Synthesis of Dense and Chiral Dendritic Polyols Using Glyconanosynthon Scaffolds

Abstract

Most classical dendrimers are frequently built-up from identical repeating units of low valency (usually AB2 monomers). This strategy necessitates several generations to achieve a large number of surface functionalities. In addition, these typical monomers are achiral. We propose herein the use of sugar derivatives consisting of several and varied functionalities with their own individual intrinsic chirality as both scaffolds/core as well as repeating units. This approach allows the construction of chiral, dense dendrimers with a large number of surface groups at low dendrimer generations. Perpropargylated β-D-glucopyranoside, serving as an A5 core, together with various derivatives, such as 2-azidoethyl tetra-O-allyl-β-D-glucopyranoside, serving as an AB4 repeating moiety, were utilized to construct chiral dendrimers using "click chemistry" (CuAAC reaction). These were further modified by thiol-ene and thiol-yne click reactions with alcohols to provide dendritic polyols. Molecular dynamic simulation supported the assumption that the resulting polyols have a dense structure.

Keywords: CuAAAC; carbohydrate; click chemistry; dendrimer; glycodendrimer; thiol-ene; thiol-yne.

Scheme 1

Syntheses of the glyconanosynthons. Reagents and conditions: (i) 2-bromoethanol, BF₃·OEt₂, DCM, rt, 2.5 h, 84%; (ii) NaN₃, DMF, 85 °C, 2 h, 94%; (iii) NaOMe, MeOH, rt, 2.5 h; (iv) DMF, 60% NaH, rt, 0.5 h; allyl bromide, 0 °C, 1 h, then at rt, 3 h, 94%; (v) DMF, 60% NaH, rt, 15 min; 0 °C, propargyl bromide, 2 h, 87%; (vi) DBU, DCM, AgCl, TMSCl, 45 °C, overnight, 83%; (vii) propargyl alcohol, BF₃·etherate, DCM, rt, 2 h, 92%; (viii) DMF, 60% NaH, 0–5 °C, 0.5 h, then propargyl bromide, 1 h at 0–5 °C, 95%.

Scheme 2

Synthesis of glycodendrimer core. Reagents and conditions: (i) CuI·P(OEt)₃, toluene, 70 °C, 20 h; 85% for 10, 90% for 13 using Hunig’s base; (ii) CuI·P(OEt)₃, toluene, microwave, 70 °C, 4 h, 80%; (iii) TBAF, THF, acetic acid, rt, 5 h, 85%; (iv) NaOMe, MeOH-water mixture (10:1), rt, 18 h, 98%; (v) DMF, propargyl bromide, 0 °C, NaH 60% in oil added in four portions every hour, then at rt, 18 h, 70%; (vi) DMF, NaH 60% in oil, 0 °C, 1 h, then at rt, 2 h; cooled to 0 °C, allyl bromide, then at rt, 18 h, 77%.

Figure 1

NMR spectra of key precursor 5 and G₁ dendrimers 10, 12 and 13. Insert: Expanded triazole signals of 12.

Scheme 3

Syntheses of dendritic polyols. Reagents and conditions: (i) AIBN, dioxane, 100°C, 15, 47%, 16, 60%; (ii) UV 365 nm, DMPA, 4 h and 6 h; 17, 56% and 18, 71%.

Scheme 4

Synthesis of G2 dendrimers. Reagents and conditions: (i) CuI·P(OEt)₃, DMF, 70 °C, 20 h; 53% for 19; 67% for 20; 57% for 21.

Figure 2

The MD simulation of 16, starting from an initially fully extended conformation. Dendrimer 16 rapidly rearranges into a 2 nm stable globular shape in water.

Figure 3

Stick representation of dendrimer 16 after equilibration by MD simulation (water molecules not shown).

Figure 4

MD characterization of dendrimer 16 in water. (a) Equilibrated configuration of 16—black: scaffold, red: OH-surface groups; (b) radial distribution functions g(r) of the atoms of 16 (black) and of the surface OH-groups (red) as a function of the distance from the dendrimer’s center of mass. The hydrodynamic radius of 16 is calculated according to the model of a rigid sphere as: R_h ≈ 1.29 R_g [28]; (c) radial distribution functions, g(r), of the water molecules (black), and number of water molecules (blue) as a function of the distance from 16’s center of mass.