Saccharide-Functionalized Organoplatinum(II) Metallacycles

Communication pubs.acs.org/Organometallics

Saccharide-Functionalized Organoplatinum(II) Metallacycles Fengyan Zhou,*,†,‡ Shijun Li,*,‡,§ Timothy R. Cook,‡ Zuoli He,‡ and Peter J. Stang*,‡ †

College of Material Chemistry and Chemical Engineering, Zaozhuang University, Zaozhuang 277160, People’s Republic of China Department of Chemistry, University of Utah, 315 South 1400 East, Room 2020, Salt Lake City, Utah 84112, United States § College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, People’s Republic of China ‡

S Supporting Information *

ABSTRACT: Coordination-driven self-assembly can be used to construct metallacycles decorated with saccharide functionalities by combining organoplatinum acceptor building blocks with glycosylated dipyridyl donors. We describe here the synthesis of a suite of donors encoded with 120° directionality. The 1,3-bis(pyridin-4-ylethynyl)benzene cores contain one of four pendant saccharide groups, resulting in a glucose-, galactose-, mannose-, and lactose-variant. The angularity of these donors makes them suitable for the self-assembly of [2 + 2] rhomboids and [3 + 3] hexagons containing two and three saccharide groups on combination with a 60 or 120° acceptor, respectively. The synthesis and characterization of eight such metallacycles are described, supported by multinuclear NMR and electrospray mass spectrometry data that confirm clean, highly symmetric products with the expected stoichiometries of formation. This work illustrates the use of coordination-driven selfassembly to obtain nanoscopic metallacycles with biologically relevant functionalities in high yields and facile synthetic methods.

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coordination-driven self-assembly. This subset of supramolecular chemistry has been used as an efficient way to construct nanoscopic 2D metallacycles and 3D cages over the past two decades.10 One method to obtain functionalized products is to use precursor molecules with pendant groups that do not interfere with the self-assembly process.11 The tunability and modularity associated with the resultant supramolecular coordination complexes has enabled a range of applications in host−guest chemistry,12 catalysis,13 biological engineering,14 amphiphilic self-assembly,15 etc. Herein, we apply the methods of coordination-driven selfassembly toward the formation of saccharide-functionalized [2 + 2] rhomboids and [3 + 3] hexagons. These metallacycles contain two and three pendant sugars, respectively. The functionality is achieved via the pre-self-assembly modification of a hydroxy-functionalized 1,3-bis(pyridin-4-ylethynyl)benzene ligand, a common 120° donor motif in the library of building blocks for self-assembly. After glycosylation with one of four saccharides, glucose, galactose, mannose, and lactose, the donors can be combined with suitable acceptors to induce self-assembly. The saccharide-functionalized 120° dipyridyl donors (6a−d) were synthesized in a six-step pathway starting from commercially available 3,5-dibromophenol (1; Scheme 1). After acylation of 1, a palladium-catalyzed Sonogashira reaction delivered a TMS-protected acetylene (3) in 82% isolated yield.

arbohydrates, which often exist on cell surfaces, play an important functional role in different biological processes, including the transfer of information, energy, and materials.1 Saccharide functionalities are important components of the cell membrane, occurring as components of glycoproteins and glycolipid conjugates. These species are associated with the growth, development, differentiation, metabolism, identification, and immune response of cells. The molecular interactions at the heart of these processes tend to occur not at monosaccharide sites, but rather at sugar cluster binding sites on protein surfaces.2,3 The biological relevance of saccharide groups underpins their use in therapeutic strategies. For example, drugs can be modified by glycosylation to improve compatibility with the biological milieu, reducing general toxicity and/or enhancing bioavailability.4 In light of this, efforts have been made to synthesize sugar clusters to study how related oligosaccharides work in the aforementioned processes. This has led to the development of synthetic routes to and subsequent studies of glycosylated molecules and macromolecules, including glycopeptides,5 glycopolymers,6 glycodendrimers,7 and glycoliposomes and synthetic glycolipids.8 These examples motivate the recent but rare examples of well-defined multisaccharide ensembles.9 Supramolecular self-assembly is a common method by which both biological and abiological macromolecules are made, wherein precursor building blocks self-organize via intermolecular interactions, oftentimes delivering a complex final structure held together by relatively simple noncovalent interactions. When these interactions involve the spontaneous formation of metal−ligand bonds, the process is called © XXXX American Chemical Society

