Controlled-Length Efficient Synthesis of Heterobifunctionalized Oligo Ethylene Glycols

Abstract

A set of heterobifunctional oligo ethylene glycols have been synthesized in a straightforward and stepwise manner starting from inexpensive, commercially available, tetraethylene glycol. Introduction of terminal allyl moieties followed by reductive ozonolysis allowed controlled elongation. Mono-allyl derivatives were used for the elongation with a functionalized moiety and for successive introduction of different functional groups on the chain terminal.

Key words

ethylene glycols - heterobifunctional - spacers - bio­molecule grafting - elongation

• References and Notes

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• 35 Monoallylation of EG; Typical Procedure: To a solution of EG 1 (1 equiv) in anhydrous DMF (0.5 M) was slowly added NaH (60% w/w in mineral oil, 2 equiv) and the mixture was reacted for 20 min. Allyl bromide (1.4 equiv) was added dropwise to the solution, which was stirred at r.t. overnight. The reaction mixture was then filtered to remove the precipitate and the solvent was removed under vacuum to afford the crude product, which was further purified by flash chromatography (petroleum ether–EtOAc, 8:2→1:9, with 2% MeOH as additive) to afford the desired product monoallyl 3 (51%). ¹H NMR (400 MHz, CDCl₃): δ = 2.82 (s, 1 H, OH), 3.51–3.66 (m, 16 H), 3.94 (d, J = 5.7 Hz, 2 H, CH₂CH=CH₂), 5.13–5.26 (m, 2 H, CH₂CH=CH₂), 5.87–5.99 (m, 1 H, CH₂CH=CH₂).
• 36 Conversion of the Allyl Unit into a Terminal Ethylene Glycol Unit; Typical Procedure: O₃ gas was bubbled, at –78 °C, into a 0.03 M solution of 8 (1 equiv) in CH₂Cl₂. The solution was stirred at r.t. until the disappearance of starting material was observed, then Ar gas was bubbled through the mixture. After 15 min, NaBH₄ (2 equiv) was added to the resulting solution, which was allowed to react at r.t. until the disappearance of ozonide intermediates was observed. After the addition of acetone to quench unreacted NaBH₄, the solvent was removed in vacuum and the crude product was purified by flash chromatography (CH₂Cl₂–EtOH, 9.5:0.5) to afford 13 (81%). ¹H NMR (400 MHz, CDCl₃): δ = 3.70–3.65 (m, 2 H, HOCH₂CH₂O), 3.65–3.58 (m, 26 H, OCH₂CH₂O and HOCH₂CH₂O), 3.56 (t, J = 5.0 Hz, 2 H, OCH₂CH₂N₃), 3.34 (t, J = 5.0 Hz, 2 H, OCH₂CH₂N₃).