Boosting Enantioselectivity of Chiral Molecular Catalysts with Supramolecular Metal–Organic Cages

Open AccessCCS ChemistryCOMMUNICATION1 Apr 2022Boosting Enantioselectivity of Chiral Molecular Catalysts with Supramolecular Metal–Organic Cages Dandan Chu, Wei Gong, Hong Jiang, Xianhui Tang, Yong Cui and Yan Liu Dandan Chu School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author , Wei Gong School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author , Hong Jiang School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author , Xianhui Tang School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author , Yong Cui School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author and Yan Liu *Corresponding author: E-mail Address: [email protected] School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202100847 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The search for new methodologies to tune and control the enantioselectivities of molecular catalysts is of great importance in the field of asymmetric catalysis. Here, we have illustrated that chiral molecular catalysts can be boosted from very low enantioselectivity to high enantioselectivity when installed in supramolecular metal–organic cages. By deliberately designing two optically active 1,1′-spirobiindane-7,7′-diol (SPINOL)-based dipyridine linkers, we synthesized two chiral Pd3 L6 cages featuring chiral dihydroxyl or dimethoxymethyl auxiliaries in the nanosized cavities. After treatment with metal ions, the cage featuring dihydroxyl groups could serve as efficient catalysts for asymmetric conjugate addition of styrylboronic acids to α,β-enones to produce γ,δ-unsaturated ketone and the asymmetric addition of diethylzinc to aldehydes to afford secondary alcohols. While the molecular SPINOL display very low enantioselectivity, restriction of its freedom in the cages led to 91−99.6% and 80−99.9% enantiomeric excess (ee) of products, respectively, which were increased by up to 35% and 78% ee, compared with the molecular control. Thus, our present work paves a way of utilizing supramolecular porous assemblies to manipulate the enantioselectivities of molecular catalysts. Download figure Download PowerPoint Introduction Chirality is a critical topic in pharmaceuticals and fine chemical products, as each enantiomer of a molecule could elicit different effects in the body;1,2 thus, the development of new methods for the preparation of single enantiomeric compounds has become an increasingly important issue in chemistry and biochemistry.3 The utilization of chiral molecular metal–organic complexes as homogeneous catalysts has been well-established as a reliable and efficient strategy for the catalytic synthesis of enantiopure compounds.4–6 Importantly, due to the significant impact on substrate activation and structures of intermediates and transition states, varying electronic and steric properties of molecular catalysts has been widely used to tailor and tune stereoselectivity in asymmetric catalysis.7,8 In this work, we demonstrate that porous cages could be a promising platform to tailor and enhance enantioselectivity of molecular catalysts, as exemplified by the axial chiral 1,1′-spirobiindane-7,7′-diol (SPINOL), which is one of the most important privileged chiral ligands/catalysts for organic synthesis,9,10 but their unmodified skeletons generally exhibit low enantioselectivity.11,12 Besides, this method also allows the ease of separation and recycling of homogeneous catalysts. Coordination cages with well-defined cavities have garnered significant attention due to their wide-ranging applications in molecular recognition,13,14 stabilization of reactive species,15,16 catalysis,17–20 structure elucidation,21,22 drug delivery,23,24 and so on.25–29 Rational combination of metal ions and bridging ligands permits the generation of unique internal cavities, in which the guest molecules often experience conformational restriction, resulting in significant alteration of chemical behaviors.30–32 Of special interest are cages with specified stereochemistry, which can be obtained by utilizing enantiopure organic bridging ligands or using optically active auxiliaries to control the stereochemistry at the metal centers in general.33–35 The chirotopic internal void enables enantioselective guest recognition and sensing, as well as providing a chiral microenvironment for asymmetric transformations.36–39 As reported, metal–organic cages can serve as efficient chiral supramolecular catalysts for several useful organic transformations, including