Stereocontrolled construction of 3H-furo[3,4-b]chromen-1(9H)-one scaffolds via organocatalyzed Michael addition and the following intramolecular dehydration

Abstract

An efficient approach for the stereocontrolled construction of 3H-furo[3,4-b]chromen-1(9H)-one skeleton has been successfully developed through a sequential Michael addition/intramolecular dehydration strategy. The Michael addition of tetronic acid to 2-((E)-2-nitrovinyl)phenols catalyzed by a bifunctional squaramide derived from L-tert-leucine, and the subsequent intramolecular dehydration promoted by concentrated sulfuric acid, proceed smoothly to give the corresponding pharmaceutically valuable 3H-furo[3,4-b]chromen-1(9H)-ones in acceptable yields with 79–97% ee.

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Introduction

The benzopyran scaffold ranks among the most commonly found heterocycles in known bioactive molecules. Functionalized benzopyran and fused cyclic molecular frameworks with benzopyran units have attracted much attention due to their considerable biological and pharmacological activities, such as use as antibacterial,¹ antitumor,² anti-anaphylactic,³ antisecretory agents,⁴ apoptosis inducers,⁵ and Chk1-inhibitors.⁶ Among them, 3H-furo[3,4-b]chromen-1(9H)-ones (benzopyran lactones) represent an important class of polycyclic benzopyrans, as they are the privileged structural motif of a number of synthetic 4-oxa-podophyllotoxin derivatives displaying an extensive array of biological activities (Fig. 1).⁷ Despite their high relevance as biologically active compounds, however, nonracemic 3H-furo[3,4-b]chromen-1(9H)-ones have been entirely unknown. Since the preparation of enantiomerically pure compounds has become a stringent requirement for pharmaceutical synthesis,⁸ the development of efficient synthesis of chiral benzopyran lactones in highly enantioselective manner will be of great importance and remains a challenge task. As a part of our continued interest in the stereoselective synthesis of biologically relevant heterocycles,⁹ herein we describe the tertiary amine-squaramide catalyzed Michael addition of tetronic acid (4-hydroxyfuran-2-one) to 2-((E)-2-nitrovinyl)phenols and the subsequent acid promoted intramolecular dehydration reaction, which provide a straightforward access to a variety of functionalized chiral benzopyran lactones in a highly enantioselective manner (Scheme 1).¹⁰

Fig. 1 Examples of bioactive compounds bearing a 3H-furo[3,4-b]chromen-1(9H)-one motif.

Scheme 1 Construction of 3H-furo[3,4-b]chromen-1(9H)-one skeleton.

Results and discussion

Initially, 2-((E)-2-nitrovinyl)phenol (1a) and 4-hydroxyfuran-2-one (2a) were chosen as the model substrates, and the initial Michael addition reaction was investigated at 20 °C in methylene chloride, the following intramolecular dehydration was performed at 100 °C in glacial acetic acid in the presence of 2 equivalents of concentrated sulfuric acid. Various thiourea-¹¹ and squaramide-based¹² hydrogen-bonding catalysts I–V (Fig. 2) were screened for the Michael addition reaction (Table 1, entries 1–8). In the presence of (1R,2R)-1,2-diphenylethane-1,2-diamine derived thiourea catalyst I, the desired polycyclic product 3aa was obtained in 75% yield with 30% ee (Entry 1). Under the same condition, sharply increased enantioselectivity (63% ee) was observed for the squaramide catalyst IIa bearing the same chiral diamine scaffold (entries 2 vs. entry 1), which indicate that the squaramide catalysts are superior to thiourea catalysts in this transformation. We then turn our attention to other chiral squaramide catalysts (entries 3–8). The effect of the tertiary amino group on reactivity and enantioselectivity was firstly investigated in more detail (entries 3 and 4). Of the tertiary amino groups surveyed, piperidinyl group resulted in an obviously improved enantioselectivity of 79% ee (entry 4). Further changing the chiral diamine skeleton of the squaramide catalyst revealed that squaramide Va, derived from L-tert-leucine, was the optimal catalyst for this sequential process and afforded the desired product 3aa with the highest ee value (entry 7, 81%).

