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lactonization catalyzed by a chiral squaramide catalyst
Tetrahedron: Asymmetry 25 (2014) 310–317
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Enantioselective synthesis of enol lactones from tandem Michael addition/lactonization catalyzed by a chiral squaramide catalyst Bo-Liang Zhao, Da-Ming Du ⇑ School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 6 November 2013 Accepted 7 January 2014
a b s t r a c t The enantioselective tandem Michael addition reaction of dimedone and related 1,3-dicarbonyl compounds with a,b-unsaturated N-acylated succinimides catalyzed by a chiral squaramide catalyst has been investigated. This reaction provides a new approach for the synthesis of chiral enol lactones in good yields with moderate to high enantioselectivities (up to 88% ee) through the enantioselective Michael addition followed by lactonization and removal of the succinimide auxiliary. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Enol lactones, such as the derivatives of coumarin, flavonoids, and neoflavonoids, are present in a number of biologically active natural products and have strong biological activity.1,2 Many compounds contain the exocyclic enol lactone substructure3 or endocyclic enol lactone ring.4 A recent report on a tetrameric 4-hydroxycoumarin-derived inhibitor provided a lead example of an HIV integrase inhibitor.5 Coumarin derivatives and related enol lactones were also found to be very efficient non-peptide HIV-1 protease inhibitors.6 In addition, endocyclic enol lactones are also useful intermediates in the synthesis of more complex natural products. Endocyclic enol lactones with optical activity have more potential value with bio-availability such as the alkaloid ()-aspidospermidine.7 However, there are few reports on the synthesis of enol lactone derivatives.8–14 Reports on the synthesis of optically active enol lactone compounds are even more rare; Kanemasa et al. reported on the reaction of dimedone with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles catalyzed by catalytic amounts of both DBFOX/Ph-nickel-(II) perchlorate trihydrate and 2,2,6,6-tetramethylpiperidine to produce the corresponding enol lactones with high enantioselectivities through enantioselective Michael addition followed by cyclization with removal of the pyrazole auxiliary.8 Therefore, to find effective and convenient methods to access optically active enol lactone compounds is of great significance and a major challenge in synthetic organic chemistry. Herein we report one effective synthetic approach to enol lactone systems via Michael addition reaction of dimedone and related 1,3-dicarbonyl compounds with a,b-unsaturated N-acylated succinimides, which rarely reported as a Michael receptor, by the catalysis of chiral squaramide organocatalyst.
We first evaluated the reaction between 5,5-dimethylcyclohexane-1,3-dione (dimendone) 1 and 1-cinnamoylpyrrolidine-2,5-dione 2a. When 5 mol % of squaramide I15 derived from hydroquinine was used, product 3a was obtained in 96% yield and with 66% ee in CH2Cl2 at room temperature for 48 h. For the sake of comparison, N-cinnamoyl pyrazole and N-cinnamoyl oxazolidinone were also examined in this reaction under the same reaction conditions. However, we found that N-cinnamoyl pyrazole as the reactant afforded the product 3a in 21% yield and 94% ee. N-Cinnamoyl oxazolidinone as the reactant did not afford the target product. We found that 2a had better reactivity. Considering the yield, enantioselectivity, and novelty of the Michael acceptor, we chose 1-cinnamoylpyrrolidine-2,5-dione 2a as the reactant. Next, we performed an optimization of the model reaction between 5,5-dimethylcyclohexane-1,3-dione (dimendone) 1 and 1-cinnamoylpyrrolidine-2,5-dione 2a. A series of chiral squaramide or thiourea catalysts I–VII were investigated in this reaction (Fig. 1). When squaramide I or II derived from hydroquinine was used, product 3a was obtained with similar yield and enantioselectivity (Table 1, entries 1 and 2). Cinchonidine derived squaramide III16 gave a slightly lower enantioselectivity than squaramides I and II. The C2-symmetric squaramide IV17 was also evaluated, but no improved enantioselectivity was observed (Table 1, entry 4). In contrast, the corresponding thiourea V or squaramide VI18 derived from (1S,2S)-cyclohexane-1,2diamine afforded lower enantioselectivity (Table 1, entries 5 and 6). The new squaramide VII19 derived from aminoglucopyranose and hydroquinine was tested, the enantioselectivity was enhanced but with a slightly lower yield (Table 1, entry 8). After screening different catalysts, using squaramide I as a catalyst was found to be the best in terms of enantioselectivity and yield. Therefore, further optimizations were carried out using squaramide I as the catalyst. In order to enhance the enantioselectivity of the desired product, further screening of reaction parameters such as the solvent,
⇑ Corresponding author. Tel./fax: +86 10 68914985. E-mail address: [email protected] (D.-M. Du). 0957-4166/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2014.01.005
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B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317
O O
Ar
OMe
O H
N H
CF3
N
N H
NH H
OMe
MeO
CF3
IV
O
OAc
O
O
OMe
CF3
N H
H
N
N III
II: Ar = 4-CF3C6H4
S
N
HN
N
I: Ar = 3,5-(CF3)2C6H3
F3C
H
N
N
N H
N H
F 3C
N
O H
O
O
AcO AcO
N F3C
N H
N H
N H
O
O
H HN
NH
N
OAc
N
OMe
N
V
VII
VI
N
Figure 1. Structures of chiral squaramides and thioureas.
Table 1 Screening of different chiral catalysts O
O +
Table 2 Optimization of reaction conditions Ph
O Ph
N
+ O
Entrya
Catalyst
1 2 3 4 5 6 7
I II III IV V VI VII
1
3a
2a
Yieldb (%) 96 94 94 91 91 92 86
Ph
O
N
Ph
eec (%) 66 66 59 42 11 17 69
a Reaction conditions: 5,5-dimethylcyclohexane-1,3-dione 1 (0.3 mmol) and 1cinnamoylpyrrolidine-2,5-dione 2a (0.2 mmol) in CH2Cl2 (0.5 mL) with 5 mol % catalyst for 36–48 h at room temperature. b Determined by HPLC on a Daicel Chiralpak AD-H column (n-hexane/2-propanol = 90:10, 1.0 mL/min). c Determined by HPLC on a Daicel Chiralpak AD-H column.
catalyst loading, and temperature was investigated. When the reaction was performed in acetonitrile, product 3a was obtained in 88% yield but with low enantioselectivity (40% ee). When toluene was used as the solvent, a significant improvement in the enantioselectivity was realized (Table 2, entry 2). Other solvents such as CHCl3, THF, or ClCH2CH2Cl afforded moderate enantioselectivities. After a brief screening of the solvent, toluene was found to be the best. The enantioselectivity and yield of the product 3a decreased slightly when decreasing the catalyst loading to 2.5 mol %. The yield of product 3a was improved slightly by increasing the catalyst loading to 10 mol % (Table 2, entry 9). Increasing the reaction temperature to 50 °C led to a decrease in the enantioselectivity. The enantioselectivity and yield both drastically decline when lowering the temperature to 10 °C. Hence we selected 10 mol % catalyst loading at room temperature for 48 h, with toluene as the solvent, as the optimum reaction conditions. After optimization of the reaction conditions, the substrate scope for the enantioselective enol lactone synthesis from dimedone 1 with 1-(2-alkenoyl)-pyrrolidine-2,5-dione 2a–j was
O
5 mol % I solvent
O
O
O 1
O
5 mol % catalyst CH2Cl2, rt, 36-48 h
O
O
O
O
O 2a
Entrya
Solvent
1 2 3 4 5 6 7 8d 9e 10f 11g
CH3CN Toluene Xylene a,a,a-Trifluorotoluene CHCl3 ClCH2CH2Cl THF Toluene Toluene Toluene Toluene
O 3a
Yieldb (%) 88 94 89 91 91 86 94 92 97 90 42
eec (%) 40 86 86 78 64 66 64 76 85 78 17
a Reaction conditions: unless noted otherwise, reactions were carried out with 5,5-dimethylcyclohexane-1,3-dione 1 (0.3 mmol) and 1-cinnamoylpyrrolidine-2,5dione 2a (0.2 mmol) in 0.5 mL of solvent with 5 mol % catalyst I for 48 h at room temperature. b Isolated yields by column chromatography. c Determined by HPLC on Daicel Chiralpak AD-H column (n-hexane/2-propanol = 90:10, 1.0 mL/min). d The reaction was conducted with 2.5 mol % catalysts loading for 72 h. e The reaction was conducted with 10 mol % catalyst loading. f The reaction was performed at 50 °C for 30 h with 10 mol % catalyst loading. g The reaction was performed at 10 °C for 144 h with 10 mol % catalyst loading.
explored. The reactions of dimedone 1 (1.5 equiv) with a,b-unsaturated N-acylated succinimide 2a–j afforded 7,7-dimethyl-4,6,7,8tetrahydro-3H-chromene-2,5-dione 3a–j in high yield (up to 97%) and with moderate to high enantioselectivities (up to 88% ee) as shown in Table 3. Electron-withdrawing and electron-rich substituents in the benzene ring of 2 (Table 3, entries 2–6) gave satisfactory results. As the alkyl chain increased in length at the b-substituted position of 2 (Table 3, entries 8–10), the enantioselectivity and yield decreased. The absolute configuration of enol lactones 3a and 3c–j was assigned according to the literature.8 Other Michael donors, such as cyclohexane-1,3-dione 4, 4-hydroxycoumarin 6, 4-hydroxy-6-methyl-2H-pyran-2-one 8, and acyclic acetoacetone 10 were also investigated in order to
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However, there was no improvement in the corresponding enantioselectivity. Cyclopentane-1,3-dione and cycloheptane-1,3-dione were also examined; these reactions produced a lot of by-products. This phenomenon may be ascribed to the increased ring tension, which means that the target products were not easy to generate. The main products were also unstable. The main product of these corresponding reactions cannot be obtained by column chromatography, which may be due to the enol lactone ring being too easy to open under the catalysis of silica gel. The experimental results indicated that the two methyl groups of 5,5-dimethylcyclohexane-1,3-dione play a very important role in the enantioselective process of the reaction. As a comparison, cyclohexane-1,3-dione 4, which lacks the two methyl groups gave lower enantioselectivities (Table 4, entries 1 and 2). The reactions of 6, 8, and 10 with a,b-unsaturated N-acylated succinimide 2 gave the corresponding products 7, 9, and 11 in low to moderate enantioselectivities (Table 4, entries 3–7). The tentative proposed reaction mechanism to explain the enantioselective generation of the final product 3a is shown in Figure 2. Squaramide I activates the 1-cinnamoylpyrrolidine-2,5dione 2a through a double hydrogen bonding interaction, while the dimendone 1 is activated by the tertiary nitrogen of the quinuclidine. The enolate anion attacks the 1-cinnamoylpyrrolidine-2,5dione from the Si-face via transition state A to form the Michael adduct intermediate B. Subsequent intramolecular protonation and tautomerization of B gave enolate transition state C. The final step involved the cyclization of C with the removal of succinimide auxiliary to give enol lactone 3a.
