Design and Assembly of Chiral Coordination Cages for Asymmetric

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Design and Assembly of Chiral Coordination Cages for Asymmetric Sequential Reactions Jingjing Jiao, Chunxia Tan, Zijian Li, Yan Liu, Xing Han, and Yong Cui J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11679 • Publication Date (Web): 18 Jan 2018 Downloaded from http://pubs.acs.org on January 18, 2018

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Journal of the American Chemical Society

Design and Assembly of Chiral Coordination Cages for Asymmetric Sequential Reactions Jingjing Jiao,† ,§ Chunxia Tan,†,§ Zijian Li,† Yan Liu,*,† Xing Han,† and Yong Cui*,†,‡ †

School of Chemistry and Chemical Engineering and State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240, China ‡ Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China Supporting Information ABSTRACT: Supramolecular nanoreactors featuring multiple catalytically active sites are of great importance, especially for asymmetric catalysis, are yet challenging to construct. Here we report the design and assembly of five chiral single- and mixed-linker tetrahedral coordination cages using six dicarboxylate ligands derived-from enantiopure Mn(salen), Cr(salen) and/or Fe(salen) as linear linkers and four Cp3Zr3 clusters as three-connected vertices. The formation of these cages was confirmed by a variety of techniques including single-crystal and powder X-ray diffraction, inductively coupled plasma optical emission spectrometer, quadrupole-time of flight mass spectrometry and energy dispersive X-ray spectrometry. The cages feature a nanoscale hydrophobic cavity decorated with the same or different catalytically active sites and the mixed-linker cage bearing Mn(salen) and Cr(salen) species is shown to be an efficient supramolecular catalyst for sequential asymmetric alkene epoxidation/epoxide ring-opening reactions with up to 99.9% ee. The cage catalyst demonstrates improved activity and enantioselectivity over the free catalysts owing to stabilization of catalytically active metallosalen units and concentration of reactants within the cavity. Manipulation of catalytic organic linkers in cages can control the activities and selectivities, which may provide new opportunities for the design and assembly of novel functional supramolecular architectures.

INTRODUCTION Metal-organic cages have been widely investigated for their bionic feature1 and potential applications (e.g. stabilization of reactive species,2 recognition,3 and catalysis4). So far these achievements have been mainly made with polyhedral complexes containing just one type of ligand and metal ion.1-4 Polyhedral architectures built from two or more different ligands have attracted much attention for their elaborate structures and functions, but the rational design of heteroleptic assemblies remains challenging.5,6 This is even challenging for chiral cages, which are of particular interest because of the increasing demand for materials for chiral recognition, asymmetric catalysis and enantioseparation.7 Although coordination cages have been widely explored for supramolecular catalysis,4,8 only a handful of them can promote enantioselective reactions.10 Several well-known examples include a Pd6L4 cage for asymmetric cycloadditions (50% ee),9a a Ga4L6 cage for asymmetric Aza-Cope rearrangement (78% ee)9b and carbonyl-ene cyclization (69% ee),9c and a Pd8L4 cage for asymmetric hydroformylation of styrenes (74% ee).9d On the other hand, tandem or sequential catalytic reactions, mastered by nature, are extremely valuable processes because reactive intermediates are quickly guided through consecutive reactions toward the desired products.10 However, the rational design of catalytic cages for tandem/sequential reactions has yet to be realized.11 In this contribution we demonstrate how to achieve this via the approach of constructing two different catalytically active sites into a single coordination cage. Metallosalen complexes, one type of privileged chiral catalysts, have been used in a variety of challenging asymmetric reactions.12 For example, Mn(salen) and Fe(salen) complexes are highly effective in catalyzing asymmetric epoxidation of olefins and Cr(salen) complexes are excellent catalysts for asymmetric

ring-opening reactions of epoxides with different nucleophiles.13 However, M(salen) complexes are readily deactivated in reactions for dimerization or oxidization.14 To inhibit deactivation pathways, M(salen) catalysts have been immobilized on solid supports including silica and metal-organic frameworks.15 In this work, we reported the synthesis of five chiral single- and mixed-linker tetrahedral coordination cages with strategically placed dual M(salen) active sites for asymmetric sequential alkene epoxidation/epoxide ring-opening reactions (Scheme S1). The incorporated M(salen) catalysts displayed improved activity and enantioselectivity over the free catalysts. A C3-symmetric Cp3Zr3(µ3-O)(µ2-OH)3(O2CR)3 cluster, which can be formed via hydrolysis of bis(cyclopentadienyl)zirconium dichloride (Cp2ZrCl2, Cp = η5-C5H5) followed by reaction with carboxylate acid, was selected as the vetex for the construction of M(salen) linker-incorporated tetrahedral coordination cages. This is because that replacing the three original carboxylates in the trinuclear cluster by linear dicarboxylates or trigonal tricarboxylates can generate the V4E6 and V4F4 (V = vertex, E = edge and F = face) types of coordination tetrahedra.16

