Active template synthesis

Abstract

The active template synthesis of mechanically interlocked molecular architectures exploits the dual ability of various structural elements (metals or, in the case of metal-free active template synthesis, particular arrangements of functional groups) to serve as both a template for the organisation of building blocks and as a catalyst to facilitate the formation of covalent bonds between them. This enables the entwined or threaded intermediate structure to be covalently captured under kinetic control. Unlike classical passive template synthesis, the intercomponent interactions transiently used to promote the assembly typically do not 'live on' in the interlocked product, meaning that active template synthesis can be traceless and used for constructing mechanically interlocked molecules that do not feature strong binding interactions between the components. Since its introduction in 2006, active template synthesis has been used to prepare a variety of rotaxanes, catenanes and knots. Amongst the metal-ion-mediated versions of the strategy, the copper(I)-catalysed alkyne-azide cycloaddition (CuAAC) remains the most extensively used transformation, although a broad range of other catalytic reactions and transition metals also provide effective manifolds. In metal-free active template synthesis, the recent discovery of the acceleration of the reaction of primary amines with electrophiles through the cavity of crown ethers has proved effective for forming an array of rotaxanes without recognition elements, including compact rotaxane superbases, dissipatively assembled rotaxanes and molecular pumps. This Review details the active template concept, outlines its advantages and limitations for the synthesis of interlocked molecules, and charts the diverse set of reactions that have been used with this strategy to date. The application of active template synthesis in various domains is discussed, including molecular machinery, mechanical chirality, catalysis, molecular recognition and various aspects of materials science.

Fig. 1. Classic examples of the passive metal template synthesis of interlocked molecules. (a) The Sauvage group's synthesis of catenane 4-Cu(i) in two sequential steps: coordination of the bidentate ligands to the metal in a tetrahedral geometry, followed by capturing of the threaded structure through covalent bond formation. (b) The Leigh group's synthesis of benzylic imine catenanes by imine formation about an octahedral Zn(ii) template, followed by reduction of the imines and extraction of the metal ions to give wholly organic catenane 5. Although the Zn(ii) ions promote formation of the imine bonds in addition to holding the ligands in place, the metal cannot be removed from the imine catenate without a subsequent reduction step to stabilise the covalent framework in the absence of the metal. The two-step synthesis of 5 is therefore an example of passive metal template synthesis.

Fig. 2. Schematic representation of (a) various common passive template strategies for rotaxane synthesis and (b) active template synthesis of rotaxanes. (a) The ‘clipping’ and ‘threading-and-stoppering’ approaches involve thermodynamically driven assembly processes followed by capturing of the interlocked structure by covalent bond formation. The ‘slipping’ or ‘slippage’ approach involves the macrocycle passing over the stoppers at an elevated temperature; at lower temperatures the macrocycle is then kinetically trapped on the axle. As a covalent bond does not need to be broken to disassemble such a threaded structure, such supramolecular assemblies are better described as kinetically stable pseudo-rotaxanes rather than as rotaxanes (see footnote 194 in ref. 21). (b) Active template synthesis is kinetically driven; component assembly and the covalent capture of the interlocked structure occur contemporaneously.

Fig. 3. Introduction of active metal template synthesis by Leigh and co-workers.

Fig. 4. Mechanism of the active template CuAAC reaction leading to [2]- or [3]rotaxanes depending on the ratio of macrocycle to Cu(i).

Fig. 5. Molecular trefoil knot 12 synthesised through active template CuAAC synthesis through the macrocyclic loop formed by Cu(i)-coordination to the two bipyridine groups.

Fig. 6. (a) Proposed mechanism for the active template synthesis of [2]rotaxanes through the Cu(i)-mediated Glaser–Hay homocoupling of terminal alkynes. (b) Selected examples of interlocked structures synthesised by active template Glaser couplings. (c) Saito's post-assembly modification a diyne rotaxane to an aryl pyrrole rotaxane.