Table 3 Chiral squaramide-catalyzed enantioselective synthesis of a variety of enol lactones O
R
O
O
O 10 mol % I
N
+
R
O
toluene, rt
O
O
O 1
a b
3a-j
2a-j
Entry
R
Time (h)
1 2 3 4 5 6 7 8 9 10
Ph 2-ClC6H4 4-BrC6H4 4-MeOC6H4 4-O2NC6H4 4-MeC6H4 2-Furyl Me Et n-Pr
48 48 60 60 48 72 48 24 96 120
Yielda (%)
Product 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j
97 88 93 95 78 83 73 96 71 63
eeb (%) 85 54 88 85 70 80 88 77 69 72
Isolated yields by column chromatography. Determined by HPLC using a chiral column.
explore the generality of this reaction. The Michael reactions of these donors to acceptors 2 can also be performed successfully, affording the corresponding enol lactones 5, 7, 9, and 11, respectively (Table 4), although the enantioselectivities were not very good in most reactions. As a result, we changed the reaction conditions, such as the temperature, solvents and using other catalysts.
Table 4 Enantioselective synthesis of other enol lactones
donor 4, 6, 8 or 10
Entry
Donor
Reactant 2
+
2
10 mol % I
Product Ph
O
1c
enol lactone 5, 7, 9 or 11
toluene
O
Yielda (%)
eeb (%)
48
96
72
48
87
60
48
77
23
24
90
50
O
2a O
Time (h)
O 5a
4 O
Me
2c
O
2h O
O
O 5b
4 Ph
OH
O O
3d
O
O
2a
O
O
6 7a OH
Me
O O
4d
O
O
2h
O
O
6 7b
313
B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317 Table 4 (continued) Entry
Donor
Reactant 2
Product
OH
R
Time (h)
Yielda (%)
eeb (%)
48
76
19
24
92
46
48
48
29
O O
5d
Me
O
2f
O
O
O
Me 9a
8
R = 4-MeC6H4 OH
O
Me
O
6d
2h Me
O
O
O
O
Me 9b
8 O
7d
Ph
O
O
2a
10
O
O 11a
a b c d
Isolated yields by column chromatography. Determined by HPLC using a chiral column. Reactions were carried out with cyclohexane-1,3-dione 4 (0.3 mmol) and 2 (0.2 mmol) in toluene (0.5 mL) with catalyst I at room temperature. Reactions were carried out with 6, 8 or 10 (0.3 mmol), and 2 (0.2 mmol) in toluene (0.5 mL) with catalyst I at 50 °C.
CF3
F3C
Ph
O
N O
O
N
N
H
H
H
OMe
N
O
2a
N
O 3a
O
H
H
O
O
1
I
OH
N N
O
H
H
H
O
O O
H
H
H
O
O N N Ph O
O Ph
O
C
O
N H
H
H
A Si-face attack
O
O
O
H
N O
Ph O B
Figure 2. Proposed reaction mechanism.
3. Conclusion In conclusion, we have developed a convenient synthesis for a variety of chiral enol lactones through the enantioselective tandem Michael addition/lactonization reaction of various nucleophile precursors to a,b-unsaturated N-acylated succinimides by
the catalysis of a chiral squaramide catalyst, and the corresponding products were obtained in high yield (up to 97%) and with moderate to good enantioselectivity (up to 88% ee). This reaction provides a very simple and valuable method to synthesize enol lactones using 1,3-dicarbonyl compounds as the raw materials.
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B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317
4. Experimental 4.1. General Unless otherwise noted, commercially available compounds were used without further purification. Column chromatography was carried out with silica gel (200–300 mesh). Melting points were measured with a melting point apparatus without correction. 1 H NMR spectra were recorded with a Varian Mercury-plus 400 MHz spectrometer. Chemical shifts were reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The data are reported as follows: chemical shift (ppm), and multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad singlet), coupling constant(s) in Hz, integration assignment. 13C NMR spectra were recorded at 100 MHz. Infrared spectra were obtained with a Perkin Elmer Spectrum One spectrometer. The high resolution MS spectra were obtained with ESI ionization using a Bruker APEX IV FTMS spectrometer. Optical rotations were measured with a WZZ-3 polarimeter at the indicated concentration with units g/100 mL. The enantiomeric excesses were determined by chiral HPLC using an Agilent 1200 LC instrument with a Daicel Chiralpak column AD-H or IB. 4.2. Materials Chiral squaramide catalysts I,15 III,16 IV,17 VI,18 and VII19 were prepared according to the reported procedures. Cyclic diketones, 4-hydroxycoumarin, 4-hydroxy-6-methyl-2H-pyran-2-one, and pyrrolidine-2,5-dione were purchased from commercial supplies. The racemic reference compounds were synthesized by the direct treatment of 1-(2-alkenoyl)-pyrrolidine-2,5-dione 2 with 1, 4, 6, 8, or 10 in the presence of triethylamine.
1.57–1.36 (m, 7H), 0.81 (t, J = 7.2 Hz, 1H), 0.66 (br s, 1H) ppm; 13 C NMR (100 MHz, DMSO-d6): d 184.6, 179.7, 168.4, 163.1, 157.8, 147.7, 144.3, 143.0, 142.3, 131.5, 127.4, 126.50, 126.46, 124.3 (q, 1JC–F = 270.2 Hz), 122.5 (q, 2JC–F = 32.0 Hz), 121.8, 118.0, 101.3, 57.1, 55.6, 40.2, 36.6, 27.8, 26.8, 25.7, 24.9, 11.8 ppm; IR (KBr): m 3226, 3184, 3002, 2962, 2940, 2869, 1800, 1675, 1655, 1621, 1606, 1575, 1542, 1513, 1475, 1460, 1443, 1420, 1377, 1329, 1322, 1269, 1241, 1192, 1172, 1162, 1119, 1070, 1042, 1016, 840, 826, 767, 728, 715, 681, 637 cm1; HRMS (ESI): m/z calcd for C31H32F3N4O3 [M+H]+ 565.24210, found 565.24180. 4.2.2. General procedure for the preparation of a,b-unsaturated N-acylated succinimide Under argon, a mixture of pyrrolidine-2,5-dione (2.97 g, 30 mmol) and pyridine (2.54 mL, 31.5 mmol) in anhydrous dichloromethane (50 mL) was added dropwise to crotonoyl chloride (2.55 mL, 31.5 mmol) in dichloromethane (100 mL) at 0 °C for more than half an hour, after which the mixture was stirred for 3 h at 0 °C. Next, the reaction mixture was allowed to warm to room temperature for 48 h. The reaction mixture was then poured into saturated sodium hydrogen carbonate and extracted with dichloromethane. The combined organic layers were washed with 30 mL of hydrochloric acid solution (1 M), brine, dried over magnesium sulfate, and concentrated in vacuo. The crude residue was passed through a flash silica gel column by eluting with dichloromethane to provide analytically pure 2f (3.3 g, 66%). Other unsaturated imide substrates were prepared according to a similar procedure from pyrrolidine-2,5-dione and the corresponding (E)-2-alkenoyl chlorides 4.3. General procedure for the enantioselective synthesis of enol lactones
4.2.1. Synthesis of organocatalysts II O
F3C
O
NH2
F3C
MeOH
+ MeO
48 h, rt
OMe
O
O
N H
OMe
H H2N
N OMe F3C
OMe
O
O
N H
N H
H
N
N CH2Cl2, 48 h, rt
N
II
In a 25 mL round-bottomed flask, 4-(trifluoromethyl)aniline (0.805 g, 5.0 mmol) was added to dimethyl squarate (0.71 g, 5.0 mmol) which was dissolved in 10 mL of methanol. The mixture was then stirred at room temperature for 48 h, after which the precipitate was filtered to afford the mono-squaramide as a white solid (1.06 g, 78% yield). To a solution of hydroquinine derivatives (325 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added mono-squaramide (272 mg, 1 mmol). After stirring for 48 h at room temperature, squaramide catalyst II was obtained by filtration as a white solid (480 mg, 85% yield). Mp 203–205 °C (decomp.), 1 ½a28 H NMR (400 MHz, DMSO-d6): d D ¼ 72:7 (c 0.30, DMSO). 10.07 (br s, 1H), 8.88 (d, J = 4.4 Hz, 1H), 8.41 (br s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.83 (br s, 1H), 7.74 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.48 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 6.09 (br s, 1H), 4.01 (s, 3H), 3.53–3.35 (m, 4H), 3.21–3.16 (m, 1H), 2.66 (br s, 1H), 2.50 (d, J = 12.8 Hz, 1H),
Procedure A: To a dried small bottle were added a,b-unsaturated N-acylated succinimide 2 (0.2 mmol) and catalyst I (12.6 mg, 0.02 mmol, 10 mol %), followed by the addition of toluene (0.5 mL). The mixture was stirred at room temperature for 15 min, then 5,5-dimethylcyclohexane-1,3-dione 1 (0.3 mmol) or cyclohexane-1,3-dione 4 (0.3 mmol) was added in one portion. After stirring at room temperature for 48–120 h, the reaction mixture was concentrated and purified directly by silica gel column chromatography to afford the desired product 3 or 5. Procedure B: To a dried small bottle were added a,b-unsaturated N-acylated succinimide 2 (0.2 mmol) and catalyst I (12.6 mg, 0.02 mmol, 10 mol %), followed by the addition of toluene (0.5 mL). The mixture was stirred at 50 °C for 15 min, then 4hydroxycoumarin 6 (0.3 mmol) or 4-hydroxy-6-methyl-2H-pyran-2-one 8 (0.3 mmol) was added in one portion. After stirring at 50 °C for 24–48 h, the reaction mixture was concentrated and purified directly by silica gel column chromatography to afford the desired products 7 or 9. 4.3.1. (R)-7,7-Dimethyl-4-phenyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 3a8 Compound 3a was obtained according to general procedure A as a white solid (52.4 mg, 97% yield), mp 110–112 °C. ½a25 D ¼ 98:8 (c 2.14, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 90:10, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 9.0 min, tminor = 16.2 min, 85% ee. 1H NMR (400 MHz, CDCl3): d 7.30–7.14 (m, 5H, ArH), 4.30 (t, J = 4.0 Hz, 1H, CH), 2.93 (t, J = 2.8 Hz, 2H, CH2), 2.53 (s, 2H, CH2), 2.32 (s, 2H, CH2), 1.15 (s, 3H, CH3), 1.10 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.1, 165.9, 165.7, 140.5, 129.0, 127.4, 126.4, 116.0, 50.5, 40.9, 36.3, 33.7, 32.5, 28.5, 28.1 ppm. Lit.8 ½a25 D ¼ 131:18 (c 0.51, CHCl3) 99% ee.
