Total Synthesis of the Natural Products Ulmoside A and (2R,3R)-Taxifolin-6-C-β-d-glucopyranoside

^# Both authors contributed equally.

Abstract

An efficient first total synthesis of highly polar ulmoside A and (2R,3R)-taxifolin-6-C-β-d-glucopyranoside, useful for the prevention of metabolic disorders, has been described. Key elements of the synthesis include a Sc(OTf)₃-catalyzed regio- and stereoselective C-glycosidation on taxifolin in 35% yield with d-glucose and chiral semipreparative reverse-phase high-performance liquid chromatography (HPLC) for the separation of both taxifolins and the diastereomeric mixture of taxifolin-6-C-β-d-glucopyranosides. Correlation of the analytical data of synthetic ulmoside A and its diastereomer with a natural ulmoside A sample confirmed the assigned absolute stereochemistry of the natural products.

Key words

flavonoids - C-glycosidation - chiral HPLC - metal triflates - aglycone

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• 14 Ulmoside A (1)A solution of (–)-taxifolin (4) (0.3 g, 0.98 mmol) and d-glucose (0.44 g, 2.46 mmol) was stirred in a mixture of solvents MeCN/H₂O (2:1, 10 mL) heated to reflux in an oil bath for 48 h in the presence of Sc(OTf)₃ (0.19 g, 0.39 mmol). Then, the reaction mixture was subjected to silica gel column chromatography (acetone/EtOAc/H₂O/AcOH 15:30:2:0.1) to afford ulmoside A (1) as a white amorphous powder yield: 0.16 g (35%); [α]_D ²⁵ = +1.56 (c = 0.1, MeOH){lit^2a[α]_D ²⁵ = +1.33 (c = 0.098, MeOH)}. IR (neat): 3325, 2945, 2833, 1646, 1450, 1413, 1017 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 12.47 (s, 1 H, HO-C(5)), 9.03 (s, 1 H, HO-C(4')), 8.98 (s, 1 H, HO-C(3')), 6.84 (s, 1 H, H-2'), 6.71 (s, 2 H, H-5', 6'), 5.87 (s, 1 H, H-8), 5.78 (s, 1 H, HO-C(3)), 4.92 (d, J = 10.9 Hz, 1 H, H-2), 4.82 (br s, 2 H, OH), 4.58 (br s, 1 H, OH), 4.46–4.47 (m, 1 H, H-6''b), 4.45 (d, J = 10.0 Hz, 1 H, H-1''), 4.43 (d, J = 10.9 Hz, 1 H, H-3), 3.96 (t, J = 9.1, 9.3 Hz, 1 H, H-2''), 3.63 (d, J = 10.9 Hz, 1 H, H-6''a), 3.04–3.15 (m, 3 H, H-3'', 4'', 5''). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 198.0 (C-4), 166.0 (C-7), 162.6 (C-5), 161.3 (C-9), 145.8 (C-3'), 145.0 (C-4'), 128.0 (C-1'), 119.4 (C-6'), 115.3 (C-2'), 115.1 (C-5'), 106.0 (C-6), 100.2 (C-10), 94.7 (C-8), 82.9 (C-2), 81.6 (C-5''), 79.1 (C-3''), 72.9 (C-1''), 71.6 (C-3), 70.7 (C-2''), 70.3 (C-4''), 61.6 (C-6''). FAB-MS: m/z 467 [M + H]⁺.