Table 1 Screening of catalyst^a

Entry	Catalyst	Time (h)	Yield^b (%)	ee^c (%)
a Michael addition reactions were carried out with 2-((E)-2-nitrovinyl)phenol (1a, 0.24 mmol), tetronic acid (2a, 0.2 mmol) and catalyst (20 mol%) in methylene chloride (1 mL) at 20 °C. Intramolecular dehydration reactions were performed in glacial acetic acid (1.5 mL) at 100 °C in the presence of 2 equivalent of concentrated sulfuric acid.b Isolated yield after two steps.c Determined by HPLC analysis with a chiral stationary phase.
1	I	52	74	−30
2	IIa	28	94	−63
3	IIb	68	97	−67
4	IIc	48	87	−79
5	III	92	77	−38
6	IV	48	95	31
7	Va	72	87	81
8	Vb	92	90	57

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Fig. 2 Screened thiourea- and squaramide-based organocatalyst.

Having confirmed squaramide Va as the optimum catalyst for the reaction, other parameters, such as solvent, reaction temperature, and catalyst loading, influencing the reaction were further investigated employing 2-((E)-2-nitrovinyl)phenol (1a) and 4-hydroxyfuran-2-one (2a) as the model substrates. The results are listed in Table 2.

Table 2 Optimization of reaction conditions^a

Entry	Solvent	Time (h)	Yield^b (%)	ee^c (%)
a Unless otherwise specified, the Michael addition reactions were carried out with 1a (0.24 mmol), 2a (0.20 mmol) and squaramide Va (20 mol%) in solvent (1 mL) at 20. The intramolecular dehydration reactions were performed in glacial acetic acid (1.5 mL) at 100 °C in the presence of 2 equivalent of concentrated sulfuric acid.b Isolated yield after two steps.c Determined by HPLC analysis using a chiral stationary phase.d Reaction was performed at 0 °C.e The catalyst loading is 10 mol%.
1	CH2Cl2	72	87	81
2	CHCl3	21	92	58
3	ClCH2CH2Cl	40	90	65
4	PhCH3	40	58	47
5	CH3CN	72	87	78
6	Et2O	144	79	54
7	EA	72	85	80
8	THF	40	81	91
9^d	THF	144	75	92
10^e	THF	59	82	97

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With 20 mol% of Va as the catalyst at 20 °C, various solvents have been examined for the initial Michael addition reaction (entries 1–8). The asymmetric Michael addition could be carried out smoothly in several conventional solvents with ee values ranged from 47–91%. THF was found to be superior to any other solvents screened, delivering the tricyclic product 3aa in 81% yield with the highest enantioselectivity of 91% ee (entry 8). Although a slightly increased enantioselectivity was observed, conducting the reaction at 0 °C resulted in a quite slower reaction (entry 9 vs. entry 8). Finally, it was gratifying that the enantioselectivity could be further improved to 97% ee by adjusting the catalyst loading to 10 mol% (entry 10). Under this condition, the Michael addition product of ortho-nitrovinylphenol 1a and tetronic acid 2a was isolated in 93% yield with a comparable enantioselectivity of 96% ee.

Having established the optimal reaction conditions (Table 2, entry 10), we next examined the scope and limitations of the above sequential process with variants of 2-((E)-2-nitrovinyl)phenols 1 (Table 3). Although the reactions of these substituted 2-((E)-2-nitrovinyl)phenols proceeded more slowly, both the electron-withdrawing and electron-donating substituents were tolerated well in this sequential Michael addition/dehydration transformation, delivering the corresponding products in good to excellent enantioselectivities irrespective of the substitution pattern (entries 1–13). The effect of electronic property of the substituent on the intramolecular dehydration process is obvious. Generally, the existence of electron-withdrawing group decreases the nucleophilicity of the phenolic hydroxy group and slows down the reaction. Especially for the dihalo-substituted substrate 1d and 1f, quite sluggish reactions were observed and provided the cyclization product 3da and 3fa in low yield even after a prolonged reaction time (entries 4 and 6). In addition, 2-hydroxynaphthalene-1-carbaldehyde derived nitroolefin 1n was also applicable, albeit the Michael addition reaction proceeded more slowly with a partial conversion of 1n and afforded the corresponding product with decreased yield (entry 14). Because all of the products were solids with high melting points, the optical purity of the product could be dramatically improved by a single recrystallization from methylene chloride/hexane (v/v, 2/1) (entry 8). Chen,^13a Sohtome and Nagasawa^13b–d have reported the formation of dimer of that structures containing both nitro and phenol group. However, the generation of the dimer was not observed in our system, in some cases, the observed low yields may be attributed to the formation of appreciable amounts of tarry residue upon treatment with concentrated sulfuric acid.

