Abstract
This study demonstrates the use of organocatalytic Brønsted base activation of 5-substituted-furan-2(3H)-ones to generate 2π-components for the diastereoselective [8 + 2]-cycloaddition involving 8,8-dicyanoheptafulvene as an 8π-component. The use of dienolates in a higher-order cycloaddition reaction leads to the formation of biologically relevant polycyclic products bearing a γ-butyrolactone structural motif, thus broadening the synthetic potential of Brønsted base activated higher-order cycloadditions.
Introduction
Lactones and their unsaturated derivatives—butenolides, are very interesting groups of chemical compounds. Naturally occurring lactones and their derivatives are present in over 13,000 natural products and have a broad spectrum of biological properties, making them a valuable synthetic target in the modern organic chemistry.1 Due to the great importance of lactones and their derivatives in the chemical and pharmaceutical environments, various methods of their synthesis are widely explored.2 Unsaturated β,γ- or α,β-butenolides [furan-2(3H)-ones or furan-2(5H)-ones] due to their high availability and reactivity constitute attractive synthons for the enantio- and diastereoselective synthesis of many biologically relevant structures containing γ-lactone rings (Scheme 1, top).3 In particular, 5-substituted-furan-2(3H)-ones deserve special attention because they are a useful group of pronucleophiles which undergo deprotonation from the α-position under organocatalytic conditions, thus transforming them into synthetically relevant dienolates with a vinylogous reactivity. This feature was successfully employed in various types of organic transformations with nucleophilic properties manifested from either α-4 or γ-position (Scheme 1, middle).3,5
Scheme 1. 5-Substituted-furan-2(3H)-ones and Tropone Derivatives in Organic Synthesis.
Heptafulvenes and their hetero-analogues are another group of compounds with interesting properties and applications (Scheme 1, bottom). The presence of conjugated double bonds in their structure allows for synthetic applications in various types of cycloaddition reactions, leading to complex molecules that often have interesting biological activities. The cycloheptatriene ring can be found in many natural products and compounds relevant for life-science industry.6 Recently, their usage in organocatalytic higher-order cycloadditions has emerged providing access to complex polycyclic structures often difficult to prepare via classical synthetic approaches.7,8
In 2019, our research group demonstrated the application of 2-benzyl-1,4-naphthoquinones as a novel group of 4π-components in the organocatalytic [6 + 4]-cycloaddition with 8,8-dicyanoheptafulvene (Scheme 2).9 A distinctive feature of the strategy was the transformation of these substrates into the corresponding dienolates under mild, organic Brønsted base catalytic conditions and their application as higherenophiles in the higher-order cycloaddition. Given the promising synthetic potential of such an approach, studies on the development of a new higher-order cycloaddition proceeding under Brønsted base catalysis were undertaken (Scheme 2). As the ability of 5-substituted-furan-2-(3H)-ones to provide the corresponding dienolates under basic conditions is well recognized, this group of compounds was selected as potential 2π-component precursors for the studies. It was anticipated that they should undergo higher-order cycloaddition with 8,8-dicyanoheptafulvene leading to the formation of polycyclic [8 + 2] cycloadducts as possible products. However, at the outset of our studies, the control of periselectivity as well as stereoselectivity of the process was of major concern.
Scheme 2. Dienolates as Higherenophiles in Higher-Order Cycloadditions—Previous Results and the Aim of the Present Studies.
Herein, we present our studies on the development of highly peri- and diastereoselective higher-order cycloaddition between 5-substituted-furan-2(3H)-ones and 8,8-dicyanoheptafulvene. The reaction was realized under Brønsted base catalysis providing polycyclic γ-lactone derivatives bearing cycloheptatriene structural motifs. Our approach benefits from operational simplicity using readily available substrates and a simple organocatalyst, providing structurally interesting products containing valuable functional groups with the potential biological activity in a diastereoselective manner.
Results and Discussion
Optimization studies were carried out using commercially available 5-methylfuran-2-(3H)-one 2a and 8,8-dicyanoheptafulvene 1a as model reactants. Initially, studies were focused on finding an appropriate base to promote the designed reaction (Scheme 3). Due to the fact that lactone 2a isomerized under the basic reaction conditions, experiments were performed utilizing 2-fold excess of 2a in order to improve the yield of the cycloaddition. A number of organic and inorganic bases were tested for their ability to promote the reaction. In the presence of either pyrrolidine 4a, 4-(dimethylamino)benzoic acid 4b, or sodium acetate 4c no formation of product 3a was observed. Utilization of cesium carbonate 4d induced the desired reactivity, but the cycloaddition proceeded in low yield and with moderate diastereoselectivity. Importantly, the use of tertiary amines 4e–h improved both the conversion and diastereoselectivity of the process with DABCO 4h providing the best results.
