Inherently Chiral 6,7-Diphenyldibenzo[ e,g ][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE24 May 2022Inherently Chiral 6,7-Diphenyldibenzo[e,g][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform Yu Luo, Xilong Wang, Weiming Hu, Yan Peng, Chaoqin Wang, Ting Yu, Sidi Cheng, Jing Li, Yimiao He, 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 , 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 , Weiming Hu 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 , Chaoqin 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 , Ting Yu 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 , 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 , Yimiao He 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 , 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 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 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202201901 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Inherently chiral 6,7-diphenyldibenzo[e,g][1,4]diazocine (DDD) has been synthesized enantioselectively for the first time via chiral phosphoric acid (CPA)-catalyzed cyclocondensation of readily available [1,1′-biphenyl]-2,2′-diamine ( 1a) and benzil ( 2a) in 82% yield, with 98% ee under mild reaction conditions. The strategy could also be applied to racemic biaryl diamines through kinetic resolution. The unexpectedly high interconversion energy barriers between the enantiomers (ΔG = 39.5 kcal/mol) and the chemical stability rendered DDD an ideal platform for developing new chiral ligands and catalysts. Unique inherently chiral DDD-based phosphoramidites, phosphoric acid, mono- and diphosphine ligands were prepared from optically pure diphenol derivative DDDOL as a common precursor. Preliminary asymmetric reactions catalyzed by Pd or Rh in the presence of newly developed ligands exhibited comparable or even better enantioselectivities than the corresponding BINOL- or SPINOL-derived ligands. Density functional theory calculation revealed the origin of the enantioselectivity during the process. Download figure Download PowerPoint Introduction The term “inherent chirality” was first introduced by Böhmer et al.1 in 1994 to describe chirality observed in calix[4]arene substituted non-symmetrically. Free interconversion between the concave conformers was restricted due to steric hindrance arising from the lower-rim modification. Thus, the stabilized curvature devoid of symmetry was not superimposable on its mirror image that was chiral by definition. In other words, inherent chirality was established as an intrinsic character of a cyclic molecule, even if it lacks conventional chiral factors such as central, axial, planar, and helical chirality (Figure 1a, left). From then on, the terminology has been gradually applied to macromolecules and supramolecules possessing similar structural characteristics, such as rotaxanes, catenanes, fullerenes, cavitands, and capsular assemblies.2–5 Since inherently chiral calixarenes and other macromolecules have played an increasingly important role in chiral recognition and asymmetric catalysis,6,7 accessing these molecules in enantiomerically pure form is of great significance but also a formidable challenge. For example, enantioenriched calix[4]arene derivatives are mainly obtained by high-performance liquid chromatography (HPLC) separation of racemic mixtures using a chiral stationary phase or by forming diastereomers with a chiral auxiliary.8 Attempts of enantioselective catalytic synthesis of inherently chiral macrocycles led to very poor results (up to 35% ee).9 In 2020, Tong et al.10 reported the first successful asymmetric synthesis of macrocyclic heteracalix[4]aromatics through Pd-catalyzed intramolecular C–N coupling with high enantioselectivity (Figure 1a, right). Figure 1 | Inherently chiral compounds and their asymmetric catalytic synthesis. Download figure Download PowerPoint Cyclic molecules with rigid non-planar conformation smaller than calix[4]arene can also exhibit inherent chirality. For instance, replacing the four methylene linkages in calix[4]arene by four σ-bonds and changing the linking substitution site from meta to ortho positions of the phenyl units leads to an