RESULTS AND DISCUSSION Synthesis and characterization. Metalation of enantiopure 1,2-cyclohexanediamine-N,N′-bis-(3-tert-butyl-5-(carboxyl)alicyli de (H4L) with MnCl2·4H2O, CrCl2 and Fe(OAc)2·4H2O afforded Mn(H2L)Cl, Cr(H2L)Cl and Fe(H2L)(OAc) respectively.17 Crystals of the single-linker cages 1Mn and 1Cr with the general formula [Cp3Zr3(µ3-O)(µ2-OH)3]4(ML)6]⋅Cl6⋅G (1Mn, M = Mn; 1Cr M = Cr; G = solvent) were obtained in ~70% yield by heating a 2:1 mixture of Cp2ZrCl2 and M(H2L)Cl (M = Mn or Cr) in N,N-dimethylformaminde (DMF) and tetrahydrofuran (THF) at 65 oC for 10 h. Under similar conditions, crystals of the

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Figure 1. (a) Structures of the ligands and trimetallic cluster. (b) Schematic representations of cages 1Mn, 1Cr, 1MnCr, 1MnFe and 1CrFe (For clarity, only one of three possible isomers of coordination tetrahedra listed in Figure S4 was shown). (c) Single-crystal X-ray structure of 1Mn and its space-filling model (light blue, Mn; green, Zr; blue, N; red, O; gray, C; the cavity are highlighted by yellow spheres)

mixed-linker cages 1MnCr, 1MnFe and 1CrFe with the general formula [Cp3Zr3(µ3-O)(µ2-OH)3]4(M1L)3(M2L)3]⋅Cl6⋅G were prepared in ~80% yield from a 4:1:1 mixture of Cp2ZrCl2, M1(H2L)Cl and M2(H2L)Cl (M1/M2 = Mn/Cr, Mn/Fe or Cr/Fe). The formulations were supported by the results of microanalysis, IR spectra, quadrupole-time of flight mass spectrometry (Q-TOF-MS) and thermogravimetry (TGA). All of the five cage crystals are stable in air and soluble in common organic solvents such as MeOH, EtOH and CH2Cl2. The molar optical rotation (ϕ) values for cage 1Mn and Mn(H2L)Cl were determined as 1719 and 40 deg cm3 dm-1 mol-1, respectively. The cage has an optical rotation per mole of ~43 times that of the ligand (~7 times per ligand unit). Similar chiral amplification was observed for the other four cages (~5 times increase per ligand unit). The circular dichroism (CD) spectra of the cages constructed from (S)- and (R)-enantiomers of M(H2L)Cl were mirror images of each other in both solution and the solid-state (Figures S13), indicative of their enantiomeric nature. We further checked the optical purity of 1,2-cyclohexane-diamine in the ligand after hydrolyzing 1Mn and 1Cr with dilute HCl solution in DMSO. The optical rotation values were close to that of the standard sample (-0.046o and -0.042o vs -0.043o deg cm3 dm-1), indicating retention of chirality of the ligand during the self-assembly process (Table S5). The formation of the family of tetrahedral cages was supported by Q-TOF-MS. For the single-linker cage, a clean spectrum was obtained with peaks displaying the expected isotopic patterns at

967.0863, 1152.8663 and 1441.6272 for 1Mn belonging to [1Mn·G-nCl]n+ (n = 4-6, G = guest molecules Figure S4a) and 992.3288, 1183.8565, and 1469.5421 for 1Cr belonging to [1Cr·G-nCl]n+ (n = 4-6, Figure S4b). For the mixed-linker cage, a clean MS spectrum was observed with peaks at 969.2042, 1155.7249, and 1452.7429 for 1MnCr, 977.5911, 1177.0945 and 1445.4212 for 1MnFe and 1164.1478, 1444.4262 and 1939.5655 for 1CrFe, corresponding to [1MnCr·G-nCl]n+ (n = 4-6, Figure S6c), [1MnFe·G-nCl]n+ (n = 4-6, Figure S6d) or [1CrFe·G-nCl]n+) (n = 3-5, Figure S6e), respectively. In principle, mixing Cp2ZrCl2 with two different linkers at a 1:1 ratio may result in the formation of homoleptic cages, heteroleptic cages or statistical mixtures of cages.5a In the present study, however, we did not observe obvious peaks in the MS spectra associated with the first and third type of cages and the experimental isotopic effects matched very well with the result calculated by 1:1 mixture. Single-crystal X-ray diffraction showed that 1Mn crystallizes in the chiral trigonal R32 space group. The structure has non-crystallographic tetrahedral symmetry and is constructed from four C3-symmetric Cp3Zr3(µ3-O)(µ2-OH)3 nodes and six linear MnL linkers. Four bowl-like Cp3Zr3(µ3-O)(µ2-OH)3 units located in the vertexes are linked by six metallosalen ligands to form a cationic cage [Cp3Zr3(µ3-O)(µ2-OH)3]4(MnL)6]6+ with a Zr-Zr distance of 18.99(3) Å. The positive charges were balanced by Cl anions. A space-filling representation of 1Mn clearly shows the

