English

• 1.   Introduction

  3, 4-Dihydropyrano[4, 3-b]pyran-5(2H)-one skeleton is a common structural unit found in a number of naturally occurring compounds, such as pyripyropene A, arisugacins A, B and territrems A, B (Figure 1). Biological studies reveal that pyripyropene A, arisugacins, territrems and their synthetic analogs are the most potent inhibitors of cholesterol acyl transferase.^[1] As a fused nitrogen and oxygen-containing heterocycle, pyrano[2, 3-c]pyrazol-6(1H)-one is also an important structural unit present in a wide range of biologically active synthetic compounds (Figure 1). For example, pyrano[2, 3-c]pyra-zol-6(1H)-one derivative 1 has been identified as a potent positive inotropic agent.^[2] 1-Benzyl-3, 4-dimethylpyrano[2, 3-c]pyrazol-6 (1H)-one (2) demonstrates antiplatelet activity.^[3] 1, 3, 4-Trimethylpyrano[2, 3-c]pyrazol-6(1H)-one has been found to possess analgesic and antiinflammatory activities.^[4] Over the past two decades, the privileged structure-based diversity-oriented synthesis has become a powerful and highly efficient tool for discovering biologically active small molecules.^[5] In view of the interesting applications of 3, 4-dihydropyrano[4, 3-b]pyran-5(2H)-one and pyrano-[2, 3-c]pyrazol-6(1H)-ones in the field of drug discovery, the fused-ring system consisting of a 3, 4-dihydropyrano-[4, 3-b]pyran-5(2H)-one skeleton and a pyrano[2, 3-c]pyra-zol-6(1H)-one skeleton will be an important structural motif that has potence among biological activities and synthetic applications. However, this type of novel enantiomerically enriched fused polycyclic 3, 4-dihydropyrano-[4, 3-b]pyran-5(2H)-ones have not been constructed until now. As a result, the development of efficient synthesis of chiral 7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyra-no[2, 3-c]-pyrazole-5, 10(1H, 6H)-diones with high levels of enantioselectivity will be of great importance and remains a challenge task.

  Figure 1

  

  Figure 1.  Nature products with the pyranopyrone skeleton and bioactive pyrano[2, 3-c]pyrazolones

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  Recently, the 1, 3-bielectrophilic nature makes 2-nitro-allyl acetates service as a versatile 1, 3-bielectrophile in the construction of fused tetrahydropyran scaffold upon treatment with different 1, 3-dinucleophiles.^[6] We envisioned that this strategy could also be used to the construction of this novel fused polycyclic 3, 4-dihydropyrano[4, 3-b]py-ran-5(2H)-one skeleton through a formal [3+3] annulation of 4-hydroxy-7-phenyl-2H-pyrano[2', 3':4, 5]pyrano[2, 3-c]-pyrazole-2, 5(7H)-dione 4 and 2-nitroallyl acetates 5 (Eq. 1).

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  2.   Results and discussion

  The study was initiated by optimization of the conditions for the reaction between model substrates of 4-hydroxy-9-methyl-7-phenyl-2H-pyrano[2', 3':4, 5]pyrano-[2, 3-c]pyrazole-2, 5(7H)-dione (4a) and (E)-2-nitroallylic acetate (5a) (Table 1). Keeping in mind our previous reports on the reaction of pyrazolin-5-one with (E)-2-nitro-allylic acetates^[6d] we first exposed 4 and 5a to the reported condition in the presence of (1R, 2R)-1, 2-diphenyl-ethane-1, 2-diamine-based bifunctional squaramide Ia in dichloromethane at room temperature. The expected cycloaddition product 6a was successfully produced with high level of stereoselectivity, albeit in quite low yield (Entry 1). Several other bifunctional squaramide-based organocatalysts were then examined (Figure 2), and bifunctional squaramide Ib turned out to be the best catalyst for this reaction, delivering annulation product 6a in 46% yield with almost perfect stereocontrol (Entry 2). Notably, a remarkable improvement in the yield with unaltered selectivity was observed when silica gel (1 g) was added as an additive (Entry 5 vs. Entry 2). It is found that the addition of silica gel favoring the transformation of the initial formed conjugate addition product to the desired annulation product through tandem elimination/oxa-Michael addition sequence. Evaluation of other solvents, including ethyl acetate, tetrahydrofuran, ether, acetonitrile and chloroform, with the aim to further improve the yield of the reaction gave no fruitful results (Entries 6~11). Adjusting the catalyst loading to 5 mol% led to a slightly dropped yield but an obviously decreased enantioselectivity (Entry 13). A considerable decrease in enantioselectivity was observed by performing the reaction either at lowed or at elevated temperature (Entries 14, 15).

  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Catalyst	Solvent	Time/h	Yieldb/%	drc	eed/%
  1	Ia	CH2Cl2	21	21	> 19/1	98
  2	Ib	CH2Cl2	5	46	> 19/1	> 99
  3	II	CH2Cl2	36	33	> 19/1	99
  4	III	CH2Cl2	72	Trace
  5 e	Ib	CH2Cl2	12	70	> 19/1	> 99
  6 e	Ib	AcOEt	78	21	> 19/1	99
  7 e	Ib	THF	78	Trace
  8 e	Ib	Et2O	78	19	> 19/1	92
  9 e	Ib	CH3CN	78	9	> 19/1	88
  10 e	Ib	CHCl3	10	72	> 19/1	98
  11 e, f	Ib	CH2Cl2	42	62	> 19/1	86
  12 e, g	Ib	CH2Cl2	72	69	> 19/1	96
  13 e.h	Ib	CH2Cl2	8	75	> 19/1	97
  a Unless otherwise specified, all reactions were carried out with 4a (0.26 mmol), 5a (0.20 mmol) in the presence of 10 mol% catalyst in solvent (4 mL) at room temperature. b Isolated yield. c Determined by 1H NMR analysis. d Determined by HPLC analysis using a chiral stationary phase. e Silica gel (1 g) was added as an additive. f In the presence of 5 mol% catalyst Ib. g The reaction was performed at 0 ℃. g The reaction was carried at 40 ℃.