B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317
4.3.2. (S)-4-(2-Chlorophenyl)-7,7-dimethyl-4,6,7,8-tetrahydro3H-chromene-2,5-dione 3b20 Compound 3b was obtained according to general procedure A as a white solid (53.6 mg, 88% yield), mp 115–116 °C. ½a25 D ¼ 36:5 (c 0.48, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 4.9 min, tminor = 5.7 min, 54% ee. 1H NMR (400 MHz, CDCl3): d 7.39 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 1H, ArH), 7.20–7.13 (m, 2H, ArH), 6.91 (dd, J1 = 7.0 Hz, J2 = 2.0 Hz, 1H, ArH), 4.74 (t, J = 4.4 Hz, H, CH), 2.94 (s, 1H, CH2), 2.92 (d, J = 1.6 Hz, 1H, CH2), 2.60 (s, 1H, CH2), 2.59 (d, J = 1.2 Hz, 1H, CH2), 1.98 (s, 2H, CH2), 1.18 (s, 3H, CH3), 1.17 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 195.5, 166.9, 165.3, 137.0, 133.4, 130.5, 128.9, 127.3, 126.7, 114.7, 50.5, 41.1, 35.2, 32.5, 31.2, 28.5, 28.4 ppm. 4.3.3. (R)-4-(4-Bromophenyl)-7,7-dimethyl-4,6,7,8-tetrahydro3H-chromene-2,5-dione 3c8 Compound 3c was obtained according to general procedure A as a white solid (64.9 mg, 93% yield), mp 173–174 °C. ½a25 D ¼ 27:7 (c 1.43, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/ 2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 7.5 min, tminor = 16.5 min. 88% ee. 1H NMR (400 MHz, CDCl3): d 7.33 (d, J = 8.4 Hz, 2H, ArH), 6.96 (d, J = 8.4 Hz, 2H, ArH), 4.17 (d, J = 6.8 Hz, 1H, CH), 2.90–2.78 (m, 2H, CH2), 2.45 (s, 2H, CH2), 2.23 (s, 2H, CH2), 1.06 (s, 3H, CH3), 1.01 (s, 3H, CH3) ppm. 13 C NMR (100 MHz, CDCl3): d 196.0, 165.9, 165.5, 139.5, 132.1, 128.2, 121.3, 115.5, 50.4, 40.9, 35.9, 33.3, 32.5, 28.5, 28.0 ppm. Lit.8 ½a25 D ¼ 130:8 (c 0.51, CHCl3) >99% ee. 4.3.4. (R)-4-(4-Methoxyphenyl)-7,7-dimethyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 3d Compound 3d was obtained according to general procedure A as a white solid (57.0 mg, 95% yield), mp 138–139 °C. ½a25 D ¼ 76:9 (c 2.04, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 8.6 min, tminor = 15.9 min, 85% ee. 1 H NMR (400 MHz, CDCl3): d 7.07 (d, J = 8.4 Hz, 2H, ArH), 6.80 (d, J = 8.0 Hz, 2H, ArH), 4.24 (d, J = 6.0 Hz, 1H, CH), 3.75 (s, 3H, CH3), 2.90 (d, J = 6.4 Hz, 2H, CH2), 2.52 (s, 2H, CH2), 2.31 (s, 2H, CH2), 1.14 (s, 3H, CH3), 1.10 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.2, 166.2, 165.5, 158.8, 132.6, 127.6, 116.4, 114.4, 109.7, 55.2, 50.6, 41.0, 36.6, 33.0, 32.6, 28.6, 28.1 ppm. IR (KBr): m 3004, 2963, 2931, 2887, 2875, 1772, 1738, 1671, 1653, 1607, 1582, 1510, 1466, 1422, 1376, 1314, 1306, 1278, 1247, 1239, 1176, 1159, 1114, 1100, 1035, 1009, 964, 860, 840, 818, 809, 764, 750, 661, 627, 603 cm1. HRMS (ESI): m/z calcd for C18H21O4 [M+H]+ 301.14344, found: 301.14392. 4.3.5. (R)-7,7-Dimethyl-4-(4-nitrophenyl)-4,6,7,8-tetrahydro3H-chromene-2,5-dione 3e Compound 3e was obtained according to general procedure A as a white solid (49.2 mg, 78% yield), mp 139–141 °C. ½a25 D ¼ 92:4 (c 1.50, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/ 2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 14.1 min, tminor = 41.7 min, 70% ee. 1H NMR (400 MHz, CDCl3): d 8.08 (d, J = 8.4 Hz, 2H, ArH), 7.27 (d, J = 8.8 Hz, 2H, ArH), 4.33 (d, J = 7.6 Hz, 1H, CH), 2.97 (dd, J1 = 16.2 Hz, J2 = 8.0 Hz, 1H, CH2), 2.86 (d, J = 16.0 Hz, 1H, CH2), 2.49 (s, 2H, CH2), 2.26 (s, 2H, CH2), 1.09 (s, 3H, CH3), 1.02 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.0, 166.5, 165.0, 147.9, 147.1, 127.6, 124.3, 114.9, 50.3, 40.9, 35.5, 33.7, 32.5, 28.5, 28.0 ppm. IR (KBr): m 3111, 3078, 2961, 2931, 2892, 2873, 1789, 1735, 1655, 1599, 1521, 1494, 1469, 1415, 1372, 1348, 1311, 1277, 1238, 1216, 1181, 1161, 1101, 1038, 1015, 969, 925, 857, 816, 783, 763, 737,
315
697, 615, 603, 584 cm1. HRMS (ESI): m/z calcd for C17H18NO5 [M+H]+ 316.11795, found: 316.11870. 4.3.6. (R)-7,7-Dimethyl-4-(p-tolyl)-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 3f Compound 3f was obtained according to the general procedure A as a white solid (47.2 mg, 83% yield), mp 134–136 °C. ½a25 D ¼ 82:1 (c 1.03, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 6.6 min, tminor = 10.6 min, 80% ee. 1H NMR (400 MHz, CDCl3): d 7.09 (d, J = 8.0 Hz, 2H, ArH), 7.03 (d, J = 8.0 Hz, 2H, ArH), 4.26 (dd, J1 = 5.6 Hz, J2 = 3.2 Hz, 1H, CH), 2.91 (t, J = 3.6 Hz, 2H, CH2), 2.53 (s, 2H, CH2), 2.31 (s, 2H, CH2), 2.29 (s, 3H, CH3), 1.15 (s, 3H, CH3), 1.10 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.2, 166.1, 165.5, 137.5, 137.1, 129.7, 126.3, 116.2, 50.6, 41.0, 36.4, 33.4, 32.5, 28.5, 28.1, 21.0 ppm. IR (KBr): m 3026, 3004, 2960, 2927, 2873, 1786, 1733, 1668, 1655, 1514, 1466, 1414, 1373, 1333, 1314, 1291, 1272, 1270, 1180, 1161, 1102, 1036, 1017, 969, 859, 822, 737, 600, 549, 520 cm1. HRMS (ESI): m/z calcd for C18H21O3 [M+H]+ 285.14852, found: 285.14860. 4.3.7. (S)-7,7-Dimethyl-4-(furan-2-yl)-4,6,7,8-tetrahydro-3Hchromene-2,5-dione 3g8 Compound 3g was obtained according to the general procedure A as a white solid (38.0 mg, 73% yield), mp 78–79 °C. ½a25 D ¼ 24:8 (c 0.99, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 6.3 min, tminor = 9.0 min, 88% ee. 1H NMR (400 MHz, CDCl3): d 7.28 (d, J = 1.2 Hz, 1H, ArH), 6.24 (dd, J1 = 3.0 Hz, J2 = 2.0 Hz, 1H, ArH), 6.06 (d, J = 3.2 Hz, 1H, ArH), 4.37 (d, J = 7.2 Hz, 1H, CH), 3.06 (dd, J1 = 16.0 Hz, J2 = 1.6 Hz, 1H, CH2), 2.83 (dd, J1 = 16.0 Hz, J2 = 7.2 Hz, 1H, CH2), 2.48 (s, 2H, CH2), 2.33 (s, 2H, CH2), 1.14 (s, 3H, CH3), 1.08 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 195.6, 166.1, 165.4, 152.6, 142.2, 113.9, 110.2, 105.9, 50.4, 40.9, 33.6, 32.4, 28.5, 27.8, 27.7 ppm. Lit.8 ½a25 D ¼ 60:7 (c 0.74, CHCl3) 89% ee. 4.3.8. (S)-4,7,7-Trimethyl-4,6,7,8-tetrahydro-3H-chromene-2,5dione 3h8 Compound 3h was obtained according to general procedure A as a white solid (40.0 mg, 96% yield), mp 55–57 °C. ½a25 D ¼ 5:0 (c 2.09, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 90:10, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 7.2 min, tminor = 11.2 min, 77% ee. 1H NMR (400 MHz, CDCl3): d 3.17–3.10 (m, 1H, CH), 2.71–2.60 (m, 2H, CH2), 2.42 (ABq, J = 18.0 Hz, 2H, CH2), 2.31 (s, 2H, CH2), 1.12 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.07 (d, J = 7.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.5, 166.7, 164.7, 118.0, 50.6, 40.8, 36.0, 32.5, 28.5, 27.9, 23.3, 19.3 ppm. Lit.8 ½a25 D ¼ 8:7 (c 0.41, CHCl3) 98% ee. 4.3.9. (S)-4-Ethyl-7,7-dimethyl-4,6,7,8-tetrahydro-2H-chromene2,5-dione 3i8 Compound 3i was obtained according to general procedure A as a white solid (31.6 mg, 71% yield), mp 67–69 °C. ½a25 D ¼ þ4:6 (c 1.14, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 5.1 min, tminor = 7.6 min, 69% ee. 1H NMR (400 MHz, CDCl3): d 2.91 (q, J = 6.8 Hz, 1H, CH), 2.69 (d, J = 16.0 Hz, 1H, CH2), 2.53 (dd, J1= 16.2 Hz, J2 = 7.2 Hz, 1H, CH2), 2.36 (ABq, J = 18.0 Hz, 2H, CH2), 2.24 (ABq, J = 16.4 Hz, 2H, CH2), 1.48–1.38 (m, 1H, CH2), 1.32– 1.22 (m, 1H, CH2), 1.05 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.820 (t, J = 7.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.6, 167.0, 165.1, 117.0, 50.6, 40.8, 33.2, 32.4, 29.3, 28.6, 27.7, 26.5, 10.8 ppm. Lit.8 ½a25 D ¼ þ11:2 (c 0.34, CHCl3) 93% ee.