Table 3 Substrate scope for the newly developed sequential process^a

Entry	3 (R)	Time (h, step 1)	Time (h, step 2)	Yield^b (%)	ee^c (%)
a Michael addition reactions were carried out with 2-((E)-2-nitrovinyl)phenol (1a, 0.24 mmol), tetronic acid (2a, 0.2 mmol) and catalyst Va (10 mol%) in tetrahydrofuran (1 mL) at 20 °C. Intramolecular dehydration reactions were performed in glacial acetic acid (1.5 mL) at 100 °C in the presence of 2 equivalent of concentrated sulfuric acid.b Isolated yield after two steps.c Determined by HPLC analysis with a chiral stationary phase.
1	3aa (H)	59	5	80	97
2	3ba (2-F)	48	10	81	87
3	3ca (2-Cl)	91	52	66	87
4	3da (2,4-Cl2)	52	168	29	87
5	3ea (2-Br)	91	52	61	86
6	3fa (2,4-Br2)	96	144	25	94
7	3ga (2-Me)	90	1.5	80	86
8	3ha (3-Me)	106	2.5	77 (46)	88 (98)
9	3ia (4-Me)	100	2.5	80	90
10	3ja (2-OMe)	168	3	61	88
11	3ka (3-OMe)	144	8	60	93
12	3la (4-OMe)	84	29	63	91
13	3ma (2,4-^tBu2)	168	2	40	79
14	3na (1,2-CH=CH–CH=CH)	240	6	27	88

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In addition, tolerance to substitution on the tetronic acid derivative 2 was also preliminarily investigated (Scheme 2). The reaction of 4-hydroxy-5,5-dimethylfuran-2(5H)-one (2b) to nitrostyrene 1a also ran smoothly to provide the desired product 3ab in acceptable yield with high enantioselectivity. Racemic, (R)- and (S)-4-hydroxy-5-methylfuran-2(5H)-ones (2c–e) were also proved to be suitable reaction partners with 2-((E)-2-nitrovinyl)phenol (1a), furnishing the desired products 3ac–3ae with 92%, 98% and >99% ee, respectively.

Scheme 2 Reaction of other tetronic acid derivatives.

In case of the reaction of optically pure tetronic acids 2d and 2e, partial racemization was observed at the C4 position of the lactone ring. To determine which step is responsible for the racemization, two additional experiments were performed: (1) Va-catalyzed simple Michael addition of 2e to 1a (eqn (1) and (2)) treatment of optically active 2e under the dehydration condition (eqn (2)). These results clearly indicate that the partial racemization was occurred in the subsequent acid promoted dehydration step rather than in the first Michael addition step.

The absolute configuration and molecular structure of 3aa was unambiguously determined by X-ray crystallography and the remaining configurations are assumed by analogy (Fig. 3).

Fig. 3 X-ray crystal structure of (R)-3aa. Most of the hydrogen atoms have been omitted for clarity.

To explanation of the observed stereochemistry outcome of the reaction, a plausible transition state for the initial Michael addition reaction is shown in Fig. 4. ortho-Nitrovinylphenol 1a is activated and fixed through double hydrogen bonding interaction with the squaramide moiety of catalyst Va. Meanwhile, tetronic acid is deprotonated by the basic tertiary amino group in the catalyst, and the resulting enolate is assumed to interact with the protonated amine by hydrogen bonding. Thereafter, nucleophilic addition of the enolate to the nitroolefin from the si-face preferentially leads to the formation of (R)-adduct.

Fig. 4 Proposed transition state for the Michael addition step.

