A chiral interlocking auxiliary strategy for the synthesis of mechanically planar chiral rotaxanes

Abstract

Rotaxanes can display molecular chirality solely due to the mechanical bond between the axle and encircling macrocycle without the presence of covalent stereogenic units. However, the synthesis of such molecules remains challenging. We have discovered a combination of reaction partners that function as a chiral interlocking auxiliary to both orientate a macrocycle and, effectively, load it onto a new axle. Here we use these substrates to demonstrate the potential of a chiral interlocking auxiliary strategy for the synthesis of mechanically planar chiral rotaxanes by producing a range of examples with high enantiopurity (93-99% e.e.), including so-called 'impossible' rotaxanes whose axles lack any functional groups that would allow their direct synthesis by other means. Intriguingly, by varying the order of bond-forming steps, we can effectively choose which end of an axle the macrocycle is loaded onto, enabling the synthesis of both hands of a single target using the same reactions and building blocks.

Figure 1. The chiral interlocking auxiliary concept for the synthesis MPC rotaxanes.

Diastereoselective mechanical bond formation gives rise to a single major diastereomer as a mixture of co-conformations in which the ring preferentially encircles the receiver portion of the axle. A stoppering reaction then traps the ring at the desired location and subsequent auxiliary cleavage liberates the product in which the mechanical bond provides the sole stereogenic unit in high enantiopurity.

Figure 2. The stereoselective synthesis of rotaxanes 4, their analysis by H NMR and SCXRD and the analysis of their co-conformational properties.

(a) Synthesis of rotaxanes 4. Reagents and conditions: (S)-1,2, 3, [Cu(MeCN)₄]PF₆, ⁱ Pr₂EtN, CH₂Cl₂, rt, 16 h (4a: 77%, 76% d.e.; 4b: 84%, ~95% d.e.). The diastereoselectivity of the reactions was determined by H NMR spectroscopic analysis of the crude reaction products (Supplementary Figs 14 and 22). The major co-conformation of rotaxanes 4 was determined by ¹H NMR spectroscopic analysis of the purified products (Supplementary Table 2). The absolute stereochemistry shown for rotaxanes 4 corresponds to the major (S,S _mp) isomer of 4b determined by X-ray diffraction analysis (c). The major isomer of rotaxane 4a was not determined. (b) Partial ¹H NMR (CDCl₃, 400 MHz, 298 K) of (i) the non-interlocked axle of rotaxane 4a, (ii) rotaxane 4a, (iii) rotaxane 4b, (iv) the non-interlocked axle of rotaxane 4b. Colours and atom labels as in panel a with the exception of macrocycle protons which are shown in blue and the CHCl3 peak which is light grey. Correlations are shown for protons Htrz, H _ether and aliphatic protons derived from the azide unit. Signals associated with the major stereoisomer are colour coded, signals attributable to the minor stereoisomer are present but not assigned. Rotaxane 4b is contaminated with a small amount of the non-interlocked axle (4%) that we could not remove, as well as the minor diastereomer (~2%), which together account for the additional signals observed. (c) Solid state structure of rac-4b in sticks and spacefilling representations with selected intercomponent interactions indicated (substituted benzyl ether unit omitted for clarity, colours as in (a), O, N and H atoms in dark grey, dark blue and white respectively).

Figure 2. The stereoselective synthesis of rotaxanes 4, their analysis by H NMR and SCXRD and the analysis of their co-conformational properties.

(a) Synthesis of rotaxanes 4. Reagents and conditions: (S)-1,2, 3, [Cu(MeCN)₄]PF₆, ⁱ Pr₂EtN, CH₂Cl₂, rt, 16 h (4a: 77%, 76% d.e.; 4b: 84%, ~95% d.e.). The diastereoselectivity of the reactions was determined by H NMR spectroscopic analysis of the crude reaction products (Supplementary Figs 14 and 22). The major co-conformation of rotaxanes 4 was determined by ¹H NMR spectroscopic analysis of the purified products (Supplementary Table 2). The absolute stereochemistry shown for rotaxanes 4 corresponds to the major (S,S _mp) isomer of 4b determined by X-ray diffraction analysis (c). The major isomer of rotaxane 4a was not determined. (b) Partial ¹H NMR (CDCl₃, 400 MHz, 298 K) of (i) the non-interlocked axle of rotaxane 4a, (ii) rotaxane 4a, (iii) rotaxane 4b, (iv) the non-interlocked axle of rotaxane 4b. Colours and atom labels as in panel a with the exception of macrocycle protons which are shown in blue and the CHCl3 peak which is light grey. Correlations are shown for protons Htrz, H _ether and aliphatic protons derived from the azide unit. Signals associated with the major stereoisomer are colour coded, signals attributable to the minor stereoisomer are present but not assigned. Rotaxane 4b is contaminated with a small amount of the non-interlocked axle (4%) that we could not remove, as well as the minor diastereomer (~2%), which together account for the additional signals observed. (c) Solid state structure of rac-4b in sticks and spacefilling representations with selected intercomponent interactions indicated (substituted benzyl ether unit omitted for clarity, colours as in (a), O, N and H atoms in dark grey, dark blue and white respectively).

Figure 3. Demonstration of the chiral interlocking auxiliary strategy for the synthesis of MPC rotaxanes in high stereopurity (determined by CSP-HPLC throughout).

