Permeable Self-Assembled Molecular Containers for Catalyst Isolation

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Permeable Self-Assembled Molecular Containers for Catalyst Isolation Enabling Two-Step Cascade Reactions Yoshihiro Ueda, Hiroaki Ito, Daishi Fujita, and Makoto Fujita* Department of Applied Chemistry, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan S Supporting Information *

ABSTRACT: Establishment of a general one-pot cascade reaction protocol would dramatically reduce the effort of multistep organic synthesis. We demonstrate that the unique structure of M12L24 self-assembled complexes gives them the potential to serve as catalyst carriers for enabling continuous chemical transformations. A stereoselective cascade reaction (allylic oxidation followed by Diels−Alder cyclization) with two intrinsically incompatible catalysts was demonstrated. Our system is advantageous in terms of availability, scalability, and predictability.

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deally, future laboratory organic synthesis should be a simple one-pot/one-step procedure.1,2 However, almost all synthetic strategies today require a sequence of multiple and stepwise chemical transformations. A methodology that enables continuous chemical transformation in a manner reminiscent of biology’s metabolic systems is one promising approach toward achieving this goal.3,4 One important concept deeply related to mimicking metabolism is catalytic site-isolation.5 Enzymes naturally possess this attribute by having the active catalytic site sterically isolated inside the proteins themselves. There have been several developments in the techniques required for synthetic site-isolation of catalysts, which include the employment of semipermeable films,6 multiphase systems,7−11 soluble polymers/dendrimers12−15 and supramolecular16 architectures acting as the catalyst carrier. Although these techniques were successfully applied, only limited transformations were reported and special instruments or elaborate procedures were necessary. Also, site-isolated catalysts often show decreased reactivity and selectivity compared to their nonisolated counterparts as a result of the difference in microenvironments surrounding the catalysts.17 Here, we report a stereocontrolled cascade reaction exploiting the unique structure of a self-assembled molecular capsule as the catalyst carrier for site-isolation (Figure 1). The two different catalysts employed in the synthesis are TEMPO for an oxidation reaction and MacMillan’s catalyst for Diels− Alder (DA) chemistry. Without an appropriate carrier, the DA catalyst is promptly oxidized by TEMPO, rendering each incompatible with the other. By encapsulating each of them separately within the cavity of an M12L24-type molecular capsule, the anticipated cascade reaction proceeded smoothly, while the asymmetric catalyst retained its stereoselectivity, an attribute of the mechanism which was highly reproducible. © 2017 American Chemical Society

Figure 1. Site-isolation strategy for a new cascade reaction. TEMPO and MacMillan’s catalyst isolated in self-assembled M12L24 spherical complexes work independently and side-by-side, whereas they are incompatible when free in solution.

The M12L24 molecular capsule 2 is a palladium metal complex quantitatively self-assembled from 12 Pd(II) ions (M) and 24 bent, ditopic ligands (1).18 This sphere-like structure possesses a rigid framework both with a cavity large enough to house tens of catalytic centers, and many apertures that are permeable to small molecule substrates. As the capsule formation is based on a high-yielding self-assembly mechanism, we anticipated that encapsulation of the catalysts could be achieved by simply covalently prelinking the catalyst of interest to ligand 1. In the past, this strategy has worked to afford a variety of capsules with different functional groups19,20 and catalysts.21,22 Also, the M12L24 complexes once formed are remarkably stable in solution and ligand exchange occurs only very slowly over weeks or months.23 Thus, we envisaged at the outset that two different M12L24 complexes should maintain their separate catalytic identities, preventing any mutual inhibition of their functions brought about by direct contact. In order to demonstrate this strategy of catalytic siteisolation, we chose a widely used oxidation catalyst, TEMPO,24 and the chiral MacMillan’s catalyst, which promotes various carbonyl-related stereoselective chemical transformations.25,26 These catalysts are typically incompatible in a two-step/one-pot synthesis, because the oxoammonium species generated from TEMPO oxidizes the free amines of Received: March 20, 2017 Published: April 12, 2017 6090

DOI: 10.1021/jacs.7b02745 J. Am. Chem. Soc. 2017, 139, 6090−6093

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Figure 2. Oxidation-sphere 2a and Diels−Alder-sphere 2b. (a−c) NMR spectra measured at 300 K in CD3NO2: (a) 1H NMR of ligand 1b; (b) 1 H NMR of sphere 2b; (c) 1H DOSY NMR of sphere 2b. (d,e) CSI-MS spectra with assignment of the observed species: (d) sphere 2a and (e) sphere 2b.