Conclusions

We have developed a new methodology to access 3H-furo[3,4-b]chromen-1(9H)-one derivatives enantioselectively through sequential Michael addition and intramolecular dehydration reactions. Bifunctional chiral squaramide Va derived from L-tert-leucine was found to be the efficient catalyst for the conjugate addition of tetronic acid to 2-((E)-2-nitrovinyl)phenols. The intramolecular dehydration of the Michael addition products was achieved in the presence of concentrated sulfuric acid. A number of 3H-furo[3,4-b]chromen-1(9H)-one derivatives were synthesized in acceptable to good yields and with good to excellent enantioselectivities.

Experimental

General methods

All reagents and solvents were commercial grade and purified prior to use when necessary. NMR spectra were acquired on Varian 400 MHz instrumental. Chemical shifts are measured relative to residual solvent peaks as an internal standard set to δ 7.26 and δ 77.0 (CDCl₃), 2.50 and 38.45 (DMSO-d₆). Specific rotations were measured on a Perkin-Elmer 341 MC polarimeter. Enantiomeric excesses were determined on a Shimadzu LC-20A instrument (chiral column; mobile phase: hexane/i-PrOH). HRMS was performed on a Varian QFT-ESI instrumental. Melting points were determined on a Taike X-4 melting point apparatus. All temperatures were uncorrected.

General procedure for sequential Michael addition–intramolecular dehydration reaction of tetronic acids and 2-((E)-2-nitrovinyl)phenols

A solution of squaramide catalyst Va (10 mol%), 2-((E)-2-nitrovinyl)phenols (1, 0.24 mmol) and tetronic acids (2, 0.2 mmol) in tetrahydrofuran (1 mL) was stirred at 20 °C. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. The Michael addition product of 1a and 2a was purified by column chromatography on silica gel (200–300 mesh, PE/EtOAc/AcOH = 80/20/1) and fully characterized by ¹H NMR, ¹³C NMR, HRMS and specific rotation data.

4-Hydroxy-3-((R)-1-(2-hydroxyphenyl)-2-nitroethyl)furan-2(5H)-one

Pale yellow oil, 93% yield, [α]²⁵_D − 5.45 (c 1.47, ethyal acetate), 96% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 10.95 (br. s, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 5.07 (dd, J = 12.8, 10.0 Hz, 1H), 4.80–4.89 (m, 2H), 4.66 (s, 2H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 175.9, 173.9, 154.6, 128.3, 128.2, 123.8, 118.9, 115.2, 96.6, 75.0, 66.5, 32.1. HRMS (ESI) m/z calcd for C₁₂H₁₂NO₆ [M + H]⁺: 266.0659, found 266.0660. HPLC analysis (Chiralpak OJ-H column, hexane : 2-propanol : TFA = 20 : 80 : 0.1, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 13.76 (major) and 20.31 min (minor).

To a solution of the crude Michael addition product in glacial acetic acid (1.5 mL) was added two equivalent of concentrated sulfuric acid, and the resulting mixture was heated to 100 °C and maintained this temperature for completion of the reaction (monitored by TLC). Upon completion of the reaction, the product was directly purified by column chromatography on silica gel (200–300 mesh, PE/EtOAc = 2/1) to afford the desired 3H-furo[3,4-b]chromen-1(9H)-ones 3. The title compounds were fully characterized by ¹H NMR, ¹³C NMR, HRMS and specific rotation data. The enantiomeric excess of the pure products was determined by HPLC analysis using a chiral stationary phase.

(R)-9-Nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3aa)

White solid, mp 138–140 °C, 80% yield, [α]²⁵_D + 12.96 (c 1.17, CHCl₃), 97% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.58 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.07–5.15 (m, 3H), 4.97 (dd, J = 12.8, 4.0 Hz, 1H), 4.59 (s, 1H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 171.0, 170.6, 150.3, 129.6 (2C), 126.0, 118.8, 117.4, 98.6, 77.8, 66.1, 30.7. HRMS (ESI) m/z calcd for C₁₂H₁₀NO₅ [M + H]⁺: 248.0553, found 248.0552. HPLC analysis (Chiralpak OJ-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 39.17 (major) and 44.54 min (minor).