Fig. 7. Proposed mechanism for the active template synthesis of [2]rotaxanes through the Cu(i)-mediated Cadiot–Chodkiewicz heterocoupling of terminal alkynes and alkyne halides.

Fig. 8. (a) Jasti's synthesis of a [c2]daisy-chain rotaxane 27 from an active template Cadiot–Chodkiewicz reaction. (b) Space-filling representation of 27.

Fig. 9. Saito's active template synthesis of a [2]rotaxane by Ullmann C–S coupling of a thiol and aryl iodide.

Fig. 10. Saito's active template synthesis of [2]rotaxanes through the Cu(i)-mediated Sonogashira-type coupling of terminal alkynes and aryl iodides.

Fig. 11. Active template synthesis of [2]rotaxanes through the Pd(ii)-mediated oxidative homocoupling of terminal alkynes.

Fig. 12. Active template synthesis of [2]rotaxanes through Pd(ii)-mediated oxidative Heck cross-coupling.

Fig. 13. Active template synthesis of [2]rotaxanes through successive Pd(ii)-mediated Michael additions of four components.

Fig. 14. Active template synthesis of traceless [2]rotaxanes through the Ni(0)-mediated homocoupling of unactivated alkyl bromides.

Fig. 15. (a) Mechanism of the active template Ni(0)-mediated active template synthesis of rotaxanes with one, two or three axles threaded through a single macrocycle. (b) Doubly and triply threaded rotaxanes formed using this method.

Fig. 16. Mechanism of the active template synthesis of traceless [2]rotaxanes through the Ni(i)-mediated heterocoupling of alkylzinc and redox-active esters.

Fig. 17. Kimizuka, Yagi, and Itami's Ni(0)-mediated active template synthesis of [8]cycloparaphenylene catenane 54.

Fig. 18. Active template synthesis of [2]rotaxanes through the Zn(ii)-mediated Diels–Alder of imidazolidones and cyclopentadiene derivatives.

Fig. 19. Megiatto's active template synthesis of [2]rotaxanes through the Co(ii)-mediated radical carbene transfer between diazo and styrene derivatives.

Fig. 20. Megiatto's active template synthesis of [2]rotaxanes via Ru(ii)-mediated N–H carbene insertion.

Fig. 21. Chaplin's active template synthesis through the Rh(i)-mediated homocoupling of terminal alkynes to form a threaded E-enyne.

Fig. 22. Chaplin's active template synthesis of diyne rotaxanes through Rh(iii)-mediated homocoupling of alkynyl Grignard reagents.

Fig. 23. Mock's synthesis of a [2]rotaxane through cucurbituril-promoted Huisgen azide–alkyne cycloaddition of ammonium-functionalised axle building blocks.

Fig. 24. Credi and Arduini's cooperative capture synthesis of a [2]rotaxane.

Fig. 25. Metal-free active template synthesis of a [2]rotaxane through transition state stabilisation.

Fig. 26. Metal-free active template synthesis of rotaxanes from primary amines, electrophiles and crown ethers.

Fig. 27. Numata's metal-free active template synthesis of wholly peptidic rotaxanes from a glycine nucleophile, a phenylalanine-nitrophenol ester electrophile and cyclo(proline) macrocycle.

Fig. 28. Zhang's metal-free active template synthesis of protein heterocatenanes. (a) SpyStapler-mediated isopeptide bond formation between SpyTag and BDTag. (b) Active template synthesis of a protein [2]catenane from a cyclic protein incorporating the SpyStapler sequence (c-SpyStapler-POI) and a linear protein terminated with the BDTag and SpyTag sequences at either end. (c) Higher order protein [n]catenanes (n = 2–5) assembled using a mutated SpyStapler sequence (SpyStapler003).

