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Synthesis of Molecular trefoil Knots (31) by passive metal template RCM approach

Using the Alexander Briggs notation, the trefoil knot (31) is considered the simplest non-trivial knot and the most amenable to chemical synthesis. Many different synthetic approaches to prepare trefoil knots have been investigated. In particular, the passive metal template-directed methodology coupled with RCM has been successfully employed to mechanically restrict the relative positions of molecular components. Sauvage et al. reported a canonical example of the covalent post assembly modification by describing the preparation of the molecular trefoil knot 238 using olefin RCM reaction to capture the metal-assembled precursor. The dinuclear Cu(I) complex 237 was quantitatively prepared by treatment of the 1,10-phenanthroline derived ligand 236 with [Cu(MeCN)4]PF6 complex. Notably, the metal coordination reorganized the terminal olefin into close proximity favoring, in the presence of G1ST catalyst, a double RCM and the formation of trefoil knot 238 (74% yield as a mixture of E/Z isomers). Finally, catalytic hydrogenation with Pd/C (5 mol% Pd) afforded quantitatively the knot 239.

As an extension of the copper template strategy, Sauvage and co-workers employed the Fe(II) template-directed assembly of trefoil knots. The diiron(II) double helix 240, obtained in good yield by reacting the terpyridine ligands with an aqueous Fe(II) sulfate solution was submitted to RCM cyclization (G2ST as catalyst) affording the trefoil knot 241 in 20% yield, as a mixture of E (55%) and Z (45%) isomers (scheme 58). In this case, the low yield can be explained by the unfavorable conformation that ligands adopt around the metal during the ring closure process.

The stereoselective preparation of a topological chiral trefoil knot was reported by Von Zelewsky and Sauvage. The synthetic approach took advantage of both Cu(I) template effect on RCM ligation and conversion from classical to topological chirality. Stereoselective reaction of the diolefinic thread 243 with [Cu(MeCN)4]PF6 complex afforded rapidly and quantitatively the dinuclear Cu(I) complex 244, which possesses a C2-symmetric arrangement. Further RCM reaction using the G1ST catalyst afforded 245 in 74% overall yield as a mixture of three isomers. Notably, the enantiopure threads induced chirality at each metal centre of the double-stranded helix, favouring thus the synthesis of a single enantiomer of trefoil knot. Quantitative catalytic hydrogenation gave the saturated compound 246, featuring the same C2 symmetry, and final demetalation with KCN afforded the corresponding chiral trefoil knot in quantitative yield.

Hunter et al. developed a Zn(II) template synthesis of a molecular trefoil knot by the folding-threading-RCM strategy. In particular, treatment of the flexible ligand strands 248a,b, containing three bipyridine units and two alkenyl chains, with Zn(ClO4)2 results in the spontaneous and quantitative folding and threading into a stable open-knot conformation. The alkene-functionalized open-knot complexes 248a,b in the presence of G1ST catalyst underwent trapping by olefin ring closure, leading to the formation of unsatured closed-knot complexes 249a,b, respectively. Further conversion into the satured Zn(II) trefoil knots 250a,b was allowed by catalytic hydrogenation. The demetalation process, achieved by Li2S, occurred just for the intermediate 243b.

Another approach, involving the Lanthanide template synthesis of achiral and chiral molecular trefoil knots, was described by the Leigh’s group. In the first case, the synthesis was based on the ability of 2,6-dicarbonylpyridyl motif to act as a tridentate ligand for lanthanide ion in a well-defined 3:1 ligand/metal-ion ratio (scheme 68). In particular, treatment of ligand 252 with a solution of Ln(CF3SO3)3 salt (Ln = Eu, Lu), followed by precipitation in dichloromethane, gave the corresponding complexes 253a and 253b in 85% (Eu) and 90% (Lu) yields, respectively.

The lanthanide complexes 253a,b underwent to RCM reaction in the presence of HG2ND catalyst, affording the 81-atom-loop trefoil knots 254a,b both in 58% yield along with the topologically trivial unknot macrocycle isomers (17%). Notably, the π-π stacking interactions of lanthanide complex proved able to reorganize the terminal alkene moieties of the ligands into close proximity, favoring the ring closure towards the knotted architecture rather than the unknoted one. Final treatment with Et4NF in DMSO-d6 smoothly afforded the organic 81-atom-loop trefoil knot 255 in quantitative yield. According to the previous strategy, the same research group demonstrated the ability of chiral tridentate ligand to transfer chiral information from asymmetric stereocenters to topological stereochemistry in the synthesis of enantiopure molecular trefoil knots.

Treatment of (R,R)-256 (99% ee) with Ln(CF3SO3)3 (Ln = Eu or Lu) gave the corresponding lanthanide complexes (R,R)-257a,b in 83% and 89% yields, respectively. The circular trimeric helicate complexes were then closed by RCM to give trefoil knots of single handedness Λ-(R6)-258a,b in 55% and 62% yields, respectively, along with the metal-free unknotted macrocycles. Final treatment with fluoride ions afforded the organic topological structure Λ-(R6)-259 in 74% yield. As an extension of this strategy, Leigh et al. reported the stereoselective synthesis of a left-handed trefoil knot starting from a single ligand strand (R6)-260 folding around the lanthanide ion. The enantiopure complexes Λ-(R6)-261a,b underwent macrocyclization by RCM, enabling the formation of single handedness trefoil knots Λ-(R6)-262a,b in high yield (>90%).

Recently, Leigh et al. (J. Am. Chem. Soc. 2018, 140, 4982-4985) described the two-step synthesis of a molecular trefoil knot trough the self-assembly of a rare 12-component trimeric circular helicate, obtained by formation of an imine bond between 263 and 264 in the presence of Zn(II). The six pendant alkenyl chains were covalently captured by RCM using HG2ND catalyst into topological trefoil knot 265.

3.3.2 Synthesis of double (51) and triple (819) helicates by passive metal template RCM approach

Leigh et al. efficiently employed the circular metal helicate methodology for the preparation of molecular pentafoil knot, a 51 knot in Alexander Briggs notation. The authors demonstrated how, by changing the experimental conditions of the self-assembly process, the tris-(2,2’-bipyridine)-strand 90 was able to interwine around five Fe(II) cations creating the five crossing points onto the low spin Fe(II) complex 266. Submitting 266 to RCM reaction using HG2ND catalyst, a related star of David catenane 267 was obtained in 98% yield, featuring chloride anion whithin its central cavity.

Further, the same research group extended the circular helicate strategy from double to triple helicate (819) structures by using the Fe(II) ion as template. In particular, the tetrameric complex 269 (60%) was formed by the reaction of more flexible tris (bypyridine) ligand strand 268 with FeCl2. Covalent capture between strands by olefin metathesis reaction in the presence of HG2ND catalyst, after quenching with ethyl vinyl ether and treatment with aqueous KPF6, gave the Fe(II) complex 270 in 62% yield. Further demetalation yielded the desired circular triple helicate 271.

Conclusions

Over the last twenty years, olefin metathesis reaction is firmly established as a powerful isodesmic process for the synthesis of macromolecules and mechanically interlocked molecules alike. Its popularity with researchers arises from the intrinsic high functional group specificity to the mild reaction conditions in which the reaction can be carried out. Moreover, the olefin metathesis compatibility towards the weak interactions mostly involved in template assembly processes makes it a magic post-assembly modification reaction for the preparation of very challenging non-covalently intertwined molecules and polymeric systems. Covalent capture by several metathesis transformations thus offers a growing set of tools for the construction of MIMs and a new generation of molecular machines with unexpected technological applications in the real world.

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