Indium-Mediated Stereoselective Synthesis of Truncated, 6- and 7-Carbon Sialic Acids

Abstract

Several 6- and 7-carbon sialic acid derivatives were synthesized, without tedious protecting group manipulations, in high overall yields. A key step of the synthesis was the chain extension of suitable α-amino aldehyde derivatives by an indium-mediated addition of ethyl 2-(bromomethyl)acrylate. Under acidic reaction conditions, the corresponding extended enoates were obtained with high trans-stereoselectivity. Ozonolysis furnished the desired 4-acylamino-substituted hexulosonic and heptulosonic acids in free form for biochemical studies.

Key words

allylations - Barbier-type reactions - indium - α-amino aldehydes - sialic acids

References

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12

Typical reaction conditions for the indium-mediated allylation: To a solution of the aminoaldehyde (1.0 mmol) and ethyl 2-(bromomethyl)-acrylate [16] (386 mg; 2.0 mmol) in a mixture made from 12.5 mL EtOH and 2.5 mL 0.1 M HCl was added indium powder (230 mg; 2.0 mmol) at r.t. The suspension was vigorously stirred until TLC indicated complete conversion of the starting material, and was then filtered through a pad of Celite. Water was added (20 mL), and the resulting mixture was concentrated to 20 mL under vacuum followed by extraction with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (1 × 20 mL) and water (1 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Without further purification, the remaining crude colorless solid was taken up in MeOH and treated with ozone at -78 °C. Ozonide reduction (Me₂S, r.t.) followed by flash chromatography provided compounds 9a-d as colorless syrups, which were hydrolyzed by treatment with 2 equivalents of aq LiOH to furnish stereoisomerically pure truncated sialic acid derivatives 10a-d.
Spectroscopic data: 10a: ¹H NMR (300 MHz, D₂O): δ = 3.82 (m, 1 H, 4-H), 3.67 (m, 2 H, 6-H), 3.53 (m, 1 H,
5-H), 2.15 (dd, 1 H, J _3eq,3ax = 13.1 Hz, J _{3eq, 4} = 4.9 Hz, 3_eq-H), 1.90 (s, 3 H, CH₃), 1.69 (dd, 1 H, J _3ax,3eq = 13.1 Hz, J _3ax,4 = 11.2 Hz, 3_ax-H); ¹³C NMR (75 MHz, D₂O): δ = 177.23 (C-1), 175.07 (C=O), 97.75 (C-2), 68.27 (C-4), 63.67 (C-6), 54.36 (C-5), 41.33 (C-3), 24.40 (CH₃); ESI-MS: m/z = 218 ([M-H]^-, 100). 10b: ¹H NMR (300 MHz, D₂O): δ = 7.26-7.38 (m, 5 H, H_ar), 3.58 (s, 2 H, CH₂), 3.48-3.96 (m, 4 H, 4-,5-,6-H), 2.14 (dd, 1 H, J _3eq,3ax = 13.0 Hz, J _3eq,4 = 4.8 Hz, 3_eq-H), 1.88 (dd, 1 H, J _3ax,3eq = 13.0 Hz, J _3ax,4 = 11.1 Hz, 3_ax-H); ¹³C NMR (75 MHz, D₂O): δ = 178.27 (C=O), 177.98 (C-1), 138.07 (C_i), 131.64, 131.29, 129.63 (CH _{o , m , p} ), 99.24 (C-2), 69.26 (C-4), 64.19 (C-6), 55.42 (C-5), 45.28 (CH₂), 42.50 (C-3); ESI-MS: m/z = 318 ([M + Na]⁺, 100), 300(40). 10c: ¹H NMR (300 MHz, D₂O): δ = 3.65-3.93 (5 H, m, 4-,5-,6-,7-H), 2.32 (1 H, dd, J _3eq,3ax = 13.0 Hz, J _3eq,4 = 5.0 Hz, 3_eq-H), 2.04 (3 H, s, CH₃), 1.87 (1 H, dd, J _3ax,3eq = 13.0 Hz, J _3ax,4 = 11.6 Hz, 3_ax-H); ¹³C NMR (75 MHz, D₂O): δ = 177.77 (C-1), 175.1 (C=O), 98.17 (C-2), 75.80 (C-6), 69.39 (C-4), 63.80 (C-7), 55.22 (C-5), 41.91 (C-3), 25.03 (CH₃); ESI-MS: m/z = 248 ([M - H]^-, 100), 230(41). 10d: ¹H NMR (300 MHz, D₂O): δ = 7.28-7.40 (5 H, m, H_ar), 3.63 (2 H, s, CH₂), 3.50-3.91 (5 H, m, 4-,5-,6-,7-H), 2.33 (1 H, dd, J _3eq,3ax = 12.9 Hz, J _{3eq, 4} = 4.9 Hz, 3_eq-H), 1.84 (1 H, dd, J _3ax,3eq = 12.9 Hz, J _{3ax, 4} = 11.8 Hz,
3_ax-H); ¹³C NMR (75 MHz, D₂O): δ = 178.16 (C=O), 175.66 (C-1), 137.72 (C_i), 131.92, 131.78, 130.19 (C _{o , m , p} ), 97.81 (C-2), 75.70 (C-6), 68.94 (C-4), 63.86 (C-7), 55.16
(C-5), 45.10 (CH₂), 41.79 (C-3); ESI-MS: m/z = 420 ([M + Na + 4 H₂O]⁺, 100), 402 ([M + Na + 3 H₂O]⁺, 95)