eight-membered ring system named tetraphenylene which has a unique saddle-shaped structure with extraordinary rigidity (ΔG approximately 80 kcal/mol!).11,12 Non-symmetrically substituted tetraphenylenes are inherently chiral molecules, which have been studied extensively by Wong and coworkers.11,13–23 Although many methods have been developed to prepare racemic tetraphenylene derivatives; the enantioenriched ones are obtained mainly by HPLC separation or resolution of racemic mixtures. A breakthrough in the asymmetric synthesis of tetraphenylenes was realized by Shibata et al. in 2009, in which a novel Rh-catalyzed [2+2+2] cycloaddition of two phenylene-bridged 1,6,10-triynes was developed to deliver inherently chiral tetraphenylenes in up to 99% ee (Figure 1b).24,25 Overall, the study of inherently chiral small molecules, including their structural characteristics, enantioselective synthesis, and applications, has been long neglected. 6,7-Diphenyldibenzo[e,g][1,4]diazocine (DDD), an intuitively achiral eight-membered N-heterocycle, possesses an inflexible saddle-shaped configuration similar to that of tetraphenlene. Density functional theory (DFT) calculation suggests that the interconversion energy barrier is as high as 39.5 kcal/mol,26 indicating the existence of inherent chirality in this aza analog of tetraphenlene (Figure 1c, left). The first report for the synthesis of racemic DDD by thermal condensation of [1,1′-biphenyl]-2,2′-diamine and benzil dates back as early as 1892.27 In 1963, an optically pure 4,4′-diester derivative of DDD was obtained by resolution; a study of its enantiomeric stability showed that no reaction or racemization took place upon heating at 200 °C in mesitylene for 24 h.28 The ignored inherent chirality in DDD stimulated our interest in considering its enantioselective preparation and synthetic application. Our initial attempt relied on the hypothesis that a palladium-catalyzed double isocyanide insertion applying 2,2′-diisocyano-1,1′-biphenylbisisocyanide A would lead to a key dibenzo[e,g][1,4]diazocine-based palladium intermediate B. Transmetallation of B with aryl boronic acid, followed by reductive elimination would furnish 6,7-diaryldibenzo[e,g][1,4]diazocine, and in the presence of chiral ligand, enantioenriched DDD derivatives C will be obtained expectantly (Figure 1c, from A to C). Unfortunately, this hypothesized reaction sequence failed to give the desired product C in the presence of aryl boronic acid. Instead, another inherently chiral saddle-shaped product D was produced with high ee when cesium carboxylate was used (Figure 1c, from A to D).26 The failure of Pd-catalyzed enantioselective synthesis of DDD made us turn back to the century-old chemistry, condensation of [1,1′-biphenyl]-2,2′-diamine with benzyl. Inspired by recent achievements involving chiral phosphoric acid (CPA) in asymmetric catalysis,29–32 we hypothesized that optically pure DDD could be accessed by CPA-catalyzed asymmetric cyclocondensation of [1,1′-biphenyl]-2,2′-diamine and benzil under metal-free conditions (Figure 1d). When racemic biaryl diamines were used, it was possible to realize kinetic resolution to give value-added axially chiral diamines and DDD derivatives ready for ligand design. Experimental Methods In air, a 35 mL reaction tube was charged with [1,1′-biphenyl]-2,2′-diamines 1 (0.11 mmol), benzil 2 (0.1 mmol), and CPA (10 mol %). The tube was evacuated and filled with argon three times. Then, tetrahydrofuran (THF) or tetrahydropyran (THP) (0.1–0.2 mL) was added to the tube and sealed with a Teflon screwcap. The mixture was stirred at 35–75 °C for 24–72 h. After cooling to room temperature, the reaction mixture was directly loaded onto a low-pressure flash column (SYNTHWARE GLASS, C184171) packed with column chromatography silica gel (Qingdao Ocean, 100–200 mesh) by a minimal amount of CH2Cl2, and using petroleum ether/ethyl acetate as eluent to give the corresponding product 3. Following the procedure of phase separation mentioned in Supporting Information Figure S1, product 3 with increased optical purity was obtained. Results and Discussion To test our hypothesis, cyclocondensation of [1,1′-biphenyl]-2,2′-diamine ( 1a) with benzil ( 2a) catalyzed by CPA was investigated (Table 1). The result of the initial test with unsubstituted 1,1′-bi-2-naphthol (BINOL)-derived C1 (30 mol %) in dioxane at 65 °C for 24 h was encouraging, delivering the desired cyclization product 3aa in 63% yield with 22% ee (entry 1). Varying solvent revealed that the reaction proceeded more efficiently in THF; even the catalyst loading was reduced to 10 mol % (entry 4). Next, BINOL-based CPAs with substituents at the 3,3′-positions were screened. Except for bulky triphenylsilyl-substituted C3, 3,3′-diphenyl BINOL-CPA C2 and all of its aryl analogs were able to promote the cyclization but with low to moderate enantioselectivities (entries 5–14). Unfortunately, 1,1′-spirobiindane-7,7′-diol (SPINOL)-derived CPAs were ineffective in this case (entries 15–18). We found that H8-BINOL-based C16 could catalyze the reaction with slightly better ee than the BINOL analog C4 (entry 19 vs. entry 7). Intriguingly, the reaction was accelerated substantially at higher concentrations. When the amount of THF was minimized to 0.15 mL, 3aa was formed almost quantitatively with 68% and 76% ee in the presence of C16 and C18, respectively (entries 21–22). The enantioselectivity increased slightly to 81% ee when the reaction was carried out at 50 °C (entry 23). Accidentally, we found that the solubility of racemic and optically pure 3aa in isopropanol was quite different.33–35 After purification by column chromatography, 2 mL of isopropanol was added to the isolated product, followed by ultrasonic mixing for 2 min and precipitation of racemic 3aa. Subsequently, the product, which remained in solution, was obtained by removing solvent to give 3aa in 82% yield with excellent optical purity (98% ee, entry 24; see the detailed procedures in Supporting Information Figure S1). Interestingly, CPAs C18 and C19 had opposite asymmetric induction, although both catalysts had the same configuration (entry 23 vs entry 24).36–40 Table 1 | Optimization of the Reaction Conditionsa Entry Catalyst Solvent Yield (%) ee (%) 1 C1b Dioxane 63 −22 2 C1b DME 56 −14 3 C1b THF 77 −31 4 C1 THF 60 −21 5 C2 THF 54 61 6 C3 THF 0 / 7 C4 THF 61 64 8 C5 THF 78 −59 9 C6 THF 69 26 10 C7 THF 59 33 11 C8 THF 63 −16 12 C9 THF 52 −57 13 C10 THF 50 −57 14 C11 THF 76 −29 15 C12 THF 0 / 16 C13 THF 34 −3 17 C14 THF Trace −11 18 C15 THF 15 5 19 C16 THF 60 66 20 C17 THF 61 65 21c C16 THF 99 68 22c C18 THF 99 76 23 c, d C18 THF 98(82) e 81(98) e 24 C19 THF 51 −40 aReaction conditions: 1a (0.11 mmol), 2a (0.10 mmol), CPA (10 mol %) in 1.0 mL of solvent, 65 °C, 24 h, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. DME, 1,2-dimethoxyethane. b30 mol %. c0.15 mL of THF. d50 °C. ePhase separation. Following the identification of optimal reaction conditions and postreaction procedures (entry 23), the scope of benzils ( 2) was first explored in reactions with 1a. The substrates were insoluble in 0.15 mL THF; thus, we increased the volume to 0.2 mL of the solvent. As shown in Scheme 1, as expected, symmetric benzils with electron-withdrawing groups, including F, Cl, and Br, at the para-positions were more reactive than those with electron-donating groups. Although an extended reaction time and a higher temperature were required for OMe-substituted benzil, all of the corresponding products 3aa–3af were obtained in 68%–82% yields with excellent enantioselectivities (94–98% ee). The reaction was sluggish for ortho-methyl-substituted benzil 1g, which required 72 h at 65 °C to give 3ag in 73% yield with 72% ee without phase separation. Interestingly, in the case of 3ah, an optically pure product was precipitated after treatment with isopropanol instead of the racemate. For unsymmetric benzil 2i, cyclocondensation also proceeded smoothly ( 3ai, 72% yield, 96% ee). However, when phenyl methyl 1,2-diketone was applied, no enantioselectivity was observed for the corresponding cyclization product 3aj. Importantly, the unique pyridine-containing structure of 3ak, a potential chiral N,N-ligand,41 was accessed with 99% ee, albeit in low yield due to unidentified side-product formation. It’s worth mentioning that when using symmetric tetraketone 2,2′-(1,4-phenylene)bis(1-phenylethane-1,2-dione) 2l in