Received: October 13, 2014

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the saccharide-functionalized assemblies 9a−d revealed similar features (Figure 1 and Figures S25−S32 (Supporting

Scheme 1. Synthesis of Saccharide-Functionalized 120° Dipyridyl Donors 6a−d

Figure 1. 31P{1H} NMR spectra (room temperature, 121.4 MHz) of (a) 7, (b) 9a, (c) 9b, (d) 9c, and (e) 9d in methanol-d4.

Information)) that are consistent with the formation of discrete, highly symmetric species. The 31P{1H} NMR spectra of 9a−d show sharp singlets at ∼14.8 ppm with concomitant 195 Pt satellites, indicative of a single phosphorus environment, as expected, given the symmetry of the rhomboid metallacycles (Figure 1). The peak of 9a, for example, shifted upfield relative to that of 7, from 7.9 to 14.8 ppm. In the 1H NMR spectrum of each assembly (Figures S26, S28, S30, and S32), downfield shifts of the α- and β-pyridyl protons relative to those of ligands 6a−d were observed. It is worth noting that the α- and βpyridyl protons are split into two sets of two doublets upon coordination (Figures S26, S28, S30, and S32). For example, the Hα proton peaks of ligand 6a, which appear at 8.57 ppm (Figure S17 (Supporting Information)), are split into two doublets at 9.01 and 8.93 ppm on 9a (Figure S26). Similarly, the Hβ proton peaks of 7 (δ 7.55 ppm) (Figure S17) are also split into two doublets at 7.96 and 7.94 ppm (Figure S26). The spectra of 9b−d also showed splitting behaviors similar to those of 9a (Figures S28, S30, and S32). The stoichiometries of formation of 9a−d were supported by electrospray ionization time-of-flight mass spectrometry (ESITOF-MS). In the mass spectrum of 9a, two peaks were observed that were consistent with the [2 + 2] structural assignment (Figure S41 (Supporting Information)), including those which corresponded to an intact assembly with charge states resulting from the loss of triflate counterions (m/z 1646.39 for [M − 2OTf]2+ (Figure 2a) and m/z 1047.95 for [M − 3OTf]3+ (Figure S41)). For 9b, two peaks were found at m/z 1646.39, corresponding to [M − 2OTf]2+ (Figure S42 (Supporting Information)) and m/z 1047.95, corresponding to [M − 3OTf]3+ (Figure 2b). Similarly, two peaks were found for 9c (Figure S43 (Supporting Information)) at m/z 1646.40, corresponding to [M − 2OTf]2+ (Figure 2c), and m/z 1047.95,

Subsequent desilylation and hydrolysis (94% isolated yield) furnished 4, which was treated with four different glucosyl donors in a Lewis acid catalyzed glycosylation to afford the 3,5bis(ethynyl)phenolic glucoside precursors 4a−d in high yields. The pyridyl donors were then installed via a second Sonogashira coupling step to afford 5a−d with reasonable yields (47−52%). The final step, hydrolysis of the acetyl groups to generate the glucose-, galactose-, mannose-, and lactosefunctionalized 120° building blocks 6a−d, occurred with 85− 92% yields. The donors 6a−d were subsequently used in the selfassembly of saccharide-functionalized rhomboids and hexagons by mixing them with either a 60° (7) or 120° (8) organoplatinum(II) acceptor. When 6a−d were combined with 7 in MeOH-d6 at 60 °C for 8 h in a 1:1 ratio, a [2 + 2] self-assembly occurred, resulting in the formation of rhomboidal metallacycles 9a−d (Scheme 2). Multinuclear NMR (1H and 31P{1H}) analyses of solutions of Scheme 2. Self-Assembly of Rhomboidal Di-Glycosyl Derivatives 9a−d and Hexagonal Tri-Glycosyl Derivatives 10a−d

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Figure 3. 31P{1H} NMR spectra (room temperature, 121.4 MHz) of (a) 8, (b) 10a, (c) 10b, (d) 10c, and (e) 10d in methanol-d4. Figure 2. Experimental (red) and calculated (blue) ESI-TOF-MS spectra of 9a [M − 2OTf]2+ (a), 9b [M − 2OTf]2+ (b), 9c [M − 2OTf]2+ (c), and 9d [M − 2OTf]2+ (d).

