Abstract
The application of organocatalytic bifunctional activation in the remote (3 + 2)-cycloaddition between 4-(alk-1-en-1-yl)-3-cyanocoumarins and imines derived from salicylaldehyde is demonstrated. Products, bearing two biologically relevant units, have been obtained with good chemical and stereochemical efficiency. The stereochemical outcome of the process results from the application of a quinine-derived catalyst. Selected transformations of the cycloadducts leading to further chemical diversity have been demonstrated.
The high demand of the life-science industry for enantiomerically pure molecules with defined absolute configurations resulted in the development of reliable methods for their preparation, with catalytic approaches being the most desired.1 Intensive studies in the area of asymmetric synthesis has led to the design of many attractive chiral catalysts for the conversion of pro-chiral substrates into enantiomerically enriched products. Until 2000, mainly transition metal complexes and enzymes were used as promoters of enantio-differentiating reactions.2 They offer many possibilities in the synthesis of nonracemic compounds, but at the same time they are not free from disadvantages related to catalyst availability and stability, toxicity, and the possibility to contaminate the reaction product with residues of the metal catalyst. Since the turn of the millennium, organocatalysis has emerged as an important alternative to these methods, providing many valuable solutions.3,4 Among the available methods, the application of organocatalysts derived from cinchona alkaloids has received great attention.4 This group of reaction promoters acts as bifunctional systems because they simultaneously activate both substrates, leading to highly efficient enantio- and diastereoselective transformations.5
Many natural products as well as synthetic analogues with significant biological activity contain the coumarin moiety and/or the pyrrolidine ring in their structure. The pharmacological properties of coumarins depend on their chemical scaffolds (core structure and substitution pattern) and the physicochemical properties of the oxaheterocyclic ring. The presence of a conjugated double bond system ensures the desired electronic properties and is crucial for the interaction with other molecules, receptors, and ions. Moreover, the planar, aromatic, and lipophilic nature of 2H-chromen-2-one results in a preference for hydrophobic interactions with aromatic amino acids, which allows for binding with the target protein.
Coumarins and their derivatives exhibit diverse bioactivities6 including antibacterial, antitubercular, antifungal, antiviral, antimutagenic, anti-inflammatory, anticancer, antioxidant, anticoagulant, and antithrombotic properties. They are also inhibitors of monoamine oxidase (MAO), cholinesterase (ChE), cyclooxygenase, and lipooxygenase and stimulants of the central nervous system (CNS) (Scheme 1).7 On the other hand, the five-membered pyrrolidine ring is a privileged structural motif in drug design.8 This structure tops the ranking of the most popular nonaromatic, five-membered nitrogen heterocycles and is present in 37 medications approved by the United States Food and Drug Administration.9 The pyrrolidine derivatives are widely distributed in alkaloids isolated from plant extracts or microorganisms10 that exhibit a broad spectrum of various biological properties, including anticancer, antimicrobial, antioxidant, antihyperglycemic, antifungal, or anti-inflammatory activities (Scheme 1). In recent years, stereocontrolled organocatalytic approaches for the preparation of both coumarin and pyrrolidine derivatives have gained increased importance.11
Scheme 1. Representative Bioactive Compounds Containing a Coumarin or Pyrrolidine Skeleton.
Given both the biological relevance of pyrrolidine or coumarin units and the synthetic potential of 4-(alk-1-en-1-yl)-3-cyanocoumarins, the task of the design and synthesis of hybrid molecules containing both biorelevant structural motifs was undertaken. The developed synthetic strategy relies on the application of the vinylogous reactivity of 4-(alk-1-en-1-yl)-3-cyanocoumarins as dienophiles in the 1,3-dipolar cycloaddition with imines (derivatives of salicyl aldehydes and appropriate amines, Scheme 2). At the outset of our studies, it was anticipated that the use of the cinchona-derived squaramide bifunctional catalyst would enable the control of both the chemical and stereochemical efficiency of the devised reactivity.
Scheme 2. Synthetic Goals of Our Research.