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Figure 2. (a) PXRD patterns of the as-prepared cages and optical microscopy images of their single crystals. (b-d) SEM images and EDS mappings of single crystals of cages 1MnCr, 1MnFe and 1CrFe. (e) TEM image and EDS mappings of 1MnCr.

formation of a porous cage with wide apertures (~12.5 × 12.5 Å2, Figure 1c). The overall size of the cage is ~27.7 × 27.7 × 27.7 Å3. The separation of µ3-O···µ3-O is about 18.88(3) Å and the internal tetrahedral volume of cage is 795 Å3 available for guest molecules inclusion. The cage has a total of twelve hydroxyl groups that are engaged in twelve O−H···Cl···H−O intercluster H-bonding interactions with adjacent clusters [O···Cl = 2.99(7)-3.04(7) Å] (Figure S2). Such H-bonds are strengthened by electrostatic interactions between cationic vertexes and Cl anions. Vetex-to-vetex intercluster interactions in 1Mn led to a 3D porous structure. Octahedral cages with a maximum inner width of ~36.0 Å are formed via the arrangement of eight tetrahedral cages (Figure S3). 1Cr is isostructural to 1Mn and has a similar tetrahedral structure built from four Cp3Zr3(µ3-O)(µ2-OH)3 nodes linked by six CrL ligands. The single-crystal X-ray diffraction data for the mixed-linker cages 1MnCr, 1MnFe and 1CrFe were extremely weak, but the unit cell parameters determined from single crystal X-ray diffraction showed that they are all isostructural to 1Mn and 1Cr (Table S4). The phase purity of the five crystalline samples was verified by consistence between their observed and simulated powder X-ray diffraction (PXRD) patterns (Figure 2a). Calculations using the PLATON program indicate that ~64% of the total volumes of both 1Mn and 1Cr are occupied by guest molecules.18 Thermal gravimetric analysis (TGA) revealed that guest molecules of the crystalline cages could be removed at 80-130 °C and the materials started to decompose at ~430 oC (Figure S7). The porosity of the apohost solids was supported by N2 adsorption isotherms at 77 K. The BET (Brunauer-Emmett-Teller) surface areas were found to be only 113, 91, 95, 104 and 110 m2/g, respectively (Figure S15), although the theoretical values are expected to be around 3150 m2/g. The discrepancy probably results from the cage framework distortion on solvent removal, which is quite common among supramolecular porous metal-organic materials.16a,20i PXRD confirmed that the evacuated samples retained their structural integrity and crystallinity, but serious structural distortions and even partial structural collapse occurred, as evidenced by the disappearance of some diffraction peaks (Figure S8). Nevertheless, the individual tetrahedral structure of the cages was well maintained at the molecular level after evacuation, as indicated by UV-vis spectra (Figure S13e). Additional experiments were carried out to prove the successful formation of the three mixed-linker cages. The 1:1 molar ratios of the metalloslaen linkers in cages 1MnCr, 1MnFe and 1CrFe were con-

firmed by inductively coupled plasma optical emission spectrometry analysis (See experimental section). To confirm that 1MnCr is a truly mixed-component compound rather than a physical mixture of homoleptic species 1Mn and 1Cr or heteroleptic species containing 1:2 or 2:1 ratios of mixed ligands, we applied energy dispersive spectra (EDS) to map the presence of various metals using scanning electron microscopy (SEM) on a single crystal. If there were a physical mixture of cages, it would be expected to observe the presence of Mn and Cr separately in their corresponding crystal specimens or their own distributions in one crystal. However, the EDS mappings on random crystals showed that both metals distributed homogenously (Figures 2b and S9). To test the homogeneous distribution of Mn and Cr at more microscale, we applied high resolution transmission electron microscope-energy X-ray spectra (TEM-EDS) analysis on the sample of 1MnCr after grinding and ultrasounding in tetrahydrofuran. Both Mn and Cr elements distributed uniformly at the scale of 7 nm where only about two tetrahedra existed, as shown in Figures 2e and S10. Taking together, the above results indicated that 1MnCr is built as a mixed-linker tetrahedral instead of heterogeneous physical mixture of different cages. In addition, EDS analyses also suggested that both cages 1MnFe and 1CrFe are homogeneous mixed-linker tetrahedra containing a 1:1 mixture of the ligands (Figure 2c, 2d, S11 and S12). The result of EDS mappings was consistent with that of the above Q-TOF-MS. The heteroleptic self-assembly from organic ligands with similar size and shape but distinct functionalities is simple and efficient and may grant access to a wide range of highly functionalized macrocyclic and polyhedral supramolecular structures.19 Even for 1:1 mixed ligand cages, one can easily list more than three isomers, for example, the 1:1 cages with one vertices linked by three identical ligands are distinct from the structure shown in Figure 1b. This phenomenon may result in co-crystals of isomeric cages, though the catalytic efficiency will not be affected. Moreover, it also should be noted that tetrahedral cages are intrinsically chiral with either a ∆ or Λ configuration at each of the four vertices. The M4L6 cages thus may have different combinations of configuration in either a homoconfigurational ∆∆∆∆- or ΛΛΛΛ-conformation or a blend of heteroconfigurational Λ∆∆∆-, ΛΛ∆∆- and ΛΛΛ∆conformers. These possible diastereomers may also exist in one crystal that cannot be precisely solved at this moment. Further studies on the assembly of more heteroleptic polyhedral structures and understanding the selective self-assembly processes and their 3



