Versatile Synthesis of Amphiphilic Oligo(Aliphatic-Glycerol) Layer-Block Dendrons with Different Hydrophilic-Lipophilic Balance Values

Abstract

A series of amphiphilic oligo(glycerol-aliphatic) layer-blocked dendrons with different hydrophilic-lipophilic balance values (3.5–15.0) was prepared for use in controlled drug delivery and self-assembly studies. The synthetic strategies involved first a convergent growth of the inner hydrophobic sector followed by a divergent growth of the outer hydrophilic sector.

Key words

dendrimers - dihydroxylation - Mitsunobu reaction

• References and Notes

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• 15 The structural properties of all compounds were characterized by ¹H and ¹³C NMR spectroscopy, mass spectrometry, and/or elemental analysis. Their good purities were also confirmed by a polydispersity index of <1.02 by size-exclusion chromatographic analysis.
• 16 See the Supporting Information for details.
• 17 Synthesis of 19: A solution of DIAD (0.53 mL, 2.67 mmol) in toluene (6 mL) was added dropwise to a stirred solution of allylic alcohol 18 (1.78 g, 2.06 mmol), Ph₃P (0.70 g, 2.67 mmol), and Meldrum’s acid (0.15 g, 1.03 mmol) in toluene (6 mL) at –10 °C. The progress of the reaction was monitored by TLC. When the reaction was complete (ca. 30 min), hexane (30 mL) was added to the mixture to precipitate Ph₃PO, which was removed by filtration. The excess solvent was removed and the yellow residue was purified by flash column chromatography on silica gel (hexane–EtOAc, 3:1→1:1, in the presence of 1% Et₃N) to afford the target compound 19 (0.76 g, 40%) as a colorless oil. R_f = 0.54 (hexane–acetone, 2:1); ¹H NMR (300 MHz, CDCl₃): δ = 0.91 (s, 24 H, CH₂CCH ₃), 1.00–1.50 (m, 76 H), 1.38 (s, 24 H, OCCH₃), 1.39 (s, 24 H, OCCH₃), 1.64 (s, 6 H, CO₂CCH₃), 1.78–1.95 (m, 2 H, CHC=C), 2.66 (d, J = 6.9 Hz, 4 H, CH₂C=C), 3.45 (AB system, J = 11.4 Hz, 16 H, COCHH), 3.55 (AB system, J = 11.4 Hz, 16 H, COCHH), 5.20 (dt, J = 15.3, 7.2 Hz, 2 H, CH₂CH=CH), 5.36 (dd, J = 15.0, 8.4 Hz, 2 H, CH₂CH=CH); ¹³C NMR (75 MHz, CDCl₃): δ = 19.8, 20.2, 23.7, 24.1, 24.5, 30.2, 32.7, 34.0, 34.5, 34.6, 35.6, 36.0, 37.4, 42.7, 43.1, 56.1, 69.6, 97.9, 105.3, 121.8, 142.3, 168.8; MS (FAB): m/z (%) = 1823 (100) [M – CH₃ ⁺]; HRMS (FAB): m/z calcd for (C₁₁₀H₁₉₆O₂₀ – CH₃)⁺: 1822.4080; found: 1822.4113.
• 18 Synthesis of G[2+2]-(OH)₃₂(OBn) 1: OsO₄ (2.5 wt% in t-BuOH, 0.44 mL, 0.044 mmol) was added dropwise to a solution of 16-ene 32 (873 mg, 0.44 mmol) and NMO (1.23 g, 10.46 mmol) in acetone–H₂O (20 mL, 10:1, v/v) at 0 °C. The mixture was stirred at 20 °C for 48 h and the progress of the reaction was monitored by NMR analysis until all allyl groups had reacted. The solvent was removed in vacuo and the dark-brown residue was purified by membrane dialysis in MeOH using regenerated cellulose (MWCO = 1,000) to give the target compound 1 (1.02 g, 92%) as a viscous brown liquid. R_f = 0.08 (EtOAc–MeOH, 1:3); ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.78 (s, 12 H, CH₃), 0.92–1.45 (m, 38 H), 1.45–1.61 (m, 1 H, CHCH₂OBn), 3.00–3.23 (m, 16 H, CH₃CCHHO), 3.23–3.46 (m, 90 H, OCHCH ₂O and CHCH ₂OBn), 3.46–3.68 (m, 32 H, OCHCH ₂O), 4.42 (t, J = 5.7 Hz, 10 H, OH and PhCH₂O), 4.47 (t, J = 5.7 Hz, 8 H, OH), 4.51 (t, J = 4.8 Hz, 8 H, OH), 4.60 (dd, J = 4.8, 1.2 Hz, 8 H, OH), 7.16–7.45 (m, 5 H, ArH); ¹³C NMR (75 MHz, DMSO-d ₆): δ = 19.6, 20.0, 23.4, 31.8, 33.7, 34.6, 35.1, 36.8, 37.8, 38.7, 63.4, 63.5, 70.7, 70.9, 71.0, 71.3, 71.89, 71.93, 72.4, 73.1, 75.5, 78.1, 127.6, 127.8, 128.4, 139.0; HRMS (MALDI-TOF): m/z calcd for (C₁₁₇H₂₂₈O₅₇ + Na)⁺: 2569.4869; found: 2569.4974.