Coumarin 1a and aldimine 2a were employed as model reactants for the optimization studies (Table 1). Initial experiments were accomplished in the presence of catalysts 4a–f in 1,2-dichloroethane as a solvent at 5 °C. Most of used catalysts 4a–e gave access to product 3a with high conversion after 72 h at 5 °C; however, 3a was obtained in its racemic or nearly racemic form (Table 1, entries 1–5, respectively). Interestingly, when the reaction was conducted using the catalyst 4f bearing a squaramide moiety and electron-withdrawing trifluoromethyl groups in the meta-positions of the aromatic substituent, a significant increase in enantioselectivity was observed without the loss of reactivity (Table 1, entry 6). The next step of our studies was devoted to the screening of solvents (Table 1, entries 7–12). A slight improvement of the conversion with a decrease of the enantiomeric ratio was observed for the reaction carried out in chloroform (Table 1, entry 7). The reaction performed in CH2Cl2 also yielded a product 3a with excellent diastereo- and enantioselectivity (Table 1, entry 8). Utilization of either acetonitrile or toluene improved the reactivity, but the stereocontrol of the process was insufficient (Table 1, entries 9 and 10). The high conversion and diastereomeric ratio were obtained in α,α,α-trifluorotoluene and 4-fluorotoluene at 5 °C, but the enantioselectivity was lower (Table 1, entries 11 and 12, respectively). Finally, the influence of concentration and temperature on the process was investigated in dichloromethane (Table 1, entries 13–15). Additionally, it was demonstrated the reaction does not take place in the absence of a hydroxyl group in the benzaldimine derivative 2 (Table 1, entry 16).
Table 1. Asymmetric Remote (3 + 2)-Cycloaddition to 4-(Alk-1-en-1-yl)-3-cyanocoumarins 1: Optimization Studiesa.
| cat. | R | solvent | conv [%]b | drc | erd | |
|---|---|---|---|---|---|---|
| 1 | 4a | OH | ClCH2CH2Cl | >95 (80) | 12:1 | 60:40 |
| 2 | 4b | OH | ClCH2CH2Cl | 19 (10) | 13:1 | rac |
| 3 | 4c | OH | ClCH2CH2Cl | >95 (68) | 14:1 | 55:45 |
| 4 | 4d | OH | ClCH2CH2Cl | 82 (42) | n.d. | 65:35 |
| 5 | 4e | OH | ClCH2CH2Cl | 62 (60) | 11:1 | rac |
| 6 | 4f | OH | ClCH2CH2Cl | 81 (73) | 12:1 | 87:13 |
| 7 | 4f | OH | CHCl3 | >95 (93) | 13:1 | 66:34 |
| 8 | 4f | OH | CH2Cl2 | 75 (70) | >20:1 | 90:10 |
| 9 | 4f | OH | CH3CN | >95 (93) | 12:1 | 80:20 |
| 10 | 4f | OH | PhCH3 | >95 (65) | 17:1 | 92:8 |
| 11 | 4f | OH | PhCF3 | >95 (88) | >20:1 | 89:11 |
| 12 | 4f | OH | 4-F-PhCH3 | 93 (81) | >20:1 | 87:13 |
| 13e | 4f | OH | CH2Cl2 | 65 (60) | >20:1 | 93:7 |
| 14e,f | 4f | OH | CH2Cl2 | 75 (70) | >20:1 | 92:7 |
| 15g | 4f | OH | CH2Cl2 | 76 (70) | >20:1 | 93:7 |
| 16g | 4f | H | CH2Cl2 | <5 | n.d. | n.d. |
Reactions were accomplished on a 0.05 mmol scale using 1a (1 equiv) and 2 (1.2 equiv) in 0.2 mL of the solvent for 72 h.
Conversion was evaluated by 1H NMR analysis of the crude reaction mixture. The isolated yield is given in parentheses.
Determined by 1H NMR analysis of the crude reaction mixture.
Determined by a chiral stationary phase UPC2.
The reaction was carried out at −25 °C.
The reaction was carried out in CH2Cl2 (0.1 mL).
The reaction was carried out at −18 °C.