Scheme 3. 5-Substituted-furan-2-(3H)-ones 2 in the [8 + 2]-Cycloaddition with 8,8-Dicyanoheptafulvene 1a—the Selection of Brønsted Base Catalyst.
Subsequently, the solvent screening was performed (Table 1, entries 1–7). Unfortunately, none of the solvents tested improved the results despite prolonged reaction times. Therefore, the influence of temperature was investigated. Neither decrease (Table 1, entry 8) nor increase (Table 1, entry 9) of the temperature was beneficial for the developed higher-order cycloaddition and the results remained unsatisfactory. Finally, the change of the reaction concentration provided a positive effect on the efficiency of the process maintaining a high diastereomeric ratio (Table 1, entries 10–11). The highest yield was observed using a concentration of 0.125 M, thus indicating final reaction parameters (Table 1, entry 11). Importantly, the possibility to perform the reaction on a 1 mmol scale was also investigated with comparable results obtained (Table 1, entry 12).
Table 1. 5-Substituted-furan-2(3H)-ones 2 in the [8 + 2]-Cycloaddition with 8,8-Dicyanoheptafulvene 1a—Optimization Studiesa.
| entry | solvent | reaction time [days] | conv. [%]b | drc |
|---|---|---|---|---|
| 1 | CHCl3 | 3 | 14 | 7:1 |
| 2 | CH2Cl2 | 3 | 53 | 13:1 |
| 3 | toluene | 3 | 19 | |
| 4 | trifluorotoluene | 3 | 17 | 9:1 |
| 5 | 2-methyltoluene | 3 | 51 | 14:1 |
| 6 | 1,4-dioxane | 3 | 60 | 6:1 |
| 7 | THF | 3 | >95 (36) | 12:1 |
| 8d | CH3CN | 4 | >95 (44) | >20:1 |
| 9e | CH3CN | 1 | >95 (48) | 15:1 |
| 10f | CH3CN | 1 | >95 (62) | >20:1 |
| 11g | CH3CN | 1 | >95 (67) | >20:1 |
| 12h | CH3CN | 1 | >95 (68) | >20:1 |
Unless otherwise stated, reactions performed on a 0.05 mmol scale using 1a (1.0 equiv), 2a (2 equiv), and catalyst 4h (20 mol %) for 1–4 days at room temperature and 0.2 mL of the corresponding solvent.
Conversion was determined by 1H NMR of a crude reaction mixture. In parentheses the isolated yield is given.
Determined by 1H NMR of a crude reaction mixture.
Reaction performed at 5 °C.
Reaction performed at 40 °C.
Reaction performed using CH3CN (0.1 mL).
Reaction performed using CH3CN (0.4 mL).
Reaction performed on a 1 mmol scale.
Having optimized the conditions for the developed reaction, its scope and limitations were investigated (Scheme 4). Furan-2(3H)-ones 2a–g with various substituents in the γ-position were reacted with 8,8-dicyanoheptafulvene 1a. All higher-order cycloadditions proceeded in a highly diastereoselective manner. Furthermore, the change of length of the carbon chain in the γ-position of substrates 2a–c had a positive effect on the efficiency of the reaction (Scheme 4, products 3a–c). However, this trend was not continued with significant lengthening of the alkyl chain (Scheme 4, product 3d). In the case of furan-2(3H)-one 2e bearing more sterically demanding i-propyl group, a lower yield was observed (Scheme 4, product 3e). The reaction proved unbiased toward the introduction of functional groups (double bond or phenyl ring) in the carbon chain in the γ-position of 2f–g as demonstrated in the synthesis of 3f–g (Scheme 4, products 3f–g). To further broaden the scope of the developed method, 5-phenylfuran-2(3H)-one 2h was employed. Unfortunately, no product formation was observed under established conditions. Attempts to re-optimize reaction conditions with 2h were unsuccessful. Endeavors to expand the scope of the method by the use of ethyl 2-cyano-2-(cyclohepta-2,4,6-trien-1-ylidene)acetate 1b were also unsuccessful as the formation of the product 3i was not observed.
Scheme 4. 5-Substituted-furan-2(3H)-ones in the [8 + 2]-Cycloaddition with 8,8-Dicyanoheptafulvene—Scope Studies.
The relative configuration of 3a was unambiguously confirmed by the single-crystal X-ray analysis (see the Supporting Information for further information). Relative configurations of the remaining cycloadducts 3b–g were assigned by analogy (Scheme 5, top). Given the configurational assignments, a plausible mechanism and stereochemical model of the higher-order cycloaddition was proposed (Scheme 5, bottom). It is postulated that in the first step the organic base deprotonates 5-substituted-furan-2(3H)-one 2 from its α-position, therefore generating a dienolate represented by three resonance structures A–C. The dienolate that acts as a higherenophile in the developed cycloaddition undergoes cycloaddition with higherene 1a to give 6. Protonation of the α-position in the lactone ring leads to the formation of a final product 3.