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4.3.10. (S)-7,7-Dimethyl-4-propyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 3j8 Compound 3j was obtained according to general procedure A as colorless oil (29.8 mg, 63% yield). ½a25 D ¼ þ1:7 (c 1.83, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 4.6 min, tminor = 5.8 min, 72% ee. 1H NMR (400 MHz, CDCl3): d 3.05 (q, J = 6.4 Hz, 1H, CH), 2.75 (dd, J1 = 16.0 Hz, J2 = 1.6 Hz, 1H, CH2), 2.60 (dd, J1 = 16.0 Hz, J2 = 6.8 Hz, 1H, CH2), 2.43 (ABq, J = 17.6 Hz, 2H, CH2), 2.31 (ABq, J = 16.4 Hz, 2H, CH2), 1.42–1.35 (m, 2H, CH2), 1.29–1.22 (m, 2H, CH2), 1.12 (s, 3H, CH3), 1.10 (s, 3H, CH3), 0.89 (t, J = 6.8 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.6, 167.0, 165.0, 117.4, 50.5, 40.8, 35.6, 33.5, 32.4, 28.6, 27.7, 19.6, 13.9 ppm. Lit.8 ½a25 D ¼ þ6:3 (c 0.38, CHCl3) 91% ee. 4.3.11. (R)-4-Phenyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 5a Compound 5a was obtained according to general procedure A as a white solid (46.5 mg, 96% yield), mp 112–113 °C. ½a25 D ¼ þ80:8 (c 1.54, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 7.0 min, tminor = 9.6 min, 72% ee. 1H NMR (400 MHz, CDCl3): d 7.30–7.20 (m, 3H, ArH), 7.15 (d, J = 7.6 Hz, 2H, ArH), 4.31 (d, J = 2.8 Hz, 1H, CH), 2.93 (ABq, J = 15.2 Hz, 2H, CH2), 2.73–2.59 (m, 2H, CH2), 2.44 (t, J = 6.4 Hz, 2H, CH2), 2.15–2.04 (m, 2H, CH2) ppm. 13C NMR (100 MHz, CDCl3): d 196.2, 167.3, 165.8, 140.4, 128.9, 127.3, 126.4, 117.1, 36.6, 36.1, 33.6, 27.2, 20.5 ppm. IR (KBr): m 3086, 3061, 3029, 2953, 2900, 2875, 1785, 1725, 1651, 1601, 1585, 1494, 1454, 1426, 1417, 1376, 1338, 1301, 1274, 1243, 1214, 1194, 1171, 1140, 1107, 1062, 1031, 1014, 961, 916, 879, 859, 841, 772, 734, 714, 700, 542, 525 cm1. HRMS (ESI): m/ z calcd for C15H15O3 [M+H]+ 243.10157, found: 243.10210. 4.3.12. (S)-4-Methyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 5b8 Compound 5b was obtained according to general procedure A as a white solid (31.3 mg, 87% yield), mp 135–137 °C. ½a25 D ¼ 7:0 (c 1.36, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 6.7 min, tminor = 9.1 min, 60% ee. 1H NMR (400 MHz, CDCl3): d 3.18–3.11 (m, 1H, CH), 2.69 (dd, J1 = 15.8 Hz, J2 = 6.8 Hz, 1H, CH2), 2.61 (dd, J1 = 15.6 Hz, J2 = 2.0 Hz, 1H, CH2), 2.56 (t, J = 6.4 Hz, 2H, CH2), 2.46–2.43 (m, 2H, CH2), 2.10–2.04 (m, 2H, CH2), 1.06 (d, J = 6.8 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.6, 166.5, 166.4, 119.2, 109.7, 36.6, 35.9, 27.1, 23.4, 23.4, 20.6, 19.3 ppm. 4.3.13. (R)-4-Phenyl-3,4-dihydropyrano[3,2-c]chromene-2,5dione 7a8 Compound 7a was obtained according to the general procedure B as a white solid (45.0 mg, 77% yield), mp 143–145 °C. ½a25 D ¼ 23:5 (c 2.15, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 12.7 min, tminor = 17.7 min, 23% ee. 1H NMR (400 MHz, CDCl3): d 7.90 (d, J = 8.0 Hz, 1H, ArH), 7.61 (t, J = 7.6 Hz, 1H, ArH), 7.39–7.24 (m, 7H, ArH), 4.53 (d, J = 7.2 Hz, 1H, CH), 3.21 (dd, J1 = 16.2 Hz, J2 = 7.6 Hz, 1H, CH2), 3.13 (d, J = 16.0 Hz, 1H, CH2) ppm. 13C NMR (100 MHz, CDCl3): d 164.2, 160.7, 157.2, 153.0, 139.3, 132.9, 129.2, 127.9, 126.5, 124.6, 122.7, 116.8, 113.4, 106.2, 35.9, 35.8 ppm. Lit.8 ½a25 D ¼ 164:86 (c 0.33, CHCl3) 91% ee. 4.3.14. (S)-4-Methyl-3,4-dihydropyrano[3,2-c]chromene-2,5dione 7b8 Compound 7b was obtained according to general procedure B as a white solid (41.4 mg, 90% yield), mp 124–126 °C. ½a25 D ¼ 19:2 (c
2.02, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 10.3 min, tminor = 12.2 min, 50% ee. 1H NMR (400 MHz, CDCl3): d 7.75 (d, J = 7.2 Hz, 1H, ArH), 7.52 (t, J = 8.4 Hz, 1H, ArH), 7.29–7.21 (m, 2H, ArH), 3.35–3.28 (m, 1H, CH), 2.89 (dd, J1 = 15.8 Hz, J2 = 7.2 Hz, 1H, CH2), 2.76 (dd, J1 = 15.8 Hz, J2 = 1.6 Hz, 1H, CH2), 1.22 (d, J = 7.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 164.8, 160.8, 156.3, 152.7, 132.5, 124.5, 122.4, 116.7, 113.5, 108.3, 35.6, 25.6, 19.1 ppm. Lit.8 ½a25 D ¼ 55:00 (c 0.32, CHCl3) 93% ee. 4.3.15. (R)-7-Methyl-4-(p-tolyl)-3,4-dihydropyrano[4,3-b]pyran2,5-dione 9a Compound 9a was obtained according to general procedure B as a white solid (41.1 mg, 76% yield), mp 117–118 °C. ½a25 D ¼ þ9:1 (c 1.77, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 10.2 min, tminor = 13.2 min, 19% ee. 1H NMR (400 MHz, CDCl3): d 7.12–7.07 (m, 4H, ArH), 5.99 (s, 1H, CH), 4.32 (dd, J1 = 6.8 Hz, J2 = 2.4 Hz, 1H, CH), 3.10–2.99 (m, 2H, CH2), 2.30 (s, 3H, CH3), 2.28 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 164.8, 163.3, 162.5, 161.5, 137.5, 136.6, 129.8, 126.3, 103.5, 98.8, 36.0, 34.7, 21.0, 20.1 ppm. IR (KBr): m 3092, 3023, 2961, 2923, 1796, 1717, 1656, 1597, 1514, 1445, 1410, 1394, 1319, 1273, 1215, 1187, 1133, 1102, 1037, 1022, 992, 956, 872, 817, 779, 740, 607, 557, 541 cm1. HRMS (ESI): m/z calcd for C16H15O4 [M+H]+ 271.09649, found: 271.09709. 4.3.16. (S)-4,7-Dimethyl-3,4-dihydropyrano[4,3-b]pyran-2,5dione 9b8 Compound 9b was obtained according to general procedure B as a white solid (35.7 mg, 92% yield), mp 132–135 °C. ½a25 D ¼ þ8:1 (c 0.15, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 8.2 min, tminor = 9.9 min, 46% ee. 1H NMR (400 MHz, CDCl3): d 5.87 (s, 1H, CH), 3.18–3.14 (m, 1H, CH), 2.77 (dd, J1 = 15.8 Hz, J2 = 7.2 Hz, 1H, CH), 2.66 (dd, J1 = 16.0 Hz, J2 = 2.0 Hz, 1H, CH), 2.21 (s, 3H, CH3), 1.15 (d, J = 7.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 165.2, 162.6, 160.8, 105.2, 98.8, 35.7, 24.9, 20.0, 19.0 ppm. Lit.8 ½a25 D ¼ þ15:60 (c 0.35, CHCl3) 98% ee. 4.3.17. (R)-5-Acetyl-3,4-dihydro-6-methyl-4-phenylpyran-2-one 11a21 Compound 11a was obtained according to general procedure B as a white solid (22.1 mg, 48% yield), mp 102–104 °C. ½a25 D ¼ 89:1 (c 0.18, CH2Cl2); HPLC (Daicel Chiralpak IB column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tminor = 6.5 min, tmajor = 7.4 min, 29% ee. 1H NMR (400 MHz, CDCl3): d 7.35–7.29 (m, 3H, ArH), 7.15 (d, J = 6.8 Hz, 2H, ArH), 4.15 (d, J = 7.6 Hz, 1H, CH), 2.97 (dd, J1 = 15.8 Hz, J2 = 7.2 Hz, 1H, CH2), 2.83 (dd, J1 = 15.8 Hz, J2 = 2.4 Hz, 1H, CH2), 2.43 (s, 3H, CH3), 2.12 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 197.8, 165.6, 160.2, 139.6, 129.4, 127.9, 126.6, 117.2, 38.8, 37.1, 29.7, 19.0 ppm. Lit.21 ½a20 D ¼ 116:1 (c 1.0, CHCl3) 92% ee. Acknowledgments We are grateful for financial support from the National Natural Science Foundation of China (Grant No. 21272024). References 1. Seo, E. K.; Wani, M. C.; Wall, M. E.; Navarro, H.; Mukherjee, R.; Farnsworth, N. R.; Kinghorn, A. D. Phytochemistry 2000, 55, 35–42. 2. Mazumder, A.; Wang, S.; Neamati, N.; Nicklaus, M.; Sunder, S.; Chen, J.; Milne, G. W. A.; Rice, W. G.; Burke, T. R., Jr.; Pommier, Y. J. Med. Chem. 1996, 39, 2472–2481.
B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317 3. Mason, C. P.; Edwards, K. R.; Carlson, R. E.; Pignatello, J.; Gleason, F. K.; Wood, J. M. Science 1982, 215, 400–402. 4. Tori, M.; Shiotani, Y.; Tanaka, M.; Nakashima, K.; Sono, M. Tetrahedron Lett. 2000, 41, 1797–1799. 5. Zhao, H.; Neamati, N.; Hong, H.; Mazumder, A.; Wang, S.; Sunder, S.; Milne, G. W. A.; Pommer, Y.; Burke, T. R., Jr. J. Med. Chem. 1997, 40, 242–249. 6. Wang, S.; Milne, G. W. A.; Yan, X.; Posey, I. J.; Nicklaus, M. C.; Graham, L.; Rice, W. G. J. Med. Chem. 1996, 39, 2047–2054. 7. Schultz, A. G.; Pettus, L. J. Org. Chem. 1997, 62, 6855–6861. 8. Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7, 979–981. 9. Lee, Y. J.; Tseng, T. H.; Lee, Y. J. Synthesis 2001, 2247–2254. 10. Speranza, G.; Morelli, C. F.; Manitto, P. Synthesis 2000, 123–126. 11. de la Hoz, A.; Moreno, A.; Vázquez, E. Synlett 1999, 608–610. 12. Speranza, G.; Di Meo, A.; Zanzola, S.; Fontana, G.; Manitto, P. Synthesis 1997, 931–936.