(R)-7-Fluoro-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ba)

White solid, mp 189–191 °C, 81% yield, [α]²⁵_D + 5.14 (c 1.40, CHCl₃), 87% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.54 (dd, J = 9.2, 2.8 Hz, 1H), 7.32 (dd, J = 9.2, 4.8 Hz, 1H), 7.26 (dt, J = 9.2, 2.8 Hz, 1H), 5.19 (dd, J = 12.8, 4.0 Hz, 1H), 5.03–5.15 (m, 2H), 4.99 (dd, J = 12.8, 3.6 Hz, 1H), 4.60 (s, 1H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 171.1, 170.4, 159.1 (d, J = 242.0 Hz), 146.7 (d, J = 2.3 Hz), 121.0 (d, J = 8.2 Hz), 119.2 (d, J = 8.8 Hz), 116.5 (d, J = 23.7 Hz), 115.8 (d, J = 24.7 Hz), 97.9, 77.3, 66.0, 31.0. HRMS (ESI) m/z calcd for C₁₂H₉FNO₅ [M + H]⁺: 266.0459, found 266.0453. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 80 : 20, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 13.22 (minor) and 14.55 min (major).

(R)-7-Chloro-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ca)

White solid, mp 203–205 °C, 66% yield, [α]²⁵_D − 14.83 (c 1.20, CHCl₃), 87% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.75 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.8, 2.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 5.20 (dd, J = 12.8, 4.0 Hz, 1H), 5.04–5.16 (m, 2H), 4.98 (dd, J = 12.8, 3.6 Hz, 1H), 4.60 (s, 1H). ¹³C NMR (100.6 MHz, DMSO-d₆) δ 170.9, 170.3, 149.2, 129.64, 129.5, 129.2, 121.1, 119.2, 98.4, 77.4, 66.0, 30.7. HRMS (ESI) m/z calcd for C₁₂H₉ClNO₆ [M + H]⁺: 282.0162, found 282.0160. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 90 : 10, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 27.36 (minor), and 29.23 min (major).

(R)-5,7-Dichloro-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3da)

Red solid, mp 218–220 °C, 29% yield, [α]²⁵_D + 37.73 (c 0.32, CHCl₃), 87% ee. ¹H NMR (400 MHz, CDCl₃): δ 7.43 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 4.91–5.03 (m, 3H), 4.82 (dd, J = 13.2, 3.6 Hz, 1H), 4.48 (s, 1H). ¹³C NMR (100.6 MHz, CDCl₃): δ 170.2, 169.8, 145.7, 131.4, 130.7, 126.9, 124.5, 121.5, 99.5, 76.3, 66.2, 31.6. HRMS (ESI) m/z calcd for C₁₂H₁₁Cl₂N₂O₅ [M + NH₄]⁺: 333.0040, found 333.0040. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 90 : 10, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 20.42 (minor) and 23.33 min (major).

(R)-7-Bromo-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ea)

Pale red solid, mp 215–217 °C, 61% yield, [α]²⁵_D + 56.80 (c 1.00, CHCl₃), 86% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.80 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 5.20 (dd, J = 12.8, 3.6 Hz, 1H), 5.04–5.15 (m, 2H), 4.97 (dd, J = 12.8, 3.6 Hz, 1H), 4.60 (s, 1H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 170.8, 170.2, 149.7, 132.4, 132.1, 121.5, 119.5, 117.6, 98.5, 77.4, 66.1, 30.6. HRMS (ESI) m/z calcd for C₁₂H₉BrNO₆ [M + H]⁺: 325.9659, found 325.9666. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 95 : 5, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 57.42 (minor) and 60.13 min (major).

(R)-5,7-Dibromo-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3fa)

Red solid, mp 254–256 °C, 25% yield, [α]²⁵_D + 43.50 (c 0.27, CHCl₃), 94% ee. ¹H NMR (400 MHz, CDCl₃): δ 7.73 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 4.91–5.03 (m, 3H), 4.82 (dd, J = 13.2, 3.6 Hz, 1H), 4.48 (s, 1H). ¹³C NMR (100.6 MHz, CDCl₃): δ 170.4, 169.8, 147.1, 136.4, 130.6, 121.8, 118.9, 113.3, 99.7, 76.4, 66.2, 31.6. HRMS (ESI) m/z calcd for C₁₂H₁₁Br₂N₂O₅ [M + NH₄]⁺: 420.9029, found 420.9013. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 90 : 10, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 20.15 (minor) and 23.63 min (major).