Scheme 5. 5-Substituted-furan-2(3H)-ones 2 in the [8 + 2]-Cycloaddition with 8,8-Dicyanoheptafulvene 1a—Mechanistic Considerations.
Attempts to perform the developed higher-order cycloaddition in an enantioselective manner were also undertaken (Scheme 6). Therefore, a number of chiral organic bases were tested in order to evaluate their ability to induce asymmetry in the studied transformation. The use of the simplest quinine 4i as a catalyst gave unsatisfactory results, both in terms of yield as well as in the diastereoselectivity and most importantly enantioselectivity of the process. Similar results concerning selectivity of the process, but even worse efficiency of the cycloaddition were obtained, when quinine squaramide derivative 4j was used. Thiourea 4k derived from cinchonidine also did not promote the reaction in an enantioselective manner. The best result was obtained when a dimeric catalyst 4l was applied—conversion and yield of the cycloaddition were at satisfactory level, but diastereoselectivity as well as enantioselectivity still remained low.
Scheme 6. 5-Substituted-furan-2(3H)-ones 2 in the [8 + 2]-Cycloaddition with 8,8-Dicyanoheptafulvene 1a—Enantioselective Approach.
Conclusions
In conclusion, the application of 5-substituted-furan-2(3H)-ones 2 under organocatalytic conditions led to the formation of the active dienolate which acted as a 2π-component in the [8 + 2]-cycloaddition with 8,8-dicyanoheptafulvene 1a as an 8π-component. It was possible to obtain cycloadducts 3a–g efficiently and in highly diastereoselective manner. As a continuation of our previous work, the above research managed to expand the application of organocatalytically activated dienolates in the higher-order cycloadditions.
Experimental Section
General Information
Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification. NMR spectra were acquired on a Bruker Ultra Shield 700 instrument, running at 700 MHz for 1H and 176 MHz for 13C, respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl3: 7.26 ppm for 1H NMR, 77.16 ppm for 13C NMR). Mass spectra were recorded on a Bruker Maxis Impact quadrupole time-of-flight spectrometer using electrospray (ES+) ionization (referenced to the mass of the charged species). Analytical thin layer chromatography was performed using pre-coated aluminum-backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation. Silica gel (Silica gel 60, 230–400 mesh, Fluka) was used for flash chromatography. 5-Methyl-furane-2(3H)-one 2a is a commercially available compound.
2-(Cyclohepta-2,4,6-trien-1-ylidene)malononitrile (1a)
Compound 1a was synthesized according to the literature procedure11 as red needles in 75% yield (115.6 mg). Analytical data were in accordance with the literature.
Ethyl 2-Cyano-2-(cyclohepta-2,4,6-trien-1-ylidene)acetate (1b)
Compound 1b was synthesized according to the literature procedure11 as a red solid in 70% yield (253.54 mg). Analytical data were in accordance with the literature.
5-Ethylfuran-2(3H)-one (2b)
Compound 2b was synthesized according to the literature procedure12 as a colorless oily liquid in 20% yield (23.8 mg). Analytical data were in accordance with the literature.
5-Propylfuran-2(3H)-one (2c)
Compound 2c was synthesized according to the literature procedure13 as a colorless oily liquid in 45% yield (20.1 mg). Analytical data were in accordance with the literature.
5-Hexylfuran-2(3H)-one (2d)
Compound 2d was synthesized according to the literature procedure13 as a yellow oily liquid in 40% yield (22.9 mg). Analytical data were in accordance with the literature.
5-Isopropylfuran-2(3H)-one (2e)
Compound 2e was synthesized according to the literature procedure14 as a light-yellow oily liquid in 41% yield (20.5 mg). Analytical data were in accordance with the literature.
5-Benzylfuran-2(3H)-one (2f)
Compound 2f was synthesized according to the literature procedure13 as a light-yellow oily liquid in 7% yield (18.1 mg). 1H NMR (700 MHz, CDCl3): δ 7.48–7.10 (m, 5H), 5.07–5.04 (m, 1H), 3.61 (q, J = 2.2 Hz, 2H), 3.17 (q, J = 2.4 Hz, 2H). 13C{1H} NMR (176 MHz, CDCl3): δ 176.6, 156.1, 135.3, 129.2 (2C), 128.8 (2C), 127.2, 99.8, 35.0, 34.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H10O2H, 175,0759; found, 175.0758.