supramolecular chirality are underway. Although a large number of coordination cages have been synthesized, only a small fraction of them are homochiral.1, 20 The present five cages are rare examples of homochiral molec ular polyhedra and, to the best of our knowledge, 1Mn and 1Cr represent the first chiral (Cp3Zr3)4L6 tetrahedra that have been crystallographically characterized,16 and 1MnCr, 1MnFe and 1CrFe Table 1. Sequential asymmetric epoxidation/ring-opening reactions of alkenes with TMSN3 catalyzed by the cages and related catalystsa

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represent the first three examples of chiral heteroleptic coordination cages.21 Supramolecular Asymmetric Catalysis. We first demonstrated that 1Mn can serve as a homogeneous catalyst for the synthetically important reactions of epoxidation of alkenes. At 0.1 mol % loading, 1Mn catalyzed epoxidation of 2,2-dimethyl-2H-chromene (DMCH) with 2-(tert-butylsulfonyl)iodosylbenzene (sPhIO) as oxidant in CH2Cl2 at 0 oC, affording 65-89% conversion and 83-94% ee of the epoxide, which were higher than the monomeric catalyst Mn(Me2L)Cl (47-84% conversions and 83-91% ee) (Scheme S1a and Table S6). 1Cr was found to be active in catalyzing ring opening of epoxide, which offers a route to prepare biologically important and enantioenriched 1,2-functionalizedβ-hydroxy compounds.14b Using 0.1 mol% 1Cr, the reactions of 2,2-dimethyl benzopyran oxide with aniline and trimethylsilylazide (TMSN3) affording 96% and 93% conversions with 20% ee of the products, respectively (Scheme 1b). This level of conversions and ee values observed for 1Cr rivals those of the monomeric catalyst Cr(Me2L)Cl (Tables S7 and S8). Table 2. Sequential asymmetric epoxidation/ring-opening reactions of alkenes with anilines catalyzed by the cages and related catalysts.a

a

For reaction details see Experimental section. b, cCalculated by 1H NMR. Determined by HPLC. e0.2 mol% 1MnCr. fCatalyzed by 0.1 mol% loading of a 1:1 mixture of 1Mn and 1Cr. gCatalyzed by 0.2 mol% loading of a 1:1 mixture of Mn(Me2L)Cl and Cr(Me2L)Cl. Data in brackets are the errors. d

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For reaction details see Experimental section. b,cCalculated by 1H NMR. Determined by HPLC. eCatalyzed by 0.2 mol% 1MnCr.f0.1 mol% loading of a 1:1 mixture of 1Mn and 1Cr. gCatalyzed by 0.2 mol% loading of a 1:1 mixture of Mn(Me2L)Cl and Cr(Me2L)Cl. Data in brackets are the errors. d

Figure 3. (a) Kinetic results with 0.2 mol% (R)-1MnCr and related catalysts. (b) Plots of sequential epoxidation/ring-opening reactions of DMCH with TMSN3 at different catalysts loadings.

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Figure 4. (a, b) Fluorescence quenching of Mn(Me2L)Cl and 1Mn upon titration with DMCH in CH2Cl2; (d, e) Fluorescence enhancement of Cr(Me2L)Cl and 1Cr upon titration with the epoxidation product of DMCH in CH2Cl2; (c, f) The Benesi-Hildebrand plots of Mn(Me2L)Cl and 1Mn; Cr(Me2L)Cl and 1Cr titration with DMCH and its epoxidation product, respectively.

