A compatibility study on the glycosylation of 4,4'-dihydroxyazobenzene

Abstract

Photoresponsive glycoconjugates based on the azobenzene photoswitch are valuable molecules which can be used as tools for the investigation of carbohydrate-protein interactions or as precursors of shape-switchable molecular architectures, for example. To access such compounds, glycosylation of 4,4'-dihydroxyazobenzene (DHAB) is a critical step, frequently giving heterogeneous results because DHAB is a challenging glycosyl acceptor. Therefore, DHAB glucosylation was studied using nine different glycosyl donors, and reaction conditions were systematically varied in order to find a reliable procedure, especially towards the preparation of azobenzene bis-glucosides. Particular emphasis was put on glucosyl donors which were differentiated at the primary 6-position (N₃, OAc) for further functionalisation. The present study allowed us to identify suitable glycosyl donors and reaction conditions matching with DHAB, affording the bis-glycosylated products in fair yields and good stereocontrol.

Fig. 1. Photoisomerisation of azobenzene and examples of photoresponsive glycoconjugates. (a) Light or heat-induced isomerisation of azobenzene; (b) mannosylation of hydroxyazobenzene mounted onto a surface leads to glyco-SAMs where glyco ligand orientation can be photoswitched; (c) glycosylation of 4,4′-dihydroxyazobenzene (DHAB) leads to shape-switchable glycoazobenzene macrocycles; (d) tautomeric equilibrium of DHAB with its hydrazoquinone form and possible intermolecular hydrogen bonding promoting the hydrazoquinone tautomer.

Chart 1. Structures of glycosyl donors used in the present study.

Scheme 1. Preparation of glucosyl donors 3 and 7–9. Reagents and conditions: (a) BzCl (6 eq.), pyridine, rt, 92%; (b) ZnI₂ (4 eq.), TMSSPh (2.5 eq.), CH₂Cl₂, μW (150 W), 120 °C, 25 min, 98%; (c) PPh₃ (1.5 eq.), DIAD (2.5 eq.), DPPA (1.5 eq.), THF, −15 °C to rt, 71%; (d) TCCA (1 eq.), acetone/H₂O (9 : 1), rt; (e) ClC(NPh)CF₃ (1.5 eq.), Cs₂CO₃ (1.5 eq.), CH₂Cl₂, rt, 76% over 2 steps; (f) TBSCl (6 eq.), NMI (7 eq.), I₂ (2.5 eq.), pyridine, rt, 80%; (g) ZnI₂ (4 eq.), TMSSPh (2.5 eq.), CH₂Cl₂, rt, 96%; (h) Ac₂O (1.5 eq.), DMAP (0.2 eq.), pyridine, rt, 95%; (i) PPh₃ (1.5 eq.), DIAD (2.5 eq.), DPPA (1.5 eq.), THF, −15 °C to rt, 85%; DIAD = diisopropyl azodicarboxylate; DPPA = diphenylphosphorylazide; TCCA = trichlorocyanuric acid; TBSCl = t-butyldimethylchlorosilane; NMI = N-methylimidazole; TMSSPh = (phenylthio)trimethylsilane.

Scheme 2. Glycosylation of DHAB with different glycosyl donors. The desired bis-glucosylated products are numbered with “a”, the monoglycosylated by-products with “b”.