  Figure 2

  

  Figure 2.  Catalyst candidates

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  With the optimized conditions in hand (10 mol% catalyst Ib in dichloromethane at room temperature), the scope of the reaction was examined, and the results are summarized in Table 2.

  Table 2

  

  Table 2.  Substrate scope and limitations of the organocatalyzed formal [3+3] annulations^a

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  Entry	R	Ar	6	Time/h	Yieldb/%	drc	eed/%
  1	Me	Ph	6aa	12	70	> 19:1	> 99
  2	Me	4-FC6H4	6ab	23	56	> 19:1	98
  3	Me	4-ClC6H4	6ac	13	60	> 19:1	96
  4	Me	3-ClC6H4	6ad	42	61	> 19:1	86
  5	Me	4-BrC6H4	6ae	54	60	> 19:1	41
  6	Me	3-CF3C6H4	6af	24	62	> 19:1	46
  7	Me	4-MeC6H4	6ag	23	55	> 19:1	95
  8	Me	3-MeC6H4	6ah	22	55	> 19:1	88
  9	Me	2-MeC6H4	6ai	48	59	> 19:1	91
  10	Me	3, 5-Me2C6H3	6aj	72	54	> 19:1	64
  11	Me	4-MeOC6H4	6ak	11	46	> 19:1	88
  12	Me	1-Naphthyl	6al	11	75	> 19:1	> 99
  13	Me	2-Naphthyl	6am	15.5	77	> 19:1	84
  14	Me	2-Furyl	6an	13	46	> 19:1	56
  15	Me	2-Thienyl	6ao	22	40	> 19:1	64
  16	CF3	1-Ph	6ba	42	57	> 19:1	NDe
  a Unless otherwise specified, all reactions were carried out with 4 (0.26 mmol), 5a (0.20 mmol), silica gel (1 g) in the presence of 10 mol% catalyst in dichloromethane (4 mL) at room temperature. b Isolated yield. c Determined by 1H NMR analysis. d Determined by HPLC analysis using a chiral stationary phase. e ND mean not determined.

  As shown in Table 2, the reaction demonstrated a broad substrate scope, a wide range of (E)-2-nitroallyl acetates 5 bearing different substituents were well tolerated, affording the corresponding annulation products 6 in acceptable yields (40%~77%) with high levels of diastereoselectivity (> 19/1 dr) regardless of the nature of the substituents and the substitution pattern. With respect to the enantioselectivity, an obvious substrate-dependent effect was observed for 2-nitroallyl acetates bearing electron-withdrawing groups (Entries 2~6). The introduction of fluoro or chloro on the phenyl ring of 2-nitroallyl acetate maintained the high levels of enantioselectivity, while the introduction of bromo-or trifluoro-methyl group caused sharp decrease in ee value. The substitution pattern has a considerable effect on the reaction of substrates with electron-donating groups (Entries 7~11). In contrast to monosubstituted substrates, for which good enantioselectivity was obtained, only moderate ee value was observed for disubstituted one. In case of (E)-2-nitroallyl acetates 5l and 5m with a naphthyl group, a significant steric effect was observed. Compared with the result observed for 2-naphthyl substituted substrate, much better stereochemical outcome was obtained for the sterically more bulky 1-naphthyl substituted one (Entry 12 vs. Entry 13). The reaction was also applicable to electron-rich heteroaromatic 2-furyl and 2-thienyl substituted (E)-2-nitroallyl acetates 5n and 5o, delivering the cyclization products 6an and 6ao in acceptable yield albeit with markedly decreased enantioselectivity (Entries 14 and 15). In addition, 3-trifluoromethyl substituted 4-hydroxy-9-methyl-7-phenyl-2H-pyrano[2', 3':4, 5]pyrano[2, 3-c]pyra-zole-2, 5(7H)-dione (4b) also works well to afford fluorinated polycyclic 3, 4-dihydropyrano[4, 3-b]pyran-5(2H)-one (6ba) in acceptable yield with high diastereoselectivity (Entry 16). Unfortunately, the ee value of this product cannot be determined since two enantiomers are inseparable on all the tested chiral stationary phases.

  Our methodology was applicable to the gram scale reaction as well (Eq. 2). The reaction of 2.02 g (6.5 mmol) of 4a and 1.36 g of (E)-2-nitroallyl acetate 5l (5 mmol) in the presence of 0.27 g (0.5 mmol, 10 mol%) of catalyst Ib afforded 1.80 g (69%) of the corresponding annulation product 6al without any appreciable change in the diastereo- and enantio-selectivities.

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  The structure and relative configuration of fused polycyclic 3, 4-dihydropyrano[4, 3-b]pyran-5(2H)-ones were further unequivocally confirmed by single crystal X-ray analysis of a representative compound 6aa (Figure 3). Furthermore, the absolute configuration of 6aa was also assigned to be (6S, 7R) based on X-ray data and the remaining configurations are assumed by analogy.^[7]

  Figure 3

  

  Figure 3.  X-ray crystal structure of (6S, 7R)-6aa (most of the hydrogen atoms have been omitted for clarity)

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  The products obtained in these [3+3] annulations would have more application in organic synthesis and medicinal chemistry. For example, as outlined in Eq. 3, upon treatment with zinc powder in acetic acid, the nitro group in compound 6al was converted to an amino group. The crude amine was further transformed into the corresponding benzamide 7 by reaction with benzoyl chloride in the presence of triethylamine as an acid binding agent in moderate yield without any loss of stereochemical integrity.

