Synthesis of Ceramide Mimics with a Pseudo Cyclic Framework

Abstract

We have designed and synthesized ceramide mimics with a pseudo cyclic framework that can be converted to ‘dimeric’ sphingomyelins and glycosphingolipids for potential components of artificial rafts. These molecules are characterized by the presence of (i) two hydrophilic head groups, (ii) a covalently bonded hydrocarbon chain, and (iii) two untethered alkyl chains. Self-assembling of a ceramide mimic into nanorods is briefly discussed.

Key words

ceramide - lipid microdomain - pseudo cyclic framework - raft - sphingolipids - self-assembly - regioselectivity

Reference

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12

Synthesis of 1a: To a solution of 15a (19 mg, 0.101 mmol) and Et₃N (10.2 mg, 0.101 mmol) in dry THF (1.0 mL) was added N-succinimidyl ester of hexadecanedioic acid (15 mg, 0.054 mmol) at r.t. After 24 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography [silica, EtOAc-MeOH-n-hexane (100:10:100 to 100:5:0)] to give 1a (23 mg, 74%).
Synthesis of 1b: To a solution of dotriacontanedioic acid (93.5 mg, 183 µmol) in CH₂Cl₂ (3.7 mL) was added oxalyl chloride (7.3 mL, 84 µmol) at r.t. After 12 h, the reaction mixture was concentrated under reduced pressure. Then, the resulting residue was added to a mixture that was composed of 15b (137 mg, 457 µmol), pyridine (3.7 mL) and CH₂Cl₂ (7.3 mL) at r.t. After stirring for 12 h, the reaction was quenched by the addition of 1.5 mL of H₂O. The mixture was then extracted with CHCl₃ (100 mL). The organic layer was washed with H₂O (5mL × 2) and brine (5mL), and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography [silica, CHCl₃-EtOAc-MeOH (10/10/1 to 5/5/1, v/v/v)] to give 1b (18.4 mg, 9.4%).

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All new compounds gave satisfactory analytical and spectral data. Compound 1a: colorless solid, [α]_D ²⁹ -18.76 (c 0.50, MeOH). ¹H NMR (500 MHz, CDCl₃): δ = 6.28 (2 H, d, J = 7.7 Hz), 5.79 (2 H, dtd, J = 15.3, 6.7, 1 Hz), 5.53 (2 H, ddt, J = 15.3, 6.4, 1 Hz), 4.32 (2 H, br s), 3.95 (2 H, br d, J = 11.9 Hz), 3.91 (2 H, m), 3.71 (2 H, m), 2.85 (4 H, br s), 2.23 (4 H, t, J = 7.4 Hz), 2.06 (4 H, dt, J = 7.5, 6.7 Hz), 1.64 (4 H, tt, J = 7.4, 7.4 Hz), 1.38 (4 H, tt, J = 7.4, 7.4 Hz), 1.25-1.30 (28 H, m), 0.89 (6 H, t, J = 7.0 Hz) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 174.0, 136.4, 128.8, 74.7, 62.5, 54.5, 36.8, 32.2, 31.4, 29.3, 29.2, 29.2, 29.2, 29.2, 28.8, 25.7, 22.5, 14.0 ppm. LRMS (ESI, m/z): 647 (M + Na). Compound 1b: colorless amorphous solid, ¹H NMR (500 MHz, CDCl₃): δ = 6.32 (2 H, m), 5.76 (2 H, dt, J = 15.3, 6.7 Hz), 5.50 (2 H, dd, J = 15.3, 6.8 Hz), 4.27 (2 H, m), 3.90 (2 H, m), 3.85 (2 H, m), 3.67 (2 H, m), 2.84 (4 H, br s), 2.25 (4 H, t, J = 7.3 Hz), 2.05 (4 H, m), 1.62 (4 H, m), 1.25-1.45 (96 H, m), 0.86 (6 H, t, J = 7.0 Hz) ppm. LRMS (ESI, m/z): 1097 (M + Na).

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Regioselective Benzoylation of 1a: Compound 1a (170 mg, 0.272 mmol) and DMAP (33 mg, 0.272 mmol) were dissolved in pyridine (3 mL) and stirred at -40 °C for 1 h in an atmosphere of nitrogen gas. After addition of benzoyl chloride (0.070 mL, 0.598 mmol), the reaction mixture was then stirred at -40 °C for 4 h. A sat. NH₄Cl aqueous solution was added to quench the reaction, and the mixture was then extracted with CHCl₃ (15 mL × 4). The organic layer was washed with brine (20 mL), dried over anhyd Na₂SO₄, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography [silica, n-hexane/EtOAc/CHCl₃ (6:6:1)] to give 16a (158 mg, 70%).