5-Allylfuran-2(3H)-one (2g)
Compound 2g was synthesized according to the literature procedure13 as a light-yellow oily liquid in 30% yield (19.1 mg). 1H NMR (700 MHz, CDCl3): δ 5.83 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 5.23–5.19 (m, 1H), 5.19–5.17 (m, 1H), 5.15 (tt, J = 2.3, 1.5 Hz, 1H), 3.18–3.17 (m, 2H), 3.07–3.04 (m, 2H). 13C{1H} NMR (176 MHz, CDCl3): δ 176.7, 155.4, 131.2, 118.9, 99.1, 34.1, 32.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H8O2H 125, 0603; found, 125.0603.
5-Phenylfuran-2(3H)-one (3h)
Compound was synthesized according to the literature procedure13 as an orange solid in 65% yield (104,0 mg). Analytical data were in accordance with the literature.
General Procedure for the Synthesis of Compounds 3a–g
In an ordinary 4 mL glass vial, equipped with a magnetic stirring bar and a screw cap, 5-substituted-furane-2(3H)-one 2 (2.0 equiv, 0.2 mmol), 8,8-dicyanoheptafulvene 1a (1.0 equiv, 0.1 mmol, 15.42 mg), and catalyst 4h (0.02 equiv, 0.02 mmol, 2,24 mg) were dissolved in acetonitrile (0.8 mL) and stirred for 24 h at room temperature. The reaction mixture was directly subjected to flash chromatography on silica gel (eluent = hexanes/ethyl acetate, 8:1) to obtain pure product 3.
(3aR*,9aS*,9bR*)-9b-Methyl-2-oxo-3,3a,9a,9b-tetrahydroazuleno[1,2-b]furan-4,4(2H)-dicarbonitrile (3a)
Following the general procedure, pure product 3a was isolated after flash silica column chromatography (eluent = hexanes/ethyl acetate, 8:1) in 67% yield (16.9 mg, >20:1 dr) as a white solid (mp 192–193 °C). 1H NMR (700 MHz, CDCl3): δ 6.77 (dd, J = 11.4, 5.9 Hz, 1H), 6.71 (dd, J = 6.2, 2.0 Hz, 1H), 6.60 (dd, J = 11.4, 6.2 Hz, 1H), 6.29 (ddd, J = 9.8, 5.9, 2.0 Hz, 1H), 5.57 (dd, J = 9.8, 4.2 Hz, 1H), 3.40 (dd, J = 8.3, 4.0 Hz, 1H), 3.10 (dd, J = 18.5, 8.3 Hz, 1H), 2.95 (dd, J = 18.5, 4.0 Hz, 1H), 2.76 (ddd, J = 4.2, 2.0, 2.0 Hz, 1H), 1.66 (s, 3H). 13C{1H} NMR (176 MHz, CDCl3): δ 171.6, 134.9, 129.0, 128.5, 127.3, 125.9, 121.4, 114.2, 112.5, 91.7, 55.6, 50.8, 41.5, 32.8, 26.3. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H12N2O2Na, 275.0796; found, 275.0798.
(3aR*,9aS*,9bR*)-9b-Ethyl-2-oxo-3,3a,9a,9b-tetrahydroazuleno[1,2-b]furan-4,4(2H)-dicarbonitrile (3b)
Following the general procedure, pure product 3b was isolated after flash silica column chromatography (eluent = hexanes/ethyl acetate, 8:1) in 65% yield (17.3 mg, >20:1 dr) as a white solid (mp 144–145 °C). 1H NMR (700 MHz, CDCl3): δ 6.79 (dd, J = 11.1, 5.9 Hz, 1H), 6.70 (dd, J = 6.1, 1.9 Hz, 1H), 6.61 (dd, J = 11.2, 6.1 Hz, 1H), 6.27 (ddd, J = 9.7, 5.9, 1.9 Hz, 1H), 5.57 (dd, J = 9.7, 4.4 Hz, 1H), 3.43 (dd, J = 8.4, 3.6 Hz, 1H), 3.08 (dd, J = 18.6, 8.4 Hz, 1H), 2.95 (dd, J = 18.6, 3.5 Hz, 1H), 2.73 (ddd, J = 4.2, 1.9, 1.9 Hz, 1H), 1.91 (dq, J = 14.6, 7.3 Hz, 1H), 1.82 (dq, J = 14.7, 7.4 Hz, 1H), 1.07 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (176 MHz, CDCl3): δ 171.9, 135.0, 128.9, 128.4, 126.7, 125.4, 122.0, 114.1, 112.6, 94.5, 54.2, 49.2, 41.7, 33.0, 32.9, 8.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H14N2O2Na, 289.0953; found, 289.0955.