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  3.   Conclusions

  In conclusion, we have developed an organocatalytic asymmetric formal [3+3] annulation of 4-hydroxy-2H-pyrano[2', 3':4, 5]pyrano[2, 3-c]pyrazole-2, 5(7H)-diones and (E)-2-nitroallyl acetates. Under the catalysis of a (1R, 2R)-1, 2-diphenylethane-1, 2-diamine derived tertiary amine-squaramide catalyst, the reactions ran smoothly to provide a series of novel fused polycyclic 3, 4-dihydro-pyrano[4, 3-b]pyran-5(2H)-ones in acceptable yields, high anti-selectivities, and moderate to excellent enantioselectivities. This method serves as a useful tool for the stereocontrolled construction of fused polycyclic 3, 4-dihydro-pyrano[4, 3-b]pyran-5(2H)-one scaffolds with two adjacent tertiary stereogenic centers.

  4.   Experimental section

  4.1   General procedure for squaramide Ib catalyzed asymmetric [3+3] annulation of 4-hydroxy-2H-pyra-no[2', 3':4, 5]pyrano[2, 3-c]pyrazole-2, 5(7H)-diones and (E)-2-nitro-allyl acetates

  To a solution of 4-hydroxy-2H-pyrano[2', 3':4, 5]pyra-no[2, 3-c]pyrazole-2, 5(7H)-dione (4) (0.26 mmol), (E)-2-nitroallyl acetate 5 (0.20 mmol), squaramide catalyst Ib (10.9 mg, 0.020 mmol) in dichloromethane (4 mL), silica gel (200~300 mesh, 1.0 g) was added, and the resulting solution was stirred at room temperature until the reaction reached completion [monitored by thin-layer chromatography (TLC)]. After the removal of the solvent under reduced pressure, the crude product was purified by chromatography on a silica gel column (200~300 mesh, PE/EtOAc, V:V＝4:1) to afford the desired fused polycyclic 3, 4-dihydropyrano[4, 3-b]pyran-5(2H)-ones 6.

  (6S, 7R)-3-Methyl-7-nitro-1, 6-diphenyl-7, 8-dihydro-pyrao[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3-c]pyrazole-5, 10(1H, 6H)-dione (6aa): White solid, 66 mg, 70% yield. m.p. 236~237 ℃; [α]_D²⁰+182.4 (c 0.92, CH₂Cl₂), > 99% ee. ¹H NMR (CDCl₃, 400 MHz) δ: 7.86 (d, J＝7.6 Hz, 2H), 7.53 (t, J＝7.6 Hz, 2H), 7.34~7.42 (m, 4H), 7.29 (d, J＝7.2 Hz, 2H), 5.12 (dt, J＝13.2, 2.4 Hz, 1H), 4.90 (br s, 1H), 4.84 (dd, J＝4.0, 2.0 Hz, 1H), 4.41 (dd, J＝13.2, 2.4 Hz, 1H), 2.62 (s, 3H); ¹³C NMR (CDCl₃, 100.6 MHz) δ: 163.0, 162.2, 158.4, 153.8, 150.8, 145.4, 138.5, 136.3, 129.6, 129.5, 128.4, 127.9, 127.8, 120.8, 95.7, 95.4, 90.8, 81.5, 63.2, 38.2, 14.1; HRMS (ESI) calcd for C₂₅H₁₈N₃O₇ [M+H]⁺ 472.1139, found 472.1141. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝71.05 (minor) and 75.95 (major) min.

  (6S, 7R)-6-(4-Fluorophenyl)-3-methyl-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3- c]pyrazole-5, 10(1H, 6H)-dione (6ab): White solid, 55 mg, 56% yield. m.p. 256~257 ℃; [α]_D²⁰+205.8 (c 1.37, CH₂Cl₂), 98% ee. ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.79 (d, J＝8.0 Hz, 2H), 7.62 (t, J＝8.0 Hz, 2H), 7.50 (dd, J＝8.4, 5.6 Hz, 2H), 7.46 (t, J＝7.6 Hz, 1H), 7.22 (t, J＝8.8 Hz, 2H), 5.40 (s, 1H), 5.05 (d, J＝13.6 Hz, 1H), 4.78 (s, 1H), 4.29 (d, J＝12.8 Hz, 1H), 2.51 (s, 3H); ¹³C NMR (DMSO-d₆, 100.6 MHz) δ: 162.5, 162.3, 161.6 (d, J＝244.1 Hz), 158.5, 153.7, 150.8, 144.5, 136.0, 135.2 (d, J＝2.7 Hz), 130.5 (d, J＝8.2 Hz), 129.7, 127.9, 120.9, 115.6 (d, J＝21.3 Hz), 95.5, 95.3, 91.3, 81.2, 63.7, 36.6, 13.7; HRMS (ESI) calcd for C₂₅H₁₇FN₃O₇ [M+H]⁺ 490.1045, found 490.1041. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝57.68 (minor) and 71.78 (major) min.

