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Visible-Light-Mediated Synthesis of Cyclobutene-Fused Indolizidines and Related Structural Analogs

2020; Chinese Chemical Society; Volume: 3; Issue: 1 Linguagem: Inglês

10.31635/ccschem.020.202000254

2096-5745

Min Zhu, Xu‐Lun Huang, Hao Xu, Xiǎo Zhang, Chao Zheng, Shu‐Li You,

Sulfur-Based Synthesis Techniques

Open AccessCCS ChemistryRESEARCH ARTICLE1 Jan 2021Visible-Light-Mediated Synthesis of Cyclobutene-Fused Indolizidines and Related Structural Analogs Min Zhu, Xu-Lun Huang, Hao Xu, Xiao Zhang, Chao Zheng and Shu-Li You Min Zhu State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 , Xu-Lun Huang State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 , Hao Xu State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 , Xiao Zhang *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Chao Zheng *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 and Shu-Li You *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 https://doi.org/10.31635/ccschem.020.202000254 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Expedient assembly of unprecedented molecular scaffolds from readily accessible starting materials in a sustainable fashion is highly pursued in modern organic chemistry. Herein, the first catalytic intramolecular dearomative [2 + 2] cycloaddition of indoles or pyrroles with alkynes is achieved via visible-light-mediated energy-transfer catalysis. This method enables the synthesis of cyclobutene-fused indolizidines, which are otherwise challenging to access, in high yields with exclusive selectivity. The reaction profiles are well documented by density functional theory (DFT) calculations. In addition, this protocol can be extended to the synthesis of cyclobutane-fused indolizidines and related structural analogs. Diverse elaborations of the products are achieved. Download figure Download PowerPoint Introduction Expansion of the chemical space via the construction of unprecedented molecular scaffolds holds a significant position in modern organic chemistry, due to its great potential in drug discovery and the synthesis of functional molecules.1–7 In this regard, there is high demand for expeditious strategies to generate previously challenging architectures, particularly desirable if achieved in an atom-economic and environmental-friendly fashion.8–11 Indolizidines are found in a large number of alkaloid natural products that display diverse biological and pharmacological activities (Scheme 1, top).12–18 Driven by their therapeutic potential, numerous methods such as radical cyclizations, aza-Michael addition, cross-coupling, and multistep syntheses have been developed to access the indolizidine-based libraries.19–33 Despite great achievements, incorporation of pharmaceutically relevant components on indolizidines is still highly pursued. On the other hand, all-carbon four-membered rings including cyclobutanes and cyclobutenes are privileged structural cores that are frequently encountered in natural products, pharmaceuticals, and agrochemicals (Scheme 1, middle).34–42 Owing to their rigid structures and well-defined spatial arrangements, they are also recognized as promising templates for drug discovery.3,43,44 In this regard, to assemble all-carbon four-membered rings and indolizidine motifs together might be of great potential, but rather challenging due to the strained fused polycyclic structures and contiguous tertiary or quaternary stereogenic centers often embedded therein. In particular, the incorporation of cyclobutenes, which are even more strained than the corresponding cyclobutanes, is of significant value as it offers chances for diverse elaborations into functionalized cyclobutanes or other valuable skeletons.45–48 Scheme 1 | Visible-light-mediated synthesis of cyclobutene-fused indolizidines and related structural analogs. Download figure Download PowerPoint Dearomatization reactionsa received considerable attention in recent years thanks to