With optimization studies accomplished, the scope studies were initiated (Table 2, Scheme 3). Initially, the significance of various substituents in coumarins 1a–l on the reaction outcome was tested (Table 2). To our delight, all reactions exhibited excellent diastereooselectivity. The application of halogen substituents in either meta- or para-positions of the styryl moiety in 1 resulted in high enantioselectivity and yields for the process (Table 2, entries 2–4). The compound 1d with fluorine in the meta-position provided 3d with a decreased yield (Table 2, entry 4). While the substrate 1e bearing a trifluoromethyl group gave an excellent result in terms of the efficiency and stereoselectivity of the process (Table 2, entries 5), the presence of the nitro group in the para-position of the styryl moiety in 1f led to deteriorated enantiomeric enrichment (Table 2, entry 6). Electron-donating substituents were well-tolerated, and cycloadditions with the substrates 1g–i proceeded in good yields and excellent diastereo- and enantioselectivities (Table 2, entries 7–9, respectively). The incorporation of substituents on the aromatic ring of the coumarin unit turned out also possible giving satisfactory results for both electron-withdrawing (Table 2, entry 10) and electron-donating groups (Table 2, entry 11). Then, the influence of the electron-withdrawing cyano group in the 3-position on the outcome of the reaction was tested, and it was found that the cycloaddition with 1l bearing a carboxylate moiety did not take place (Table 2, entry 12).
Table 2. Asymmetric Remote (3 + 2)-Cycloaddition to 4-(Alk-1-en-1-yl)-3-cyanocoumarins 1a–k: Scope Studiesa.
| R1 | R2 | R3 | yield [%]b | erc | |
|---|---|---|---|---|---|
| 1 | H | H | CN | 73 | 93:7 |
| 2 | H | 4-Cl | CN | 85 | 94:6 |
| 3 | H | 3-Cl | CN | 71 | 93:7 |
| 4d | H | 3-F | CN | 58 | 93.5:6.5 |
| 5 | H | 4-CF3 | CN | 71 | 96:4 |
| 6 | H | 4-NO2 | CN | 78 | 87:13 |
| 7 | H | 4-Me | CN | 73 | 95:5 |
| 8 | H | 3-Me | CN | 56 | 90:10 |
| 9 | H | 4-OMe | CN | 74 | 92:8 |
| 10 | 6-Br | H | CN | 74 | 94:6 |
| 11 | 7-OMe | H | CN | 40 | 96:4 |
| 12 | H | H | CO2Et |
Reactions were accomplished on a 0.05 mmol scale using 1a–k (1 equiv), 2a (1.2 equiv), and catalyst 4f (20% mol) in CH2Cl2 (0.2 mL) at −18 °C for 72 h.
The isolated yield is given.
Determined by chiral stationary phase UPC2.
The reaction was carried out for 5 days.
Scheme 3. Asymmetric Remote (3 + 2)-Cycloaddition of o-Hydroxy Aromatic Aldimines 2b–g to 4-(Alk-1-en-1-yl)-3-cyanocoumarin 1a: Scope Studies.
The possibility of employing various aldimines 2 in the investigated reaction was subsequently examined (Scheme 3). The cycloaddition of 2b–g bearing different electron-withdrawing or electron-donating groups on the aromatic ring in 2 proceeded efficiently, providing the desired products in a highly enantioselective fashion (Scheme 3, compounds 3m–s, respectively). Additionally, for 2b, 2c, 2e, and 2f, excellent diastereomeric ratios were observed (Scheme 3, compounds 3m, 3n, 3p, and 3r, respectively). Interestingly, a worsening of the diastereoselectivity of the process was observed for 2d and 2g, while its high efficiency and enantioselectivity were maintained (Scheme 3, compounds 3o and 3s, respectively).
Subsequently, the transformation of 3a, 3b, and 3m into 5a, 5b, and 5c, respectively, was demonstrated (Scheme 4). Therefore, the above substrates were subjected to the reaction with 1,1′-carbonyldiimidazole. The reaction was performed in dichloromethane at room temperature for 14 h, giving compounds 5. Notably, the stereomeric composition of the starting material was not maintained under the employed conditions, resulting in the formation of 5 with slightly reduced diastereo- and enantioselectivity.