Fig. 29. Yagai's self-assembling polycatenanes consisting of ∼13 nm diameter supramolecular rings. The molecules with a polar head group, rigid segment and non-polar tail assemble into rosettes that stack to form helical strands and toroids. The internal surface of the toroids seed the formation of new stacks, leading to supramolecular polycatenanes.

Fig. 30. Active template Cadiot–Chodkiewicz synthesis of molecular shuttle 97. The position of the macrocycle on the axle is governed by relatively weak intercomponent interactions.

Fig. 31. Goldup's active template synthesis of mechanically planar chiral rotaxanes (S_mp)- and (R_mp)-102.

Fig. 32. Goldup's diastereoselective active template synthesis of mechanically planar chiral rotaxane (S_mp)-103.

Fig. 33. Goldup's mechanical interlocking chiral auxiliary for the active template synthesis of ‘impossible’ mechanically planar chiral rotaxanes.

Fig. 34. Single-step asymmetric metal-free active template synthesis of mechanically planar [2]rotaxanes.

Fig. 35. Mechanically chiral [2]rotaxane 109, synthesised through a Goldberg active template reaction, and its scope as a ligand for the nickel-catalysed enantioselective Michael addition of diethyl malonate and trans-β-nitrostyrenes.

Fig. 36. Goldup's [2]rotaxane precatalyst 113-Au(i) prepared by an active template CuAAC reaction, and the effect of additives on its catalytic efficacy in the Toste–Ohe–Uemura cyclopropanation reaction.

Fig. 37. (a) Goldup's active template synthesis of mechanically planar chiral rotaxane precatalyst (R_mp)-114-Au(i). (b) Example of a diastereoselective and enantioselective Toste–Ohe–Uemura cyclopropanation reaction promoted by 114-Au(i). (c) Computationally modelled transition state.

Fig. 38. Goldup's [3]rotaxane anion–π organocatalyst 118 for the Michael addition of malonic acid monothioester to β-nitrostyrene.

Fig. 39. (a) Beer's active template synthesis of [2]rotaxane 120-Re(i) for anion sensing. (b) Other examples from the Beer group of halogen- and chalcogen-bonding rotaxane hosts prepared by active template synthesis.

Fig. 40. Papot and Leigh's active template CuAAC synthesis of β-galactosidase-cleavable [2]rotaxane 124, which releases paclitaxel in tumour cells.

Fig. 41. Anderson's assembly of [4]- and [7]catenanes from [2]rotaxanes prepared by active template Glaser homocouplings.

Fig. 42. Jasti's assembly of interlocked nanocarbons via active template Cadiot–Chodkiewicz synthesis.

Fig. 43. Anderson's extended polyyne rotaxane 136 synthesised via a Cadiot–Chodkiewicz active template reaction followed by oxidative unmasking of the bridging alkynes.

Fig. 44. Spontaneous assembly by metal-free active template synthesis of compact rotaxane superbase 137.

Fig. 45. Goldup's synthesis of homo[6]rotaxane 134 through iterative high-yielding active template CuAAC reactions.

Fig. 46. A rotaxane-based peptide synthesiser 135, assembled through CuAAC active template synthesis.

Fig. 47. (a) A stepwise-operated molecular pump that makes use of successive metal-free active template transamidation reactions. Macrocycles are pumped onto the axles by a sequence of: (1) an active template transamidation reaction, (2) Boc-addition, and (3) substitution by an activated ester. (b) [5]Rotaxane 148 formed after two pumping cycles from a thread with pump motifs at either terminus. X-Ray crystal structure of 148. (c) [4]Rotaxane 149, in which the macrocycles have been threaded onto the axle in a controlled sequence.

Fig. 48. An autonomous catalysis-driven artificial molecular pump 150 which operates continuously in the presence of chemical fuel 151.

Fig. 49. Proposed mechanism of the tandem active template CuAAC rearrangement reported by Goldup and co-workers.

Romain Jamagne

Martin J. Power

Zhi-Hui Zhang

Germán Zango

Benjamin Gibber

David A. Leigh