Design, Synthesis, and Self-Assembly
of an Ether and Amide Linkage-Based Cyclic Lipid

Motonari Shibakami; Shin Miyoshi; Makoto Nakamura; Rie Goto

doi:10.1055/s-0029-1217756

LETTER

Design, Synthesis, and Self-Assembly of an Ether and Amide Linkage-Based Cyclic Lipid

Motonari Shibakami*, Shin Miyoshi, Makoto Nakamura, Rie Goto
Institute of Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology (AIST), Central 5th, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
Fax: +81(29)8614547; e-Mail: moto.shibakami@aist.go.jp;

Abstract

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Abstract

A novel 48-membered cyclic lipid, in which two ether and two amide groups serve as a linker between its hydrophilic and hydrophobic moiety, was synthesized starting from d-1,2-O-isopropylidene-sn-glycerol. The synthetic scheme is featured by the selective removal of protecting groups, followed by the introduction of mesylate and carboxylic acid, which sequentially leads to the formation of ether and amide bonds, respectively. Transmission electron microscopic observation confirmed that this lipid forms submicrosized helical ribbons.

Key words

lipids - macrocycles - ether bond - amide bond - self-assembly

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References

References and Notes

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To a solution of 11 (15.9 mg, 12.9 µmol) in MeOH (0.5 mL) and CHCl₃ (1 mL) was added p-TsOH˙H₂O (250 µg, 1.3 µmol). After stirring at r.t. for 22 h, the reaction was diluted with CHCl₃ (20 mL). The solution was then washed subsequently with sat. aq NaHCO₃ (10 mL) and brine (10 mL). The organic layer was dried over anhyd Na₂SO₄ and concentrated under reduced pressure. Purification of the residue was done by flash chromatography (silica, CHCl₃-MeOH, 20:1) on a Biotage SP1 flash system to give 1 (6.8 mg, 72%) as a white solid.

All new compounds gave satisfactory analytical and spectral data. Selected physical data are as follows. Compound 9: R _f 0.57 (hexane-EtOAc, 10:1). ^¹H NMR (CDCl₃): δ = 7.43 (d, J = 7.0 Hz, 12 H), 7.30 (t, J = 7.5 Hz, 12 H), 7.24 (t, J = 7.3 Hz, 6 H), 3.29-3.56 (m, 10 H), 3.14-3.24 (m, 4 H), 2.22 (t, J = 7.0 Hz, 4 H), 1.46-1.59 (m, 8 H), 1.24-1.38 (m, 16 H). ^¹³C NMR (CDCl₃): δ = 143.72, 128.52, 127.72, 126.97, 86.71, 78.31, 77.37, 77.26, 70.56, 65.28, 63.11, 52.29, 29.87, 29.29, 29.15, 28.90, 28.65, 28.20, 27.37, 26.57, 25.88, 19.07. MS (TOF): m/z [M + Na]⁺ calcd for C₆₄H₇₂N₆O₄Na: 1011.55073; found: 1011.54383. Compound 10: R _f 0.29-0.44 (hexane-EtOAc, 2:1; tailing). ^¹H NMR (CDCl₃): δ = 7.44 (d, J = 7.3 Hz, 12 H), 7.30 (t,
J = 7.5 Hz, 12 H), 7.24 (t, J = 7.2 Hz, 6 H), 5.76 (br s, 2 H), 3.11-3.59 (m, 14 H), 2.05-2.25 (m, 8 H), 2.08 (m, 4 H), 1.93 (m, 2 H), 1.20-1.75 (m, 44 H). ^¹³C NMR (CDCl₃): δ = 172.94, 143.72, 128.60, 127.81, 127.04, 86.72, 84.59, 77.44, 70.10, 68.12, 65.26, 63.76, 40.62, 36.73, 29.97, 29.29, 29.08, 29.04, 28.76, 28.50, 28.35, 28.28, 26.12, 25.63, 19.14, 18.31. MS (TOF): m/z [M + Na]⁺ calcd for C₈₄H₁₀₄N₂O₆Na: 1259.77866; found: 1259.77685. Compound 11: R _f 0.65 (hexane-EtOAc, 1:1). ^¹H NMR (CDCl₃): δ = 7.44 (d, J = 7.6 Hz, 12 H), 7.30 (t, J = 7.6 Hz, 12 H), 7.23 (t, J = 7.2 Hz, 6 H), 5.80 (br s, 2 H), 3.30-3.74 (m, 8 H), 3.08-3.24 (m, 6 H), 2.03-2.34 (m, 12 H), 1.44-1.69 (m, 16 H), 1.24-1.42 (m, 28 H). ^¹³C NMR (CDCl₃): δ = 172.92, 143.77, 128.65, 127.83, 127.06, 86.75, 70.11, 65.40, 63.83, 40.70, 36.84, 30.01, 29.31, 29.08, 28.80, 28.72, 28.63, 28.28, 28.23, 26.26, 25.74, 19.16. MS (TOF): m/z
[M + H]⁺ calcd for C₈₄H₁₀₃N₂O₆: 1235.78107; found: 1235.76957. Compound 1: R _f 0.32 (CHCl₃-MeOH, 20:1). ^¹H NMR (CDCl₃): δ = 5.90 (br s, 2 H), 3.32-3.69 (m, 14 H), 3.21 (br s, 2 H), 2.17-2.34 (m, 12 H), 1.48-1.68 (m, 16 H), 1.24-1.44 (m, 28 H). ^¹³C NMR (CDCl₃-CD₃OD, 20:1): δ = 78.03, 77.37, 69.89, 65.30, 60.81, 50.17, 49.30, 39.58, 36.48, 29.86, 29.12, 28.91, 28.87, 28.63, 28.52, 28.47, 28.09, 28.04, 25.93, 25.59, 19.03. MS (TOF): m/z [M]⁺ calcd for C₄₆H₇₄N₂O₆: 750.55414; found: 750.54743.

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We often observed that the aggregates made from diacetylenic cyclic lipids were frizzling on the grid during the TEM observations. Thus we think that the electron beam irradiation triggered the formation of the helical ribbons.

Similar helical ribbons were observed in our previous studies, although they differed in size.^6c,¹6

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One reason for such a high degree of stability of the ribbons is the polydiacetylene structure that was formed during the first TEM observation.