Scheme 4. Condensation of 3 with 1,1′-Carbonyldiimidazole.
The absolute configuration of product 5a was unambiguously confirmed by the X-ray structural analysis (for details, see the SI).12 The stereochemistry of compounds 3b–s has been assigned by analogy assuming the same mechanism for all cycloadditions performed. Given the configurational assignments, the mechanism and stereochemical model of the studied cycloaddition were proposed (Scheme 5). The process is initiated by the deprotonation of the corresponding aldimine 2a, thus generating an ylide that forms a chiral ion pair with a catalyst 4f. Simultaneously, 4-(alk-1-en-1-yl)-3-cyanocoumarin 1 is activated by the H-bond interactions with the squaramide moiety of the catalyst 4f.13 This leads to a completely stereoselective generation of a five-membered heterocyclic ring by 1,3-dipolar cycloaddition, giving access to a wide range of derivatives 3.
Scheme 5. Asymmetric Remote (3 + 2)-Cycloaddition to 4-(Alk-1-en-1-yl)-3-cyanocoumarins 1: Mechanistic Considerations.
In conclusion, we have elaborated a new highly efficient enantio- and diastereoselective method for the preparation of pyrrolidine derivatives 3. Our approach utilized organocatalytic (3 + 2)-cycloaddition between 4-(alk-1-en-1-yl)-3-cyanocoumarins 1 and imines 2 (derived from salicylaldehydes and diethyl aminomalonates), which proceeded selectively at the remote double bond in 1. Target products bearing three adjacent stereogenic centers and a new heterocyclic pyrrolidine moiety were obtained with high chemical and stereochemical efficiency.
Acknowledgments
This project was realized within the Sheng program (Grant UMO-2018/30/Q/ST5/00466) from the National Science Centre, Poland. Thanks are expressed to Dr. Lesław Sieroń (Faculty of Chemistry, Lodz University of Technology) for performing the X-ray analysis.
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c01189.
Experimental procedures, characterization of the products, crystal and X-ray data for 5a, NMR data, and UPC2 traces (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
- Busacca C. A.; Fandrick D. R.; Song J. J.; Senanayake C. H. The Growing Impact of Catalysis in the Pharmaceutical Industry. Adv. Synth. Catal. 2011, 353, 1825–1864. 10.1002/adsc.201100488. [DOI] [Google Scholar]
- a Comprehensive Asymmetric Catalysis; Jacobsen E. N., Pfaltz A., Yamamoto H., Eds.; Springer: Berlin, Germany, 1999. [Google Scholar]; b Acc. Chem. Res. 2000, 33( (6), ) (Special Issue “Catalytic Asymmetric Synthesis”). [DOI] [PubMed] [Google Scholar]; c New Frontiers in Asymmetric Catalysis; Mikami K., Lautens M., Eds.; Wiley-Interscience, 2007. [Google Scholar]; d Strohmeier G.-A.; Pichler M.; May O.; Gruber-Khadjawi M. Application of Designed Enzymes in Organic Synthesis. Chem. Rev. 2011, 111, 4141–4164. 10.1021/cr100386u. [DOI] [PubMed] [Google Scholar]
