A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent

Abstract

Open AccessCCS ChemistryCOMMUNICATION5 Sep 2022A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent Yu Luo, Sidi Cheng, Yan Peng, Xilong Wang, Jing Li, Chunfang Gan, Shuang Luo and Qiang Zhu Yu Luo State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Google Scholar More articles by this author , Sidi Cheng State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Google Scholar More articles by this author , Yan Peng State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Google Scholar More articles by this author , Xilong Wang State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Google Scholar More articles by this author , Jing Li State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Google Scholar More articles by this author , Chunfang Gan Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, College of Chemistry and Materials, Nanning Normal University, Nanning 530001 Google Scholar More articles by this author , Shuang Luo *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005 Google Scholar More articles by this author and Qiang Zhu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, College of Chemistry and Materials, Nanning Normal University, Nanning 530001 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101486 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail (Z)-7-Aryl-5-acyldibenzo[e,g][1,4]diazocin-6(5H)-one, a unique saddle-shaped bridged biaryl containing synchronized aryl–aryl and N-aryl stereogenic axes, was constructed for the first time in good yields with up to 96% enantiomeric excess (ee). The three-component coupling reaction, involving aryl iodide, 2,2′-diisocyano-1,1′-biphenyl, and carboxylate, constructs the eight-membered ring in an atroposelective manner through palladium-catalyzed double isocyanide insertion followed by C–O bond formation during reductive elimination and amide formation after acyl transfer. The N-acyl amide moiety in this twisted and atropisomerically stable (ΔG ≈ 35.9 kcal/mol) scaffold can serve as a recyclable acylating reagent to acylate racemic primary amines through kinetic resolution with moderate enantioselectivities. Download figure Download PowerPoint Introduction Tetraphenylene consists of four phenyl units that are ortho-annulated in an extraordinarily stable saddle-shaped geometry, and the inversion barrier is as high as 80.6 kcal/mol between the two conformers (Figure 1a, I).1–4 The scaffold gains chirality when substituted unsymmetrically. The preparation and related applications of chiral tetraphenylene derivatives have been widely studied, especially by Wong and co-workers.5–16 However, the enantiomers are accessed mainly by resolution of the diastereomeric derivatives, and reports on enantioselective synthesis of substituted tetraphenylenes17,18 and other similar saddle-shaped chiral molecules are few.19,20 Simplifying the tetraphenylene framework by replacing one or two of the phenyl rings with aza functionalities would generate aza analogs II– IV, which still prefer the saddle-shaped orientation. Although the energy barriers of inversion of these aza analogs are significantly lower than those for tetraphenylene, they are still atropisomerically stable enough (31–40 kcal/mol) to tolerate routine conditions for asymmetric catalysis.a More importantly, these skeletons are easier to access, thereby rendering more opportunities for enantioselective synthesis. Very recently, Zhang et al.21 developed a novel preparation of racemic or diastereomeric derivatives of 9,10-dihydrotribenzo[b,d,f]azocine ( II) through Pd-catalyzed cross coupling of 2-iodobiphenyls with 2-bromobenzylamines. Both aza analogs III and IV are stable chiral molecules with multiple synchronized stereogenic axes,22–25 but optically pure enantiomers are not available catalytically. Undoubtedly, designing new analogs such as V and exploring catalytic enantioselective synthesis of this unique class of aza saddle-shaped architectures is of great importance for the development of new chiral