(3aR*,9aS*,9bR*)-2-Oxo-9b-propyl-3,3a,9a,9b-tetrahydroazuleno[1,2-b]furan-4,4(2H)-dicarbonitrile (3c)
Following the general procedure, pure product 3c was isolated after flash silica column chromatography (eluent = hexanes/ethyl acetate, 8:1) in 75% yield (21.0 mg, >20:1 dr) as a yellow oil. 1H NMR (700 MHz, CDCl3): δ 6.78 (dd, J = 11.2, 5.9 Hz, 1H), 6.69 (dd, J = 6.0, 1.9 Hz, 1H), 6.61 (dd, J = 11.0, 5.9 Hz, 1H), 6.27 (ddd, J = 9.7, 5.9, 1.9 Hz, 1H), 5.56 (ddd, J = 9.8, 4.4, 0.9 Hz, 1H), 3.42 (dd, J = 8.3, 3.3 Hz, 1H), 3.08 (dd, J = 18.6, 8.3 Hz, 1H), 2.95 (dd, J = 18.6, 3.3 Hz, 1H), 2.74 (ddd, J = 4.2, 2.0, 2.0 Hz, 1H), 1.86–1.79 (m, 1H), 1.76–1.71 (m, 1H), 1.63–1.56 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (176 MHz, CDCl3): δ 171.9, 135.0, 129.0, 128.4, 126.7, 125.3, 122.0, 114.1, 112.5, 94.2, 54.7, 49.5, 42.2, 33.0, 29.8, 17.2, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H16N2O2Na, 303.1109; found, 303.1113.
(3aR*,9aS*,9bR*)-9b-Hexyl-2-oxo-3,3a,9a,9b-tetrahydroazuleno[1,2-b]furan-4,4(2H)-dicarbonitrile (3d)
Following the general procedure, pure product 3d was isolated after flash silica column chromatography (eluent = hexanes/ethyl acetate, 8:1) in 59% yield (19.0 mg, >20:1 dr) as a yellow oil. 1H NMR (700 MHz, CDCl3): δ 6.79 (dd, J = 11.2, 5.9 Hz, 1H), 6.70 (dd, J = 5.8, 2.2 Hz, 1H), 6.61 (dd, J = 11.9, 6.1 Hz, 1H), 6.27 (ddd, J = 9.7, 5.9, 1.9 Hz, 1H), 5.56 (dd, J = 9.7, 4.4 Hz, 1H), 3.42 (dd, J = 8.3, 3.4 Hz, 1H), 3.08 (dd, J = 18.6, 8.3 Hz, 1H), 2.95 (dd, J = 18.6, 3.4 Hz, 1H), 2.73 (ddd, J = 4.1, 1.9, 1.9 Hz, 1H), 1.87–1.80 (m, 1H), 1.79–1.72 (m, 1H), 1.37–1.26 (m, 8H), 0.87 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (176 MHz, CDCl3): δ 171.9, 135.0, 129.0, 128.4, 126.8, 125.4, 122.1, 114.1, 112.6, 94.2, 54.6, 49.5, 40.1, 33.0, 31.6, 29.9, 29.3, 23.7, 22.6, 14.1. . HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H22N2O2Na, 345.1579; found, 345.1581.
(3aR*,9aS*,9bR*)-9b-Isopropyl-2-oxo-3,3a,9a,9b-tetrahydroazuleno[1,2-b]furan-4,4(2H)-dicarbonitrile (3e)
Following the general procedure, pure product 3e was isolated after flash silica column chromatography (eluent = hexanes/ethyl acetate, 8:1) in 43% yield (12.1 mg, >20:1 dr) as a white solid (mp 100–101 °C). 1H NMR (700 MHz, CDCl3): δ 6.82 (dd, J = 11.0, 5.9 Hz, 1H), 6.69 (dd, J = 6.0, 1.8 Hz, 1H), 6.63 (dd, J = 11.1, 6.0 Hz, 1H), 6.27 (ddd, J = 9.6, 5.9, 1.8 Hz, 1H), 5.60 (dd, J = 9.6, 4.5 Hz, 1H), 3.55 (dd, J = 8.4, 2.6 Hz, 1H), 3.08 (dd, J = 18.7, 8.4 Hz, 1H), 2.97 (dd, J = 18.8, 2.6 Hz, 1H), 2.70 (ddd, J = 4.3, 1.8, 1.8 Hz, 1H), 1.96 (hept, J = 6.7 Hz, 1H), 1.07 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (176 MHz, CDCl3): δ 172.1, 135.2, 128.8, 128.3, 126.3, 124.5, 122.7, 114.0, 112.6, 97.2, 52.6, 47.5, 42.4, 36.7, 33.3, 17.3, 17.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H16N2O2H, 281.1290; found, 281.1296.