- a Bertelsen S.; Jørgensen K. A. Organocatalysis—after the gold rush. Chem. Soc. Rev. 2009, 38, 2178. 10.1039/b903816g. [DOI] [PubMed] [Google Scholar]; b Hughes D. L. Asymmetric Organocatalysis in Drug Development—Highlights of Recent Patent Literature. Org. Process Res. Dev. 2018, 22, 574–584. 10.1021/acs.oprd.8b00096. [DOI] [Google Scholar]; c Vetica F.; de Figueiredo R. M.; Orsini M.; Tofani D.; Gasperi T. Recent Advances in Organocatalytic Cascade Reactions toward the Formation of Quaternary Stereocenters. Synthesis 2015, 47, 2139–2184. 10.1055/s-0034-1378742. [DOI] [Google Scholar]; d Xiang S.-H.; Tan B. Advances in asymmetric organocatalysis over the last 10 years. Nature Commun. 2020, 11, 3786. 10.1038/s41467-020-17580-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Bella M.; Gasperi T. Organocatalytic Formation of Quaternary Stereocenters. Synthesis 2009, 2009 (10), 1583–1614. 10.1055/s-0029-1216796. [DOI] [Google Scholar]; b Palomo C.; Oiarbide M.; López R. Asymmetric organocatalysis by chiral Brønsted bases: implications and applications. Chem. Soc. Rev. 2009, 38, 632–653. 10.1039/B708453F. [DOI] [PubMed] [Google Scholar]; c Marcelli T.; Hiemstra H. Cinchona Alkaloids in Asymmetric Organocatalysis. Synthesis 2010, 2010 (8), 1229–1279. 10.1055/s-0029-1218699. [DOI] [Google Scholar]; d Alemán J.; Parra A.; Jiang H.; Jørgensen K. A. Squaramides: Bridging from Molecular Recognition to Bifunctional Organocatalysis. Chem.-Eur. J. 2011, 17, 6890–6899. 10.1002/chem.201003694. [DOI] [PubMed] [Google Scholar]; e Melchiorre P. Cinchona-based Primary Amine Catalysis in the Asymmetric Functionalization of Carbonyl Compounds. Angew. Chem., Int. Ed. 2012, 51, 9748–9770. 10.1002/anie.201109036. [DOI] [PubMed] [Google Scholar]; Katalyse mit primären Cinchona-Aminen zur asymmetrischen Funktionalisierung von Carbonylverbindungen. Angew. Chem. 2012, 124, 9886 - 9909.10.1002/ange.201109036; f Duan J.; Li P. Asymmetric organocatalysis mediated by primary amines derived from cinchona alkaloids: recent advances. Catal. Sci. Technol. 2014, 4, 311–320. 10.1039/C3CY00739A. [DOI] [Google Scholar]
- a Rouf A.; Tanyeli C. Squaramide based organocatalysts in organic transformations. Curr. Org. Chem. 2016, 20, 2996–3013. 10.2174/1385272820666160805113749. [DOI] [Google Scholar]; b Sinibaldi A.; Nori V.; Baschieri A.; Fini F.; Arcadi A.; Carlone A. Organocatalysis and Beyond: Activating Reactions with Two Catalytic Species. Catalysts 2019, 9, 928. 10.3390/catal9110928. [DOI] [Google Scholar]; c Xu S.; Chen J.; Chen J.; Xiao W. Recent Progress in Applications of Cinchona Alkaloids and Their Derivatives in Asymmetric Catalysis. Chin. J. Org. Chem. 2020, 40, 3493–3516. 10.6023/cjoc202007004. [DOI] [Google Scholar]
- a Coumarins: Biology, Applications, and Mode of Action; O’Kennedy R., Thornes R. D., Eds.; John Wiley & Sons: New York, NY, 1997. [Google Scholar]; b Khan K. M.; Saify Z. S.; Khan M. Z.; Zia-Ullah; Choudhary M. I.; Atta-ur-Rahman; Perveen S.; Chohan Z. H.; Supuran C. T. Synthesis of Coumarin Derivatives with Cytotoxic, Antibacterial and Antifungal Activity. J. Enzyme Inhib. Med. Chem. 2004, 19, 373–379. 10.1080/14756360409162453. [DOI] [PubMed] [Google Scholar]; c Kontogiorgis C. A.; Hadjipavlou-Litina D. J. Synthesis and Antiinflammatory Activity of Coumarin Derivatives. J. Med. Chem. 2005, 48, 6400–6408. 