ligands, catalysts, and reagents. Figure 1 | (a–c) Saddle-shaped tetraphenylene and its aza-analogs. Download figure Download PowerPoint By trapping the imidoyl palladium intermediate with an intramolecular functionality following isocyanide insertion to a Pd(II) species, a variety of five- to seven-membered nitrogen-containing heterocycles could be generated.26–31 In addition, N-heterocycles bearing central, planar, and axial chirality have been successfully constructed by applying this strategy, opening an avenue for isocyanide in transition-metal-catalyzed asymmetric synthesis.32–37 Particularly, the chemistry of using 2-isocyano-1,1′-biphenyl for the synthesis of 6-arylphenanthridine inspires the hypothesis that a structurally similar 2,2′-diisocyano-1,1′-biphenyl would proceed through an unprecedented double isocyanide insertion followed by termination with an intermolecular nucleophile (Figure 1b).38 As a result, an eight-membered aza-bridged biaryl, most likely possessing a comfortable saddle-shaped geometry, could be formed. However, two independent C–H activations after one isocyanide insertion are foreseeable side reactions. Herein, we report the first enantioselective synthesis of a saddle-shaped aza analog of tetraphenylene V and its primary application as a novel acylating reagent of primary amines through kinetic resolution (Figure 1c). Results and Discussion For the investigation, 2,2′-diisocyano-1,1′-biphenyl ( 1–1), a bench-stable white solid, was prepared for the first time in good yield by dehydration of the corresponding diformamide.39,40 Initial attempts to induce double isocyanide insertion involving 2,2′-diisocyano-1,1′-biphenyl ( 1–1), iodobenzene ( 2–1), and aryl boronic acid or olefin catalyzed by Pd(dppf)Cl2 were unsuccessful at forming the desired eight-membered N-heterocycle, yet the side reaction of double phenanthridine formation was also excluded. No new product was detectable by thin-layer chromatography analysis, although isocyanide 1–1 was consumed. Gratifyingly, an unexpected pivalate-incorporated product was isolated when using CsOPiv as a base. The product was identified as (Z)-7-phenyl-5-pivaloyldibenzo[e,g][1,4]diazocin-6(5H)-one 3–1, a new saddle-shaped aza analog of tetraphenylene (vide infra), formed most likely through acyl transferring amide formation (entry 1, Table 1). Encouraged by the results, a range of chiral ligands was evaluated in the enantioselective synthesis of 3–1 in the presence of Pd(OAc)2 as the catalyst. Chiral phosphoramidite ligands, successfully applied in our previous Pd-catalyzed asymmetric imidoylative annulation, did not drive the reaction to occur (see Supporting Information 2.1 for details).32–37 Considering the effectiveness of dppf in forming racemic 3–1, structurally diversified and commercially available bidentate phosphorus Josiphos ligands ( L1– L10) were then tested. It is intriguing that when both substitutions on phosphine are aryl groups (R, R′ = Ar), such as L1, 3–1 was obtained in 52% yield with no enantiomeric bias. In contrast, when both R and R′ are alkyl groups ( L10), enantiomer enriched 3–1 [75% enantiomeric excess (ee)] was produced, but in trace amounts (entry 11, Table 1). As expected, L2 with mixed substituents (R = Cy, R′ = Ph) was effective in product formation, as well as in asymmetric induction (37% yield, 42% ee, entry 3). Then, the optimal ligand L8 was identified, although the yield was still unsatisfactory (26% yield, 81% ee, entry 9). Ferrocene-based heteronuclear bidentate ligands L11– L13 with cyclic phosphines also failed to promote the current three-component coupling in acceptable yields, even after varying the solvent and altering the addition time of isocyanide via a syringe pump (entries 12–20). Next, by changing the catalyst to Pd2(dba)3·CHCl3 in the presence of L12, the enantioselectivity increased surprisingly to 93% ee, but the yield was still low (entry 21). To our delight, 3–1 can be obtained in 73% yield with 90% ee by switching the ligand back to L8 (entry 22) in the presence of Pd2(dba)3 •CHCl3. Finally, the