the possibility of constructing diverse three-dimensional architectures by directly functionalizing readily available aromatic compounds.49–59 To this end, we envisioned that the dearomative [2 + 2] cycloaddition of indoles with a tethered alkyne moiety might be an enabling strategy for the synthesis of cyclobutene-fused indolizidines with complete atom and step economy. However, to date, there have been only isolated reports on the intermolecular [2 + 2] cycloaddition of substituted indoles with specialized alkynes, including dimethyl acetylenedicarboxylate (DMAD) and electronically biased ynenamides, where a stoichiometric amount of strong acid was required.60–62 Notably, [2 + 2] photocycloaddition of indoles with DMAD was also achieved under the irradiation of ultraviolet light. Nevertheless, the reactions suffer from narrow substrate scope and poor functional-group tolerance. More importantly, the resultant cycloadducts were easily sensitized again to be converted into ring-opening compounds under UV conditions.63–66 Thus, the development of a mild and catalytic process that allows the dearomative [2 + 2] cycloadditions using nonactivated alkynes is desirable. The emergence of visible-light catalysis has provided a new opportunity for [2 + 2] dearomative cycloaddition reactions.67–91 Strikingly, related studies have shown advantages in the rapid and selective generation of molecular complexity, including those structures previously difficult to access, under environmentally friendly conditions. The groups of Glorius,87,90,91 Meggers,88 and Bach89 have made important contributions to this field.87–91 Our laboratory also reported the synthesis of cyclobutane-fused tetracyclic spiroindolines via visible-light catalysis.92 Notably, these examples mainly involve the reactions of aromatic compounds with alkenes.93 In sharp contrast, there is no precedent for visible-light-induced cycloaddition of aromatic compounds with alkynes, which might be attributed to the diminished reactivity of alkynes relative to alkenes, and the more significant ring strain of the products.94,c Based on these considerations, we discovered that under the irradiation of blue LEDs, the designed dearomative [2 + 2] reactions of indole-tethered alkynes proceeded smoothly with rationally chosen iridium-based photosensitizers based on the calculated triplet–singlet energy gaps [ΔG(T1 − S0)].95,96 A wide scope of cyclobutene-fused indolizidines were synthesized in high yields (up to 98%) with exclusive diastereoselectivity (>20∶1 dr). The involvement of diradical species in the excited states and the detailed energy profile of the reaction were explored by controlled experiments and DFT calculations. In addition, this method is applicable to the synthesis of cyclobutane-fused indolizidines and related structural analogs. The products are readily involved in diverse downstream synthetic transformations. Herein, we report the results from this study (Scheme 1, bottom). Experimental Method Indole derivative 1a (54.0 mg, 0.2 mmol) and photosensitizer V (4.4 mg, 0.004 mmol) and dry DMSO (20 mL) were added to a flame-dried tube. The reaction mixture was degassed via three freeze–pump–thaw cycles. After the reaction mixture was thoroughly degassed, the vial was sealed and positioned approximately 5 cm from 24 W blue LEDs. Then the reaction mixture was stirred at room temperature for the indicated time (monitored by thin layer chromatography) under argon atmosphere. Afterward, the reaction mixture was concentrated by rotary evaporation. Then the residue was purified by silica gel column chromatography (PE/EtOAc = 10/1) to afford the desired product 2a. More experimental details and characterization are available in Supporting Information. Results and Discussion Optimization of the reaction conditions Our studies were launched with the evaluation of conditions of the intramolecular dearomative [2 + 2] cycloaddition of indole-tethered terminal alkyne 1a (Table 1). Upon exposure