(R)-7-Methyl-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ga)

White solid, mp 212–214 °C, 80% yield, [α]²⁵_D + 29.00 (c 1.40, CHCl₃), 86% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.38 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.02–5.12 (m, 3H), 4.95 (dd, J = 12.8, 3.6 Hz, 1H), 4.53 (s, 1H), 2.30 (s, 3H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 171.1, 170.6, 148.4, 135.2, 130.1, 129.6, 118.4, 117.1, 98.4, 77.7, 66.0, 30.7, 20.3. HRMS (ESI) m/z calcd for C₁₃H₁₂NO₅ [M + H]⁺: 262.0710, found 262.0714. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 85 : 15, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 12.97 (minor) and 14.18 min (major).

(R)-6-Methyl-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ha)

White solid, mp 144–146 °C, 77% yield (46% yield after a single recrystallization), [α]²⁵_D + 131.23 (c 1.30, CHCl₃), 88% ee (98% ee after a single recrystallization). ¹H NMR (400 MHz, DMSO-d₆): δ 7.44 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 5.02–5.13 (m, 3H), 4.93 (dd, J = 12.4, 3.6 Hz, 1H), 4.52 (s, 1H), 2.31 (s, 3H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 171.1, 170.6, 150.1, 139.6, 129.2, 126.8, 117.5, 115.6, 98.6, 77.7, 66.0, 30.5, 20.4. HRMS (ESI) m/z calcd for C₁₃H₁₂NO₅ [M + H]⁺: 262.0710, found 262.0712. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 90 : 10, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 21.87 (major) and 23.62 min (minor).

(R)-5-Methyl-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ia)

Pale yellow solid, mp 201–203 °C, 80% yield, [α]²⁵_D + 12.60 (c 1.00, CHCl₃), 90% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.38 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.05–5.16 (m, 3H), 4.95 (dd, J = 12.8, 4.0 Hz, 1H), 4.58 (s, 1H), 2.28 (s, 3H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 170.9, 170.6, 148.6, 130.9, 127.1, 126.2, 125.3, 118.4, 98.5, 77.9, 66.2, 30.9, 15.5. HRMS (ESI) m/z calcd for C₁₃H₁₂NO₅ [M + H]⁺: 262.0710, found 262.0715. HPLC analysis (Chiralpak OJ-H column, hexane : 2-propanol = 80 : 20, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 50.05 (major) and 57.38 min (minor).

(R)-7-Methoxy-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ja)

White solid, mp 168–170 °C, 61% yield, [α]²⁵_D + 47.23 (c 1.03, CHCl₃), 88% ee. ¹H NMR (400 MHz, CDCl₃): δ 7.07 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 9.2, 2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 4.81–4.92 (m, 4H), 4.50 (br. s, 1H), 3.80 (s, 3H). ¹³C NMR (100.6 MHz, CDCl₃): δ 171.1, 170.8, 157.5, 144.6, 119.0, 118.8, 115.4, 113.0, 98.1, 76.9, 66.1, 55.7, 31.6. HRMS (ESI) m/z calcd for C₁₃H₁₂NO₆ [M + H]⁺: 278.0659, found 278.0664. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 9.57 (minor) and 10.78 min (major).

(R)-6-Methoxy-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ka)

White solid, mp 158–160 °C, 60% yield, [α]²⁵_D − 12.46 (c 0.87, CHCl₃), 94% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.47 (d, J = 8.8 Hz, 1H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 5.03–5.13 (m, 3H), 4.92 (dd, J = 12.4, 3.6 Hz, 1H), 4.50 (s, 1H), 3.78 (s, 3H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 171.0, 170.5, 159.9, 151.1, 130.2, 112.4, 110.2, 102.5, 99.0, 77.8, 66.0, 55.6, 30.3. HRMS (ESI) m/z calcd for C₁₃H₁₂NO₆ [M + H]⁺: 278.0659, found 278.0660. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 11.13 (major) and 12.31 min (minor).