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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of enol lactones from tandem Michael addition/lactonization catalyzed by a chiral squaramide catalyst Bo-Liang Zhao, Da-Ming Du ⇑ School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 6 November 2013 Accepted 7 January 2014
a b s t r a c t The enantioselective tandem Michael addition reaction of dimedone and related 1,3-dicarbonyl compounds with a,b-unsaturated N-acylated succinimides catalyzed by a chiral squaramide catalyst has been investigated. This reaction provides a new approach for the synthesis of chiral enol lactones in good yields with moderate to high enantioselectivities (up to 88% ee) through the enantioselective Michael addition followed by lactonization and removal of the succinimide auxiliary. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Enol lactones, such as the derivatives of coumarin, flavonoids, and neoflavonoids, are present in a number of biologically active natural products and have strong biological activity.1,2 Many compounds contain the exocyclic enol lactone substructure3 or endocyclic enol lactone ring.4 A recent report on a tetrameric 4-hydroxycoumarin-derived inhibitor provided a lead example of an HIV integrase inhibitor.5 Coumarin derivatives and related enol lactones were also found to be very efficient non-peptide HIV-1 protease inhibitors.6 In addition, endocyclic enol lactones are also useful intermediates in the synthesis of more complex natural products. Endocyclic enol lactones with optical activity have more potential value with bio-availability such as the alkaloid ()-aspidospermidine.7 However, there are few reports on the synthesis of enol lactone derivatives.8–14 Reports on the synthesis of optically active enol lactone compounds are even more rare; Kanemasa et al. reported on the reaction of dimedone with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles catalyzed by catalytic amounts of both DBFOX/Ph-nickel-(II) perchlorate trihydrate and 2,2,6,6-tetramethylpiperidine to produce the corresponding enol lactones with high enantioselectivities through enantioselective Michael addition followed by cyclization with removal of the pyrazole auxiliary.8 Therefore, to find effective and convenient methods to access optically active enol lactone compounds is of great significance and a major challenge in synthetic organic chemistry. Herein we report one effective synthetic approach to enol lactone systems via Michael addition reaction of dimedone and related 1,3-dicarbonyl compounds with a,b-unsaturated N-acylated succinimides, which rarely reported as a Michael receptor, by the catalysis of chiral squaramide organocatalyst.
We first evaluated the reaction between 5,5-dimethylcyclohexane-1,3-dione (dimendone) 1 and 1-cinnamoylpyrrolidine-2,5-dione 2a. When 5 mol % of squaramide I15 derived from hydroquinine was used, product 3a was obtained in 96% yield and with 66% ee in CH2Cl2 at room temperature for 48 h. For the sake of comparison, N-cinnamoyl pyrazole and N-cinnamoyl oxazolidinone were also examined in this reaction under the same reaction conditions. However, we found that N-cinnamoyl pyrazole as the reactant afforded the product 3a in 21% yield and 94% ee. N-Cinnamoyl oxazolidinone as the reactant did not afford the target product. We found that 2a had better reactivity. Considering the yield, enantioselectivity, and novelty of the Michael acceptor, we chose 1-cinnamoylpyrrolidine-2,5-dione 2a as the reactant. Next, we performed an optimization of the model reaction between 5,5-dimethylcyclohexane-1,3-dione (dimendone) 1 and 1-cinnamoylpyrrolidine-2,5-dione 2a. A series of chiral squaramide or thiourea catalysts I–VII were investigated in this reaction (Fig. 1). When squaramide I or II derived from hydroquinine was used, product 3a was obtained with similar yield and enantioselectivity (Table 1, entries 1 and 2). Cinchonidine derived squaramide III16 gave a slightly lower enantioselectivity than squaramides I and II. The C2-symmetric squaramide IV17 was also evaluated, but no improved enantioselectivity was observed (Table 1, entry 4). In contrast, the corresponding thiourea V or squaramide VI18 derived from (1S,2S)-cyclohexane-1,2diamine afforded lower enantioselectivity (Table 1, entries 5 and 6). The new squaramide VII19 derived from aminoglucopyranose and hydroquinine was tested, the enantioselectivity was enhanced but with a slightly lower yield (Table 1, entry 8). After screening different catalysts, using squaramide I as a catalyst was found to be the best in terms of enantioselectivity and yield. Therefore, further optimizations were carried out using squaramide I as the catalyst. In order to enhance the enantioselectivity of the desired product, further screening of reaction parameters such as the solvent,
⇑ Corresponding author. Tel./fax: +86 10 68914985. E-mail address: [email protected] (D.-M. Du). 0957-4166/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2014.01.005
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B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317
O O
Ar
OMe
O H
N H
CF3
N
N H
NH H
OMe
MeO
CF3
IV
O
OAc
O
O
OMe
CF3
N H
H
N
N III
II: Ar = 4-CF3C6H4
S
N
HN
N
I: Ar = 3,5-(CF3)2C6H3
F3C
H
N
N
N H
N H
F 3C
N
O H
O
O
AcO AcO
N F3C
N H
N H
N H
O
O
H HN
NH
N
OAc
N
OMe
N
V
VII
VI
N
Figure 1. Structures of chiral squaramides and thioureas.
Table 1 Screening of different chiral catalysts O
O +
Table 2 Optimization of reaction conditions Ph
O Ph
N
+ O
Entrya
Catalyst
1 2 3 4 5 6 7
I II III IV V VI VII
1
3a
2a
Yieldb (%) 96 94 94 91 91 92 86
Ph
O
N
Ph
eec (%) 66 66 59 42 11 17 69
a Reaction conditions: 5,5-dimethylcyclohexane-1,3-dione 1 (0.3 mmol) and 1cinnamoylpyrrolidine-2,5-dione 2a (0.2 mmol) in CH2Cl2 (0.5 mL) with 5 mol % catalyst for 36–48 h at room temperature. b Determined by HPLC on a Daicel Chiralpak AD-H column (n-hexane/2-propanol = 90:10, 1.0 mL/min). c Determined by HPLC on a Daicel Chiralpak AD-H column.
catalyst loading, and temperature was investigated. When the reaction was performed in acetonitrile, product 3a was obtained in 88% yield but with low enantioselectivity (40% ee). When toluene was used as the solvent, a significant improvement in the enantioselectivity was realized (Table 2, entry 2). Other solvents such as CHCl3, THF, or ClCH2CH2Cl afforded moderate enantioselectivities. After a brief screening of the solvent, toluene was found to be the best. The enantioselectivity and yield of the product 3a decreased slightly when decreasing the catalyst loading to 2.5 mol %. The yield of product 3a was improved slightly by increasing the catalyst loading to 10 mol % (Table 2, entry 9). Increasing the reaction temperature to 50 °C led to a decrease in the enantioselectivity. The enantioselectivity and yield both drastically decline when lowering the temperature to 10 °C. Hence we selected 10 mol % catalyst loading at room temperature for 48 h, with toluene as the solvent, as the optimum reaction conditions. After optimization of the reaction conditions, the substrate scope for the enantioselective enol lactone synthesis from dimedone 1 with 1-(2-alkenoyl)-pyrrolidine-2,5-dione 2a–j was
O
5 mol % I solvent
O
O
O 1
O
5 mol % catalyst CH2Cl2, rt, 36-48 h
O
O
O
O
O 2a
Entrya
Solvent
1 2 3 4 5 6 7 8d 9e 10f 11g
CH3CN Toluene Xylene a,a,a-Trifluorotoluene CHCl3 ClCH2CH2Cl THF Toluene Toluene Toluene Toluene
O 3a
Yieldb (%) 88 94 89 91 91 86 94 92 97 90 42
eec (%) 40 86 86 78 64 66 64 76 85 78 17
a Reaction conditions: unless noted otherwise, reactions were carried out with 5,5-dimethylcyclohexane-1,3-dione 1 (0.3 mmol) and 1-cinnamoylpyrrolidine-2,5dione 2a (0.2 mmol) in 0.5 mL of solvent with 5 mol % catalyst I for 48 h at room temperature. b Isolated yields by column chromatography. c Determined by HPLC on Daicel Chiralpak AD-H column (n-hexane/2-propanol = 90:10, 1.0 mL/min). d The reaction was conducted with 2.5 mol % catalysts loading for 72 h. e The reaction was conducted with 10 mol % catalyst loading. f The reaction was performed at 50 °C for 30 h with 10 mol % catalyst loading. g The reaction was performed at 10 °C for 144 h with 10 mol % catalyst loading.
explored. The reactions of dimedone 1 (1.5 equiv) with a,b-unsaturated N-acylated succinimide 2a–j afforded 7,7-dimethyl-4,6,7,8tetrahydro-3H-chromene-2,5-dione 3a–j in high yield (up to 97%) and with moderate to high enantioselectivities (up to 88% ee) as shown in Table 3. Electron-withdrawing and electron-rich substituents in the benzene ring of 2 (Table 3, entries 2–6) gave satisfactory results. As the alkyl chain increased in length at the b-substituted position of 2 (Table 3, entries 8–10), the enantioselectivity and yield decreased. The absolute configuration of enol lactones 3a and 3c–j was assigned according to the literature.8 Other Michael donors, such as cyclohexane-1,3-dione 4, 4-hydroxycoumarin 6, 4-hydroxy-6-methyl-2H-pyran-2-one 8, and acyclic acetoacetone 10 were also investigated in order to
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B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317
However, there was no improvement in the corresponding enantioselectivity. Cyclopentane-1,3-dione and cycloheptane-1,3-dione were also examined; these reactions produced a lot of by-products. This phenomenon may be ascribed to the increased ring tension, which means that the target products were not easy to generate. The main products were also unstable. The main product of these corresponding reactions cannot be obtained by column chromatography, which may be due to the enol lactone ring being too easy to open under the catalysis of silica gel. The experimental results indicated that the two methyl groups of 5,5-dimethylcyclohexane-1,3-dione play a very important role in the enantioselective process of the reaction. As a comparison, cyclohexane-1,3-dione 4, which lacks the two methyl groups gave lower enantioselectivities (Table 4, entries 1 and 2). The reactions of 6, 8, and 10 with a,b-unsaturated N-acylated succinimide 2 gave the corresponding products 7, 9, and 11 in low to moderate enantioselectivities (Table 4, entries 3–7). The tentative proposed reaction mechanism to explain the enantioselective generation of the final product 3a is shown in Figure 2. Squaramide I activates the 1-cinnamoylpyrrolidine-2,5dione 2a through a double hydrogen bonding interaction, while the dimendone 1 is activated by the tertiary nitrogen of the quinuclidine. The enolate anion attacks the 1-cinnamoylpyrrolidine-2,5dione from the Si-face via transition state A to form the Michael adduct intermediate B. Subsequent intramolecular protonation and tautomerization of B gave enolate transition state C. The final step involved the cyclization of C with the removal of succinimide auxiliary to give enol lactone 3a.