olefin photoaddition,40 Aza-Cope rearrangements,41 carbonyl-ene cyclizations,42 hydroformylation of styrenes,43 oxidative kinetic resolution of secondary alcohols,44 and epoxidation of olefins.45 Furthermore, it has been demonstrated that multiple catalytically active sites can be incorporated within a cage to enable efficient asymmetric sequential catalysis.45 Nonetheless, examples of enantioselective transformations carried out in cages are still limited, with an even smaller number displaying satisfactory stereoselectivity due to the intrinsic difficulties in controlling stereoinduction. By deliberately designing enantiopure 6,6′-dipyridyl-functionalized SPINOL ligands, here, we report the synthesis of two new Pd3 L6 cages decorated with chiral dihydroxyl or dimethoxymethyl auxiliaries (Scheme 1). The cage decorated with dihydroxyl groups could serve as a supramolecular catalyst for asymmetric conjugate addition of styrylboronic acids to α,β-enones and the addition of diethylzinc to aldehydes, and the chiral induction is greatly enhanced, compared with the nonimmobilized analogue. Scheme 1 | Synthesis of Pd3L6-type cages 1 and 2. Download figure Download PowerPoint Results and Discussion The ligand L1 was synthesized through three steps from enantiopure (R)-/(S)-SPINOL in 60% overall yields. L2 was obtained in 98% yield by deprotecting the phenolic methoxymethyl ether of L1 using hydrochloric acid ( Supporting Information Figure S9). Heating a 2:1 mixture of L and Pd(CH3CN)4(BF4)2 in CH3CN at 60 °C for 48 h afforded complexes [Pd3( L1)6]·6BF4·8H2O ( 1) and [Pd3( L2)6]·6BF4·6CH3CN·10CH3COCH3 ( 2) in good yields. Pale yellow crystals of 1 and 2 suitable for crystallographic analysis were successfully obtained from the CH3CN/xylene/acetone solution of 1 by slow evaporation or by diffusion of acetone vapor into the CH3CN/H2O solution of 2 at room temperature. The two complexes were soluble in common organic solvents, including MeOH, dimethyl sulfoxide (DMSO), and CH3CN, and were characterized by a variety of techniques, including nuclear magnetic resonance (NMR), electrospray ionization mass spectrometry (ESI-MS), single-crystal X-ray diffraction (SC-XRD), elemental analysis, infrared (IR) ( Supporting Information Figure S6), circular dichroism (CD), and optical rotation spectroscopy. The 1H NMR spectra of 1 and 2 displayed only one set of ligand resonances in solution, and the sharp signals of the two complexes indicated the formation of discrete and highly symmetric assemblies (Figure 1a). The signals corresponding to pyridyl moiety protons exhibited significant downfield shifts (Ha-Py, Δδ = 0.13 ppm for 1, and 0.08 ppm for 2; Hb-Py, Δδ = 0.19 ppm for 1, and 0.29 ppm for 2), probably resulting from the loss of electron density upon coordination of the pyridine nitrogen with the metal center. Complementary evidence for the formation of the two aggregates was provided by high-resolution ESI-MS, which displayed intense peaks corresponding to various [Pd3 L6 + nBF4](6-n)+. In the mass spectrum of 1, peaks at m/z 865.0167, 1182.3572, and 1817.0464 corresponding to [Pd3( L1)6 + 2BF4]4+, [Pd3( L1)6 + 3BF4]3+, and [Pd3( L1)6 + 4BF4]2+ were observed (Figure 1b). Clean mass spectrum of 2 gave intense signals of [Pd3( L2)6 + BF4]5+, [Pd3( L2)6 + 2BF4]4+, [Pd3( L2)6 + 3BF4]3+, and [Pd3( L2)6 + 4BF4]2+ at m/z 568.9486, 732.9371, 1005.9168, and 1552.3796, respectively (Figure 1c). In all cases, experimental isotopic patterns were found to be in good agreement with the calculated distributions. Figure 1 | (a) 1H NMR spectra of 1, L1, 2, and L2 in CD3CN (400 MHz, 298 K). (b and c) ESI-MS spectra of 1 and 2. Download figure Download PowerPoint SC-XRD study unambiguously revealed the formation of chiral trimetallic coordination cages. Cage 1 crystallized in the chiral trigonal space group P3121 with a whole formula in the asymmetric unit ( Supporting Information Tables S1 and S2). Each Pd ion adopted a nearly idealized square-planar geometry defined by four pyridyl N atoms from four ligands. Each SPINOL ligand possessed the same handedness of chirality and coordinated to two Pd atoms through its two pyridyl groups with an average metal–metal separation of approximately 10.3 Å. The bite angle of the SPINOL skeleton in 1 is calculated to be 61.8(2)°. Six L1 ligands doubly bridge each edge of the Pd3 triangular core to afford a Pd3 L6-type cationic cage, the positive charges of which were balanced by BF4− anions (Figures 2a and 2b). The dimension of the cage is ∼23.0 × 20.8 × 17.6 Å3, and the internal cavity volume is about 