(R)-5-Methoxy-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3la)

White solid, mp 182–184 °C, 63% yield, [α]²⁵_D + 56.8 (c 1.10, CHCl₃), 91% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.22 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 6.4 Hz, 1H), 7.08 (d, J = 6.4 Hz, 1H), 5.03–5.15 (m, 3H), 4.94 (dd, J = 12.8, 3.6 Hz, 1H), 4.56 (s, 1H), 3.84 (s, 3H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 170.7, 170.5, 147.9, 139.9, 125.8, 120.2, 119.6, 112.3, 98.5, 77.8, 66.2, 55.8, 30.8. HRMS (ESI) m/z calcd for C₁₃H₁₂NO₆ [M + H]⁺: 278.0659, found 278.0665. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 11.77 (minor) and 13.52 min (major).

(R)-5,7-Di-tert-butyl-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ma)

White solid, mp 213–215 °C, 40% yield, [α]²⁵_D + 35.14 (c 0.70, CHCl₃), 79% ee. ¹H NMR (400 MHz, CDCl₃): δ 7.35 (dd, J = 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.86 (dd, J = 16.4, 1.6 Hz, 1H), 4.83 (d, J = 4.8 Hz, 2H), 4.54 (t, J = 4.4 Hz, 1H), 1.40 (s, 9H), 1.30 (s, 9H). ¹³C NMR (100.6 MHz, CDCl₃): δ 170.8, 170.36, 148.5, 147.3, 138.1, 124.7, 123.5, 117.6, 98.6, 77.8, 66.1, 35.4, 34.7, 32.0, 31.2, 30.2. HRMS (ESI) m/z calcd for C₂₀H₂₆NO₅ [M + H]⁺: 360.1805, found 360.1808. HPLC analysis (Chiralpak AS-H column, hexane : 2-propanol = 70 : 30, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 5.58 (minor) and 8.75 min (minor).

(R)-11-Nitromethyl-8H-benzo[f]furo[3,4-b]chromene-10(11H)-one (3na)

Yellow solid, mp 246–248 °C, 27% yield, [α]²⁵_D + 70.80 (c 0.57, CHCl₃), 88% ee. ¹H NMR (400 MHz, CDCl₃): δ 7.35 (dd, J = 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.86 (dd, J = 16.4, 1.6 Hz, 1H), 4.83 (d, J = 4.8 Hz, 2H), 4.54 (t, J = 4.4 Hz, 1H), 1.40 (s, 9H), 1.30 (s, 9H). ¹³C NMR (100.6 MHz, CDCl₃): δ 171.2, 170.4, 149.1, 131.4, 130.8, 130.4, 129.0, 127.9, 125.8, 123.0, 117.4, 111.5, 99.5, 78.0, 66.1, 29.1. HRMS (ESI) m/z calcd for C₁₆H₁₂NO₅ [M + H]⁺: 298.0710, found 298.0713. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 92 : 8, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 33.85 (minor) and 36.57 min (major).

(R)-3,3-Dimethyl-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ab)

White solid, mp 150–152 °C, 38% yield, [α]²⁵_D + 12.24 (c 0.83, CHCl₃), 88% ee. ¹H NMR (400 MHz, DMSO-d₆): δ 7.59 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.10 (dd, J = 12.8, 3.6 Hz, 1H), 4.96 (dd, J = 12.8, 3.6 Hz, 1H), 4.58 (t, J = 3.6 Hz, 1H), 1.54 (s, 3H), 1.53 (s, 3H). ¹³C NMR (100.6 MHz, DMSO-d₆): δ 175.3, 168.5, 150.5, 129.6 (2C), 126.0, 118.6, 117.5, 97.2, 80.8, 78.0, 30.7, 23.8, 23.3. HRMS (ESI) m/z calcd for C₁₄H₁₄NO₅ [M + H]⁺: 276.0866, found 276.0869. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 90 : 10, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 11.81 (minor) and 13.37 min (major).