optimal conditions were identified as outlined in entry 23. Table 1 | Optimization of the Reaction Conditionsa Entry [Pd] L Solvent Yield (%) ee (%) 1 Pd(dppf)Cl2 NA Toluene 70 NA 2 Pd(OAc)2 L1 Toluene 52 0 3 Pd(OAc)2 L2 Toluene 37 42 4 Pd(OAc)2 L3 Toluene 65 12 5 Pd(OAc)2 L4 Toluene 34 0 6 Pd(OAc)2 L5 Toluene 0 NA 7 Pd(OAc)2 L6 Toluene 46 30 8 Pd(OAc)2 L7 Toluene 7 −25 9 Pd(OAc)2 L8 Toluene 26 81 10 Pd(OAc)2 L9 Toluene 11 30 11 Pd(OAc)2 L10 Toluene Trace 75 12 Pd(OAc)2 L11 Toluene 34 −75 13 Pd(OAc)2 L12 Toluene 8 84 14 Pd(OAc)2 L13 Toluene 0 NA 15b Pd(OAc)2 L12 Toluene 7 83 16b Pd(OAc)2 L12 Xylene <5 78 17b Pd(OAc)2 L12 Mesitylene Trace 73 18b Pd(OAc)2 L12 PhCF3 5 55 19b Pd(OAc)2 L12 Dioxane Trace 81 20b Pd(OAc)2 L12 CH3CN 0 NA 21b Pd2(dba)3·CHCl3 L12 Toluene 20 93 22b Pd2(dba)3·CHCl3 L8 Toluene 73 90 23b,c Pd2(dba)3·CHCl3 L8 Toluene 74 93 24b,d Pd2(dba)3·CHCl3 L8 Toluene 67 86 aReaction conditions: 2–1 (0.12 mmol), Pd catalyst (5 mol %), ligand (10 mol %), CsOPiv (0.15 mmol), 80 °C, in solution (1 mL), under Ar. A solution of 1–1 (0.1 mmol, 1 mL) was added to the reaction mixture via a syringe pump within 2 h. Isolated yields. Ee was determined by high-performance liquid chromatography analysis using a chiral stationary phase. bA solution of 1–1 (0.1 mmol, 1 mL) was added via a syringe pump within 1 h. cCsOPiv (0.1 mmol). dCs2CO3 (0.1 mmol) and PivOH (0.1 mmol). Following the identification of the optimal reaction conditions, the scope of aryl iodides was first explored with the other two reaction components unchanged. As shown in Scheme 1, aryl iodides bearing a wide range of substituents at the para position, including Me, OMe, halogen, COOEt, CN, and CF3, reacted smoothly to give corresponding products 3–2 to 3–12 in moderate to good yields (52–87%) with excellent enantioselectivities (86–95% ee). However, 1-iodo-4-nitrobenzene was less compatible in the reaction, delivering 3–13 in low yield with 72% ee. In general, meta-substituted aryl iodides were also suitable substrates to initiate the tandem process with slightly diminished but still good enantioselectivities (mostly 89–92% ee). Substitution at the ortho position of iodides apparently hindered enantioselectivity. For example, 3–22 was formed with 81% ee, while the corresponding meta- and para-analogs 3–14 and 3–2 were obtained in 90% ee and 93% ee, respectively. Sterically hindered 1-naphthyl iodide participated in the reaction with acceptable yield but low ee ( 3–24). It is notable that when the reaction was run at 1 mmol scale, 3–1 was isolated with comparable 65% yield and 92% ee (versus 74% yield and 93% ee at 0.1 mmol scale). When bromobenzene was used in place of iodobenzene under otherwise identical conditions, the desired product 3–1 was not detected. Scheme 1 | Scope of aryl iodide.aaReaction conditions: 2 (0.12 mmol), Pd2(dba)3·CHCl3 (2.5 mol %), L8 (10 mol %), CsOPiv (0.10 mmol), 80 °C, in toluene (1 mL), under Ar. A solution of 1–1 (0.1 mmol) in toluene (1 mL) was added to the reaction mixture via a syringe pump within 1 h. Isolated yields. Ee was determined by high-performance liquid chromatography analysis using a chiral stationary phase. Download figure Download PowerPoint Next, the scope of carboxylic acids applicable to the reaction was investigated; cesium carboxylates not commercially available were obtained by combining carboxylic acids and Cs2CO3 (Scheme 2). Acetate was a poor nucleophile in the reaction (33% yield, 3–28), probably due to its sluggish reductive elimination. The steric bulk of aliphatic acids was beneficial for the reaction, and adamantine-1-carbonylated 3–30 was obtained in 76% yield with 91% ee. Four- to six-membered cyclic carboxylates also served as effective nucleophiles to terminate the domino process in good yields with excellent ee ( 3–31 to 3–33). X-ray diffraction analysis of crystalized 3–31 clearly depicted its absolute saddle-shaped configuration.b However, the N–H free amide derivative 3–34 generated through in situ hydrolysis was isolated when using benzoic acid as the nucleophile. Scheme 2 | The scope of