  (6S, 7R)-6-(4-Chlorophenyl)-3-methyl-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3-c]pyrazole-5, 10(1H, 6H)-dione (6ac): White solid, 61 mg, 60% yield. m.p. 257~258 ℃; [α]_D²⁰+41.2 (c 0.81, CH₂Cl₂), 96% ee. ¹H NMR (Acetone-d₆, 400 MHz) δ: 7.87 (d, J＝7.6 Hz, 2H), 7.61 (t, J＝7.6 Hz, 2H), 7.56 (d, J＝8.8 Hz, 2H), 7.45 (t, J＝7.6 Hz, 1H), 7.43 (d, J＝8.4 Hz, 2H), 5.36 (dd, J＝3.6, 2.0 Hz, 1H), 5.16 (dt, J＝13.6, 2.0 Hz, 1H), 4.93 (s, 1H), 4.50 (dd, J＝13.6, 2.0 Hz, 1H), 2.56 (s, 3H); ¹³C NMR (Acetone-d₆, 100.6 MHz) δ: 163.9, 163.8, 159.3, 154.3, 145.7, 139.4, 137.6, 134.1, 131.7, 131.1, 130.4, 129.8, 128.6, 121.6, 96.3, 96.2, 92.0, 82.3, 64.5, 38.4, 14.1; HRMS (ESI) calcd for C₂₅H₁₇ClN₃O₇ [M+H]⁺ 506.0750, found 506.0747. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝69.74 (minor) and 72.71 (major) min.

  (6S, 7R)-6-(3-Chlorophenyl)-3-methyl-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3-c]pyrazole-5, 10(1H, 6H)-dione (6ad): White solid, 62 mg, 61% yield. m.p. 178~179 ℃; [α]_D²⁰+155.8 (c 2.10, CH₂Cl₂), 86% ee; ¹H NMR (CDCl₃, 400 MHz) δ: 7.85 (d, J＝8.0 Hz, 2H), 7.53 (t, J＝8.0 Hz, 2H), 7.40 (t, J＝8.0 Hz, 1H), 7.30~7.36 (m, 2H), 7.09~7.21 (m, 1H), 5.16 (dt, J＝13.2 Hz, 1H), 4.88 (s, 1H), 4.82 (dd, J＝1.2 Hz, 1H), 4.40 (dd, J＝13.2, 2.0 Hz, 1H), 2.63 (s, 3H); ¹³C NMR (CDCl₃, 100.6 MHz) δ: 163.1, 162.5, 158.3, 153.7, 150.8, 145.5, 140.6, 136.25, 135.5, 130.8, 129.6, 128.8, 127.95, 126.1, 120.9, 95.4, 95.0, 90.7, 81.2, 63.1, 37.9, 14.1; HRMS (ESI) calcd for C₂₅H₁₇ClN₃O₇ [M+H]⁺ 506.0750, found 506.0748. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝50.00 (minor) and 57.00 (major) min.

  (6S, 7R)-6-(4-Bromophenyl)-3-methyl-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3-c]pyrazole-5, 10(1H, 6H)-dione (6ae): White solid, 66 mg, 60% yield. m.p. 250~251 ℃; [α]_D²⁰+20.1 (c 0.84, CH₂Cl₂), 41% ee; ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.80 (d, J＝8.0 Hz, 2H), 7.57~7.64 (m, 4H), 7.41~7.52 (m, 3H), 5.40 (s, 1H), 5.04 (d, J＝14.0 Hz, 1H), 4.75 (s, 1H), 4.29 (d, J＝13.2 Hz, 1H), 2.52 (s, 3H); ¹³C NMR (DMSO-d₆, 100.6 MHz) δ: 162.7, 162.4, 158.6, 153.7, 150.9, 144.6, 138.5, 136.0, 131.7, 130.8, 129.8, 128.0, 121.1, 121.0, 95.3, 95.2, 91.4, 81.0, 63.8, 36.9, 13.8. HRMS (ESI) calcd for C₂₅H₁₇BrN₃O₇ [M+H]⁺ 550.0244, found 550.0241. HPLC analysis [Chiralpak IG-H column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝79.02 (minor) and 90.75 (major) min.

  (6S, 7R)-3-Methyl-7-nitro-1-phenyl-6-(3-(trifluorome-thyl)phenyl)-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3': 4, 5]pyrano[2, 3-c]pyrazole-5, 10(1H, 6H)-dione (6af): White solid, 67 mg, 62% yield. m.p. 230~231 ℃; [α]_D²⁰+67.3 (c 1.24, CH₂Cl₂), 46% ee; ¹H NMR (CDCl₃, 400 MHz) δ: 7.86 (d, J＝8.0 Hz, 2H), 7.64 (d, J＝7.6 Hz, 1H), 7.51~7.58 (m, 5H), 7.41 (t, J＝7.2 Hz, 1H), 5.18 (dt, J＝13.2, 2.0 Hz, 1H), 4.98 (s, 1H), 4.83 (d, J＝2.0 Hz, 1H), 4.38 (dd, J＝13.2, 2.4 Hz, 1H), 2.64 (s, 3H); ¹³C NMR (CDCl₃, 100.6 MHz) δ: 163.2, 162.8, 158.3, 153.7, 150.8, 145.5, 139.7, 136.2, 132.0 (q, J＝32.6 Hz), 131.3, 130.1, 129.6, 128.0, 125.5 (q, J＝3.5 Hz), 124.5 (q, J＝3.7 Hz), 123.6 (q, J＝272.6 Hz), 120.9, 95.4, 94.8, 90.7, 81.1, 63.1, 38.1, 14.1; HRMS (ESI) calcd for C₂₆H₁₇F₃N₃O₇ [M+H]⁺ 540.1013, found 540.1014. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝30.62 (minor) and 41.65 (major) min.