902.4 Å3 ( Supporting Information Figure S4a). Highly directional supramolecular interactions direct the association of such cages forming a three-dimensional (3D) porous network: (1) CH···π interactions between the cyclopentyl group and pyridyl ring of adjacent cages (2.755–2.899 Å); (2) CH···O interactions between methoxymethyl (MOM) group and neighboring ligand skeleton (MOM, cyclopentyl, or phenyl group) of different cages (2.230–2.765 Å) ( Supporting Information Figures S1a and S2). PLATON calculations (∼ https://www.platonsoft.nl/spek/xraysoft/) indicate that 1 contains ∼51.4% void space accessible to guest molecules.46 Cage 2 crystallized in the chiral monoclinic space group P21 with a whole formula in the asymmetric unit ( Supporting Information Tables S1 and S3). It had a similar Pd3 L6 structure to 1 with an inner cavity of ∼1323.4 Å3, and the six pairs of hydroxyl groups of SPINOL moieties were oriented toward the internal cavity (Figures 2c and 2d and Supporting Information Figure S4b). Each cage interacted with neighboring five cages through CH···π interactions between the cyclopentyl groups and phenyl rings of adjacent cages (2.753–3.040 Å) to generate an extended 3D porous supramolecular framework with ∼71.6% free volume, occupied by guest molecules ( Supporting Information Figures S1b and S3).46 Figure 2 | Single-crystal X-ray structures of (a) 1 and (c) 2 and the space-filling modes of (b) 1 and (d) 2. Atoms: Pd, green; N, light blue; C, gray; O, red. The hydrogen atoms were omitted for clarity, and the cavities were highlighted by spheres. Download figure Download PowerPoint Thermogravimetric analysis (TGA) revealed that the two cage materials started to decompose at ∼300 °C ( Supporting Information Figure S5). The porosity of 1 and 2 was supported by CO2 adsorption isotherms at 195 K, and the Brunauer–Emmett–Teller (BET) surface areas were calculated to be 120 and 137 m2/g, respectively ( Supporting Information Figure S8). The obvious hysteresis of desorption in the isotherms, presumably, was caused by the interstices between cages. The phase purity of the bulk samples was established by comparing their simulated and observed powder X-ray diffraction (PXRD) patterns. The slight discrepancy between the simulated and observed PXRD patterns of 1 probably resulted from framework distortion caused by partial loss of guest molecules of the samples after being exposed to air ( Supporting Information Figure S7). Compared with the corresponding ligands L, the absorption maxima of the two cages were bathochromically shifted to ∼30 nm due to the incorporation of multiple ligands in one coordination cage structure ( Supporting Information Figure S10). CD spectra of the cages made from (S)- and (R)-enantiomers of ligands L were mirror images of each other, indicative of their enantiomeric nature ( Supporting Information Figure S11). The optical rotation analysis gave the molar optical rotation (φ) values as −90 and −2509 deg cm3 dm−1 mol−1 for (R)- L1 and (R)- 1, −79, and −1904 deg cm3 dm−1 mol−1 for (R)- L2 and (R)- 2, respectively. Thus, the cage materials have optical rotation values per mole of ∼24–28 times that of the ligands (∼4–4.7 times per ligand); that is, chiral amplification occurred during the self-assembly processes. The presence of chiral cavities and available chiral dihydroxyl groups of SPINOL in 2 promoted the exploration of enantioselective catalysis. Initial studies identified 2 as an efficient supramolecular catalyst for asymmetric conjugate addition of boronic acids to enones, an extremely valuable synthetic procedure for preparing enantiomerically pure chiral compounds.47,48 The reaction of 4-hydroxychalcone with trans-styrylboronic acid was selected as a model reaction. After optimizing the reaction conditions, including solvent, temperature, and the molar ratio of the catalytic components ( Supporting Information Table S4), the reaction was conducted with 5 mol % loading of (R)- 2 in dry acetonitrile under N2 atmosphere at 80 °C. The addition of 4 Å molecular sieves and Mg(OEt)2 (40 mol %) as additives was critical to accelerate the reaction; otherwise, the yields were low.48 The control experiment showed that no product could be obtained with a model compound [Pd(Py)4](BF4)2 as a catalyst, indicating that the Pd ion in the cage had no effect on increasing the conversion of the catalytic reaction. The arylvinylation of 4-hydroxychalcone afforded 25%, 27%, and 60% yields after 12, 24, and 48 h, respectively, and the desired product 5a was acquired in 92% yield and 87% enantiomeric