carboxylates.aaReaction conditions: 2–1 (0.12 mmol), Pd2(dba)3·CHCl3 (2.5 mol %), L8 (10 mol %), RCOOH (0.10 mmol), Cs2CO3 (0.10 mmol), 80 °C, in toluene (1 mL), under Ar. A solution of 1–1 (0.1 mmol) in toluene (1 mL) was added to the reaction mixture via a syringe pump within 1 h. Isolated yields. Ee was determined by high-performance liquid chromatography analysis using a chiral stationary phase. bCsOAc (0.10 mmol) was used. cBenzoic acid was used. Download figure Download PowerPoint Finally, the compatibility of substituted 2,2′-diisocyano-1,1′-biphenyls ( 1) was investigated (Scheme 3). When biaryl diisocyanides containing symmetrical substituents, including Me, OMe, COOMe, and F, at the para positions were coupled with iodobenzene and pivalate, the yields and enantioselectivities were basically maintained ( 3–35 to 3–38). However, in the case of the chlorinated derivative 3–39, a significant amount of hydrolyzed byproduct was found. When 2,2′-diisocyano-1,1′-biphenyl substituted with more electron deficient CF3 was applied, product 3–40 was fully hydrolyzed in 76% isolated yield with 94% ee. Methyl- and methoxy-substituted derivatives 3–41 and 3–42 were obtained with slightly lower ee. Unfortunately, substituents at the ortho-position of the isocyano group severely diminished the enantioselectivity ( 3–44 and 3–45); however, the yields for product formation were unaffected. It is worth mentioning that the X-ray diffraction analysis shows that the configuration of 3–44 is opposite to other products.b It was not surprising that the unsymmetrical biaryldiisocyanide was non-regioselective upon the initial isocyanide insertion, leading to a 1:1 inseparable mixture of isomers ( 3–46 and 3–47). Scheme 3 | Scope of biaryl diisocyanides.aaReaction conditions: 2–1 (0.12 mmol), Pd2(dba)3·CHCl3 (2.5 mol %), L8 (10 mol %), CsOPiv (0.10 mmol), 80 °C, in toluene (1 mL), under Ar. A solution of 1 (0.1 mmol) in toluene (1 mL) was added to the reaction mixture via a syringe pump within 1 h. Isolated yields. Ee was determined by high-performance liquid chromatography analysis using a chiral stationary phase. Download figure Download PowerPoint Notably, a small amount of byproduct, the N–H free amide derivative generated through hydrolysis, was always detected during the reaction. Therefore, a one-pot coupling and hydrolysis procedure was conducted by the addition of HCl solution (1.0 M, 1 mL) after the standard coupling reaction. Fully hydrolyzed N–H free amide 3–34 was obtained in 95% yield with 92% ee (Scheme 4). Interestingly, treatment of amide 3–34 with NaH, followed by addition of the acylation reagent PivCl, gave 3–1 in 94% yield without loss of enantioselectivity. By applying this protocol, products that could not be produced under the standard coupling reaction conditions were accessed, which greatly expanded the product diversity. The absolute configuration of compound 3–48 was also confirmed by X-ray crystal diffraction.b In addition, the enantiomerization study revealed that the racemization half-lives of compounds 3–1 and 3–34 were approximately 16 and 32 h at 100 °C, respectively. Correspondingly, the racemization energy barrier Δ G 100 ⧧ for 3–1 and 3–34 were 31.0 and 31.5 kcal/mol, respectively (see Supporting Information for details). Scheme 4 | One-pot synthesis and transformations of 3–34. aDetermined at 100 °C. rt, room temperature. Download figure Download PowerPoint The application of 3–1 as a novel chiral acylation reagent was briefly evaluated with racemic primary amines (Scheme 5). When a solution of 3–1 (0.1 mmol) in tetrahydrofuran (THF) was added dropwise to a solution of racemic naphthalen-1-yl(phenyl)methanamine ( 4–1, 0.2 mmol) in THF at −10 °C and the reaction mixture was maintained at this temperature overnight, the corresponding enantiomer-enriched amide 5–1 was obtained in 44% yield (based on 3–1) with 85% ee, whereas unreacted 4–1 was recovered in 55% yield and with 63% ee. At the same time, deprotected compound 3–34 was recycled almost quantitatively with the enantiomeric purity unchanged. This