(3aR*,9aS*,9bR*)-9b-Benzyl-2-oxo-3,3a,9a,9b-tetrahydroazuleno[1,2-b]furan-4,4(2H)-dicarbonitrile (3f)
Following the general procedure, pure product 3f was isolated after flash silica column chromatography (eluent = hexanes/ethyl acetate, 8:1) in 60% yield (19.7 mg, >20:1 dr) as a white solid (mp 209–210 °C). 1H NMR (700 MHz, CDCl3): δ 7.44–7.34 (m, 3H), 7.32–7.25 (m, 2H), 6.79 (dd, J = 11.1, 5.9 Hz, 1H), 6.72 (dd, J = 6.1, 1.9 Hz, 1H), 6.63 (dd, J = 11.2, 6.1 Hz, 1H), 6.27 (ddd, J = 9.7, 5.9, 1.9 Hz, 1H), 5.55 (dd, J = 9.8, 4.3 Hz, 1H), 3.47 (dd, J = 8.6, 3.9 Hz, 1H), 3.35 (d, J = 14.5 Hz, 1H), 2.96 (d, J = 14.5 Hz, 1H), 2.83 (ddd, J = 4.1, 1.9, 1.9 Hz, 1H), 2.66 (dd, J = 18.4, 3.9 Hz, 1H), 2.22 (dd, J = 18.4, 8.6 Hz, 1H). 13C{1H} NMR (176 MHz, CDCl3): δ 171.9, 135.0, 133.5, 130.5 (2C), 129.4 (2C), 128.5, 128.5, 128.3, 127.0, 125.6, 121.6, 114.2, 112.7, 93.4, 53.1, 50.7, 45.4, 41.8, 33.3. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H16N2O2Na, 351.1109; found, 351.1111.
(3aR*,9aS*,9bR*)-9b-Allyl-2-oxo-3,3a,9a,9b-tetrahydroazuleno[1,2-b]furan-4,4(2H)-dicarbonitrile (3g)
Following the general procedure, pure product 3g was isolated after flash silica column chromatography (eluent = hexanes/ethyl acetate, 8:1) in 43% yield (11.9 mg, >20:1 dr) as a white solid (mp 121–122 °C). 1H NMR (700 MHz, CDCl3): δ 6.78 (dd, J = 11.2, 5.9 Hz, 1H), 6.70 (dd, J = 6.0, 1.9 Hz, 1H), 6.61 (dd, J = 11.2, 5.7 Hz, 1H), 6.28 (ddd, J = 9.8, 5.9, 2.0 Hz, 1H), 5.83–5.76 (m, 1H), 5.54 (dd, J = 9.8, 4.3 Hz, 1H), 5.33–5.26 (m, 2H), 3.50 (dd, J = 8.6, 4.3 Hz, 1H), 3.06 (dd, J = 18.5, 8.6 Hz, 1H), 2.92 (dd, J = 18.5, 4.3 Hz, 1H), 2.76 (ddd, J = 4.1, 2.0, 2.0 Hz, 1H), 2.66–2.56 (m, 2H). 13C{1H} NMR (176 MHz, CDCl3): δ 171.8, 134.9, 129.8, 128.5, 128.5, 127.0, 125.7, 122.4, 121.5, 114.1, 112.7, 93.3, 53.2, 49.4, 43.6, 41.5, 33.2. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H14N2O2Na, 301.0953; found, 301.0949.
Acknowledgments
National Science Centre, Poland, Opus programme (grant number: 2021/41/B/ST4/03385). We are grateful to Jakub Sobieszczyk for initial contributions.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c00101.
Full account of screening results, X-ray structure, and copies of 1H and 13C NMR spectra (PDF)
Accession Codes
CCDC 2107237 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Author Contributions
All authors have given approval to the final version of the manuscript.
The authors declare no competing financial interest.