Given that the Mn3+ and Cr3+ centers in cages 1Mn and 1Cr can promote epoxidation of alkenes and ring opening of epoxides, respectively, we reasoned that cage 1MnCr featuring two different catalytic centers may catalyze sequential reactions initiated by epoxidation of alkene followed by ring opening of epoxide. The evaluation of the sequential reaction started with exposure of DMCH to sPhIO and 1MnCr, and then TMSN3 was added. The reaction was performed with 0.2 mol% (R)-1MnCr and 1 equiv sPhIO in CH2Cl2 at 0 oC. Only one pair of enantiomers out of all possible four pairs was detected, and the azido alcohol (upon TFA-mediated elimination of the TMS group) was obtained in 85% DMCH conversion and 79% yield with 93% ee (Table 1, entry 1). The substrates containing methyl and nitro groups were also tolerated, affording 78% and 88% alkene conversions and 73% and 81% yields with 92% and 93% ee, respectively. To study the confinement effect of a cage on a molecular catalyst, the activity of a 1:1 mixture of Mn(Me2L)Cl and Cr(Me2L)Cl was studied (Table 1, entries 7-9). The observed conversions/yields/ee's for the sequential reactions of 4a, 4b and 4c were 72/66/86%, 67/61/88% and 75/68/89%, which were 11-13%/12-13%/4-7% lower than those observed for 1MnCr, respectively. The reaction kinetics of the sequential reaction of DMCH was studied and shown in Figure 3a. The calculated initial turnover frequencies (TOFini) from the kinetic curve were 99 and 60 h-1 for 1MnCr and the mixture of Mn(Me2L)Cl/Cr(Me2L)Cl. The reaction kinetics revealed that the incorporation of Mn(salen) and Cr(salen) catalysts into a cage did enhance their catalytic activities and enantioselectivities. Moreover, Figure 3b showed that the difference became larger as the catalyst loading decreased. Specially, 1MnCr remained active at a very low loading (0.005-0.01 mol %), but the counterpart mixture was totally inactive. The low activity and enantioselectivity of the monomeric M(salen) catalysts at low loadings typically are associated with their dimeriza-

tion and/or oxidation, some conversion of catalytic sites into less selective species in dilute solutions.13 In contrast, the self-assembled cage behaves as a supramolecular ligand for incorporated catalytically active metal ions, which can extend the lifetime of the catalyst by eliminating bimolecular decomposition pathways and potentially provide additional selectivity by pore shape and size. Meanwhile, the hydrophobic cage cavity can encapsulate substrates and concentrate reactants, giving rise to enhanced reactivity. Hence, the M(salen) catalysts confined in the cage framework displayed improved reactivity and stereoselectivity with respective to the cage counterparts, especially at low catalyst loading. We further compared the catalytic activity of the heteroleptic cage 1MnCr with that of a 1:1 mixture of 1Mn and 1Cr. When only cage 1Mn or 1Cr was used, no sequential reaction was observed, whereas the mixture of cages 1Mn and 1Cr can catalyze the sequential reactions efficiently (Table 1, entries 4-6) with slightly decreased conversions and ee values compared with 1MnCr. The TOFini value of cages 1Mn/1Cr was 84 h-1, lower than that of 1MnCr (99 h-1). Like 1MnCr, the cage mixture remained active at very low loading (0.005 mol %). Moreover, when the loading was decreased continuously, 1MnCr displayed increasingly higher activity and steroselectivity than the cage mixture. This difference indicated that 1MnCr was not a simple addition of cages 1Mn and 1Cr, and integrating Mn(salen) and Cr(salen) catalysts into a single cage generated additional cooperative effects to improve the catalytic performances. Besides, the heteroleptic cage catalyst can complete the sequential reaction in one cavity and avoid mass transfer of intermediates between cages, thereby speeding up the overall reaction. As a result, the heteroleptic cage gives better catalytic activity and enantioselectivity than the cage mixture. It is worth noting that, compared with 1MnCr, the cost of the materials is considerable in the hybrid case and the intrinsically high Zr and 5