10.1021/jm0580149. [DOI] [PubMed] [Google Scholar]; d Neyts J.; Clercq E. D.; Singha R.; Chang Y. H.; Das A. R.; Chakraborty S. K.; Hong S. C.; Tsay S.-C.; Hsu M.-H.; Hwu J. R. Structure–Activity Relationship of New Anti-Hepatitis C Virus Agents: Heterobicycle–Coumarin Conjugates. J. Med. Chem. 2009, 52, 1486–1490. 10.1021/jm801240d. [DOI] [PubMed] [Google Scholar]; e Sashidhara K. V.; Kumar A.; Kumar M.; Sarkar J.; Sinha S. Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents. Bioorg. Med. Chem. Lett. 2010, 20, 7205–7211. 10.1016/j.bmcl.2010.10.116. [DOI] [PubMed] [Google Scholar]; f Abdelhafez O. M.; Amin K. M.; Batran R. Z.; Maher T. J.; Nada S. A.; Sethumadhavan S. Synthesis, anticoagulant and PIVKA-II induced by new 4-hydroxycoumarin derivatives. Bioorg. Med. Chem. 2010, 18, 3371–3378. 10.1016/j.bmc.2010.04.009. [DOI] [PubMed] [Google Scholar]; g Jain M.; Surin W. R.; Misra A.; Prakash P.; Singh V.; Khanna V.; Kumar S.; Siddiqui H. H.; Raj K.; Barthwal M. K.; Dikshit M. Antithrombotic Activity of a Newly Synthesized Coumarin Derivative 3-(5-Hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide. Chem. Biol. Drug Des. 2013, 81, 499–508. 10.1111/cbdd.12000. [DOI] [PubMed] [Google Scholar]; h Bubols G. B.; Vianna D. d. R.; Medina-Remon A.; von Poser G.; Lamuela-Raventos R. M.; Eifler-Lima V. L.; Garcia S. C. The antioxidant activity of coumarins and flavonoids. Mini-Rev. Med. Chem. 2013, 13, 318–334. 10.2174/1389557511313030002. [DOI] [PubMed] [Google Scholar]; i Advances in Structure and Activity Relationship of Coumarin Derivatives; Penta S., Ed.; Academic Press: Amsterdam, The Netherlands, 2015. [Google Scholar]; j Keri R. S.; B.S. S.; Nagaraja B. M.; Santos M. A. Recent progress in the drug development of coumarin derivatives as potent antituberculosis agents. Eur. J. Med. Chem. 2015, 100, 257–269. 10.1016/j.ejmech.2015.06.017. [DOI] [PubMed] [Google Scholar]; k Al-Majedy Y. K.; Al-Amiery A. A.; Kadhum A. A. H.; Mohamad A. B. Antioxidant Activities of 4-Methylumbelliferone Derivatives. PLoS One 2016, 11, e0156625. 10.1371/journal.pone.0156625. [DOI] [PMC free article] [PubMed] [Google Scholar]; l Matsumoto T.; Takahashi K.; Kanayama S.; Nakano Y.; Imai H.; Kibi M.; Imahori D.; Hasei T.; Watanabe T. Structures of antimutagenic constituents in the peels of Citrus limon. J. Nat. Med. 2017, 71, 735–744. 10.1007/s11418-017-1108-3. [DOI] [PubMed] [Google Scholar]
- a Nargotra S.; Sharma S.; Alam M. I.; Ahmed Z.; Bhagat A.; Taneja S. C.; Qazi G. N.; Koul S. In silico identification of viper phospholipaseA2 inhibitors: validation by in vitro, in vivo studies. J. Mol. Model. 2011, 17, 3063–3073. 10.1007/s00894-011-0994-7. [DOI] [PubMed] [Google Scholar]; b Kwon O. S.; Choi J. S.; Islam M. N.; Kim Y. S.; Kim H. P. Inhibition of 5-lipoxygenase and skin inflammation by the aerial parts of Artemisia Capillaris and its constituents. Arch. Pharm. Res. 2011, 34, 1561–1566. 10.1007/s12272-011-0919-0. [DOI] [PubMed] [Google Scholar]; c Patil P. O.; Bari S. B.; Firke S. D.; Deshmukh P. K.; Donda S. T.; Patil D. A. Bioorg. Med. Chem. 2013, 21, 2434–2450. 10.1016/j.bmc.2013.02.017. [DOI] [PubMed] [Google Scholar]
