(1H, dd, J6B,6A 17.6, J6B,5 4.5, H-6B), 3.68 (3H, s, OCH3), 4.37 (1H,
dd, J4,5 6.9, J4,3 6.0, H-4), 4.73 (1H, dd, J3,4 6.0, J3,2 3.6, H-3), 5.75
(1H, ddd, J5,6A 7.1, J5,4 6.9, J5,6B 4.5, H-5), 6.89 (1H, m, H-2), 6.90
(1H, dd, J 1.7 and 0.9, H-imidazole), 7.48 (1H, s, H-imidazole) and
8.18 (1H, s, H-imidazole); dC (75.5 MHz, C2HCl3) 25.87 (CH3),
25.90 (C-6), 27.73 (CH3), 52.24 (OCH3), 71.92 (C-4), 73.53 (C-
3), 79.21 (C-5), 110.45 (C-9), 117.91 (C-imidazole), 129.30 (C-1),
130.88 (C-imidazole), 134.09 (C-2), 136.75 (C-imidazole), 165.80
colour of the solution changed from green to brown upon addition
of the peroxide. The mixture was stirred at room temperature for
24 h, the solution was cooled to 0 ◦C and the excess tert-butyl
hydroperoxide was destroyed by addition of saturated aqueous
sodium sulfite (2 ml). After stirring for 30 min at room temperature
the solution was filtered through a thin pad of silica gel and the
solvents were removed in vacuo to give a yellow oil which was
purified by column chromatography on silica gel eluting with ethyl
acetate to give methyl (1R,2S)-1,2-epoxy-5-deoxyshikimate 24 as
=
(ester) and 183.12 (C S).
colourless crystals (157 mg, 57%), mp 63.5–64 ◦C; [a]D −64.5
22
(c 0.45, MeOH); m/z (ES+) found 206.1029, [C8H12O5 + NH4]+
Methyl 3,4-O-isopropylidine-5-deoxyshikimate (22)
requires 206.1028; mmax (KBr)/cm−1 3381 (OH) and 1734 (ester);
2
A solution of methyl 3,4-O-isopropylidine-5-O-thicarbonylimida-
zoleshikimate 21 (8.7 g, 25.7 mmol) and AIBN (380 mg,
2.30 mmol) in toluene (200 ml) was heated at reflux under argon.
Tri-n-butyltin hydride (7.8 ml, 28.9 mmol) was added dropwise
over 10 min and the solution was heated at reflux for 3 h. The
mixture was cooled to room temperature and the solvent was
removed in vacuo to give an orange oil. The crude product was
purified by column chromatography on silica gel eluting with
petroleum ether–ethyl acetate (9 : 1) to remove tin residues,
and petroleum ether–ethyl acetate (3 : 2) to give methyl 3,4-O-
isopropylidine-5-deoxyshikimate 22 as a colourless oil (3.91 g,
dH (500 MHz, C6 H6) 0.99 (1H, m, J5A,5B 14.4, J5A,6A 7.4, J5A,6B 6.6,
J5A,4 3.0, H-5A), 1.34 (1H, dddd, J5B,5A 14.4, J5B,4 7.4, J5B,6B 6.8,
J5B,6A 5.6, H-5B), 1.80 (1H, dddd, J6A,6B 15.8, J6A,5A 7.4, J6A,5B 5.6,
J6A,2 0.9, H-6A), 2.11 (1H, ddd, J6B,6A 15.8, J6B,5B 6.8, J6B,5A 6.6,
H-6B), 3.19 (3H, s, OCH3), 3.25 (1H, br ddd, J4,5B 7.4, J4,3 4.7,
J4,5A 3.0, H-4), 3.35 (1H, dt, J2,3 3.4, J2,6A = J2,4 = 1.5, H-2) and
3.42 (1H, dd, J3,4 4.7, J3,2 3.4, H-3); irradiation at H-4 converted
H-2 to dd, J2,3 3.4, J2,6A 1.5; dC (75.5 MHz, C2HCl3) 20.30 (C-5),
24.86 (C-6), 53.20 (OCH3), 60.33 (C-1), 61.16 (C-2), 66.50 (C-4),
68.81 (C-3) and 169.68 (ester).
25
72%); [a]D +30.6 (c 5, CHCl3); m/z (ES+) found 230.1391,
Methyl (1R,2S)-3,4-O-isopropylidine-1,2-epoxy-5-deoxyshikimate
(25)
[C11H16O4 + NH4]+ requires 230.1392; m/z (CI) 213 [M + H]+;
mmax (film)/cm−1 1717 (ester); dH (300 MHz, C2HCl3) 1.34 (3H, s,
CH3), 1.36 (3H, s, CH3), 1.76 (1H, m, H-6A), 2.02 (1H, m, H-6B),
2.20–2.33 (2H, m, H-5), 3.74 (3H, s, OCH3), 4.33 (1H, ddd, J4,5A
5.6, J4,3 5.3, J4,5B 2.9, H-4), 4.57 (1H, m, J3,4 5.3, J3,2 3.5, H-3) and
6.76 (1H, m, H-2); dC (75.5, C2HCl3) 19.41 (C-5), 25.25 (CH3),
26.45 (C-6), 28.10 (CH3), 52.12 (OCH3), 71.83 (C-4), 72.35 (C-3),
109.17 (C-9), 132.87 (C-1), 135.30 (C-2) and 167.49 (ester).