Supplementary Material
References
- For selected reviews, see:; a Hoffmann H. M. R.; Rabe J. Synthesis and Biological Activity of α-Methylene-γ-butyrolactones. Angew. Chem., Int. Ed. Engl. 1985, 24, 94–110. 10.1002/anie.198500941. [DOI] [Google Scholar]; b Seitz M.; Reiser O. Synthetic approaches towards structurally diverse γ-butyrolactone natural-product-like compounds. Curr. Opin. Chem. Biol. 2005, 9, 285–292. 10.1016/j.cbpa.2005.03.005. [DOI] [PubMed] [Google Scholar]; c Kitson R. R. A.; Millemaggi A.; Taylor R. J. K. The Renaissance of α-Methylene-γ-butyrolactones: New Synthetic Approaches. Angew. Chem., Int. Ed. 2009, 48, 9426–9451. 10.1002/anie.200903108. [DOI] [PubMed] [Google Scholar]; d Bhat B. A.; Rashid S.; Mehta G. Progress in the Total Synthesis of Natural Products Embodying Diverse Furofuranone Motifs: A New Millennium Update. Asian J. Org. Chem. 2020, 9, 1726–1753. 10.1002/ajoc.202000401. [DOI] [Google Scholar]
- a Triandafillidi I.; Raftopoulou M.; Savvidou A.; Kokotos C. G. Organocatalytic Synthesis of Lactones by the Oxidation of Alkenoic Acids. ChemCatChem 2017, 9, 4120–4124. 10.1002/cctc.201700837. [DOI] [Google Scholar]; b Triandafillidi I.; Savvidou A.; Kokotos C. G. Synthesis of γ-Lactones Utilizing Ketoacids and Trimethylsulfoxonium Iodide. Org. Lett. 2019, 21, 5533–5537. and references cited therein 10.1021/acs.orglett.9b01852. [DOI] [PubMed] [Google Scholar]
- Ray Choudhury A.; Mukherjee S. Deconjugated Butenolide: A Versatile Building Block For Asymmetric Catalysis. Chem. Soc. Rev. 2020, 49, 6755–6788. 10.1039/c9cs00346k. [DOI] [PubMed] [Google Scholar]
- a Griswold J. A.; Horwitz M. A.; Leiva L. V.; Johnson J. S. Diastereoselective Organocatalytic Addition of α-Angelica Lactone to β-Halo-α-ketoesters. J. Org. Chem. 2017, 82, 2276–2280. 10.1021/acs.joc.6b03059. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Li C.; Jiang K.; Chen Y.-C. Diastereodivergent and Enantioselective [4+2] Annulations of γ-Butenolides with Cyclic 1-Azadienes. Molecules 2015, 20, 13642–13658. 10.3390/molecules200813642. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Boukouvalas J.; Jean M.-A. Streamlined Biomimetic Synthesis of Paracaseolide a Via Aerobic Oxidation of a 2-Silyloxyfuran. Tetrahedron Lett. 2014, 55, 4248–4250. 10.1016/j.tetlet.2014.05.054. [DOI] [Google Scholar]; d Egorova A. Y.; Timofeeva Z. Y. Common and Specific Features of the Michael Condensation in the Series of 3-R-3H-Furan-2-ones. Russ. J. Gen. Chem. 2003, 73, 655–658. 10.1023/a:1025625511411. [DOI] [Google Scholar]; e Jefford C. W.; Jaggi D.; Boukouvalas J. Regioselective aldol condensations of boron and tin furanolates with aldehydes: an improved synthesis of 2-(1′-hydroxyalkyl)butenolides. Chem. Commun. 1988, 24, 1595–1596. 10.1039/c39880001595. [DOI] [Google Scholar]
- For recent examples see:; a Ishii D.; Hirashima S.-i.; Nakashima K.; Akutsu H.; Sakai T.; Matsushima Y.; Kawada M.; Miura T. Asymmetric Direct Vinylogous Conjugate Addition of Substituted Furanone Derivatives to Benzoyl Acrylonitrile: Stereoselective Synthesis Toward Bicyclic γ-Lactams. Org. Lett. 2021, 23, 480–485. 10.1021/acs.orglett.0c04004. [DOI] [PubMed] [Google Scholar]; b Romaniszyn M.; Sieroń L.; Albrecht Ł. Asymmetric vinylogous Michael addition of 5-substituted-furan-2(3H)-ones to an α,β-unsaturated-γ-lactam. Org. Biomol. Chem. 2020, 18, 8633–8637. 10.1039/d0ob01750g. [DOI] [PubMed] [Google Scholar]; c Sakai T.; Hirashima S.-i.; Matsushima Y.; Nakano T.; Ishii D.; Yamashita Y.; Nakashima K.; Koseki Y.; Miura T. Synthesis of Chiral γ,γ-Disubstituted γ-Butenolides via Direct Vinylogous Aldol Reaction of Substituted Furanone Derivatives with Aldehydes. Org. Lett. 2019, 21, 2606–2609. 10.1021/acs.orglett.9b00574. [DOI] [PubMed] [Google Scholar]