condensation with 1.0 equiv of 1a, 3al containing unreacted 1,2-diketone moiety was obtained in 82% yield with 80% ee. When 2l reacted with an excess amount of 1a, double condensation occurred smoothly, giving a mixture of diastereomers 3am in 98% ee and 3an as a meso-isomer in a 5∶1 ratio. Scheme 1 | The scope of benzyls.aaReaction conditions: 1a (0.11 mmol), 2 (0.10 mmol), (R)-C18 (10 mol %), THF (0.15 mL), 50 °C, 24 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. bTHF (0.2 mL). c40 °C. d36 h. e65 °C, 48 h. f65 °C, 72 h, without phase separation. g(R)-C19, 48 h, the optical product was precipitated. h(R)-C16. i1a (0.1 mmol), 2 (0.3 mmol), THP (0.1 mL), 35 °C, 72 h, without phase separation. j1a (0.3 mmol), 2 (0.1 mmol), THP (0.1 mL), 35 °C, 72 h, without phase separation. kNo racemization and decomposition were observed upon heating in dry mesitylene at 250 °C for 24 h. THP, tetrahydropyran. Download figure Download PowerPoint Next, the compatibility of substituted [1,1′-biphenyl]-2,2′-diamines ( 1) was investigated (Scheme 2). When diamines ( 1) bearing OMe, Me, or F at the 4,4′ positions were applied, the corresponding cyclocondensation products 3ba, 3ca, and 3fa were obtained in moderate yields with excellent enantioselectivities catalyzed by C19 following the standard phase separation. However, diamines 1d and 1g substituted with strong electron-withdrawing CF3 or CN groups were found unsuitable in condensation with 2a, resulting in low yields of 3da and 3ga. Less electron-deficient 4,4′-diester-substituted derivative 3ea was accessed in 80% yield with 82% ee. We found that substituents at the para positions of 1 had little effect on both yield and enantioselectivity. For example, the yield for electron-withdrawing F substituted 1h was slightly lower than that for 1k substituted with electron-donating OMe ( 3ha vs. 3ka). Both 3ia (Cl) and 3ja (Me) were obtained in excellent yields with high ee. Unsymmetrical isopropyl-substituted 1l could cyclize with 2a very efficiently; however, the enantiomeric purity of the corresponding product 3la could not be enriched by precipitation of the racemate (99% yield, 86% ee). It was not surprising that condensation of sterically hindered 1m with 2a was inefficient in terms of both yield and enantioselectivity ( 3ma, 42% yield, 60% ee). Scheme 2 | The scope of [1,1′-biphenyl]-2,2′-diamines.aaReaction conditions: 1 (0.11 mmol), 2a (0.10 mmol), (R)-C19 (10 mol %), THF (0.15 mL), 50 °C, 36 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. b48 h. c(R)-C16, THF (0.2 mL), 65 °C. d(R)-C18. e1 (0.1 mmol), 2a (0.3 mol), THP (0.1 mL), 72 h. f1 (0.1 mmol), 2a (0.3 mol), THP (0.1 mL), 35 °C, 48 h. gWithout phase separation. Download figure Download PowerPoint Next, 6,6′-mono- and disubstituted [1,1′-biphenyl]-2,2′-diamines in which rotation around the aryl-aryl axis was hindered under varying degrees were investigated in condensation with 2a (Scheme 3). Racemic 6,6′-difluoro-[1,1′-biphenyl]-2,2′-diamine 1n reacted with 2a smoothly to give 3na in 86% yield with 85% ee through dynamic kinetic resolution (DKR) (for enantiomerization study of 1n see the Supporting Information Tables S2 and S3 and Figures S2 and S3). In addition, other biaryldiamines with unstable chiral axis such as 6-methyl-[1,1′-biphenyl]-2,2′-diamine 1o and 1-(2-aminophenyl)naphthalen-2-amine 1p were also fully converted to the corresponding products 3oa and 3pa in good yields, with 90% and 97% ee, respectively. After the DKR of biaryldiamines with unstabilized axial chirality, the kinetic resolution of stabilized biaryldiamines was studied. Unfortunately, only moderate enantioselectivities (50%–55% ee) were observed for DDD analogs 3qa– 3sa, and unreacted 1q– 1s were recovered in low enantiomeric purity (30–36% ee). However, when 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diamine 1t was applied to condense with 2a in the presence of (R)- C18 as a catalyst, 3ta was isolated in 49% yield with a moderate 68% ee. Enantioenriched 3ta (35% yield, 99% ee) was obtained through the simple operation of phase separation in sacrificing an acceptable amount of the racemate. The absolute configuration of 3ta was confirmed by X-ray diffraction.a Notably, the