MacMillan’s catalyst, rendering it inactive.27 To solve this problem, we hypothesized that the poisoning of MacMillan’s catalyst by TEMPO could be prevented by isolating each separately in the self-assembled molecular cages, affording a novel oxidation and asymmetric DA28 cascade reaction in the same solution. Ligands tethered with TEMPO (1a) and MacMillan’s catalyst (1b) were readily synthesized (see Supporting Information). Each ligand was then self-assembled individually to M12L24 complex 2a and 2b, respectively on treatment with [Pd(CH3CN)4](BF4)2 in CD3NO2 (room temperature for 30 min). We used NMR spectroscopy to monitor the formation of the M12L24 complexes, structures of which were then confirmed by mass spectrometry. In the 1H NMR spectrum of 2b, notable downfield shifts of the pyridine protons, particularly the α proton (Δδ = 0.53 ppm), were observed. The shifts are a result of the coordination bond between the pyridyl groups and PdII ions. The signal broadening is indicative of the formation of a huge molecular structure that tumbles slowly on the NMR time scale (Figure 2a,b). Diffusion-ordered NMR spectroscopy (DOSY) also supported the quantitative formation of a large structure by the observation of a single band at log D = −10.20 (Figure 2c). In contrast, no significant 1H NMR signal was detected for 2a due to the paramagnetic shifts derived from the nitroxyl radical (Figure 3c and 3d). Nevertheless, cold-spray ionization mass spectrometry (CSI-MS)29 provided evidence for the formation of 2a as well as 2b. The formation of 2a was successfully confirmed by detection of prominent peaks for [M − x(BF4)]x+ (x = 11−15) (Figure 2d). The highresolution mass spectra allowed the determination of the molecular weight of 2a (15556.28 Da). The elemental composition of sphere 2b was also determined (Figure 2e). We first evaluated the oxidative catalytic activity of 2a by using the simple alcohol 6 as a model substrate (Figure 3). In the presence of 10/24 mol% of 2a (= 10 mol% based on TEMPO) and 1.2 equiv of PhI(OAc)2 as a co-oxidant, the oxidation reaction of 6 was completed within 1 h to furnish aldehyde 7 in 96% yield (Figure 3a). In addition, kinetic monitoring of the oxidation reaction revealed that TEMPO

Figure 3. Oxidation reaction profile catalyzed by sphere 2a. (a) Oxidation reaction of 6 in the presence of 2a (10/24 mol %) and PhI(OAc)2 (1.2 equiv) in CD3NO2 at room temperature. (b) Molecular modeling of sphere 2a. (c−e) 1H NMR spectra measured at 300 K in CD3NO2: (c) ligand 1a; (d) sphere 2a; (e) reaction solution after 2 h.

retained the same level of reactivity as that of the nonisolated catalyst (TOFini of 2a = 23.6 h−1, TOFini of TEMPO = 11.2 h−1, see Supporting Information). We propose that the large, several nanometer-sized, interior space of the M12L24 cavity (Figure 3b) allows the catalyst, substrate and solvent molecules to behave as if in bulk solution.30 Notably, the catalyst sphere 2a is stable, and maintains its structure during the course of the catalytic reaction and after its completion; 6091

DOI: 10.1021/jacs.7b02745 J. Am. Chem. Soc. 2017, 139, 6090−6093

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Journal of the American Chemical Society by comparing the 1H NMR spectra of 1a, 2a and the reaction solution, no signals for the dissociated ligand 1a were detected in the reaction mixture (Figure 3c−e). We then applied our new system to the designed oxidation and subsequent stereoselective DA cascade reaction (Scheme 1). To a premixed solution of 2a and 2b were added