to blue LEDs, the desired reaction proceeded smoothly with iridium-based photosensitizer V (2 mol%) in MeOH at room temperature. The tetracyclic cyclobutene-fused benzindolizidine 2a was delivered as a single isomer in 53% NMR yield after 12 h (entry 1). Further experiments revealed a profound solvent effect on the reaction outcomes (entries 2–7), with the optimal yield of 2a (84%) obtained with DMSO (entry 7). The structure and the relative configuration of 2a were determined by X-ray crystallographic analysis. A series of organic and transition-metal-based photosensitizers I– VI were further examined with DMSO as the solvent (entries 8–12). A clear correlation between the ΔG(T1 − S0) values of the photosensitizer96 and the reaction efficiency emerged. Only the photosensitizers having similar or higher triplet state energies compared to that of 1a (54.6 kcal/mol), such as III (49.2 kcal/mol), IV (57.8 kcal/mol), V (60.8 kcal/mol), and VI (63.5 kcal/mol),97,98 could promote the reaction. The higher ΔG(T1 − S0) value the photosensitizer has, the higher the yield of 2a (or the shorter the reaction time) is observed. On the other hand, there was no significant correlation between the oxidation/reduction potentials of the photosensitizers with the reaction outcomes. Control experiments verified that both the photosensitizer and visible light are essential for the reaction (entries 13 and 14). Collectively, these results suggest that the dearomative [2 + 2] cycloaddition might proceed through an energy-transfer mechanism rather than an electron transfer mechanism (vide infra). Table 1 | Optimization of the Reaction Conditionsa Entry Photosensitizer Solvent Time (h) Yield (%)b 1 V MeOH 12 53 2 V CH2Cl2 12 58 3 V acetone 12 66 4 V THF 36 0 5 V DMF 36 36 6 V CH3CN 12 80 7 V DMSO 10 89 (84c) 8 I DMSO 36 0 9 II DMSO 36 0 10 III DMSO 36 24 11 IV DMSO 36 24 12 VI DMSO 10 88 13d – DMSO 36 0 14e V DMSO 36 0 aReaction conditions: a solution of 1a (0.2 mmol) and photosensitizer (2 mol%) in DMSO (c = 0.01 M) was irradiated by 24 W blue LEDs at room temperature under argon. bNMR yield of 2a. cIsolated yield of 2a in parenthesis. dAbsence of a photosensitizer. eIn dark. Substrate scope With the optimized reaction conditions in hand (entry 7, Table 1), the substrate scope was explored (Scheme 2). A variety of C2-substituted indole substrates produced tetracyclic cyclobutene-fused benzindolizidines ( 2a–2d; R2 = CO2Et, CO2Me, Ph, and p-FC6H4) in good to excellent yields (79–98%). The incorporation of an aryl group at the C2 position of the indole ring proved to be beneficial for the desired reactions ( 2c and 2d) because of the decrease of the corresponding triplet energies of the substrates. The calculated ΔG(T1 − S0) value of 1c dropped to 52.3 kcal/mol. In addition, the C3-substituted indole substrates were also tolerated. However, their higher triplet state energies, exemplified by the large ΔG(T1 − S0) value of 1e (59.9 kcal/mol), required the utilization of VI as the photosensitizer to reach reasonable yields of 2e– 2g (R1 = CO2Me, COMe, and CN; 21–57%). The substituents on the other positions of the indole ring did not affect the reaction efficiency significantly. In general, the desired products bearing an electron-withdrawing group at the C5 or C6 positions were obtained in slightly higher yields ( 2j–2m; R3 = 5-F, 5-Cl, 5-Br, and 6-Cl; 79–86%) compared with those bearing an electron-donating group ( 2h and 2i; R3 = 5-OMe and 5-Me; 70–75%). When the substrate with an extended linkage was employed, a seven-membered ring lactam could be incorporated in 2n (34%). Remarkably, a 7-azaindole ring was compatible with the reaction, producing the pyridine-fused tetracyclic compound 2o in 49% yield. The substrate scope was further broadened to pyrrole-derived analogs. Although the absence of the benzene ring raised the energy of the triplet state of the pyrrole substrates due to the lack of resonance stabilization of the unpaired electrons [the ΔG(T1 − S0) value of 1p was 58.4 kcal/mol], the corresponding cyclobutene-fused indolizidines ( 2p–2r) were delivered in moderate yields (44–58%) with photosensitizer VI. In all cases, the cyclobutene products were obtained with exclusive diastereoselectivity (>20∶1 dr). Notably, when switching tethered alkynes to C2 or C3 position of indoles, dimerization was observed instead. Scheme 2 | Substrate scope. Reaction conditions: asolution of 1 (0.2 mmol) and V (2 mol%) in DMSO (c = 0.01 M) was irradiated by 24 W blue LEDs at room temperature under argon for 12 h. bVI (2 mol%) was used. Download figure Download PowerPoint The reactivity of internal alkynes was next considered (Scheme 3). The bromo-substituted alkyne 3a underwent the reaction under the optimal conditions smoothly, leading to the bromo-substituted cyclobutene 4a in 89% yield. However, the reactions of the phenyl- and benzoyl-substituted alkynes 3b and 3c were relatively sluggish in the presence of photosensitizers III and V, respectively. The corresponding products 4b and 4c were only isolated in decreased yield (43%) with the coformation of other unidentified side products. Examination of the triplet–singlet energy gaps of these compounds revealed that, instead of the indole ring, the conjugated ynone moieties of 3c would be excited by the visible light, with ΔG(T1 − S0) values of 59.9 kcal/mol for 3c. In contrast to other cyclobutenes, the substituted styrene and enone moieties in the products were more easily excited ( 4b; 50.9 kcal/mol and 4c; 51.7 kcal/mol). Thus, the undesired photo-induced transformations of 4b and 4c were unavoidable. Scheme 3 | Reactions with internal alkynes. Download figure Download PowerPoint Mechanistic studies To shed light on the mechanism of this dearomative [2 + 2] reaction, combined experimental and theoretical investigations were conducted (see the Supporting Information for details). The Stern–Volmer studies and triplet quenching experiments suggested the involvement of triplet diradical species via an energy-transfer mechanism. The dearomative [2 + 2] reactions of 1a and 3c were then explored by DFT calculations. Although the patterns of the spin population of the triplet-state diradical species 1a-T1 (54.6 kcal/mol) and 3c-T1 (59.9 kcal/mol) are quite different, similar facile kinetic profiles on the exited states are observed in both cases. As shown in Figure 1, the first bond-formation event occurs at the C2 position of the indole ring via transition states TS1 (65.4 kcal/mol) and TS3 (62.7 kcal/mol). Notably, there are only minor energetic barriers on the triplet states (10.8 kcal/mol for TS1 relative to 1a-T1, and 2.8 kcal/mol for TS3 relative to 3c-T1), indicating the fast formation of the first C–C bond upon excitation. The subsequent spin inversion and radical–radical recombination on the open-shell singlet states via TS2 (44.0 kcal/mol) and TS4 (39.0 kcal/mol), respectively, are also energetically insignificant. Finally, the overall dearomative [2 + 2] reactions are thermodynamically favorable. The calculated Gibbs free energies of 2a and 4c are lower than 1a and 3c by 5.1 kcal/mol and 3.3 kcal/mol, respectively. All these results agree well with the efficient synthesis of cyclobutene-fused indolizidines observed experimentally. Figure 1 | Optimized structures of the key intermediates and transition states and Gibbs free energies (in kcal/mol) relative to the corresponding substrates in the ground state. Calculated at the (U)B3LYP/6-31 G** level of theory. The spin densities are shown with isosurface in purple (Isovalue = 0.03) or pink (Isovalue = –0.03). Underlined values are Mulliken spin populations at certain atoms. The forming C–C bonds are highlighted with yellow dashes. Values in brown are the bond distances in angstrom. E = CO2Et. Download figure Download PowerPoint Extension to the synthesis of cyclobutane-fused (benz)indolizidines As expected, the protocol could be extended to the synthesis of cyclobutane-fused indolizidines