excess (ee) after 72 h (Figure 3a). Figure 3 | (a) Kinetic results for asymmetric conjugate addition reaction of 4-hydroxychalcone and trans-styrylboronic acid with 5 mol % (R)-2 and related catalysts; (b) recycle results for (R)-2-catalyzed asymmetric conjugate addition of 4-hydroxychalcone with trans-styrylboronic acid. Download figure Download PowerPoint Subsequently, the scope and generality of the catalytic system were investigated under optimized conditions. As shown in Table 1, good to excellent yields and high enantioselectivities were obtained for the chalcone derivatives studied. The electronic nature or positions of the substituents have limited effects on the catalytic results, and the highest 99.6% ee was achieved when 2-hydroxychalcone was subjected to the reaction ( 5d). The trans-styrylboronic acid with 4-trifluoromethyl substituent could also undergo the desired transformation to afford the corresponding products with satisfactory yields (88–94%) and excellent enantioselectivities (91–99%; 5e– 5h). Notably, the afforded enantioselectivities were comparable with those of the most enantioselective homogeneous systems.47–50 Table 1 | Asymmetric Conjugate Addition of Substituted α,β-Enones and Styrylboronic Acids Catalyzed by (R)-2a aFor reaction details, see the experimental section in the Supporting Information; the data in blue are results catalyzed by (R)- L2; isolated yields; ee values are determined by high-performance liquid chromatography (HPLC). The activity of the ligand L2 was then studied to examine the confinement effect of the cage catalyst. With the same loading of SPINOL as the cage catalyst, L2 afforded the addition products in 65–90% ee and 67–91% isolated yields. Thus, the cage catalyst gave higher yields (enhance up to 20%) and ee values (enhance up to 35%) in producing 5a– 5h, compared with the molecular analogue. The kinetic study of conjugate addition of 4-hydroxychalcone with trans-styrylboronic acid revealed that incorporating SPINOL catalyst into a cage enhanced the enantioselectivities ( Supporting Information Figure S15). In the whole catalytic process, the ee values of the products generated by the cage were consistently higher than those by the ligand, whereas the yields were comparable with each other. To investigate the role of the cage cavity in catalysis, two sterically more demanding substrates bearing naphthyl and anthryl groups, respectively, were synthesized and subjected to conjugate addition reactions. The yields of the products catalyzed by cage 2 greatly depended on the substituent size, and the yield of the desired product steadily decreased ( 5i, 42%; 5j, trace amount) as the size of the substituent increased ( Supporting Information Figure S16). In contrast, the reaction catalyzed by the corresponding molecular catalyst was not affected by the substituent size ( 5i, 76%; 5j, 32%). The extremely low yields of cage catalysis were consistent with hindered access to the internal dihydroxy groups, indicating that the catalysis occurred predominantly within the inner cavities. The binding behavior of the cage with the substrate was studied by using the fluorescence titration technique. Upon gradual addition of 4-hydroxychalcone to the CH3CN solution of 2, the quenching of fluorescent emission band was observed, and the wavelength shift of fluorescence emission for 2 from 366 to 403 nm indicated the formation of host−guest complex (Figures 4a and 4b). The association constant (Ka) was estimated to be 24409 ± 991 M−1 based on the Stern–Volmer equation, much higher than the Ka of 7073 ± 167 M−1 between L2 and 4-hydroxychalcone ( Supporting Information Figure S13). In contrast, the target product was associated with the cage catalyst by weaker interactions with Ka of 2036 M−1 (Figures 4c and 4d). The substrate and product have different fluorescence-quenching effects on 2, both of which arose from the photoinduced electron transfer (PET) mechanism in the host–guest system. The static quenching proceeded through the formation of host–guest adducts by combining hydrogen-bonding with hydrophobic effects, suggested by consistent fluorescence lifetimes of 2 before and after addition of 4-hydroxychalcone and corresponding product, respectively (lifetime, τ0, 1.335 vs 1.334 ns; 1.335 vs 1.313 ns, Supporting Information Figure S14).35,51 The different Ka values suggested that 2 catalyzed the conjugate addition reaction as a turnover process based on the product released and the substrate uptake. Therefore, incorporating chiral molecular catalysts into the cage could