314
R. Csuk – S. Albert · A Short Synthesis of Rhaponticin and its 3”-Fluoroanalog
The combined organic phases were dried (Na2SO4), the 2,4,6-Tri-O-acetyl-3-deoxy-3-fluoro-α-D-glucopyranosyl
solvent was evaporated and the crude product purified by bromide (10)
chromatography (silica gel, dichloromethane/hexane 3:1)
A solution of 3-deoxy-3-fluoro-1,2:5,6-di-O-isopropylid-
to afford 8 (1.77 g, 84 %) as a slightly yellowish solid.
ene-α-D-glucofuranose (9) (4.0 g, 15.2 mmol) in water
(25 mL) con◦taining conc. sulfuric acid (98 %, 2 mL) was
stirred at 25 C for 24 h. The reaction mixture was neutral-
ized by careful addition of solid sodium hydrogencarbonate,
and the solvents were removed under reduced pressure. The
residue was suspended in methanol (50 mL), the mixture
filtered and the filtrate evaporated. The residue was slowly
added to a mixture of HClO4 (70 %, 0.25 mL) in Ac2O
(5 mL) keeping the temperature < 30 ◦C. After completion of
the reaction (as monitored by tlc), water (20 mL) was added,
and the product was extracted with dichloromethane (4 ×
25 mL). The organic layer was washed (aq. NaHCO3, water,
brine, 10 mL each) and dried (Na2SO4), and the solvents
were evaporated. The residue was re-dissolved in dry di-
chloromethane (30 mL), and HBr in AcOH (6 mL, 30 %) was
added. Stirring in the dark at 25 ◦C was continued for another
12 h. The reaction mixture was poured onto ice/water and
extracted with dichloromethane (5 × 25 mL). The organic
phase was washed (NaHCO3, water, brine, 10 mL each),
dried (Na2SO4) and evaporated to yield 10 (3.1 g, 55 %) as a
highly viscous oil [28]. – [α]D = + 174.4◦ (c = 0.3, CHCl3). –
IR (KBr): ν = 2948s, 2119m, 1747s, 1434s, 1371s, 1326m,
1215s, 1156s, 1112s, 1041s cm−1. – 1H NMR (400 MHz,
M. p. 57 – 58 ◦C (lit. [25]: 56 – 57 ◦C). – IR (KBr): ν =
3317br, 3088m, 3005m, 2961m, 2933m, 2839m, 1612m,
1579s, 1512s, 1461m, 1440s, 1341s, 1271s, 1263s cm−1. –
1
UV/vis (MeOH): λmax (log ε) = 233 nm (4.37). – H NMR
(400 MHz, CDCl3): δ = 7.03 (d, 1 H, J = 1.9 Hz, 6-H), 6.84
(dd, 1 H, J = 8.2, 1.9 Hz, 4-H), 6.77 (d, 1 H, J = 8.2 Hz,
3
3
3-H), 6.61 (dd, 1 H, JH,H (trans) = 17.6 Hz, JH,H (cis)
=
3
17.6 Hz, 7-H), 5.58 (d, 1 H, JH,H(transꢀ) = 17.6 Hz, 8’a-H),
5.09 (d, 1 H, JH,H(cis) = 10.8 Hz, 8’b-H), 3.87 (s, 3 H,
3
OCH3). – 13C NMR (100 MHz, CDCl3): δ = 146.4 (C-2),
145.6 (C-1), 136.3 (C-7), 131.5 (C-5), 118.8 (C-4), 112.1
(C-8), 111.6 (C-6), 110.5 (C-3), 56.0 (OCH3). – MS (EI,
70 eV): m/z (%) = 150 (57), 135 (100), 120 (53), 107 (32),
77 (37). – C9H10O2 (150.17): calcd. C 71.98, H 6.71; found
C 71.92, H 6.65.
