenic centers [14]. Previous work using chiral squaramide-based organ catalysts in similar enantioselective Michael additions have been reported [15,16], and asymmetric cyclopropanation of chalcones using bromomalonates as the nucleophiles in a Michael-Initiated Ring Closing reaction was developed by Waser [17]. The reaction performed well for electron neutral and electron deficient chalcones, giving the products in yields of up to 98% and with enantiomeric ratios up to 91: 9. Surprisingly, the use of chiral squaramide catalysts and nitromethane to facilitate addition reactions was described only a few times. Based on this concept and the knowledge gathered therein we surmised that some catalyst structures Q1-Q4 might be efficient in the direct addition reactions between nitromethane (1) with chalcone derivatives 2 ( Figure 1). Herein we described our work toward preparation of such interesting chiral moieties in the presence of a variety of known chiral cinchona alkaloid squaramides (Scheme 1).

Optimization Studies
To optimize the reaction regime, the synthesis of chiral compound (−)-3g was carried out under several conditions. The effects of different solvents, reaction time and temperature were investigated using Q4 as catalyst; the results are shown in Table 2. From the data presented in the table it can be concluded that dichloromethane appeared to be the best solvent to obtain high ee values; other solvents provided much poorer enantioselectivities ranging between 50%-67% ee ( Table 2, entry 1, entry 2 and entry 3). Moreover, the effects of reaction temperature and time on the addition reaction were also investigated ( Table 2, entries 5-7). When the reaction time was prolonged from 42 to 72 h, the ee value of (−)-3g was increased from 88% to 96% (Table 2, entries 4 and 6). Extending the reaction time up to 100 h resulted in only a tiny improvement of the ee value (97%, Table 2, entry 8) if compared with that obtained after 72 h of reaction (96%, Table 2, entry 4). As for the reaction temperature, it could be observed that when the reaction temperature was increased from 0 °C to room temperature and 40 °C, the ee values of (−)-3g were 79%, 96% and 85%, respectively (Table 2, entries 1, 5-6). Hence, the optimal reaction conditions were selected as following: CH2Cl2 as a solvent, room temperature, 72 h reaction time, Q4 as a catalyst.

Synthesis of Chiral Chalcones Derivatives
The optimized protocol was then expanded to a wide variety of chalcone derivatives and the results are summarized in Table 3. The relationships of the enantioselectivity to different R1 and R2 values were observed. Table 3. Synthesis of chiral chalcones derivatives (-)-3a-i [a] . The data indicated that compounds (−)-3e, (−)-3g, and (−)-3h exhibited higher enantioselectivity than other compounds, with ee values of 99.0%, 95.9%, and 96.0%, respectively. When R1 was H, 2-Cl, 4-Cl or 2-F and R2 was H or 6-Me the corresponding target chiral chalcones exhibited excellent enantioselectivity. The strongest enantioselectivity was observed when R1 was 4-Cl, 2-Cl and R2 was substituted with H, 6-Me-groups. Compared with (−)-3h, the target compounds (−)-3b, (−)-3d, (−)-3f, and (−)-3i also displayed good enantioselectivity, with ee values of 91.5%, 91.8%, 92.0% and 92.5%, respectively. The presence of 4-Cl or 2-Cl atoms in a benzene moiety and 6-Me group or H-atom in a quinazoline ring of chalcones 2 did not significantly affect the reactivity and enantioselectivity of the reaction. An H atom as R1 and 6-Me or 8-Me as R2 in substrates 2 had some effect on the enantioselectivity of the addition reactions; compounds (−)-3a and (−)-3c afforded moderate enantioselectivity with ee values of 81.4% and 86.0%, respectively.

General Information
Unless otherwise stated, all the reagents and reactants were purchased from commercial suppliers; melting points were uncorrected and determined on a XT-4 binocular microscope (Beijing Tech Instrument Co., Beijing, China). The 1 H-NMR and 13 C-NMR spectra were recorded on an ECX 500 NMR spectrometer (JEOL, Ltd., Tokoy, Japan) at room temperature operating at 500 MHz for 1 H-NMR and 125 MHz for 13 C-NMR, using CDCl3, or DMSO-d6 as solvents and TMS as an internal standard; infrared spectra were recorded in KBr on a VECTOR 22 spectrometer (Bruker Ltd., Ettlingen, German); mass spectral studies were conducted on an Agilent 5973 organic mass spectrometer (Agilent Technologies Inc., Santa Clara, CA, USA). The course of the reactions was monitored by TLC; analytical TLC was performed on silica gel GF254 plates; column chromatographic purification was carried out using silicagel. The enantiomeric excess was determined by HPLC using a Chiral pak AD-H column.

Preparation of Chiral Catalyst Q4
3-(3,5-Ditrifluoromethylphenylamino)4-methoxybutane-3-en-1,2-dione (1.0 mmol) was slowly added with stirring to a mixture of dichloromethane (4 mL) and 9-aminodeoxyquinine (1.02 mmol). After completion of the addition, the stirring was continued for 12 h at room temperature. The mixture was concentrated, and the crude product was purified by preparative TLC with a mixture of petroleum

Preparation of Intermediates 2
4-Hydroxychalcone (3 mmol), 4-chloroquinazoline (3 mmol), K2CO3 (6.3 mmol), and acetone (15 mL) were added to an oven-dried one-neck 50 mL round-bottom flask equipped with a magnetic stirring bar. The resulting mixture was stirred at 40 °C for 10 h, poured into ice water (40 mL), and then separated. The aqueous phase was acidified with 10% HCl to pH 5-7 and then filtered. The residue was dried and recrystallized from ethanol to obtain compounds 2a-i as white solids [20].

Preparation of Title Chiral Compounds (−)-3a-3i
To a well stirred solution of nitromethane (0.9 mmol) and chalcone derivative 2 (0.45 mmol) in 4 mL of dichloromethane, Q4 (0.045 mmol) was added. The resulting mixture was stirred at room temperature and monitored by TLC. After stirring for 72 h, the mixture was concentrated, and the crude product was purified by preparative TLC with a mixture of petroleum ether and ethyl acetate (V:V = 2:1) as developing solvent to give title chiral compounds (−)-3a-3i.

Author Contributions
DYH conceived and designed the experiments. DDX and YX performed the experiments and analyzed the data; YX and YD tested all the ee values of the compounds; DYH analyzed the data and wrote the paper, JW revised the paper. All authors contributed to this study, read and approved the final manuscript.

Conflicts of Interest
The authors declare that they have no competing interests