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Synlett 2009(16): 2651-2654  
DOI: 10.1055/s-0029-1217756
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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;
Further Information

Publication History

Received 27 May 2009
Publication Date:
04 September 2009 (online)

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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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11

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.

12

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.

14

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.

15

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

17

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