- Bhat C.; Tilve S. G. Recent advances in the synthesis of naturally occurring pyrrolidines, pyrrolizidines and indolizidine alkaloids using proline as a unique chiral synthon. RSC Adv. 2014, 4, 5405–5452. 10.1039/c3ra44193h. [DOI] [Google Scholar]
- Vitaku E.; Smith D. T.; Njardarson J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. 10.1021/jm501100b. [DOI] [PubMed] [Google Scholar]
- a Higashiyama K.; Inoue H.; Takahashi H. Diastereoselective addition of chiral imines and 1,3-oxazolidines with Grignard reagents; Asymmetric synthesis of (R)-2-aryl- and (R,R)-2,5-bis(aryl)pyrrolidines. Tetrahedron 1994, 50, 1083–1092. 10.1016/S0040-4020(01)80819-X. [DOI] [Google Scholar]; b Dalko P. I.; Moisan L. In the Golden Age of Organocatalysis. Angew. Chem., Int. Ed. 2004, 43, 5138–5175. 10.1002/anie.200400650. [DOI] [PubMed] [Google Scholar]; c Llopis S.; Garcia T.; Cantin A.; Velty A.; Diaz V.; Corma A. Chiral hybrid materials based on pyrrolidine building units to perform asymmetric Michael additions with high stereocontrol. Catal. Sci. Technol. 2018, 8, 5835–5847. 10.1039/C8CY01650J. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Engl O. D.; Fritz S. P.; Käslin A.; Wennemers H. Organocatalytic Route to Dihydrocoumarins and Dihydro-quinolinones in All Stereochemical Configurations. Org. Lett. 2014, 16, 5454–5457. 10.1021/ol502697s. [DOI] [PubMed] [Google Scholar]; b Hu H.; Liu Y.; Guo J.; Lin L.; Xu Y.; Liu X.; Feng X. Enantioselective synthesis of dihydrocoumarin derivatives by chiral scandium(iii)-complex catalyzed inverse-electron-demand hetero-Diels–Alder reaction. Chem. Commun. 2015, 51, 3835–37. 10.1039/C4CC10343B. [DOI] [PubMed] [Google Scholar]; c Kowalczyk D.; Albrecht Ł. Vinylogous Nucleophiles Bearing the Endocyclic Double Bond in the Allylic Alkylation with Morita-Baylis-Hillman Carbonates. Adv. Synth. Catal. 2018, 360, 406–410. 10.1002/adsc.201701185. [DOI] [Google Scholar]; d Bojanowski J.; Albrecht A. The First Vinylogous, Decarboxylative Michael Reaction with 3-Cyano-4-methylcoumarins as Pronucleophiles. Chemistry Select 2019, 4, 4588–4592. 10.1002/slct.201900579. [DOI] [Google Scholar]; e Liu Q.; Wang Z.-X.; Chen X.-Y. Highly enantioselective 1,6-addition of dienolates to coumarins and chromones through N-heterocyclic carbene catalysis. Org. Chem. Front. 2020, 7, 3692–3697. 10.1039/D0QO00963F. [DOI] [Google Scholar]; f Romaniszyn M.; Gronowska K.; Albrecht Ł. Remote Functionalization of 4-(Alk-1-en-1-yl)-3-Cyanocoumarins via the Asymmetric Organocatalytic 1,6-Addition. Adv. Synth. Catal. 2021, 363, 5116–5121. 10.1002/adsc.202100660. [DOI] [Google Scholar]
- CCDC 2226810 (5a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
- For a related mechanistic proposal confirmed by computational methods, see:; Cao J.; Fang R.; Liu J.-Y.; Lu H.; Luo Y.-C.; Xu P.-F. Organocatalytic Regiodivergent C-C Bond Cleavage of Cyclopropenones: A Highly Efficient Cascade Approach to Enantiopure Heterocyclic Frameworks. Chem.-Eur. J. 2018, 24, 18863–18867. 10.1002/chem.201803861. [DOI] [PubMed] [Google Scholar]
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Supplementary Materials
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.