organic linkers of the cages are not really valorized. Although the catalytic reactions were performed under homogeneous conditions, the cage catalyst 1MnCr could be recovered as precipitate by addition diethyl ether into solution after reaction, and washed with diethyl ether for several times. It can be recycled and reused as a homogeneous catalyst for at least five times with slight deterioration in enantioselectivity (>75% conversions and 92%, 90%, 84%, 82% and 81% ee for 1-5 runs, respectively) (Table S9). The recovered 1MnCr retained the original structure, as evidenced by Q-TOF-MS, CD and UV-vis spectra (Figures S6h, S13d and S14a). (R)-1MnCr can also catalyze the sequential epoxidation/ ring-opening reactions of DMCH and its derivatives with anilines (Table 2). The afforded ee’s (91-99.9%) are slightly higher (76% conversions and 91%, 87%, 85%, 83% and 80% ee for 1-5 runs, respectively). The recovered catalyst maintained its cage structure (Figures S13d and S14a). Two more experiments were carried out to probe the role of the cage cavity in catalysis. First, we designed a series of anilines of varying sizes. Molecular mechanics simulations indicated that these anilines have estimated sizes ranging from 6.6 to 16.2 Å. As expected, the efficiency for the sequential reaction catalyzed by the counterpart mixture is not affected by the substituent size (Table 2, entries 18-21). In contrast, the yields of the reaction products catalyzed by the heteroleptic cage greatly depend on the substituent size: as the size of the aniline increases, the yield of the final product steadily decreases (82, 51, 18, 13 and 8%; entries 1 and 6-9). In particular, only 8-18% yields of the desired products were detected for three sterically more demanding anilines G2-PhNH2, G3-PhNH2 and G4-PhNH2, which were much lower than 68-70% yields obtained with the counterpart mixture, presumably because they cannot access the catalytic sites in the cavity through the windows (12.5 × 12.5 Å2) as a result of their large diameters (10.2 × 11.2, 10.2 × 15.6 and 10.2 × 16.2 Å2, respectively). Second, we added an excess of a strongly bind competing guest (0.3 M methy organge Ka = 5.9 × 104 M-1, Figure S16g) to the sequential reaction system catalyzed by 1MnCr. With the dye present, the conversion of DMCH and yield of the final product dropped to 37 and 31%, respectively, because the competing guest prevented substrate binding in the cavity. Taking together, the above findings indicated that the sequential reaction was indeed associated with the substrates being bound in the cage cavity. To further understand the host-guest interactions, we examined the ability of the cages to encapsulate substrates and products. Fluorescence titrations experiments were carried out with concentration of cages fixed at 1.0 × 10-5 M at room temperature, and the guest was varied from 1.0 × 10-5 M to 5.0 × 10-5 M in CH2Cl2 (Figures 4 and S16). The gradual quenching or enhancement of fluorescent emission band at about 342 nm, and wavelength shift of fluorescence emission for 1Cr from 343 nm to 346 nm (Figure 3e) upon addition of guest indicated the formation of host-guest complex. The association constant (Ka) was estimated based on Hildebrand-Benesi plots a 1:1 (host:guest) binding model. 1Mn and 1MnCr bound DMCH Ka of 4.6 × 104 and 3.8 × 104 M-1, respectively, while 1Cr and 1MnCr bound the epoxide 3a with Ka of 2.6 × 104 and 3.6 ×104 M-1, respectively. From control experiments,

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these Ka values were much higher than the related Ka of 1.9 × 104 M-1 between Mn(Me2L)Cl and DMCH and Ka of 1.6 × 104 M-1 between Cr(Me2L)Cl and 3a. Comparing with the epoxide, the amino alcohol product 5a associated with 1Cr and 1MnCr by weaker interactions, with Ka of 1.8 × 104 and 2.3 × 104 M-1, respectively. The quite different Ka values suggested that 1MnCr catalyzed the sequential reaction as a turnover process based on the product release and the substrate uptake.

CONCLUSIONS In summary, we have designed and synthesized five chiral single- and mixed-linker coordination cages by controlling incorporation of dicarboxylate ligands derived-from enantiopure Mn(salen), Cr(salen) and Fe(salen) catalysts. The cages were characterized by single-crystal and powder X-ray diffraction, elemental analysis, ICP-OES, Q-TOF-MS, IR, UV-vis, CD, optical rotation and SEM/TEM-EDS mappings. Each of these isostructural tetrahedral cages possess a nanoscale hydrophobic cavity decorated with the same or different catalytically active sites. The mixed-linker cage built of Mn(salen) and Cr(salen) unit was demonstrated to be an efficient and recyclable supramolecular catalyst for asymmetric sequential alkene epoxidation/epoxide ring-opening reactions. The rigid and porous cage can not only stabilize metallosalen catalysts against their dimerization but also encapsulate substrates and concentrate reactants, leading to improved chemical reactivity and stereo-selectivity compared with the physical mixture of the individual catalytic components or the single-linker cages. This work therefore advances mixed-linker cages as a new platform to engineer supramolecular catalysts featuring multiple active sites for sequential catalysis in organic syntheses. The fact that manipulation of catalytically active organic linkers in coordination cages can control the activities and selectivities would facilitate the design of novel supramolecualr assemblies and materials for enantioselective processes.