  (6S, 7R)-3-Methyl-7-nitro-1-phenyl-6-(p-tolyl)-7, 8-dihy-dropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3-c]pyra-zole-5, 10(1H, 6H)-dione (6ag): White solid, 53 mg, 55% yield. m.p. 254~255 ℃; [α]_D²⁰+203.8 (c 1.36, CH₂Cl₂), 95% ee; ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.78 (d, J＝8.0 Hz, 2H), 7.60 (t, J＝8.0 Hz, 2H), 7.45 (t, J＝7.2 Hz, 1H), 7.31 (d, J＝7.6 Hz, 2H), 7.20 (d, J＝8.0 Hz, 2H), 5.36 (s, 1H), 5.05 (d, J＝13.6 Hz, 1H), 4.74 (s, 1H), 4.27 (d, J＝13.6 Hz, 1H), 2.50 (s, 3H), 2.30 (s, 3H); ¹³C NMR (DMSO-d₆, 100.6 MHz) δ: 162.4, 162.3, 158.5, 153.7, 150.8, 144.5, 137.0, 136.2, 136.0, 129.7, 129.5, 128.3, 127.9, 120.8, 95.5, 95.3, 91.3, 81.4, 63.6, 37.0, 20.6, 13.8; HRMS (ESI) calcd for C₂₆H₂₀N₃O₇ [M+H]⁺ 486.1296, found 486.1293. HPLC analysis [Chiralpak IA-H column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝54.441 (minor) and 94.522 (major) min.

  (6S, 7R)-3-Methyl-7-nitro-1-phenyl-6-(m-tolyl)-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3-c]-pyrazole-5, 10(1H, 6H)-dione (6ah): White solid, 53 mg, 55% yield. m.p. 245~246 ℃; [α]_D²⁰+150.5 (c 1.47, CH₂Cl₂), 88% ee; ¹H NMR (CDCl₃, 400 MHz) δ: 7.85 (d, J＝7.6 Hz, 2H), 7.52 (t, J＝7.6 Hz, 2H), 7.39 (t, J＝7.6 Hz, 1H), 7.28 (t, J＝7.2 Hz, 1H), 7.14 (d, J＝7.6 Hz, 1H), 7.08 (s, 1H), 7.07 (d, J＝8.0 Hz, 1H), 5.12 (dt, J＝13.2, 2.0 Hz, 1H), 4.82~4.85 (m, 2H), 4.41 (dd, J＝13.2, 2.0 Hz, 1H), 2.62 (s, 3H), 2.35 (s, 3H); ¹³C NMR (CDCl₃, 100.6 MHz) δ: 162.9, 162.1, 158.4, 153.9, 150.7, 145.4, 139.3, 138.4, 136.2, 129.5, 129.3, 129.2, 128.4, 127.9, 124.8, 120.8, 95.7, 95.4, 90.8, 81.5, 63.2, 38.0, 21.4, 14.1. HRMS (ESI) calc'd for C₂₆H₂₀N₃O₇ [M+H]⁺ 486.1296, found 486.1289. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝55.56 (minor) and 61.06 (major) min.

  (6S, 7R)-3-Methyl-7-nitro-1-phenyl-6-(o-tolyl)-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3- c]pyrazole-5, 10(1H, 6H)-dione (6ai): White solid, 57 mg, 59% yield. m.p. 246~247 ℃; [α]_D²⁰+190.2 (c 0.92, CH₂Cl₂), 91% ee; ¹H NMR (CDCl₃, 400 MHz) δ: 7.86 (d, J＝8.0 Hz, 2H), 7.53 (t, J＝8.0 Hz, 2H), 7.40 (t, J＝7.6 Hz, 1H), 7.29 (d, J＝7.2 Hz, 1H), 7.24 (t, J＝7.2 Hz, 1H), 7.18 (t, J＝7.2 Hz, 1H), 6.98 (d, J＝7.2 Hz, 1H), 5.14 (d, J＝13.2 Hz, 1H), 5.03 (s, 1H), 4.68 (s, 1H), 4.43 (d, J＝13.2 Hz, 1H), 2.62 (s, 3H), 2.58 (s, 3H); ¹³C NMR (CDCl₃, 100.6 MHz) δ: 162.9, 162.3, 158.3, 153.9, 150.7, 145.4, 136.6, 136.25, 136.2, 131.6, 129.6, 128.4, 127.9, 127.0, 126.7, 120.8, 95.9, 95.4, 90.8, 79.7, 62.8, 35.2, 19.3, 14.1; HRMS (ESI) calcd for C₂₆H₂₀N₃O₇ [M+H]⁺ 486.1296, found 486.1293. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝81.10 (major) and 118.09 (minor) min.

  (6S, 7R)-6-(3, 5-Dimethylphenyl)-3-methyl-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]-pyrano[2, 3-c]pyrazole-5, 10(1H, 6H)-dione (6aj): White solid, 54 mg, 54% yield. m.p. 181~182 ℃; [α]_D²⁰+108.4 (c 1.21, CH₂Cl₂), 63% ee; ¹H NMR (CDCl₃, 400 MHz) δ: 7.84 (d, J＝8.0 Hz, 2H), 7.52 (t, J＝8.0 Hz, 2H), 7.38 (t, J＝7.6 Hz, 1H), 6.96 (s, 1H), 6.86 (s, 2H), 5.10 (d, J＝13.2 Hz, 1H), 4.81 (s, 2H), 4.42 (d, J＝13.2 Hz, 1H), 2.62 (s, 3 H), 2.30 (s, 6H); ¹³C NMR (CDCl₃, 100.6 MHz) δ: 162.9, 162.1, 158.4, 154.0, 150.7, 145.4, 139.2, 138.5, 136.3, 130.1, 129.6, 127.9, 125.5, 120.8, 95.8, 95.5, 90.9, 81.6, 63.2, 38.0, 21.3, 14.1; HRMS (ESI) calcd for C₂₇H₂₂N₃O₇ [M+H]⁺: 500.1452, found 500.1457. HPLC analysis [Chiralpak IG-H column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝53.50 (minor) and 68.22 (major) min.