Rhaponticin (1)
To a solution of 6 (1.66 g, 2.9 mmol) in triethanolamine
(10 mL) containing palladium acetate (10 mg, 0.04 mmol),
compound 8 (0.44 g, 2.9 mmol) was added, and the mix-
◦
◦
ture was heated at 100 C for 4 h. After cooling to 25 C,
ethanol (50 mL) was added, the mixture was filtered, and the
solvents were removed from the filtrate under reduced pres-
sure. The crude product was purified by chromatography (sil-
ica gel, dichloromethane/methanol 9:1) to a◦fford 2 (1.03◦g,
82 %) as a colorless solid. M. p. 235 – 238 C (lit.: 230 C
[10], 236 – 238 ◦C [26]); [α]D = −60.45◦ (c = 0.5, acetone),
(lit. [27]: −59.5◦ (acetone)). – IR (KBr): ν = 3482br, 2900w,
2361w, 1758w, 1611w, 1584w, 1513w, 1460w, 1439w,
1317w, 1292w, 1260w, 1213w, 1175w, 1145w, 1132w,
1085w, 1059w, 1026w cm−1. – UV/Vis (MeOH): λmax (log
ε) = 343 nm (4.45). – 1H NMR (400 MHz, [D6]DMSO): δ =
3
CDCl3): δ = 6.57 (d, 1 H, J1-H,2-H = 3.9 Hz, 1-H), 5.27
3
3
3
(ddd, 1 H, J3-H,4-H = 8.9 Hz, J4-H,5-H = 8.9 Hz, JF,4-H
=
=
=
12.8 Hz, 4-H) 4.88 (ddd, 1 H, 2J3-H,F = 54.5 Hz, 3J3-H,2-H
9.2 Hz, J3-H,4-H = 8.9 Hz, 3-H), 4.87 (ddd, 1 H, J2-H,F
9.4 Hz J2-H,H-1 = 3.9 Hz, J2-H,3-H = 8.9 Hz, H-2), 4.26 –
3
3
3
3
4.16 (m, 2 H, 6a,b-H), 4.19 (m, 1 H, H-5), 2.13, 2.11 and
2.07 (each s, 3 H, CH3). – 13C NMR (100 MHz, CDCl3): δ =
2
170.3 (C=O), 169.6 (C=O), 169.0 (C=O), 89.4 (d, JC,F
183.3 Hz, C-3), 86.2 (d, 4JC,F = 9.3 Hz, C-1), 72.1 (d, 4JC,F
7.0 Hz, C-5), 70.9 (d, 3JC,F = 18.4 Hz, C-4), 71.9 (d, 3JC,F
=
=
=
7.00 (d, 1 H, 4J2-H,6-H = 1.9 Hz, 2-H), 6.96 (d, 1 H, 3JH,H
=
=
19.2 Hz, C-2), 67.2 (s, C-6) 20.6 (s, CH3), 20.6 (s, CH3),
3
4
20.5 (s, CH3). – 19F NMR (188 MHz, CDCl3): δ = −202.5
16.3 Hz, 1-H), 6.93 (dd, J5-H,6-H = 8.5 Hz, J2-H,6-H
1.9 Hz, 6-H), 6.87 (d, 1 H, 3J5-H,6-H = 8.5 Hz, 5-H), 6.82 (d,
1 H, 3JH,H = 16.3 Hz, 2-H), 6.71 (s, 1 H, 2’-H), 6.56 (s, 1 H,
6’-H), 6.33 (s, 1 H, 4’-H), 4.79 (d, 1 H, 3J1”-H,2”-H = 7.6 Hz,
1”-H), 3.75 (s, 3 H, OCH3), 3.59 (m, 2 H, 6”-CH2), 3.33 (m,
2
3
3
(ddd, 1 F, JF,3-H = 54.5 Hz, JF,2-H = 9.4 Hz, JF,4-H
=
12.8 Hz). – MS (EI, 70 eV): m/z (%) = 372 (0.05), 370 (0.05),
291 (3), 169 (24), 139 (3), 127 (9), 109 (18), 43 (100). –
HRMS for C12H16BrFO4 (371.15): calcd. 370.00634, found
370.00632.
1 H, 5”-H), 3.27 (m, 1 H, 3”-H), 3.21 (d, 1 H, 3J1”-H,2”-H
=
7.6 Hz, 2”-H), 3.15 (m, 1 H, 4”-H). – 13C NMR (100 MHz,
[D6]DMSO): δ = 159.0 (C-3’), 158.4 (C-5’), 147.8 (C-4),
146.7 (C-3), 139.2 (C-1’), 130.1 (C-1), 128.7 (CH=), 126.2
(CH=), 118.7 (C-6), 113.0 (C-2), 112.3 (C-5), 107.3 (C-6’),
105.0 (C-2’), 103.0 (C-4’), 100.7 (C-1”), 77.2 (C-5”), 76.8
(3-Hydroxy-5-iodophenyl) 2,4,6-tri-O-acetyl-3-deoxy-3-
fluoro-β-D-glucopyranoside (11)
To a solution of 5 (2.1 g, 8.5 mmol) in acetonitrile
◦
(C-3”), 73.4 (C-2”), 69.9 (C-4”), 60.8 (C-6”), 55.7 (OCH3). – (20 mL) at 25 C, compound 10 (3.15 g, 8,5 mmol) was
MS (EI, 70 eV): m/z (%) = 420 (7), 278 (5), 258 (100), 225 added, and the mixture was stirred for 30 min. Silver car-
(15), 197 (36), 169 (11), 150 (41), 135 (34). – C21H24O9 bonate (2.4 g, 8.7 mmol) was added, and the mixture was
.0.5 H2O (429.42): calcd. C 58.74, H 5.87; found C 58.59, stirred for another 8 h and filtered, and the solvents were
H 5.91.
removed from the filtrate. Chromatography (silica gel, hex-
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