and related structural analogs (Scheme 4).60,99–104 Various substituents including –CO2Me, –CO2Et, –CO2tBu, –C6H5, and 4-FC6H4– were well tolerated at the C2 position of indole derivatives ( 5a– 5e), delivering the corresponding cyclobutane-fused benzindolizidines 6a– 6e bearing three continuous stereogenic centers—including a quaternary one—in 80–99% yields with exclusive selectivity. The reaction was also amenable to indole derivatives even without a 2-substituent ( 6f; 27% and 6g; 35%). In addition, the intramolecular dearomatization reactions of 3-substituted indoles ( 6h– 6k) were tested. We were delighted to find that a variety of commonly encountered functionalities such as aldehyde ( 5h), ester ( 5i), ketone ( 5j), and cyano ( 5k) remained intact during the processes and were smoothly embedded in cyclobutane-fused indolizidines bearing an all-carbon quaternary center ( 6h– 6k; 85–97%). Substrates possessing either electron-donating ( 5l: 6-MeO; 5m: 5-Me) or electron-withdrawing ( 5n: 5-F; 5o: 5-Cl; 5p: 5-Br) groups on the indole ring all reacted well to give the desired products 6l– 6p in excellent yields (81–99%). The indole 5q with a prolonged carbon chain and aza-indole derivative 5r were also suitable substrates, leading to the compounds 6q in 92% yield and 6r in 98% yield, respectively. As an illustrative example, a structurally distinct tetracyclic compound 6s was constructed in 78% yield by simply introducing an olefin-tethered link at C2 position ( 5s).93,b Scheme 4 | Synthesis of cyclobutane-fused (benz)indolizidines. aReaction conditions for indole derivatives (5→6): a solution of 5 (0.2 mmol) and V (1 mol%) in MeOH (c = 0.1 M) was irradiated by 24 W blue LEDs at room temperature under argon for 6 h. bReaction conditions for pyrrole derivatives (7→8): a solution of 7 (or 5r) (0.2 mmol) and VI (1 mol%) in CH2Cl2 (c = 0.01 M) was irradiated by 24 W blue LEDs at room temperature under argon for 36 h. c48 h. dV was used. e6 h. Download figure Download PowerPoint Similarly, pyrrole derivatives are also compatible with the current method.105–107 Under slightly modified conditions, different electron-withdrawing substitution patterns including esters ( 7a: –CO2Et; 7b: –CO2Me), ketones ( 7c: –COCH3; 7d– 7i: –COAr), and even a sensitive aldehyde ( 7j: –CHO) at the C2 position of pyrrole derivatives were accommodated. The resultant cyclobutane-fused indolizidines 8a– 8j were isolated with 43–87% yields with a single all-cis-fused configuration. Notably, various groups irrespective of electronic properties ( 7e: 4-MeO; 7f: 4-F; 7g: 3-Cl; 7h: 3-Br; 7i: 2-Me) could be efficiently incorporated in the phenyl moiety of aromatic ketones. Furthermore, 2-CO2Et pyrroles bearing an additional aryl group at the 3-position ( 7k– 7n) underwent the desired reaction smoothly, providing highly strained cyclobutane-fused indolizidines possessing three continuous stereogenic centers—including two vicinal quaternary ones—in good yields ( 8k– 8n; 75–85%). Lastly, formation of cyclobutane-fused pyrrolo[1,2-a]azepine was also feasible ( 8o; 37%). Gram-scale reactions and synthetic transformations The synthetic utility of this protocol was next evaluated (Scheme 5). First, the gram-scale reactions of 1a, 5i, and 5p were performed under standard conditions, giving the corresponding products 2a, 6i, and 6p in 78% yield (0.70 g), 98% yield (1.10 g), and 89% yield (0.89 g), respectively, which showed comparable efficiency with those on a 0.2 mmol-scale (a, Scheme 5). Subjecting 2a to a Pd/C-catalyzed hydrogenation reaction delivered the corresponding cyclobutane 6a in 98% yield (eq 1). Upon treatment with LiOH, the ester moiety of 2a could be easily hydrolyzed to deliver the corresponding carboxylic acid 9 in 80% yield (eq 2). Cyclopropanation of 2a was achieved with Et2Zn/CH2I2 to produce 10 in 92% yield (eq 3). Epoxidation of 2a with m-CPBA occurred smoothly, affording 11 in 75% yield (eq 4). The structure and relative configuration of 11 were confirmed