create a confined microenvironment with multiple chiralities, responsible for the observed high enantioselectivity by generating additional asymmetric induction. Figure 4 | (a and c) Fluorescence quenching of (R)-2 upon titration with 4-hydroxychalcone and the product in CH3CN. (b and d) The Stern–Volmer plots. Download figure Download PowerPoint Upon completion of each round of catalysis, the cage catalyst could be recovered as precipitate by addition diethyl ether into the reaction and washed with diethyl ether several times, and repeatedly used with a slight decrease in yields and enantioselectivities (Figure 3b; 83–92% yields, and 98%, 96%, 95%, 94%, and 92% ee for runs 1–5, respectively) ( Supporting Information Table S5). The recovered cage catalyst remained structurally intact, as evidenced by UV–vis spectrometry, CD, and ESI-MS ( Supporting Information Figures S10–S12). We evaluated the contribution of –OH groups of SPINOL units in (R)- 2 to the above chiral catalysis process by conducting the reaction with (R)- 1 that contained MOM-protected SPINOL units. In contrast to 2, cage 1 could not catalyze the conjugate addition reaction under otherwise identical conditions. This result indicated that the chiral –OH group was crucial for the highly enantioselective catalysis, which could participate in the transesterification to form more reactive boronate to promote subsequent catalytic processes.47,52 Besides the asymmetric conjugate addition reaction, cage 2 was capable of catalyzing the addition of diethylzinc to aromatic aldehydes to produce enantiopure secondary alcohols after postsynthetic modification of the chiral dihydroxy groups with Ti(OiPr)4. The benzaldehyde reacted with diethylzinc in the presence of 10 mol % 2 in 1,2-dichloroethane (DCE) at −78 °C for 72 h to give 1-phenyl-1-propanol ( 7a) in 96% conversion with 96% ee. Then the reaction was explored further; benzaldehydes, either para- or ortho-substituted, were well tolerated, providing the corresponding products in good conversions (94–99%) and asymmetric induction (80–99.9%) (Table 2). The much higher enantioselectivities observed for 2 than those obtained by L2 further indicated the confinement effect of cage-based catalysis. Besides, several tests confirmed the aldehyde addition reaction was mainly performed in the cage cavity. The cage catalyst could also be recycled and reused with negligible loss of efficiency and enantioselectivity ( Supporting Information Table S6). Table 2 | Addition of Diethylzinc to Aromatic Aldehydes Catalyzed by (R)-2/Tia aFor reaction details, see the experimental section in the Supporting Information. The data in blue are results catalyzed by (R)- L2. The conversions are calculated by 1H NMR, and the ee values are determined by HPLC. Conclusion We have described the self-assembly of two nanosized chiral SPINOL-based metal–organic cages functionalized with pendant interior dihydroxyl or dimethoxymethyl groups. The cages were characterized by single-crystal X-ray diffraction, NMR, MS, elemental analysis, IR, CD, and optical rotation spectroscopy. Controlled assembly of chiral SPINOL into the cage enabled the low enantioselective diol, after treatment with Mg2+ or Ti4+ ions, to enantioselectively catalyze the conjugate addition of α,β-enones with styrylboronic acids or addition of diethylzinc to aromatic aldehydes to afford the targeted products with 91−99.6% ee and 80−99.9% ee, respectively. We presumed that the enhancement of stereoselectivity was due to the steric hindrance and confinement effect of the supramolecular porous cage. This work, thus, provides an interesting strategy to tailor the stereoselectivity of molecular catalysts and promises the further development of a variety of new supramolecular porous assemblies for enantioselective catalysis. Supporting Information Supporting Information is available and includes experimental procedures, synthesis, crystal data, and additional figures. Crystal structure data of cages 1 and 2 (CCDC: 2055203 and 2055204) have been deposited in the Cambridge Structural Database. Conflict of Interest There is no conflict of interest to report. Funding Information This work was supported by the National Natural Science Foundation of China (grant nos. 91956124, 21875136, 21620102001, and 91856204), the National Key Basic Research Program of China (grant no. 2016YFA0203400), Key Project of Basic Research of Shanghai (grant nos. 19JC1412600 and 18JC1413200), and Shanghai Rising-Star Program (grant no. 19QA1404300). 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