Methyl (1R,2S)-1,2-epoxy-5-deoxyshikimate 24 (250 mg,
1.32 mmol) was dissolved in dichloromethane (10 ml) and
2,2-dimethoxypropane (10 ml) and stirred with ( )-10-
camphorsulfonic acid (25 mg) at room temperature for 3 h.
The solution was washed with aqueous sodium carbonate (1 M,
10 ml) and dried (MgSO4), and the solvents were removed in
vacuo to give methyl (1R,2S)-3,4-O-isopropylidine-1,2-epoxy-5-
deoxyshikimate 25 as a colourless oil (301 mg, quant.) which was
Methyl 5-deoxyshikimate (23)
37
not further purified; [a]D −69.5 (c 3, CHCl3); m/z (ES+) found
A mixture of methyl 3,4-O-isopropylidine-5-deoxyshikimate 22
(2.0 g, 9.43 mmol) and Amberlite IR-120 (H+) (1.5 g) in methanol
(50 ml) was heated at reflux for 16 h and allowed to cool to room
temperature. The solution was filtered and the resin was washed
with methanol (2 × 50 ml). The filtrates were combined and the
solvent was removed in vacuo to give a yellow oil which was purified
by column chromatography on silica gel eluting with ethyl acetate
to give methyl 5-deoxyshikimate 23 as a colourless solid (1.27 g,
246.1330, [C11H16O5 + NH4]+ requires 246.1341; mmax (film)/cm−1
1738 (ester); dH (300 MHz, C2H3CO2H) 1.31 (3H, s, CH3), 1.42
(3H, s, CH3), 1.51 (1H, m, H-5A), 1.73 (1H, m, H-5B), 2.13 (2H,
m, H-6), 3.66 (1H, d, J2,3 3.3, H-2), 4.02 (1H, ddd, J4,5 6.5, J4,3
ꢀ
7.3, J4,5 10.5, H-4) and 4.45 (1H, dd, J3,4 7.3, J3,2 3.3, H-3); dC
(75.5 MHz, C2HCl3) 20.27 (C-6), 24.27 (C-5), 25.51 (CH3), 27.59
(CH3), 53.15 (OCH3), 56.67 (C-2), 59.01 (C-1), 71.89 (C-4), 72.45
(C-3), 109.5 (C-9) and 170.63 (ester).
79%), mp 68.5–69.8 ◦C; [a]D −86.2 (c 1.0, MeOH); m/z (EI)
22
found 172.0735, C8H12O4 requires 172.0736; m/z (EI) 172 [M]+;
mmax (KBr)/cm−1 1711 (ester); dH (300 MHz, C2HCl3) 1.75 (1H, m,
H-6A), 1.96 (1H, m, H-6B), 2.28 (1H, m, H-5A), 2.49 (1H, m,
H-5B), 3.76 (3H, s, OCH3), 3.69 (1H, m, H-4), 4.29 (1H, m, H-3)
and 6.80 (1H, m, H-2); dC (C2HCl3) 21.58 (C-5), 26.36 (C-6), 52.27
(OCH3), 67.26 (C-4), 67.79 (C-3), 132.92 (C-1), 137.43 (C-2) and
167.53 (ester).
(1R,2R,3R,4S)-[2-2H1]-3,4-O-Isopropylidine-1-hydroxy-D-1-[C2H2-
hydroxymethyl]-cyclohexan-3,4-diol (26) from the epoxide (25)
Lithium aluminium deuteride (37 mg, 0.88 mmol) was added to
a solution of methyl (1R,2S)-3,4-O-isopropylidine-1,2-epoxy-5-
deoxyshikimate 25 (100 mg, 0.44 mmol) in diethyl ether (10 ml)
at −78 ◦C under argon. The mixture was stirred at −78 ◦C for
5 h, methanol (1 ml) was added and the mixture was stirred at
0
◦C for 1 h. The solvent was removed in vacuo. The resulting
Methyl (1R,2S)-1,2-epoxy-5-deoxyshikimate (24)
solid was dissolved in ethyl acetate and filtered. The solvent was
removed in vacuo to give a white solid which was purified by
column chromatography on silica gel eluting with ethyl acetate to
yield (1R,2R,3R,4S)-[2-2H1]-3,4-O-isopropylidine-1-hydroxy-D-1-
[C2H2-hydroxymethyl]-cyclohexan-3,4-diol 26 as a colourless oil
Freshly prepared tert-butyl hydroperoxide in dichloromethane16
(3.5 M in dichloromethane, 0.84 ml, 2.94 mmol) was added
dropwise to a stirred solution of methyl-5-deoxyshikimate 23
(250 mg, 1.47 mmol) and vanadyl acetylacetonate (20 mg, 7.35 ×
◦
28
10−5 mol) in dichloromethane (20 ml) at 0 C under argon. The
(74 mg, 83%); [a]D −38.6 (c 6.0, CHCl3); mmax (film)/cm−1 3399
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 569–580 | 575
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