EXPERIMENTAL SECTION Synthesis of The Single-Linker Cages. A mixture of Mn(H2L)Cl (20 mg, 0.034 mmol) and Cp2ZrCl2 (40 mg, 0.068 mol) was dissolved in 1.5 mL DMF and 1.5 mL THF in a 20 mL vial. The vial was sealed and heated at 65 oC for 24 h and then allowed to cool to r. t.. The cubic crystals were collected, washed with DMF and diethyl ether and dried in air. 1Cr was synthesized in a similar procedure by using Cr(H2L)Cl. The product can be best formulated as {[Cp3Zr3(µ3-O)(µ2-OH)3]4[(MnL)6]}Cl6⋅3DMF⋅2H2O for 1Mn and [Cp3Zr3(µ3-O)(µ2-OH)3]4[(CrL)6]Cl6⋅5DMF for 1Cr on the basis of microanalysis, IR, TGA, Q-TOF-MS and single-crystal diffraction. 1Mn. Dark brown crystals. Yield: 72%. Elemental analysis: Anal (%). Calcd for C249H289Cl6Mn6N15O60.5Zr12: C, 49.23; H, 4.70; N, 3.46. Found: C, 49.35; H, 4.67; N, 3.51. IR (KBr pellet, v/cm-1): 2950 (s), 2865 (m), 2770 (m), 1648 (s), 1602(s), 1556 (s), 1511(m), 1487 (m), 1447 (m), 1419 (s), 1393 (vs), 1383 (vs), 1340 (s), 1269 (m), 1236 (m), 1019 (m), 906 (m), 813 (m), 790 (m), 623 (m), 466 (m). 1Cr. Light brown crystals. Yield: 70%. Elemental analysis: Anal (%). Calcd for C255H299Cl6Cr6N17O66.5Zr12: C, 49.05; H, 4.41; N, 3.81. Found: C, 49.16; H, 4.51; N, 3.45. IR (KBr pellet, v/cm-1): 2936 (s), 2861(m), 1650 (m), 1631(s), 1602 (vs), 1560 (vs), 1515(m), 1469 (m), 1421 (m), 1392 (vs), 1378 (vs), 1336 (vs), 1289 (m), 1232 (m), 833 (m), 810(s), 792 (s), 710 (s), 618 (s), 576 (m) and 469 (m). Synthesis of The Mixed-Linker Cages. A mixture of Mn(H2L)Cl (10 mg, 0.017 mmol), Cr(H2L)Cl (10 mg, 0.017 mmol), Cp2ZrCl2 (40 mg, 0.068 mmol), were dissolved in 1.5 mL 6


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Journal of the American Chemical Society DMF and 1.5 mL THF in a 20 mL vial. The vial was sealed abd heated at 65 oC for 10 h and then allowed to cool to r. t. The cubic crystals of 1MnCr were collected, washed with DMF and diethyl ether and dried at air. 1MnFe and 1CrFe were synthesized in a similar procedure by using a 1:1 mixtrue of Mn(H2L)Cl and Fe(H2L)(OAc) or of Cr(H2L)Cl and Fe(H2L)(OAc). Based on microanalysis, ICP and IR, TGA and Q-TOF-MS, The product can be best ormulated as {[Cp3Zr3(µ3-O)(µ2-OH)3]4[(MnL)3(CrL)3]}Cl6⋅3DMF⋅H2O for 1MnCr, [Cp3Zr3(µ3-O)(µ2-OH)3]4(MnL)3 (FeL)3Cl6⋅2DMF⋅H2O for 1MnFe and Cp3Zr3(µ3-O)(µ2-OH)3]4 (CrL)3(FeL)3Cl6⋅H2O for 1CrFe. 1MnCr. Brown crystals. Yield: 80%. Elemental analysis: Anal (%). Calcd for C249H283Cl6Mn3Cr3N15O60.5Zr12: C, 49.30; H, 4.67; N, 3.47. Found: C, 49.26; H, 4.78; N, 3.42. ICP indicated the ratio of Mn:Cr = 1.05:1. IR (KBr pellet, v/cm-1): 2946 (vs), 2866 (s), 2869 (m), 1655 (vs), 1601(vs), 1561(vs), 1519 (m), 1466 (m), 1380 (vs), 1336 (vs), 1316 (s), 1296 (m), 1233 (m), 1201(m), 1185 (m), 1141 (m), 1100 (m), 1020 (s), 934 (m), 832 (s), 811 (vs), 735 (m), 710 (vs), 618 (m) and 469 (m). Unit cell parameter (Trigonal): a = b = 33.8357(82) Å, c = 82.788(23) Å, V = 82081(31) Å3. 1MnFe. Dark red crystals.Yield: 80%. Elemental analysis: Anal (%). Calcd for C248H256Cl6Mn3Fe3N14O64.5Zr12: C, 48.92; H, 4.21; N, 3.22. Found: C, 48.67; H, 4.58; N, 3.42. ICP indicated the ratio of Mn:Fe = 1.01:1. IR (KBr pellet, v/cm-1): 2948(m), 2867(w), 2869(m), 1852(w), 1655(vs), 1602(s), 1561(s), 1518(m), 1449(w), 1392(vs), 1382(vs), 1335(s), 1233(w), 1203(w), 1020(m), 934(w), 812(s), 791(m), 710(m), 617(m), 577(m). Unit cell parameter (Trigonal): a = b = 34.0326(79) Å, c = 83.440(29) Å, V = 83694(26) Å3. 1CrFe. Dark red crystals.Yield: 80%. Elemental analysis: Anal (%). Calcd for C240H242Cl6Cr3Fe3N12O62.5Zr12: C, 48.78; H, 4.10; N, 2.85. Found: C, 48.78; H, 4.38; N, 3.02. ICP measurement indicated the ratio of Cr:Fe = 1.05:1. IR (KBr pellet, v/cm-1): 2931(s), 2348 (m), 1604 (vs), 1563 (s), 1449 (m), 1384 (vs), 1336 (s), 1313(s), 1141 (w), 1021 (m), 811 (m), 787 (m), 711(m), 616(m), 578 (m), 467 (m). Unit cell parameter (Trigonal): a = b = 33.7888(26) Å, c = 82.801(17) Å, V = 81307(11) Å3. General Procedure for Asymmertric Epoxidation Reaction of Alkene: Alkene (0.1 mmol) was added to a solution of 1Mn (0.2 mg, 0.1 mol%) or 1MnCr (0.4 mg, 0.2 mol%) in dry DCM (1.0 mL) at 0 oC. 2-(tert-butylsulfonyl)iodosylbenzene (0.1mmol, 34 mg) was added (2 mg per 10 min), and the reaction was allowed to proceed for 8h at 0 oC. After that, the mixture was centrifuged at 9000 rpm for 5 min, and the supernatant was concentrated under vacuum. The conversion was analyzed by 1H NMR and ee value was obtained by HPLC. General Procedure for Asymmetric Ring Opening of Epoxide with TMSN3: Epoxide (0.1 mmol) was added to a solution of 1 Cr (0.2 mg, 0.1 mol %) or 1MnCr (0.4 mg, 0.2 mol%) in dried DCM (1.0 mL) at 0 oC. After stirring for 15 min, TMSN3 (0.1 mmol) was added and the reaction mixture was stirred for 8 h. After that, the mixture was centrifuged at 9000 rpm for 5 min, and the supernatant was concentrated under vacuum. The conversion was analyzed by 1H NMR and ee value was obtained by HPLC. General Procedure for Asymmetric Ring Opening of Epoxide with Aniline: Epoxide (0.1 mmol) was added to a solution of 1Cr (0.2 mg, 0.1 mol%) or 1MnCr (0.4 mg, 0.2 mol%) in dried DCM (1.0 mL) was added at 0 oC. After stirring for 15 min, aniline (0.05 mmol) was added and the reaction mixture was stirred until the disappearance of the amine. After that, the mixture was centrifuged at 9000 rpm for 5 min, and the supernatant was concentrated under vacuum. The conversion was analyzed by 1H NMR and ee value was obtained by HPLC. General Procedure for a Sequential Asymmetric Epoxidation/ring-opening Reactions of Alkenes with TMSN3: Alkene