other enantiomer of 3ta could be accessed by reaction of the recovered (R)- 1t (57% ee) with 2a in the presence (S)- C18 under otherwise identical conditions (see the detailed requirements in the Supporting Information). Therefore, both of the enantiomers of 3ta were accessed in excellent optical purity (99% ee). Scheme 3 | Kinetic resolution of racemic 1.aaReaction conditions: 1 (0.1 mmol), 2a (0.3 mol), (R)-C18 (10 mol %), THP (0.1 mL), 35 °C, 48 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. b(R)-C4, rt, 3 days. c(R)-C4, 35 °C, 48 h. d(R)-C4, rt, 4 days. e1t (0.5 mmol), 2a (1 mmol), THF (0.35 mL), 50 h. fphase separation. gs = ln[(1 − C)(1 − ees)]/ln[(1 − C)(1 + ees)], Conversion (C) = ees/(ees + eep). Download figure Download PowerPoint Scheme 4 | Preparation of DDD-based phosphoramidites, CPA, and phosphorus ligands. Conditions: (a) hexamethylphosphorous triamide (HMPT), toluene, 115 °C, 6 h; or hexaethylphosphoruo triamide (HEPT), toluene, 115 °C, 6 h; or (1) diisopropylamine, PCl3, NEt3, DCM, 0 °C, 7 h, (2) (-)-DDDOL, NEt3, DCM, rt, 18 h; or (1) (R)-bis((R)-1-phenylethyl)amine, PCl3, NEt3, DCM, 0 °C, 7 h, (2) (-)-DDDOL, NEt3, DCM, rt, 18 h. (b) (1) POCl3, pyridine, 80 °C, 5 h, (2) H2O, 50 °C, 12 h, (3) 3 N HCl, 100 °C, 30 min. (c) (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, dppp, DIPEA, HP(O)Ph2, DMSO, 100 °C, 24 h, (3) HSiCl3, PhNMe2, toluene, 100 °C, 24 h, (4) Pd(OAc)2, dppb, DIPEA, HP(O)Ph2, DMSO, 100 °C, 14 h. (d) (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, dppb, DIPEA, HPPh2, DMSO, 125 °C, 18 h. (e) (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, dppp, DIPEA, HP(O)Ph2, DMSO, 100 °C, 24 h, (3) HSiCl3, PhNMe2, toluene, 100 °C, 24 h. DMSO, dimethyl sulfoxide; DIPEA, N,N-diisopropylethylamine. Download figure Download PowerPoint The crystal structure of 3ta demonstrated that the biaryl dihedral angle was approximately 71°, which was similar to that of BINOL.42 The rigid configuration and feasible accessibility of enantiomeric 3ta prompted us to develop new ligands based on this scaffold. As shown in Scheme 4, demethylation of (-)- 3ta gave (-)-6,7-diphenyldibenzo[e,g][1,4]diazocine-1,12-diol ((-)- DDDOL) as a key intermediate in 72% yield together with 16% of the monomethylated byproduct ( 4) (Scheme 4). First, a series of phosphoramidite ligands DDD1-4 were readily prepared by one-step conversion from (-)- DDDOL in 56%–72% yields. Next, CPA DDD5 was prepared with a moderate yield. Finally, DDD-based mono- and bis-phosphine ligands DDD6-9 were synthesized in 2–4 steps in 14%–34% overall yields. In addition, 4 could also serve as a precursor to form monophosphorus ligand DDD10 in 63% yield after three steps of routine transformations. It is worth mentioning that neither racemization nor decomposition was observed during these transformations, although some harsh conditions were applied, such as heating at 125 °C for 18 h in Pd-catalyzed phosphination, using B(C6F5)3 in demethylation, and using HSiCl3 in reduction of phosphine oxide to phosphine. Besides, the absolute configurations of phosphoramidite DDD1 and bisphosphine DDD7 were confirmed by X-ray diffraction (Scheme 4).a Scheme 5 | Applications of DDD1-10 in asymmetric catalysis. Download figure Download PowerPoint With these (-)- DDDOL derivatives in hand, their applications as potential chiral ligands in transition-metal-catalyzed asymmetric reactions were investigated. Rh-catalyzed asymmetric hydrogenation of enamide 5 was initially selected to test DDD1-4 with three other commercially available phosphoramidites as control ligands (Scheme 5a).43,44 Under the specified reaction conditions, DDD1 outperformed DDD2-3, giving phenylalanine derivative 6 quantitatively in 95% ee. The widely used MonoPhos and SIPhos led to equal or slightly better results.45,46 Importantly, the diimino moiety in DDD was inert upon hydrogenation, even under high hydrogen pressure. Next, the efficiency of DDD7 acting as a bidentate phosphorous ligand was evaluated in the 1,4-addition of arylboronic acid to cyclohex-2-en-1-one 7 catalyzed by [Rh(C2H4)Cl]2 (Scheme 5b).47,48 Although DDD7 and the control ligand BINAP showed comparable asymmetric induction, the yield of 9 was much better