(a) A chiral interlocking auxiliary synthesis of MPC rotaxane (S _mp)-8 using an esterification stoppering strategy. Reagents and conditions: i. (S)-1, 2, 5a, [Cu(MeCN)₄]PF₆, ⁱ Pr₂EtN, CH₂Cl₂, rt, 16 h (80%); ii. TFA, CH₂Cl₂, rt, 16 h; iii. TMSCHN₂ (2.0 M in hexanes), MeCN, rt, 16 h then MeOH, K₂CO₃, rt, 3 h (65% over two steps, 94% ee). (b) A chiral interlocking auxiliary synthesis of MPC rotaxane (S _mp)-10 using a cross-coupling stoppering strategy. Reagents and conditions: i. (S)-1, 2, 9, [Cu(MeCN)₄]PF₆, ⁱ Pr₂EtN, CH₂Cl₂, rt, 16 h (89%); ii. PhCCH, PdCl₂(PPh₃)₂, CuI, ⁱ Pr₂NH, 110 °C, 16 h (94%); iii. K₂CO₃, MeOH, CH₂Cl₂, rt, 16 h (87%, 96% ee). (c) A chiral interlocking auxiliary synthesis of phosphine oxide-containing MPC rotaxane (S _mp)-12. Reagents and conditions: i. (S)-1, 2, 11, [Cu(MeCN)₄]PF₆, ⁱ Pr₂EtN, CH₂Cl₂, rt, 16 h (85%); ii. PhB(OH)₂, Pd(OAc)₂, PPh₃, K₃PO₄.H₂O, THF, 80 °C, 16 h (93%); iii. K₂CO₃, MeOH, CH₂Cl₂, rt, 16 h (70%, 98% ee). PMB, p-methoxybenzyl; TFA, trifluoroacetic acid; TMS, trimethylsilyl.

Figure 4. Synthesis of ‘impossible’ MPC rotaxanes in high stereopurity (determined by CSP-HPLC) using the chiral interlocking auxiliary strategy.

(a) Rotaxanes (S _mp)-13-15 synthesized using the esterification stoppering approach. The yields of rotaxanes (S _mp)-13-15 refer to the overall isolated yield over 4 steps from the corresponding alkyne-PMB ester half-axle. Rotaxane (S _mp)-15 was also synthesized over 3 steps from the corresponding alkyne-carboxylic acid half-axle (yield given). (b) Late-stage diversification of rotaxane (S,S _mp)-17 to give MPC rotaxanes (S _mp)-18-20 through a Pd⁰-mediated stoppering approach. Reagents and conditions: i. (S)-1, 2, 16, [Cu(MeCN)₄]PF₆, ⁱ Pr₂EtN, CH₂Cl₂, rt, 16 h (99%); ii. PhCCH, PdCl₂(PPh₃)₂, CuI, ⁱ Pr₂NH, 110 °C, 16 h, (aqueous work up), then MeOH, K₂CO₃, CH₂Cl₂, rt, 16 h (58%, 94% e.e.); iii. PhB(OH)₂, Pd(OAc)₂, PPh₃, K₃PO₄.H₂O, THF, 80 °C, 16 h (aqueous work up), then MeOH, K₂CO₃, CH₂Cl₂, rt, 16 h (61%, 98% e.e.); iv. Pyrene-1-B(OH)₂, Pd(OAc)₂, PPh₃, K₃PO₄.H₂O, THF, 80 °C, 16 h (aqueous work up), then MeOH, K₂CO₃, CH₂Cl₂, rt, 16 h (61%, >98% e.e.; no trace of the other enantiomer was observed by CSP-HPLC. However, baseline separation could not be achieved and thus we assign the e.e. as >98%.).

Figure 5. Combining the chiral interlocking auxiliary approach with a grafting strategy and application of this methodology to the stereodivergent synthesis of rotaxane 28 from a single set of building blocks.

(a) Chiral interlocking auxiliary synthesis of MPC rotaxanes (S _mp)-23 using an aminolysis grafting reaction. Reagents and conditions: 21, 22a (Ar = 3,5- ^t BuC₆H₃), CH₂Cl₂, 60 °C, 16 h (23a: 62%, 96% e.e.; 23b: <10%, e.e. n.d.). (b) Synthesis of both enantiomers of MPC rotaxane 28 by varying the order of amide bond forming steps. Reagents and conditions: i. (S)-1, 2, 26, [Cu(MeCN)₄]PF₆, ⁱ Pr₂EtN, CH₂Cl₂, rt, 16 h ((S,S _mp)-27a: 78%; (S,S _mp)-27b: 71%); ii. 22, CH₂Cl₂, 60 °C, 16 h ((S _mp)-28: 75%, 97% e.e.; (R _mp)-28: 90%, 94% ee).

Figure 6. Stereochemical analysis of rotaxane 28 demonstrating that the two different routes (as shown in Figure 5) yield opposite enantiomers in high stereopurity.

(a) Circular dichroism spectra (CHCl₃, 46 and 44 mM for (S _mp)-28 and (R _mp)-28 respectively, 10 mm path length, 293 K) of the enantiomers of rotaxane 28. (b) CSP-HPLC (RegisCell, n-hexane-EtOH 80 : 20, 1.0 mLmin^-1) analysis of (R _mp)-28 (+98% e.e.) and (S _mp)-28 (-94% e.e.).