Table 3 Chiral squaramide-catalyzed enantioselective synthesis of a variety of enol lactones O
R
O
O
O 10 mol % I
N
+
R
O
toluene, rt
O
O
O 1
a b
3a-j
2a-j
Entry
R
Time (h)
1 2 3 4 5 6 7 8 9 10
Ph 2-ClC6H4 4-BrC6H4 4-MeOC6H4 4-O2NC6H4 4-MeC6H4 2-Furyl Me Et n-Pr
48 48 60 60 48 72 48 24 96 120
Yielda (%)
Product 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j
97 88 93 95 78 83 73 96 71 63
eeb (%) 85 54 88 85 70 80 88 77 69 72
Isolated yields by column chromatography. Determined by HPLC using a chiral column.
explore the generality of this reaction. The Michael reactions of these donors to acceptors 2 can also be performed successfully, affording the corresponding enol lactones 5, 7, 9, and 11, respectively (Table 4), although the enantioselectivities were not very good in most reactions. As a result, we changed the reaction conditions, such as the temperature, solvents and using other catalysts.
Table 4 Enantioselective synthesis of other enol lactones
donor 4, 6, 8 or 10
Entry
Donor
Reactant 2
+
2
10 mol % I
Product Ph
O
1c
enol lactone 5, 7, 9 or 11
toluene
O
Yielda (%)
eeb (%)
48
96
72
48
87
60
48
77
23
24
90
50
O
2a O
Time (h)
O 5a
4 O
Me
2c
O
2h O
O
O 5b
4 Ph
OH
O O
3d
O
O
2a
O
O
6 7a OH
Me
O O
4d
O
O
2h
O
O
6 7b
313
B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317 Table 4 (continued) Entry
Donor
Reactant 2
Product
OH
R
Time (h)
Yielda (%)
eeb (%)
48
76
19
24
92
46
48
48
29
O O
5d
Me
O
2f
O
O
O
Me 9a
8
R = 4-MeC6H4 OH
O
Me
O
6d
2h Me
O
O
O
O
Me 9b
8 O
7d
Ph
O
O
2a
10
O
O 11a
a b c d
Isolated yields by column chromatography. Determined by HPLC using a chiral column. Reactions were carried out with cyclohexane-1,3-dione 4 (0.3 mmol) and 2 (0.2 mmol) in toluene (0.5 mL) with catalyst I at room temperature. Reactions were carried out with 6, 8 or 10 (0.3 mmol), and 2 (0.2 mmol) in toluene (0.5 mL) with catalyst I at 50 °C.
CF3
F3C
Ph
O
N O
O
N
N
H
H
H
OMe
N
O
2a
N
O 3a
O
H
H
O
O
1
I
OH
N N
O
H
H
H
O
O O
H
H
H
O
O N N Ph O
O Ph
O
C
O
N H
H
H
A Si-face attack
O
O
O
H
N O
Ph O B
Figure 2. Proposed reaction mechanism.
3. Conclusion In conclusion, we have developed a convenient synthesis for a variety of chiral enol lactones through the enantioselective tandem Michael addition/lactonization reaction of various nucleophile precursors to a,b-unsaturated N-acylated succinimides by
the catalysis of a chiral squaramide catalyst, and the corresponding products were obtained in high yield (up to 97%) and with moderate to good enantioselectivity (up to 88% ee). This reaction provides a very simple and valuable method to synthesize enol lactones using 1,3-dicarbonyl compounds as the raw materials.
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B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317
4. Experimental 4.1. General Unless otherwise noted, commercially available compounds were used without further purification. Column chromatography was carried out with silica gel (200–300 mesh). Melting points were measured with a melting point apparatus without correction. 1 H NMR spectra were recorded with a Varian Mercury-plus 400 MHz spectrometer. Chemical shifts were reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The data are reported as follows: chemical shift (ppm), and multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad singlet), coupling constant(s) in Hz, integration assignment. 13C NMR spectra were recorded at 100 MHz. Infrared spectra were obtained with a Perkin Elmer Spectrum One spectrometer. The high resolution MS spectra were obtained with ESI ionization using a Bruker APEX IV FTMS spectrometer. Optical rotations were measured with a WZZ-3 polarimeter at the indicated concentration with units g/100 mL. The enantiomeric excesses were determined by chiral HPLC using an Agilent 1200 LC instrument with a Daicel Chiralpak column AD-H or IB. 4.2. Materials Chiral squaramide catalysts I,15 III,16 IV,17 VI,18 and VII19 were prepared according to the reported procedures. Cyclic diketones, 4-hydroxycoumarin, 4-hydroxy-6-methyl-2H-pyran-2-one, and pyrrolidine-2,5-dione were purchased from commercial supplies. The racemic reference compounds were synthesized by the direct treatment of 1-(2-alkenoyl)-pyrrolidine-2,5-dione 2 with 1, 4, 6, 8, or 10 in the presence of triethylamine.
1.57–1.36 (m, 7H), 0.81 (t, J = 7.2 Hz, 1H), 0.66 (br s, 1H) ppm; 13 C NMR (100 MHz, DMSO-d6): d 184.6, 179.7, 168.4, 163.1, 157.8, 147.7, 144.3, 143.0, 142.3, 131.5, 127.4, 126.50, 126.46, 124.3 (q, 1JC–F = 270.2 Hz), 122.5 (q, 2JC–F = 32.0 Hz), 121.8, 118.0, 101.3, 57.1, 55.6, 40.2, 36.6, 27.8, 26.8, 25.7, 24.9, 11.8 ppm; IR (KBr): m 3226, 3184, 3002, 2962, 2940, 2869, 1800, 1675, 1655, 1621, 1606, 1575, 1542, 1513, 1475, 1460, 1443, 1420, 1377, 1329, 1322, 1269, 1241, 1192, 1172, 1162, 1119, 1070, 1042, 1016, 840, 826, 767, 728, 715, 681, 637 cm1; HRMS (ESI): m/z calcd for C31H32F3N4O3 [M+H]+ 565.24210, found 565.24180. 4.2.2. General procedure for the preparation of a,b-unsaturated N-acylated succinimide Under argon, a mixture of pyrrolidine-2,5-dione (2.97 g, 30 mmol) and pyridine (2.54 mL, 31.5 mmol) in anhydrous dichloromethane (50 mL) was added dropwise to crotonoyl chloride (2.55 mL, 31.5 mmol) in dichloromethane (100 mL) at 0 °C for more than half an hour, after which the mixture was stirred for 3 h at 0 °C. Next, the reaction mixture was allowed to warm to room temperature for 48 h. The reaction mixture was then poured into saturated sodium hydrogen carbonate and extracted with dichloromethane. The combined organic layers were washed with 30 mL of hydrochloric acid solution (1 M), brine, dried over magnesium sulfate, and concentrated in vacuo. The crude residue was passed through a flash silica gel column by eluting with dichloromethane to provide analytically pure 2f (3.3 g, 66%). Other unsaturated imide substrates were prepared according to a similar procedure from pyrrolidine-2,5-dione and the corresponding (E)-2-alkenoyl chlorides 4.3. General procedure for the enantioselective synthesis of enol lactones
4.2.1. Synthesis of organocatalysts II O
F3C
O
NH2
F3C
MeOH
+ MeO
48 h, rt
OMe
O
O
N H
OMe
H H2N
N OMe F3C
OMe
O
O
N H
N H
H
N
N CH2Cl2, 48 h, rt
N
II
In a 25 mL round-bottomed flask, 4-(trifluoromethyl)aniline (0.805 g, 5.0 mmol) was added to dimethyl squarate (0.71 g, 5.0 mmol) which was dissolved in 10 mL of methanol. The mixture was then stirred at room temperature for 48 h, after which the precipitate was filtered to afford the mono-squaramide as a white solid (1.06 g, 78% yield). To a solution of hydroquinine derivatives (325 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added mono-squaramide (272 mg, 1 mmol). After stirring for 48 h at room temperature, squaramide catalyst II was obtained by filtration as a white solid (480 mg, 85% yield). Mp 203–205 °C (decomp.), 1 ½a28 H NMR (400 MHz, DMSO-d6): d D ¼ 72:7 (c 0.30, DMSO). 10.07 (br s, 1H), 8.88 (d, J = 4.4 Hz, 1H), 8.41 (br s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.83 (br s, 1H), 7.74 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.48 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 6.09 (br s, 1H), 4.01 (s, 3H), 3.53–3.35 (m, 4H), 3.21–3.16 (m, 1H), 2.66 (br s, 1H), 2.50 (d, J = 12.8 Hz, 1H),
Procedure A: To a dried small bottle were added a,b-unsaturated N-acylated succinimide 2 (0.2 mmol) and catalyst I (12.6 mg, 0.02 mmol, 10 mol %), followed by the addition of toluene (0.5 mL). The mixture was stirred at room temperature for 15 min, then 5,5-dimethylcyclohexane-1,3-dione 1 (0.3 mmol) or cyclohexane-1,3-dione 4 (0.3 mmol) was added in one portion. After stirring at room temperature for 48–120 h, the reaction mixture was concentrated and purified directly by silica gel column chromatography to afford the desired product 3 or 5. Procedure B: To a dried small bottle were added a,b-unsaturated N-acylated succinimide 2 (0.2 mmol) and catalyst I (12.6 mg, 0.02 mmol, 10 mol %), followed by the addition of toluene (0.5 mL). The mixture was stirred at 50 °C for 15 min, then 4hydroxycoumarin 6 (0.3 mmol) or 4-hydroxy-6-methyl-2H-pyran-2-one 8 (0.3 mmol) was added in one portion. After stirring at 50 °C for 24–48 h, the reaction mixture was concentrated and purified directly by silica gel column chromatography to afford the desired products 7 or 9. 4.3.1. (R)-7,7-Dimethyl-4-phenyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 3a8 Compound 3a was obtained according to general procedure A as a white solid (52.4 mg, 97% yield), mp 110–112 °C. ½a25 D ¼ 98:8 (c 2.14, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 90:10, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 9.0 min, tminor = 16.2 min, 85% ee. 1H NMR (400 MHz, CDCl3): d 7.30–7.14 (m, 5H, ArH), 4.30 (t, J = 4.0 Hz, 1H, CH), 2.93 (t, J = 2.8 Hz, 2H, CH2), 2.53 (s, 2H, CH2), 2.32 (s, 2H, CH2), 1.15 (s, 3H, CH3), 1.10 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.1, 165.9, 165.7, 140.5, 129.0, 127.4, 126.4, 116.0, 50.5, 40.9, 36.3, 33.7, 32.5, 28.5, 28.1 ppm. Lit.8 ½a25 D ¼ 131:18 (c 0.51, CHCl3) 99% ee.