Several control experiments verified that the self-assembled catalyst carriers indeed served as vehicles for site-isolation, and were thus indispensable for the cascade reaction (Table 1). When TEMPO was used instead of sphere 2a, only oxidation to 4 proceeded, and the yield of 5 dropped to 4% (entry 2). Similarly, when MacMillan’s catalyst was used instead of sphere 2b, Diels−Alder product 5 was obtained in only 3% yield (entry 3). Simple combination of TEMPO and MacMillan’s catalyst also yielded only a trace amount of 5 but provided aldehyde 4 in 90% yield (entry 4). These experiments support the claim that MacMillan’s catalyst is incompatible with the conditions for TEMPO-catalyzed oxidation reaction. In addition, the presence of empty sphere 2c assembled from [Pd(CH3CN)4](BF4)2 and ligand 1c did not improve the yield of 5 (entry 5); apparently, neither the framework alone nor its components participated directly in the catalytic process. Only the combined use of both of the caged catalysts (2a and 2b) allowed the desired cascade reaction to proceed. In conclusion, we demonstrated a new nanotechnological development for catalyst isolation by structures made possible through molecular self-assembly. M12L24 spherical frameworks functioned as a stable containers for catalysts, which like an enzyme, protects the catalytically active site from unwanted reactivity. This isolation enables the one-pot catalysis of two and potentially more transformations, when without such isolation, the two catalysts normally would be incompatible. The outcome of such advantages is, for instance, the novel cascade reaction designed and described herein. The key to this site-isolation strategy is the M12L24 molecular structure itself, which possesses the unique properties of having substantial inner space sterically insulated by a rigid selfassembled shell, while at the same time allowing for small molecular permeability by virtue of its numerous apertures. These catalysts protected by M12L24 complexes are advantageous for organic synthesis, because of their easy preparation and that their catalytic reactivity/selectivity is comparable to the free, nonisolated catalysts in solution. Such useful properties have the potential to allow chemists to easily predict and therefore design one-pot chemical cascade reactions based on known catalytic transformations, bringing us one step closer to the goal of realizing one-pot multistep syntheses.

Scheme 1. Oxidation and Asymmetric DA Cascade Reaction Catalyzed by 2a and 2b

PhI(OAc)2, trifluoroacetic acid, and allyl alcohol 3. First, substrate 3 was oxidized to the α,β-unsaturated aldehyde 4, followed by the intramolecular DA cyclization. This two-step cascade successfully converted 3 to the desired bicyclic compound 5 with four adjacent stereogenic centers in high enantio- and diastereoselectivity (93% ee); this experimental result indicated that both catalysts worked cooperatively as designed. It is also noteworthy that stereoselectivity (both enantio- and diastereoselectivity) in the DA reaction is the same as the reported value in the case of the non-site-isolated system (93% ee).28 This comparable reactivity provides evidence that this strategy of catalytic site-isolation holds promise for fine chemical synthesis by means of one-pot cascade reactions.

Table 1. Site-Isolation Effects on Yields for Catalysts Encapsulated within M12L24 Spherical Complexes

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DOI: 10.1021/jacs.7b02745 J. Am. Chem. Soc. 2017, 139, 6090−6093

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(24) Vogler, T.; Studer, A. Synthesis 2008, 1979. (25) Lelais, G.; MacMillan, D. Aldrichimica Acta 2006, 39, 79. (26) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2012, 475, 183. (27) Sasano, Y.; Nagasawa, S.; Yamazaki, M.; Shibuya, M.; Park, J.; Iwabuchi, Y. Angew. Chem., Int. Ed. 2014, 53, 3236 and references cited therein. (28) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616. (29) Yamaguchi, K. J. Mass Spectrom. 2003, 38, 473. (30) Sato, S.; Iida, J.; Suzuki, K.; Kawano, M.; Ozeki, T.; Fujita, M. Science 2006, 313, 1273.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b02745. Additional experiments, experimental procedures, and physical properties (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Daishi Fujita: 0000-0001-5726-0645 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Grants-in-Aid for Specially Promoted Research (24000009) and JST-ACCEL. REFERENCES

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DOI: 10.1021/jacs.7b02745 J. Am. Chem. Soc. 2017, 139, 6090−6093