(9R)-3-Methyl-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ac)

White solid, mp 140–142 °C, 52% yield, [α]²⁵_D + 14.10 (c 0.67, CHCl₃), 60/40 dr, 92% ee for the major isomer, 98% ee for the minor isomer. ¹H NMR (400 MHz, CDCl₃): δ 7.29–7.37 (m, 2H), 7.22–7.26 (m, 1H), 7.14–7.17 (m, 1H), 5.04–5.15 (m, 1H), 4.90–4.98 (m, 1H), 4.83–4.88 (m, 1H), 4.49–4.54 (m, 1H), 1.62 (d, J = 6.8 Hz, 1.80H), 1.59 (d, J = 6.8 Hz, 1.20H). ¹³C NMR (100.6 MHz, CDCl₃): δ major isomer: 174.1, 170.0, 150.8, 129.9, 128.8, 126.3, 118.0, 117.9, 98.3, 77.2, 74.1, 31.4, 17.4. Minor isomer: 173.9, 169.9, 150.7, 129.9, 128.7, 126.4, 118.1, 118.0, 98.2, 77.1, 74.0, 31.3, 17.3. HRMS (ESI) m/z calcd for C₁₃H₁₂NO₅ [M + H]⁺: 262.0710, found 262.0713. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 98 : 2, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 56.55 (minor for the major diastereomer), 61.70 (minor for the minor diastereomer), 65.10 (major for the minor diastereomer) and 69.38 min (major for the major diastereomer).

(3S,9R)-3-Methyl-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ad)

White solid, mp 140–142 °C, 52% yield, [α]²⁵_D + 3.50 (c 0.80, CHCl₃), 89/11 dr, 98% ee for the major isomer. ¹H NMR (400 MHz, CDCl₃): δ 7.35 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 5.12 (q, J = 6.8 Hz, 0.11H), 5.06 (q, J = 6.8 Hz, 0.89H), 4.96 (dd, J = 12.4, 4.4 Hz, 0.89H), 4.92 (dd, J = 12.4, 4.8 Hz, 0.11H), 4.85 (dd, J = 12.4, 3.6 Hz, 1H), 4.50 (s, 1H), 1.62 (d, J = 6.8 Hz, 2.67H), 1.58 (d, J = 6.8 Hz, 0.33H). ¹³C NMR (100.6 MHz, CDCl₃): δ major isomer: 174.1, 170.0, 150.8, 129.9, 128.8, 126.3, 118.0, 117.9, 98.3, 77.2, 74.1, 31.4, 17.4. Minor isomer: 173.9, 169.9, 150.7, 129.9, 128.7, 126.4, 118.1, 118.0, 98.2, 77.1, 74.0, 31.3, 17.3. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 98 : 2, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 55.32 (minor for the major diastereomer), 60.09 (major for the minor diastereomer), 63.49 (minor for the minor diastereomer) and 68.07 min (major for the major diastereomer).

(3R,9R)-3-Methyl-9-nitromethyl-3H-furo[3,4-b]chromen-1(9H)-one (3ae)

White solid, mp 140–142 °C, 52% yield, [α]²⁵_D + 28.11 (c 1.17, CHCl₃), 83/17 dr, >99% ee for the major isomer. ¹H NMR (400 MHz, CDCl₃): δ 7.35 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 5.12 (q, J = 6.8 Hz, 0.83H), 5.06 (q, J = 6.8 Hz, 0.17H), 4.96 (dd, J = 12.4, 4.4 Hz, 0.17H), 4.92 (dd, J = 12.4, 4.8 Hz, 0.83H), 4.86 (dd, J = 12.4, 3.6 Hz, 1H), 4.53 (t, J = 4.4 Hz, 1H), 1.62 (d, J = 6.8 Hz, 0.51H), 1.58 (d, J = 6.8 Hz, 2.49H). ¹³C NMR (100.6 MHz, CDCl₃): δ minor isomer: 174.1, 170.0, 150.8, 129.9, 128.8, 126.3, 118.0, 117.9, 98.3, 77.2, 74.1, 31.4, 17.4. Minor isomer: 173.9, 169.9, 150.7, 129.9, 128.7, 126.4, 118.1, 118.0, 98.2, 77.1, 74.0, 31.3, 17.3. HPLC analysis (Chiralpak AD-H column, hexane : 2-propanol = 98 : 2, flow rate = 1.0 mL min⁻¹, wavelength = 220 nm): R_t = 57.13 (minor for the minor diastereomer), 65.83 (major for the major diastereomer) and 69.38 min (major for the minor diastereomer).

Acknowledgements

We are grateful to the National Naturaaience Foundation of China (No. 21421062), the Key laboratory of Elemento-Organic Chemistry and Collaborative Innovation Center of Chemical Science and Engineering for generous financial support for our programs.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1421230. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra17503h

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