catalyst- and additive-free acyl transferring strategy was also applicable to α-amino acid derivatives, methyl 2-amino-2-(1-naphthyl)acetate 4–2, and 2-amino-2-phenylacetate 4–3, with similar efficiency. Scheme 5 | Applications of 3–1 in asymmetric acyl transfer amidation through kinetic resolution.aaReaction conditions: 4 (0.2 mmol) in THF (1 mL), under Ar, at −10 °C, the solution of 3–1 (0.1 mmol) in THF (1 mL) was added to the reaction mixture via a syringe pump within 2 h. Isolated yields were based on the quantity of 4, and ee was determined by high-performance liquid chromatography analysis using a chiral stationary phase. Download figure Download PowerPoint A plausible reaction mechanism is proposed in Figure 2a. The reaction is initiated by oxidative addition of phenyl iodide to Pd(0) to afford the phenyl palladium(II) species. Then, coordination and migratory insertion of the first isocyano moiety of 1–1 to Pd(II) generates imidoyl palladium species INT-I, followed by coordination of the second isocyano moiety to the Pd center. The second migratory insertion of the isocyano group yields intermediate INT-III, which undergoes reductive elimination to afford intermediate INT-IV. Finally, migration of the Piv group to N delivers the product.41 To elucidate the origins of the enantioselectivity, density functional theory (DFT) calculations of the enantiomeric product-formation pathways were conducted (Figures 2b and 2c). The formation of the enantiomer involves a chirality generating isocyanide-insertion step via TS- R and TS- S. Comparing the determining steps ( TS- R vs TS- S), the formation of the major enantiomer is 3.6 kcal/mol more favorable than that of the minor enantiomer, which corroborated the excellent enantioselectivities in experimental observations. For TS- R and TS- S, the distortion-interaction analysis42–45 reveals that the major contributor to the activation energy (∆∆Eact) is the distortion of the palladium catalyst and the chiral ligand (Figure 2b), probably because of the coordination distance and dihedral angle of the chiral ligand to Pd center. Figure 2 | (a–c) Mechanistic studies. Download figure Download PowerPoint Conclusion We developed a novel three-component coupling reaction involving aryl iodide, 2,2′-diisocyano-1,1′-biphenyl, and carboxylate to construct a unique saddle-shaped aza analog of tetraphenylene for the first time in good yields and excellent enantioselectivities. The reaction proceeds through palladium-catalyzed double isocyanide insertion followed by carboxylate participating in reductive elimination and acyl transferring amide formation. The N-acyl amide moiety in this twisted and atropisomerically stable (ΔG approximately 35.9 kcal/mol) scaffold can serve as a recyclable acylating reagent to acylate racemic primary amines through kinetic resolution in moderate enantioselectivities. Footnotes a Calculation method of energy barrier for I–IV compounds reference Supporting Information. b Deposition numbers 2100805 (for 3–31), 2116805 (for 3–44), and 2116806 (for 3–48) contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/structures Supporting Information Supporting Information is available and includes experimental procedure, nuclear magnetic resonance (NMR) spectra, high-performance liquid chromatography (HPLC), X-ray crystallographic data, and DFT calculation. Correspondence and requests for materials should be addressed to the corresponding author. Conflict of Interest The authors declare no competing financial interest. Funding Information We gratefully acknowledge the National Natural Science Foundation of China (nos. 21772198, 21871268, and 22071250), the Frontier Research Program of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) (no. 2018GRZ110105017), the Natural Science Foundation of Guangdong Province of China (no. 2020A1515011428), the “BAGUI Scholar” Program of Guangxi Province of China, and SKLRD Open Project (no. SKLRD-Z-202014) for financial support. The authors also gratefully thank the Guangzhou Branch of the Supercomputing Center of CAS for support.