by X-ray crystallographic analysis. Notably, the pentacyclic compounds 10 and 11 were afforded with exclusive diastereoselectivity. The diverse transformations of cyclobutenes showcase the great potential of this dearomative [2 + 2] reaction in the rapid assembly of polycyclic molecules with increased complexity. Moreover, hydrogenation of 8a afforded the corresponding C(sp3)-rich cyclobutane-fused indolizidine 12 in 97% yield (eq 5). The amide and ester moieties in 6i were reduced simultaneously upon treatment with LiAlH4, leading to product 13 in 54% yield (eq 6). As a further illustration, palladium-catalyzed Suzuki coupling between bromo-containing product 6p and 4-MeOC6H4B(OH)2 was conducted to furnish 14 in 82% yield (eq 7), demonstrating that an external functionality (e.g., 4-MeOC6H4−) could be efficiently incorporated at a late stage. Scheme 5 | Gram-scale reactions and synthetic transformations. Reaction conditions: (a) Pd/C (10%), H2 (1 atm), MeOH, rt. (b) LiOH (3.0 equiv), THF/H2O (1/1). (c) Et2Zn (8.0 equiv), CH2I2 (8.0 equiv), toluene. (d) m-CPBA (4.0 equiv), NaHCO3 (4.0 equiv), CH2Cl2. Download figure Download PowerPoint Conclusion In conclusion, we have developed a general, sustainable, and by-product-free approach for the expedient synthesis of cyclobutene-fused indolizidines and related structural analogs. This method capitalizes on the visible-light-induced intramolecular dearomative [2 + 2] cycloaddition reaction of indole or pyrrole derivatives with carbon–carbon multiple bonds via an energy-transfer mechanism. With rationally chosen iridium complexes as the photosensitizers, the desired reactions proceeded smoothly under mild conditions, affording the polycyclic heterocycles bearing continuous stereocenters in high yields with exclusive regio- and diastereoselectivity. The optimization of the reaction conditions was guided by the calculated triplet–singlet energy gaps of the photosensitizers and the substrates. The reaction profiles were well established by DFT calculations. Notable features of this method also include broad substrate scope, tolerance to diverse functional groups, and an operationally simple procedure. Importantly, the demonstrated capacity for scale-up and late-stage functionalizations further demonstrates the potential utilities in pharmaceutical and agrochemical research. Footnotes a For selected reviews on dearomatization reactions, see references by Roche and Porco,49 and Zhang and You.50 b During the preparation of this paper, Oderinde and co-workers93 reported a related intramolecular [2 + 2] cycloaddition of indoles with an olefin moiety tethered at the C2-position for the construction of cyclobutane-fused tetracyclic scaffolds. c Successful examples of [2 + 2] cyclization of alkynes under visible light were rather limited. Glorius and co-workers94 elegantly reported a visible-light induced [2 + 2] cycloaddition reaction of internal alkynes with cyclohexenones. Supporting Information Supporting Information is available. Conflict of Interest The authors declare no competing interest. Acknowledgments The authors thank MOST (2016YFA0202900), the NSFC (21772219, 21821002, 21801248), the Science and Technology Commission of Shanghai Municipality (18JC1411302, 18QA1404900, 18YF1428900), the Chinese Academy of Sciences (XDB20030000, QYZDY-SSW-SLH012), and the Youth Innovation Promotion Association (2017302, 2019255) of CAS for generous financial support. References 1. Murray C. W.; Rees D. C.The Rise of Fragment-Based Drug Discovery.Nat. Chem.2009, 1, 187–192. Google Scholar 2. Lovering F.; Bikker J.; Humblet C.Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success.J. Med. Chem.2009, 52, 6752–6756. Google Scholar 3. Marson C. M.New and Unusual Scaffolds in Medicinal Chemistry.Chem. Soc. Rev.2011, 40, 5514–5533. Google Scholar 4. Lovering F.Escape from Flatland 2: Complexity and Promiscuity.MedChemComm2013, 4, 515–519. Google Scholar 5. 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