- a Bentley R. A fresh look at natural tropolonoids. Nat. Prod. Rep. 2008, 25, 118–138. 10.1039/b711474e. [DOI] [PubMed] [Google Scholar]; b Cox R. J.; Al-Fahad A. Chemical Mechanisms Involved During the Biosynthesis of Tropolones. Curr. Opin. Chem. Biol. 2013, 17, 532–536. 10.1016/j.cbpa.2013.06.029. [DOI] [PubMed] [Google Scholar]; c Cai X.; Shi Y.-M.; Pöhlmann N.; Revermann O.; Bahner I.; Pidot S. J.; Wesche F.; Lackner H.; Büchel C.; Kaiser M.; Richter C.; Schwalbe H.; Stinear T. P.; Zeeck A.; Bode H. B. Structure and Biosynthesis of Isatropolones, Bioactive Amine-Scavenging Fluorescent Natural Products from Streptomyces Gö66. Angew. Chem., Int. Ed. 2017, 56, 4945–4949. 10.1002/anie.201701223. [DOI] [PubMed] [Google Scholar]; d al Fahad A.; Abood A.; Simpson T. J.; Cox R. J. The Biosynthesis and Catabolism of the Maleic Anhydride Moiety of Stipitatonic Acid. Angew. Chem., Int. Ed. 2014, 53, 7519–7523. 10.1002/anie.201403450. [DOI] [PubMed] [Google Scholar]; e Duan Y.; Petzold M.; Saleem-Batcha R.; Teufel R. Bacterial Tropone Natural Products and Derivatives: Overview of their Biosynthesis, Bioactivities, Ecological Role and Biotechnological Potential. Chembiochem 2020, 21, 2384–2407. 10.1002/cbic.201900786. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Yan Y.; Ma Y.-T.; Yang J.; Horsman G. P.; Luo D.; Ji X.; Huang S.-X. Tropolone Ring Construction in the Biosynthesis of Rubrolone B, a Cationic Tropolone Alkaloid from Endophytic Streptomyces. Org. Lett. 2016, 18, 1254–1257. 10.1021/acs.orglett.6b00074. [DOI] [PubMed] [Google Scholar]; g Leung Y. Y.; Yao Hui L. L.; Kraus V. B. Colchicine-Update on mechanisms of action and therapeutic uses. Semin. Arthritis Rheum. 2015, 45, 341–350. 10.1016/j.semarthrit.2015.06.013. [DOI] [PMC free article] [PubMed] [Google Scholar]; h Zhao J.; Zhao J. Plant Troponoids: Chemistry, Biological Activity, and Biosynthesis. Curr. Med. Chem. 2007, 14, 2597–2621. 10.2174/092986707782023253. [DOI] [PubMed] [Google Scholar]
- For selected review see:Frankowski S.; Romaniszyn M.; Skrzyńska A.; Albrecht Ł. The Game of Electrons: Organocatalytic Higher-Order Cycloadditions Involving Fulvene- and Tropone-Derived Systems. Chem.—Eur. J. 2020, 26, 2120–2132. 10.1002/chem.201904157. [DOI] [PubMed] [Google Scholar]; and references cited therein
- a Bertuzzi G.; McLeod D.; Mohr L. M.; Jørgensen K. A. Organocatalytic Enantioselective 1,3-Dipolar [6+4] Cycloadditions of Tropone. Chem.—Eur. J. 2020, 26, 15491–15496. 10.1002/chem.202003329. [DOI] [PubMed] [Google Scholar]; b Li J.; Mo Y.; Yan L.; Feng X.; Su Z.; Liu X. Organocatalytic Stereoselective [8+2] Cycloaddition of Tropones with Azlactones. CCS Chem. 2022, 4, 650–659. 10.31635/ccschem.021.202000664. [DOI] [Google Scholar]; c Chen X.; Thøgersen M. K.; Yang L.; Lauridsen R. F.; Xue X.-S.; Jørgensen K. A.; Houk K. N. [8+2] vs [4+2] Cycloadditions of Cyclohexadienamines to Tropone and Heptafulvenes-Mechanisms and Selectivities. J. Am. Chem. Soc. 2021, 143, 934–944. 10.1021/jacs.0c10966. [DOI] [PubMed] [Google Scholar]
- Romaniszyn M.; Gronowska K.; Albrecht Ł. 2-Substituted 1,4-Naphthoquinones in [6 + 4]-Cycloaddition with 8,8-Dicyanoheptafulvene. J. Org. Chem. 2019, 84, 9929–9936. 10.1021/acs.joc.9b01091. [DOI] [PubMed] [Google Scholar]
- Mose R.; Preegel G.; Larsen J.; Jakobsen S.; Iversen E. H.; Jørgensen K. A. Organocatalytic Stereoselective [8+2] and [6+4] Cycloadditions. Nat. Chem. 2017, 9, 487–492. 10.1038/nchem.2682. [DOI] [PubMed] [Google Scholar]
- Quintard A.; Lefranc A.; Alexakis A. Highly Enantioselective Direct Vinylogous Michael Addition of γ-Butenolide to Enals. Org. Lett. 2011, 13, 1540–1543. 10.1021/ol200235j. [DOI] [PubMed] [Google Scholar]
- Muratore M. E.; Holloway C. A.; Pilling A. W.; Storer R. I.; Trevitt G.; Dixon D. J. Enantioselective Brønsted Acid-Catalyzed N-Acyliminium Cyclization Cascades. J. Am. Chem. Soc. 2009, 131, 10796–10797. 10.1021/ja9024885. [DOI] [PubMed] [Google Scholar]
- Wu Y.; Singh R. P.; Deng L. Asymmetric Olefin Isomerization of Butenolides via Proton Transfer Catalysis by an Organic Molecule. J. Am. Chem. Soc. 2011, 133, 12458–12461. 10.1021/ja205674x. [DOI] [PMC free article] [PubMed] [Google Scholar]
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