  (6S, 7R)-6-(4-Methoxyphenyl)-3-methyl-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]-pyrano[2, 3-c]pyrazole-5, 10(1H, 6H)-dione (6ak): White solid, 46 mg, 46% yield. m.p. 244~245 ℃; [α]_D²⁰+142.8 (c 0.79, CH₂Cl₂), 88% ee; ¹H NMR (CDCl₃, 400 MHz) δ: 7.85 (d, J＝8.0 Hz, 2H), 7.53 (t, J＝8.0 Hz, 2H), 7.39 (t, J＝7.2 Hz, 1H), 7.19 (d, J＝8.4 Hz, 2H), 6.91 (d, J＝8.4 Hz, 2H), 5.12 (d, J＝13.2 Hz, 1H), 4.81 (d, J＝9.2 Hz, 1H), 4.41 (dd, J＝13.2, 2.4 Hz, 1H), 3.79 (s, 3H), 2.62 (s, 3H); ¹³C NMR (CDCl₃, 100.6 MHz) δ: 162.9, 162.1, 159.6, 158.4, 153.9, 150.7, 145.4, 136.3, 130.4, 129.6, 128.9, 127.9, 120.9, 114.9, 96.0, 95.4, 90.8, 81.6, 63.1, 55.4, 37.5, 14.1; HRMS (ESI) calcd for C₂₆H₂₀N₃O₈ [M+H]⁺502.1245, found 502.1241. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝60:40), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝108.43 (minor) and 134.87 (major) min.

  (6S, 7R)-3-Methyl-6-(naphthalen-1-yl)-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3- c]pyrazole-5, 10(1H, 6H)-dione (6al): White solid, 78 mg, 75% yield. m.p. 267~268 ℃; [α]_D²⁰+75.9 (c 0.87, CH₂Cl₂), > 99% ee; ¹H NMR (CDCl₃, 400 MHz) δ: 8.29 (d, J＝8.4 Hz, 1H), 7.95 (d, J＝8.0 Hz, 1H), 7.84~7.88 (m, 3H), 7.71 (dt, J＝8.0, 1.2 Hz, 1H), 7.60 (t, J＝7.2 Hz, 1H), 7.54 (t, J＝8.0 Hz, 2H), 7.39~7.43 (m, 2H), 7.21 (d, J＝7.2 Hz, 1H), 5.72 (s, 1H), 5.14 (dt, J＝13.2, 2.0 Hz, 1H), 4.98 (d, J＝1.2 Hz, 1 H), 4.35 (dd, J＝13.2, 2.4 Hz, 1H), 2.64 (s, 3H); ¹³C NMR (CDCl₃, 100.6 MHz) δ: 163.0, 162.8, 158.3, 153.8, 150.8, 145.5, 136.3, 134.3, 134.0, 130.2, 129.6, 129.6, 129.5, 127.9, 127.8, 126.6, 125.7, 125.2, 121.8, 120.8, 95.4, 95.2, 90.8, 79.6, 63.1, 35.1, 14.2; HRMS (ESI) calcd for C₂₉H₂₀N₃O₇ [M+H]⁺ 522.1296, found 522.1288. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝60:40), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝45.41 (major) and 104.94 (minor) min.

  (6S, 7R)-3-Methyl-6-(naphthalen-2-yl)-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3- c]pyrazole-5, 10(1H, 6H)-dione (6am): White solid, 80 mg, 77% yield. m.p. 253~254 ℃; [α]_D²⁰+147.8 (c 1.36, CH₂Cl₂), 84% ee; ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.97 (d, J＝8.8 Hz, 1H), 7.87~7.94 (m, 3H), 7.81 (d, J＝8.0 Hz, 2H), 7.71 (dd, J＝8.8, 1.6 Hz, 1H), 7.63 (t, J＝8.0 Hz, 2H), 7.50~7.54 (m, 2H), 7.47 (t, J＝7.6 Hz, 1H), 5.51 (d, J＝1.6 Hz, 1H), 5.07 (d, J＝13.6 Hz, 1H), 4.94 (s, 1H), 4.37 (dd, J＝13.6, 1.6 Hz, 1H), 2.52 (s, 3H); ¹³C NMR (DMSO-d₆, 100.6 MHz) δ: 162.6, 162.4, 158.6, 153.7, 150.8, 144.5, 136.8, 136.0, 133.0, 132.4, 129.8, 128.6, 128.0, 127.9, 127.5, 127.2, 126.6, 126.4, 126.3, 121.0, 95.5, 95.3, 91.4, 81.1, 63.7, 37.6, 13.8;HRMS (ESI) calcd for C₂₉H₂₀N₃O₇ [M+H]⁺ 522.1296, found 522.1291. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝106.42 (minor) and 128.52 (major) min.