for the reaction using DDD7 as a ligand. To our satisfaction, in the asymmetric Tsuji-Trost reaction catalyzed by [Pd(η3-C3H5)Cl]2,49,50 DDD7 was proven again to be an excellent ligand, delivering 12 in 98% yield with 92% ee (Scheme 5c). The application of DDD7 in Pd-catalyzed allylic amination reaction was also investigated to construct C–N atropisomeric anilide derivatives (Scheme 6).51–53 Initial results for the reactions of anilide 13a with allyl acetate catalyzed by [Pd(η3-C3H5)Cl]2 in the presence of DDD7 and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) demonstrated that both of the ligands could promote the reaction in high yields but with poor enantioselectivities ( 14aa, 20–22% ee). We found that introducing a methyl substituent on the terminal vinyl carbon of allyl acetate was beneficial for the atroposelectivity of the corresponding anilide 14ab (62% ee). However, when cinnamyl acetate was used as the electrophile, both the yield and atroposelectivity decreased significantly ( 14ac, 71% yield, 42% ee). Gratifyingly, when a branched cinnamyl acetate derivative was applied, in which an additional chiral center was generated, the enantioselectivity for the major diastereomer reached 95% ee ( 14ad). Finally, after tuning both structures of anilide nucleophile and allyl electrophile, Pd-catalyzed allylic amination reaction in the presence of DDD7 furnished anilide derivative 14ce containing both C–N axial chirality and central chirality in excellent yield (81% yield), enantioselectivity (96% ee) and diastereoselectivity (dr > 20∶1). It is notable that 14ce was produced in a much lower yield (68%) with (R)-BINAP as the ligand under otherwise identical conditions. Although substantial methods have been developed to synthesize axially chiral C–N compounds atroposelectively, to the best of our knowledge, simultaneous introduction of central and axis chirality through Pd-catalyzed allylic amination has not been reported previously.56,57 These results demonstrated that DDD7 could be a complementary bis-phosphine chiral ligand to BINAP in transition-metal catalyzed asymmetric reactions. Scheme 6 | Application of DDD7 in the asymmetric construction of C–N axis chirality.aaThe configuration is inferred from similar reports.51–55bKOtBu, DCM, rt. Download figure Download PowerPoint The encouraging result of these inherently chiral DDD-based ligands in several different types of reactions prompted us to study the interaction of transition metals with ligands in detail. To this end, mixing DDD7 and Pd(PhCN)Cl2 in dichloromethane (DCM) yielded a precipitate that was crystallized from toluene. X-ray crystallographic analysis of the complex Pd( DDD7)Cl2 revealed that the dihedral angle was 62.5°, much smaller than that in Pd(BINAP)Cl2 (70.2°) and closer to that in Pd(SEGPHOS)Cl2 (60.1°) (Scheme 7a).58,59,a As we know, the dihedral angle of a ligand usually plays a decisive role in the chiral control of an asymmetric reaction.60 Therefore, to verify the correlation of the dihedral angle in these palladium complexes with asymmetric induction, a known reaction, Pd-catalyzed 5-endo-hydroaminocycliztion of N-(ortho-tert-butylphenyl)-2-ynylaniline 15 was investigated (Scheme 7b).61 Under the same reaction conditions, in the presence of (R)-BINAP and oxa-spirodiphosphine ligand SEGEPHOS, indole derivative 16 bearing N-aryl axial chirality was obtained with 0 and 60% ee, respectively. When DDD7 was tested, 16 was obtained in 32% ee. This preliminary result indicated that DDD7 could be an ideal candidate complementary to BINAP and SEGEPHOS when screening chiral bisphosphine ligands for specific asymmetric catalytic reactions. Scheme 7 | Research and application of Pd(DDD7)Cl2. Download figure Download PowerPoint Next, we explored the reaction mechanism and origins of enantioselectivity employing DFT calculations with diamine 1a and benzil 2a as model compounds. Since the first imine formation was not responsible for the chirality generation, the calculation started with INT-A (Figure 2). The energy profile of the mechanism for the second condensation step was performed (Figure 2a). After activation by CPA ( ( R )-C18), the ketone moiety of INT-A underwent an intramolecula