(0.1 mmol) was added to a solution of 1MnCr (0.4 mg, 0.2 mol%) in dry DCM (1 mL) at 0 oC. 2-(tert-butylsulfonyl)iodosylbenzene (0.1 mmol, 34 mg) was added (2 mg per 10 min), and the reaction was carried out for 8 h at 0 oC. And then aniline (0.11mmol) was added and the reaction mixture stirred for another 8 h at 0 oC. Then the mixture was centrifuged at 9000 rpm for 5 min, and the supernatant was concentrated under vacuum. The conversion was analyzed by 1H NMR and ee value was obtained by HPLC. General Procedure for a Sequential Asymmetric Epoxidation/ring-opening Reactions of Alkenes with Aniline: To a solution of 1MnCr (0.4 mg, 0.2 mol%) in dry DCM (1.0 mL), alkene (0.1 mmol) and then 2-(tert-butylsulfonyl)iodosylbenzene (0.1 mmol, 34 mg) was added slowly (2 mg/10 min) and the reaction was carried out 8 h at 0 oC. After that aniline (0.11 mmol) was added and the reaction mixture was stirred at 0 oC for another 4 h. The mixture was centrifuged at 9000 rpm for 5 min, and the supernatant was concentrated under vacuum. The conversion was analyzed by 1H NMR and ee value was obtained by HPLC. General Procedure for Fluorescence Titration: The titration experiments were carried out by adding 30.0 uL solution of substrates (1.0 × 10-3 mol/L) in CH2Cl2 to a solution of 1Mn, 1Cr, Mn(Me2L)Cl or Cr(Me2L)Cl (1.0 × 10-5 mol/L) in 3.0 mL CH2Cl2 every 5 minutes. The excitation wavelength is 225 nm and the slit width is set as 5 nm/5 nm.

ASSOCIATED CONTENT Supporting Information. Experimental procedures and characterization data. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected] Notes § J.J, and C.T contributed equally.

ACKNOWLEDGMENTS This work was financially supported by the National Science Foundation of China (Grants 21431004, 21522104 and 21620102001), the National Key Basic Research Program of China (Grants 2014CB932102 and 2016YFA0203400), Key Project of Basic Research of Shanghai (17JC1403100), and the Shanghai “Eastern Scholar” Program.

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