B.-L. Zhao, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 310–317
4.3.2. (S)-4-(2-Chlorophenyl)-7,7-dimethyl-4,6,7,8-tetrahydro3H-chromene-2,5-dione 3b20 Compound 3b was obtained according to general procedure A as a white solid (53.6 mg, 88% yield), mp 115–116 °C. ½a25 D ¼ 36:5 (c 0.48, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 4.9 min, tminor = 5.7 min, 54% ee. 1H NMR (400 MHz, CDCl3): d 7.39 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 1H, ArH), 7.20–7.13 (m, 2H, ArH), 6.91 (dd, J1 = 7.0 Hz, J2 = 2.0 Hz, 1H, ArH), 4.74 (t, J = 4.4 Hz, H, CH), 2.94 (s, 1H, CH2), 2.92 (d, J = 1.6 Hz, 1H, CH2), 2.60 (s, 1H, CH2), 2.59 (d, J = 1.2 Hz, 1H, CH2), 1.98 (s, 2H, CH2), 1.18 (s, 3H, CH3), 1.17 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 195.5, 166.9, 165.3, 137.0, 133.4, 130.5, 128.9, 127.3, 126.7, 114.7, 50.5, 41.1, 35.2, 32.5, 31.2, 28.5, 28.4 ppm. 4.3.3. (R)-4-(4-Bromophenyl)-7,7-dimethyl-4,6,7,8-tetrahydro3H-chromene-2,5-dione 3c8 Compound 3c was obtained according to general procedure A as a white solid (64.9 mg, 93% yield), mp 173–174 °C. ½a25 D ¼ 27:7 (c 1.43, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/ 2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 7.5 min, tminor = 16.5 min. 88% ee. 1H NMR (400 MHz, CDCl3): d 7.33 (d, J = 8.4 Hz, 2H, ArH), 6.96 (d, J = 8.4 Hz, 2H, ArH), 4.17 (d, J = 6.8 Hz, 1H, CH), 2.90–2.78 (m, 2H, CH2), 2.45 (s, 2H, CH2), 2.23 (s, 2H, CH2), 1.06 (s, 3H, CH3), 1.01 (s, 3H, CH3) ppm. 13 C NMR (100 MHz, CDCl3): d 196.0, 165.9, 165.5, 139.5, 132.1, 128.2, 121.3, 115.5, 50.4, 40.9, 35.9, 33.3, 32.5, 28.5, 28.0 ppm. Lit.8 ½a25 D ¼ 130:8 (c 0.51, CHCl3) >99% ee. 4.3.4. (R)-4-(4-Methoxyphenyl)-7,7-dimethyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 3d Compound 3d was obtained according to general procedure A as a white solid (57.0 mg, 95% yield), mp 138–139 °C. ½a25 D ¼ 76:9 (c 2.04, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 8.6 min, tminor = 15.9 min, 85% ee. 1 H NMR (400 MHz, CDCl3): d 7.07 (d, J = 8.4 Hz, 2H, ArH), 6.80 (d, J = 8.0 Hz, 2H, ArH), 4.24 (d, J = 6.0 Hz, 1H, CH), 3.75 (s, 3H, CH3), 2.90 (d, J = 6.4 Hz, 2H, CH2), 2.52 (s, 2H, CH2), 2.31 (s, 2H, CH2), 1.14 (s, 3H, CH3), 1.10 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.2, 166.2, 165.5, 158.8, 132.6, 127.6, 116.4, 114.4, 109.7, 55.2, 50.6, 41.0, 36.6, 33.0, 32.6, 28.6, 28.1 ppm. IR (KBr): m 3004, 2963, 2931, 2887, 2875, 1772, 1738, 1671, 1653, 1607, 1582, 1510, 1466, 1422, 1376, 1314, 1306, 1278, 1247, 1239, 1176, 1159, 1114, 1100, 1035, 1009, 964, 860, 840, 818, 809, 764, 750, 661, 627, 603 cm1. HRMS (ESI): m/z calcd for C18H21O4 [M+H]+ 301.14344, found: 301.14392. 4.3.5. (R)-7,7-Dimethyl-4-(4-nitrophenyl)-4,6,7,8-tetrahydro3H-chromene-2,5-dione 3e Compound 3e was obtained according to general procedure A as a white solid (49.2 mg, 78% yield), mp 139–141 °C. ½a25 D ¼ 92:4 (c 1.50, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/ 2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 14.1 min, tminor = 41.7 min, 70% ee. 1H NMR (400 MHz, CDCl3): d 8.08 (d, J = 8.4 Hz, 2H, ArH), 7.27 (d, J = 8.8 Hz, 2H, ArH), 4.33 (d, J = 7.6 Hz, 1H, CH), 2.97 (dd, J1 = 16.2 Hz, J2 = 8.0 Hz, 1H, CH2), 2.86 (d, J = 16.0 Hz, 1H, CH2), 2.49 (s, 2H, CH2), 2.26 (s, 2H, CH2), 1.09 (s, 3H, CH3), 1.02 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.0, 166.5, 165.0, 147.9, 147.1, 127.6, 124.3, 114.9, 50.3, 40.9, 35.5, 33.7, 32.5, 28.5, 28.0 ppm. IR (KBr): m 3111, 3078, 2961, 2931, 2892, 2873, 1789, 1735, 1655, 1599, 1521, 1494, 1469, 1415, 1372, 1348, 1311, 1277, 1238, 1216, 1181, 1161, 1101, 1038, 1015, 969, 925, 857, 816, 783, 763, 737,
315
697, 615, 603, 584 cm1. HRMS (ESI): m/z calcd for C17H18NO5 [M+H]+ 316.11795, found: 316.11870. 4.3.6. (R)-7,7-Dimethyl-4-(p-tolyl)-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 3f Compound 3f was obtained according to the general procedure A as a white solid (47.2 mg, 83% yield), mp 134–136 °C. ½a25 D ¼ 82:1 (c 1.03, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 6.6 min, tminor = 10.6 min, 80% ee. 1H NMR (400 MHz, CDCl3): d 7.09 (d, J = 8.0 Hz, 2H, ArH), 7.03 (d, J = 8.0 Hz, 2H, ArH), 4.26 (dd, J1 = 5.6 Hz, J2 = 3.2 Hz, 1H, CH), 2.91 (t, J = 3.6 Hz, 2H, CH2), 2.53 (s, 2H, CH2), 2.31 (s, 2H, CH2), 2.29 (s, 3H, CH3), 1.15 (s, 3H, CH3), 1.10 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.2, 166.1, 165.5, 137.5, 137.1, 129.7, 126.3, 116.2, 50.6, 41.0, 36.4, 33.4, 32.5, 28.5, 28.1, 21.0 ppm. IR (KBr): m 3026, 3004, 2960, 2927, 2873, 1786, 1733, 1668, 1655, 1514, 1466, 1414, 1373, 1333, 1314, 1291, 1272, 1270, 1180, 1161, 1102, 1036, 1017, 969, 859, 822, 737, 600, 549, 520 cm1. HRMS (ESI): m/z calcd for C18H21O3 [M+H]+ 285.14852, found: 285.14860. 4.3.7. (S)-7,7-Dimethyl-4-(furan-2-yl)-4,6,7,8-tetrahydro-3Hchromene-2,5-dione 3g8 Compound 3g was obtained according to the general procedure A as a white solid (38.0 mg, 73% yield), mp 78–79 °C. ½a25 D ¼ 24:8 (c 0.99, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 6.3 min, tminor = 9.0 min, 88% ee. 1H NMR (400 MHz, CDCl3): d 7.28 (d, J = 1.2 Hz, 1H, ArH), 6.24 (dd, J1 = 3.0 Hz, J2 = 2.0 Hz, 1H, ArH), 6.06 (d, J = 3.2 Hz, 1H, ArH), 4.37 (d, J = 7.2 Hz, 1H, CH), 3.06 (dd, J1 = 16.0 Hz, J2 = 1.6 Hz, 1H, CH2), 2.83 (dd, J1 = 16.0 Hz, J2 = 7.2 Hz, 1H, CH2), 2.48 (s, 2H, CH2), 2.33 (s, 2H, CH2), 1.14 (s, 3H, CH3), 1.08 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 195.6, 166.1, 165.4, 152.6, 142.2, 113.9, 110.2, 105.9, 50.4, 40.9, 33.6, 32.4, 28.5, 27.8, 27.7 ppm. Lit.8 ½a25 D ¼ 60:7 (c 0.74, CHCl3) 89% ee. 4.3.8. (S)-4,7,7-Trimethyl-4,6,7,8-tetrahydro-3H-chromene-2,5dione 3h8 Compound 3h was obtained according to general procedure A as a white solid (40.0 mg, 96% yield), mp 55–57 °C. ½a25 D ¼ 5:0 (c 2.09, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 90:10, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 7.2 min, tminor = 11.2 min, 77% ee. 1H NMR (400 MHz, CDCl3): d 3.17–3.10 (m, 1H, CH), 2.71–2.60 (m, 2H, CH2), 2.42 (ABq, J = 18.0 Hz, 2H, CH2), 2.31 (s, 2H, CH2), 1.12 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.07 (d, J = 7.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.5, 166.7, 164.7, 118.0, 50.6, 40.8, 36.0, 32.5, 28.5, 27.9, 23.3, 19.3 ppm. Lit.8 ½a25 D ¼ 8:7 (c 0.41, CHCl3) 98% ee. 4.3.9. (S)-4-Ethyl-7,7-dimethyl-4,6,7,8-tetrahydro-2H-chromene2,5-dione 3i8 Compound 3i was obtained according to general procedure A as a white solid (31.6 mg, 71% yield), mp 67–69 °C. ½a25 D ¼ þ4:6 (c 1.14, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 5.1 min, tminor = 7.6 min, 69% ee. 1H NMR (400 MHz, CDCl3): d 2.91 (q, J = 6.8 Hz, 1H, CH), 2.69 (d, J = 16.0 Hz, 1H, CH2), 2.53 (dd, J1= 16.2 Hz, J2 = 7.2 Hz, 1H, CH2), 2.36 (ABq, J = 18.0 Hz, 2H, CH2), 2.24 (ABq, J = 16.4 Hz, 2H, CH2), 1.48–1.38 (m, 1H, CH2), 1.32– 1.22 (m, 1H, CH2), 1.05 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.820 (t, J = 7.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.6, 167.0, 165.1, 117.0, 50.6, 40.8, 33.2, 32.4, 29.3, 28.6, 27.7, 26.5, 10.8 ppm. Lit.8 ½a25 D ¼ þ11:2 (c 0.34, CHCl3) 93% ee.