Information)). These peaks were isotopically resolved and were consistent with their theoretical distributions. In conclusion, we have demonstrated the use of coordination-driven self-assembly to obtain multifunctionalized rhomboids and hexagons decorated with one of four saccharide groups. This functionality was achieved via the pre-selfassembly modification of a 120° donor by glycosylation reactions, thereby expanding the molecular library of building blocks for directional bonding. Given the importance of saccharide-functionalized molecules and macromolecules in biological processes, these donors provide a facile route to form well-defined supramolecular coordination complexes that may serve as functional models for polysaccharide ensembles. The pendant functionalities do not inhibit the self-assembly process, as all eight metallacycles were obtained in high yields without the formation of polymeric or oligomeric side products. Continuing efforts to investigate the biological applications of such metallacycles, expanding this strategy to 3D metallacages, and exploring the possibility of hierarchical self-assembly schemes are underway.

corresponding to [M − 3OTf]3+ (Figure S43 (Supporting Information)). For 9d, one peak was found (Figure S44 (Supporting Information)) at m/z 1088.44, corresponding to [M − 2OTf]2+ (Figure 2d). All of these peaks were isotopically resolved and agreed very well with their calculated theoretical distributions. The hexagonal metallacycles were prepared in a fashion analogous to that for the rhomboids, with donors 6a−d combined in an equimolar amount with a 120° acceptor, 8, in methanol-d4 overnight (Scheme 2). Multinuclear NMR (1H and 31P{1H}) analyses of solutions of the resultant hexagons, 10a−d, indicated the formation of discrete, highly symmetric species. The 31P{1H} spectra of these assemblies showed single peaks at 17.3−17.4 ppm (Figure 3), which were shifted upfield from that of 8 by ∼4.0 ppm. In the 1H NMR spectrum of each assembly, the hydrogen atom signals of the pyridine rings exhibited small downfield shifts (α-H, 0.23−0.25 ppm; β-H, 0.25−0.27 ppm) upon coordination. The structures of the hexagonal metalloglycosides 10a−d were further confirmed by ESI-TOF-MS spectrometry. In the ESI mass spectrum of 10a, a peak attributable to the loss of triflate counterions, [M − 3OTf]3+ (m/z 1594.38, Figure S45 (Supporting Information)), where M represents the intact assembly, was observed. The ESI mass spectrum of galactoside assembly 10b showed two charged states at m/z 1594.38 and 1158.31 (Figure S46 (Supporting Information)), corresponding to [M − 3OTf]3+ and [M − 4OTf]4+ species, respectively. The ESI mass spectrum of 10c showed three charged states at m/z 1594.39, 1158.31, and 896.85 (Figure S47 (Supporting Information)) corresponding to [M − 3OTf]3+, [M − 4OTf]4+, and [M − 5OTf]5+, respectively. For 10d, a peak at m/z 994.28 [M − 5OTf]5+ was found (Figure S48 (Supporting

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ASSOCIATED CONTENT

S Supporting Information *

Text and figures giving synthetic procedures and characterization data (1H NMR, 31P{1H} NMR, ESI-MS) for the metallacycles. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for F.Z.: [email protected]. *E-mail for S.L.: [email protected]. *E-mail for P.J.S.: [email protected]. Notes

The authors declare no competing financial interest. C

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ACKNOWLEDGMENTS P.J.S. thanks the NSF (Grant 1212799) for financial support. F.Z. thanks the Natural Science Foundation of Shandong Province (ZR2010BL005) and the Shandong Provincial Science and Technology Funds (2011GSF11818). S.L. thanks the National Natural Science Foundation of China (21072039 and 91127010), the Program for Changjiang Scholars and Innovative Research Team in Chinese University (IRT 1231), the Zhejiang Provincial Natural Science Foundation of China (LZ13B030001), and the Special Funds for Key Innovation Team of Zhejiang Province (2010R50017).

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