A new class of customisable stable boronic ester assemblies

Abstract

An efficient, customisable approach for the assembly of covalent macrocycles and cages has been developed using the reaction of fused polynorbornane based bis-diols and commercially available boronic acids. The ability to customise the requisite bis-diol to various lengths and dihedral angles (here both 90° and 180°) and then combine with di or triboronic acids allows access to range of architectures. The resultant constructs were resistant to hydrolysis including 24-hour exposure to dilute solutions of either acetic or trifluoroacetic acid.

Fig. 1. Approaches to stable boronic ester architectures.

Scheme 1. Synthesis of 90° tecton 3_Me. (i) DMAD (2.2 eq.), RuH₂(CO)(PPh₃)₃ (4 mol%), DMF, 100 °C, 24 h. (ii) CPD (8 eq.), DMF, RT, 7 days. (iii) OsO₄ (1 mol%), NMO (3.6 eq.), acetone : H₂O (7 : 1), RT, 3 days. Synthesis of 180° tecton 4. (iv). DMF, 150 °C, 75 min, µw. (v) DMAD (1.5 eq.), RuH₂(CO)(PPh₃)₃ (2.5 mol%), acetone, 100 °C, 60 minutes, µw. (vi) t-BuOOH (2.5 eq.), t-BuOK (0.5 eq.), THF, RT, 12 h. (vii) THF, 150 °C, µw. (viii) MeOH : H₂O (9 : 1), Cs₂CO₃ (3 eq.), reflux, 2 h.

Scheme 2. Synthesis of [1 + 2] assemblies and [4 + 4] macrocycle. (i) EtOH, 130 °C, 5 min, μw. (ii) CHCl₃, 100 °C, 12 h.

Scheme 3. Tuning of physical properties through ester modification. (i) KOH, H₂O : THF : MeOH (4 : 1 : 1), reflux, 24 h. (ii) SOCl₂, CHCl₃, reflux, 1.5 h. (iii) Benzyl alcohol or diethylene glycol monomethyl ether (4.5 eq.), CHCl₃, reflux, 2 h. (iv) CPD (8 eq.), DMF, RT, 7 days. (v) OsO₄ (1 mol%), NMO (3.0 eq.), acetone: H₂O, RT, 3 days. (vi) CHCl₃, 100 °C, 24 h.

Fig. 2. (A) SC-XRD structure of macrocycle [4 + 4]_Bn, a portion of the unit cell is highlighted to emphasise the packing arrangement. (B) nESI-HRMS spectrum of macrocycle [4 + 4]_DEG.

Scheme 4. (A) Synthesis of [2 + 2] macrocycles. [2 + 2]_Ph 79%, [2 + 2]_BiPh 90%, [2 + 2]_Py 63% (B) SC-XRD structure of [2 + 2]_BiPh, the packing of the macrocycle is highlighted. (C) (1) Solution of methoxyethylamine-3,6-dinitro napthalimide in CDCl₃, (2) solution of macrocycle [2 + 2]_Py in CDCl₃, (3) solution of macrocycle [2 + 2]_Py with 20 equiv. of 3,6-dinitro-1,8-naphthalimide in CDCl₃.

Fig. 3. (A) Cage [3 + 2]_Ph (25%) and molecular model. (B) Molecular model viewed along the phenyl rings highlighting the esters (methyl groups in blue). (C) Cage [3 + 2]_TZ (96%) and X-ray crystal structure. (D) Unit cell viewed along b axis (top) and c* axis (bottom).

Fig. 4. Stability study of macrocycle [4 + 4]_DEG. (A) Expected resonances of hydrolysis products. (B) Stacked ¹H NMR spectra of macrocycle [4 + 4]_DEG 24 hours after addition of AcOH or TFA. (C) Ion signals detected by nESI-HRMS of the samples after 24 hours, (D) highlights intact macrocycle.