  (6S, 7R)-6-(Furan-2-yl)-3-methyl-7-nitro-1-phenyl-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3- c]pyrazole-5, 10(1H, 6H)-dione (6an): White solid, 42 mg, 46% yield. m.p. 264~265 ℃; [α]_D²⁰+53.3 (c 1.01, CH₂Cl₂), 56% ee; ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.78 (d, J＝7.6 Hz, 2H), 7.70 (d, J＝0.8 Hz, 1H), 7.61 (t, J＝7.6 Hz, 2H), 7.46 (t, J＝7.6 Hz, 1H), 6.44~6.47 (m, 2H), 5.59 (d, J＝1.6 Hz, 1H), 5.17 (dt, J＝11.6, 2.0 Hz, 1H), 4.81 (s, 1H), 4.44 (dd, J＝13.2, 1.6 Hz, 1H), 2.51 (s, 3H); ¹³C NMR (DMSO-d₆, 100.6 MHz) δ: 162.4, 162.3, 158.5, 153.7, 150.9, 144.6, 143.5, 136.0, 129.8, 128.0, 121.0, 111.0, 109.3, 95.3, 93.8, 91.3, 78.4, 64.4, 32.0, 13.8; HRMS (ESI) calcd for C₂₃H₁₆N₃O₈ [M+H]⁺ 462.0932, found 462.0930. HPLC analysis [Chiralpak IG-H column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝64.42 (minor) and 87.42 (major) min.

  (6S, 7R)-3-Methyl-7-nitro-1-phenyl-6-(thiophen-2-yl)-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3- c]pyrazole-5, 10(1H, 6H)-dione (6ao): White solid, 38 mg, 40% yield. m.p. 231~232 ℃; [α]_D²⁰+170.9 (c 0.66, CH₂Cl₂), 64% ee; ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.78 (d, J＝8.0 Hz, 2H), 7.61 (t, J＝7.6 Hz, 2H), 7.52 (dd, J＝5.2, 1.2 Hz, 1H), 7.46 (t, J＝7.6 Hz, 1H), 7.16 (d, J＝3.6 Hz, 1H), 7.05 (dd, J＝5.2, 3.6 Hz, 1H), 5.51 (d, J＝1.6 Hz, 1H), 5.13 (dt, J＝13.6, 2.0 Hz, 1H), 4.99 (s, 1H), 4.44 (dd, J＝13.6, 2.0 Hz, 1H), 2.52 (s, 3H); ¹³C NMR (DMSO-d₆, 100.6 MHz) δ: 162.4, 162.0, 158.5, 153.7, 150.9, 144.6, 142.3, 136.0, 129.8, 128.0, 127.5, 127.3, 126.3, 121.0, 96.2, 95.3, 80.8, 64.1, 32.7, 13.8; HRMS (ESI) calcd for C₂₃H₁₆N₃O₇S [M+H]⁺ 478.0703, found 478.0697. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V: V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝62.61 (minor) and 71.33 (major) min.

  (6S, 7R)-7-Nitro-1, 6-diphenyl-3-(trifluoromethyl)-7, 8-dihydropyrano[2", 3":4', 5']pyrano[2', 3':4, 5]pyrano[2, 3-c]-pyrazole-5, 10(1H, 6H)-dione (6ba): White solid, 60 mg, 57% yield. 268~269 ℃; [α]_D²⁰－0.19 (c 1.08, CH₂Cl₂); ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.83 (d, J＝7.6 Hz, 2H), 7.69 (t, J＝7.6 Hz, 2H), 7.59 (t, J＝7.6 Hz, 1H), 7.33~7.45 (m, 5H), 5.43 (d, J＝1.6 Hz, 1H), 5.08 (dt, J＝13.6, 2.0 Hz, 1H), 4.79 (s, 1H), 4.32 (dd, J＝13.6, 1.6 Hz, 1H); ¹³C NMR (DMSO-d₆, 100.6 MHz) δ: 161.9, 159.6, 158.1, 152.8, 151.4, 138.9, 135.1, 134.5 (q, J＝40.3 Hz), 130.0, 129.5, 129.0, 128.4, 127.8, 122.4, 119.9 (d, J ＝269.5 Hz), 97.1, 93.9 (2 C), 81.2, 63.9, 37.4; HRMS (ESI) calcd for C₂₅H₁₅F₃N₃O₇ [M+H]⁺ 526.0857, found 526.0855.

  4.2   Transformation of fused polycyclic 3, 4-dihydro-pyrano[4, 3-b]pyran-5(2H)-one (6al) to the corresponding benzamide 7

  To a stirred solution of 6al (156.3 mg, 0.30 mmol) in 1.5 mL of acetic acid was added zinc powder (195 mg, 3.0 mmol) in one portion at 0 ℃. Then, the resulting mixture was stirred at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure. The residue was dissolved in aqueous sodium carbonate (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was dried over anhydrous magnesium sulfate and filtered. Removal of solvent under reduced pressure afforded the crude amine as a pale yellow viscous oil, which was used directly in the next step without further purification. To a solution of the crude amine and triethylamine (104 μL, 0.90 mmol) in 1 mL of dichloromethane was added benzoyl chloride (125 μL, 0.90 mmol) at 0 ℃. The resulting mixture was stirred at the same temperature until the reaction was complete (monitored by TLC). The reaction mixture was purified directly by column chromatography on silica gel (200~300 mesh, dichloromethane/methanol, V:V＝100:1) to afford the desired benzamide 7.