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4.3.10. (S)-7,7-Dimethyl-4-propyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 3j8 Compound 3j was obtained according to general procedure A as colorless oil (29.8 mg, 63% yield). ½a25 D ¼ þ1:7 (c 1.83, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 4.6 min, tminor = 5.8 min, 72% ee. 1H NMR (400 MHz, CDCl3): d 3.05 (q, J = 6.4 Hz, 1H, CH), 2.75 (dd, J1 = 16.0 Hz, J2 = 1.6 Hz, 1H, CH2), 2.60 (dd, J1 = 16.0 Hz, J2 = 6.8 Hz, 1H, CH2), 2.43 (ABq, J = 17.6 Hz, 2H, CH2), 2.31 (ABq, J = 16.4 Hz, 2H, CH2), 1.42–1.35 (m, 2H, CH2), 1.29–1.22 (m, 2H, CH2), 1.12 (s, 3H, CH3), 1.10 (s, 3H, CH3), 0.89 (t, J = 6.8 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.6, 167.0, 165.0, 117.4, 50.5, 40.8, 35.6, 33.5, 32.4, 28.6, 27.7, 19.6, 13.9 ppm. Lit.8 ½a25 D ¼ þ6:3 (c 0.38, CHCl3) 91% ee. 4.3.11. (R)-4-Phenyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 5a Compound 5a was obtained according to general procedure A as a white solid (46.5 mg, 96% yield), mp 112–113 °C. ½a25 D ¼ þ80:8 (c 1.54, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 7.0 min, tminor = 9.6 min, 72% ee. 1H NMR (400 MHz, CDCl3): d 7.30–7.20 (m, 3H, ArH), 7.15 (d, J = 7.6 Hz, 2H, ArH), 4.31 (d, J = 2.8 Hz, 1H, CH), 2.93 (ABq, J = 15.2 Hz, 2H, CH2), 2.73–2.59 (m, 2H, CH2), 2.44 (t, J = 6.4 Hz, 2H, CH2), 2.15–2.04 (m, 2H, CH2) ppm. 13C NMR (100 MHz, CDCl3): d 196.2, 167.3, 165.8, 140.4, 128.9, 127.3, 126.4, 117.1, 36.6, 36.1, 33.6, 27.2, 20.5 ppm. IR (KBr): m 3086, 3061, 3029, 2953, 2900, 2875, 1785, 1725, 1651, 1601, 1585, 1494, 1454, 1426, 1417, 1376, 1338, 1301, 1274, 1243, 1214, 1194, 1171, 1140, 1107, 1062, 1031, 1014, 961, 916, 879, 859, 841, 772, 734, 714, 700, 542, 525 cm1. HRMS (ESI): m/ z calcd for C15H15O3 [M+H]+ 243.10157, found: 243.10210. 4.3.12. (S)-4-Methyl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione 5b8 Compound 5b was obtained according to general procedure A as a white solid (31.3 mg, 87% yield), mp 135–137 °C. ½a25 D ¼ 7:0 (c 1.36, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 6.7 min, tminor = 9.1 min, 60% ee. 1H NMR (400 MHz, CDCl3): d 3.18–3.11 (m, 1H, CH), 2.69 (dd, J1 = 15.8 Hz, J2 = 6.8 Hz, 1H, CH2), 2.61 (dd, J1 = 15.6 Hz, J2 = 2.0 Hz, 1H, CH2), 2.56 (t, J = 6.4 Hz, 2H, CH2), 2.46–2.43 (m, 2H, CH2), 2.10–2.04 (m, 2H, CH2), 1.06 (d, J = 6.8 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 196.6, 166.5, 166.4, 119.2, 109.7, 36.6, 35.9, 27.1, 23.4, 23.4, 20.6, 19.3 ppm. 4.3.13. (R)-4-Phenyl-3,4-dihydropyrano[3,2-c]chromene-2,5dione 7a8 Compound 7a was obtained according to the general procedure B as a white solid (45.0 mg, 77% yield), mp 143–145 °C. ½a25 D ¼ 23:5 (c 2.15, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 12.7 min, tminor = 17.7 min, 23% ee. 1H NMR (400 MHz, CDCl3): d 7.90 (d, J = 8.0 Hz, 1H, ArH), 7.61 (t, J = 7.6 Hz, 1H, ArH), 7.39–7.24 (m, 7H, ArH), 4.53 (d, J = 7.2 Hz, 1H, CH), 3.21 (dd, J1 = 16.2 Hz, J2 = 7.6 Hz, 1H, CH2), 3.13 (d, J = 16.0 Hz, 1H, CH2) ppm. 13C NMR (100 MHz, CDCl3): d 164.2, 160.7, 157.2, 153.0, 139.3, 132.9, 129.2, 127.9, 126.5, 124.6, 122.7, 116.8, 113.4, 106.2, 35.9, 35.8 ppm. Lit.8 ½a25 D ¼ 164:86 (c 0.33, CHCl3) 91% ee. 4.3.14. (S)-4-Methyl-3,4-dihydropyrano[3,2-c]chromene-2,5dione 7b8 Compound 7b was obtained according to general procedure B as a white solid (41.4 mg, 90% yield), mp 124–126 °C. ½a25 D ¼ 19:2 (c
2.02, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 10.3 min, tminor = 12.2 min, 50% ee. 1H NMR (400 MHz, CDCl3): d 7.75 (d, J = 7.2 Hz, 1H, ArH), 7.52 (t, J = 8.4 Hz, 1H, ArH), 7.29–7.21 (m, 2H, ArH), 3.35–3.28 (m, 1H, CH), 2.89 (dd, J1 = 15.8 Hz, J2 = 7.2 Hz, 1H, CH2), 2.76 (dd, J1 = 15.8 Hz, J2 = 1.6 Hz, 1H, CH2), 1.22 (d, J = 7.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 164.8, 160.8, 156.3, 152.7, 132.5, 124.5, 122.4, 116.7, 113.5, 108.3, 35.6, 25.6, 19.1 ppm. Lit.8 ½a25 D ¼ 55:00 (c 0.32, CHCl3) 93% ee. 4.3.15. (R)-7-Methyl-4-(p-tolyl)-3,4-dihydropyrano[4,3-b]pyran2,5-dione 9a Compound 9a was obtained according to general procedure B as a white solid (41.1 mg, 76% yield), mp 117–118 °C. ½a25 D ¼ þ9:1 (c 1.77, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 10.2 min, tminor = 13.2 min, 19% ee. 1H NMR (400 MHz, CDCl3): d 7.12–7.07 (m, 4H, ArH), 5.99 (s, 1H, CH), 4.32 (dd, J1 = 6.8 Hz, J2 = 2.4 Hz, 1H, CH), 3.10–2.99 (m, 2H, CH2), 2.30 (s, 3H, CH3), 2.28 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 164.8, 163.3, 162.5, 161.5, 137.5, 136.6, 129.8, 126.3, 103.5, 98.8, 36.0, 34.7, 21.0, 20.1 ppm. IR (KBr): m 3092, 3023, 2961, 2923, 1796, 1717, 1656, 1597, 1514, 1445, 1410, 1394, 1319, 1273, 1215, 1187, 1133, 1102, 1037, 1022, 992, 956, 872, 817, 779, 740, 607, 557, 541 cm1. HRMS (ESI): m/z calcd for C16H15O4 [M+H]+ 271.09649, found: 271.09709. 4.3.16. (S)-4,7-Dimethyl-3,4-dihydropyrano[4,3-b]pyran-2,5dione 9b8 Compound 9b was obtained according to general procedure B as a white solid (35.7 mg, 92% yield), mp 132–135 °C. ½a25 D ¼ þ8:1 (c 0.15, CH2Cl2); HPLC (Daicel Chiralpak AD-H column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tmajor = 8.2 min, tminor = 9.9 min, 46% ee. 1H NMR (400 MHz, CDCl3): d 5.87 (s, 1H, CH), 3.18–3.14 (m, 1H, CH), 2.77 (dd, J1 = 15.8 Hz, J2 = 7.2 Hz, 1H, CH), 2.66 (dd, J1 = 16.0 Hz, J2 = 2.0 Hz, 1H, CH), 2.21 (s, 3H, CH3), 1.15 (d, J = 7.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 165.2, 162.6, 160.8, 105.2, 98.8, 35.7, 24.9, 20.0, 19.0 ppm. Lit.8 ½a25 D ¼ þ15:60 (c 0.35, CHCl3) 98% ee. 4.3.17. (R)-5-Acetyl-3,4-dihydro-6-methyl-4-phenylpyran-2-one 11a21 Compound 11a was obtained according to general procedure B as a white solid (22.1 mg, 48% yield), mp 102–104 °C. ½a25 D ¼ 89:1 (c 0.18, CH2Cl2); HPLC (Daicel Chiralpak IB column, n-hexane/2propanol = 80:20, flow rate 1.0 mL min1, detection at 254 nm): tminor = 6.5 min, tmajor = 7.4 min, 29% ee. 1H NMR (400 MHz, CDCl3): d 7.35–7.29 (m, 3H, ArH), 7.15 (d, J = 6.8 Hz, 2H, ArH), 4.15 (d, J = 7.6 Hz, 1H, CH), 2.97 (dd, J1 = 15.8 Hz, J2 = 7.2 Hz, 1H, CH2), 2.83 (dd, J1 = 15.8 Hz, J2 = 2.4 Hz, 1H, CH2), 2.43 (s, 3H, CH3), 2.12 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d 197.8, 165.6, 160.2, 139.6, 129.4, 127.9, 126.6, 117.2, 38.8, 37.1, 29.7, 19.0 ppm. Lit.21 ½a20 D ¼ 116:1 (c 1.0, CHCl3) 92% ee. Acknowledgments We are grateful for financial support from the National Natural Science Foundation of China (Grant No. 21272024). References 1. Seo, E. K.; Wani, M. C.; Wall, M. E.; Navarro, H.; Mukherjee, R.; Farnsworth, N. R.; Kinghorn, A. D. Phytochemistry 2000, 55, 35–42. 2. Mazumder, A.; Wang, S.; Neamati, N.; Nicklaus, M.; Sunder, S.; Chen, J.; Milne, G. W. A.; Rice, W. G.; Burke, T. R., Jr.; Pommier, Y. J. Med. Chem. 1996, 39, 2472–2481.
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