  N-((6S, 7R)-3-Methyl-6-(naphthalen-1-yl)-5, 10-dioxo-1-phenyl-1, 5, 6, 7, 8, 10-hexahydropyrano[2", 3":4', 5']pyrano- [2', 3':4, 5]pyrano[2, 3-c]pyrazol-7-yl)benzamide (7): White solid, 97 mg, 54% yield. m.p. 205~206 ℃; [α]_D²⁰+80.8 (c 0.50, CH₂Cl₂), > 99% ee; ¹H NMR (400 MHz, CDCl₃) δ: 8.73 (d, J＝8.8 Hz, 1H), 7.90 (d, J＝8.4 Hz, 1H), 7.84 (d, J＝7.6 Hz, 2H), 7.80 (t, J＝8.0 Hz, 3H), 7.68 (t, J＝8.0 Hz, 1H), 7.57 (t, J＝7.6 Hz, 1H), 7.47 (t, J＝7.6 Hz, 3H), 7.33~7.41 (m, 4H), 7.14 (d, J＝6.8 Hz, 2H), 5.08 (s, 1H), 4.73 (d, J＝6.4 Hz, 1H), 4.64 (d, J＝12.0 Hz, 1H), 4.30 (d, J＝12.0 Hz, 1H), 2.48 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 167.7, 163.2, 162.7, 159.1, 154.1, 150.4, 145.1, 136.4, 136.1, 134.2, 133.6, 131.8, 131.2, 129.5, 129.0, 128.7, 128.5, 127.8, 127.3, 126.3, 125.4, 124.8, 123.3, 120.5, 97.4, 95.2, 91.1, 66.3, 46.9, 37.5, 14.0; HRMS (ESI) calcd for C₃₆H₂₆N₃O₆ [M+H]⁺ 596.1816, found 596.1817. HPLC analysis [Chiralpak IG column, hexane/2-propanol (V:V＝70:30), flow rate＝1.0 mL/min, wavelength＝254 nm]: t_R＝91.73 (major) and 109.75 (minor) min.

  Supporting Information Crystallography data, copies of NMR and HRMS spectra as well as chiral HPLC chromatograms of the prepared optically active fused polycyclic 3, 4-dihydropyrano[4, 3-b]pyran-5(2H)-ones. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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• 

  Figure 1  Nature products with the pyranopyrone skeleton and bioactive pyrano[2, 3-c]pyrazolones

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  Figure 2  Catalyst candidates

  下载: 全尺寸图片 幻灯片
  

  Figure 3  X-ray crystal structure of (6S, 7R)-6aa (most of the hydrogen atoms have been omitted for clarity)

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of the reaction conditions^a

  Entry	Catalyst	Solvent	Time/h	Yieldb/%	drc	eed/%
  1	Ia	CH2Cl2	21	21	> 19/1	98
  2	Ib	CH2Cl2	5	46	> 19/1	> 99
  3	II	CH2Cl2	36	33	> 19/1	99
  4	III	CH2Cl2	72	Trace
  5 e	Ib	CH2Cl2	12	70	> 19/1	> 99
  6 e	Ib	AcOEt	78	21	> 19/1	99
  7 e	Ib	THF	78	Trace
  8 e	Ib	Et2O	78	19	> 19/1	92
  9 e	Ib	CH3CN	78	9	> 19/1	88
  10 e	Ib	CHCl3	10	72	> 19/1	98
  11 e, f	Ib	CH2Cl2	42	62	> 19/1	86
  12 e, g	Ib	CH2Cl2	72	69	> 19/1	96
  13 e.h	Ib	CH2Cl2	8	75	> 19/1	97
  a Unless otherwise specified, all reactions were carried out with 4a (0.26 mmol), 5a (0.20 mmol) in the presence of 10 mol% catalyst in solvent (4 mL) at room temperature. b Isolated yield. c Determined by 1H NMR analysis. d Determined by HPLC analysis using a chiral stationary phase. e Silica gel (1 g) was added as an additive. f In the presence of 5 mol% catalyst Ib. g The reaction was performed at 0 ℃. g The reaction was carried at 40 ℃.

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  Table 2.  Substrate scope and limitations of the organocatalyzed formal [3+3] annulations^a

  Entry	R	Ar	6	Time/h	Yieldb/%	drc	eed/%
  1	Me	Ph	6aa	12	70	> 19:1	> 99
  2	Me	4-FC6H4	6ab	23	56	> 19:1	98
  3	Me	4-ClC6H4	6ac	13	60	> 19:1	96
  4	Me	3-ClC6H4	6ad	42	61	> 19:1	86
  5	Me	4-BrC6H4	6ae	54	60	> 19:1	41
  6	Me	3-CF3C6H4	6af	24	62	> 19:1	46
  7	Me	4-MeC6H4	6ag	23	55	> 19:1	95
  8	Me	3-MeC6H4	6ah	22	55	> 19:1	88
  9	Me	2-MeC6H4	6ai	48	59	> 19:1	91
  10	Me	3, 5-Me2C6H3	6aj	72	54	> 19:1	64
  11	Me	4-MeOC6H4	6ak	11	46	> 19:1	88
  12	Me	1-Naphthyl	6al	11	75	> 19:1	> 99
  13	Me	2-Naphthyl	6am	15.5	77	> 19:1	84
  14	Me	2-Furyl	6an	13	46	> 19:1	56
  15	Me	2-Thienyl	6ao	22	40	> 19:1	64
  16	CF3	1-Ph	6ba	42	57	> 19:1	NDe
  a Unless otherwise specified, all reactions were carried out with 4 (0.26 mmol), 5a (0.20 mmol), silica gel (1 g) in the presence of 10 mol% catalyst in dichloromethane (4 mL) at room temperature. b Isolated yield. c Determined by 1H NMR analysis. d Determined by HPLC analysis using a chiral stationary phase. e ND mean not determined.

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