showed 98.2% 8 and 0.2% 7. The reaction mixture was
neutralized with Et3N (0.216 kg; 2.13 mol) and concentrated
at e35 °C under reduced pressure (20 mbar). Residual
3-pentanone (ca. 3%) in the crude product was removed by
azeotropic distillation with cyclohexane (2 × 9.0 L) at 150-
50 mbar and 30 °C. The remaining oil was dissolved in
CH2Cl2 (6.0 L), and the solution was extracted with aqueous
NaHCO3 (7.5%, 13.5 kg). The organic layer was washed
with H2O (8.1 L) and concentrated under reduced pressure
(200-50 mbar, 30 °C) to afford pentylideneketal 8 as a
yellow oil in 98% yield (7.97 kg, HPLC assay 98.7% w/w,
22.6 mol). 8 can be stored as a 40% solution in CH2Cl2 at 5
°C.
under reduced pressure (200 mbar, 35 °C) to a residual
volume of 28 L. The pale yellow solution was cooled to
-18 °C in 3 h. At 15 °C, the product crystallized spontane-
ously. The suspension was stirred at -18 °C for 2 h. The
product was collected by centrifugation and washed with cold
(-15 °C) n-hexane (2.2 L). It was dried (30 °C, 20 mbar, 4
h) to constant weight to yield 1.55 kg 10 (6.03 mol, HPLC
assay 98.9% w/w, 80 % yield) as a fluffy white solid.
Shikimic Acid Route. Ethyl (3R,4S,5R)-3,4,5-Trihy-
droxy-cyclohex-1-ene-carboxylate (Ethyl Shikimate) (24).
To a stirred suspension of (-)-shikimic acid ((3R,4S,5R)-
3,4,5-trihydroxy-cyclohex-1-ene-carboxylic acid) 23 (2.00 kg,
GC assay 91.6% m/m, 10.5 mol) in EtOH (8.0 L) was added
SOCl2 (0.61 kg, 5.13 mol) in 30 min, followed by toluene
(0.8 L) to rinse the lines. During the addition of SOCl2 the
temperature rose from rt to 35 °C. Upon completion of the
addition, the reaction mixture was heated to boiling tem-
perature for 3 h. After about 1 h, all of the shikimic acid
had dissolved, and a dark brown solution resulted. The
reaction mixture was cooled to 40 °C in 45 min and
concentrated under reduced pressure (100 mbar) at this
temperature. GC analysis of the reaction mixture showed
1.7% of 23 and 90.7% of 24. Ethyl shikimate 24 was
obtained as viscous, brown oil (2.2-2.7 L), containing
approximately 20% of EtOH. It was used in the next step
without further purification.
For spectroscopic characterization a sample of 24 was
prepared by reacting 23 (GC assay 98%) with EtOH in the
presence of H2SO4 (0.05 equiv) at boiling temperature for
23 h. Crude 24 was recrystallized from t-BuOMe. Data for
24: 1H NMR (250 MHz, d6-DMSO) 1.22 (t, J ) 7.1, 3H),
2.05, 2.42 (2dm, J ) 17.8, 2H), 3.58 (m, 1H), 3.85 (m, 1H),
4.12 (q, J ) 7.1, 2H), 4.22 (m, 1H), 4.64 (d, J ) 4.2, 1H),
4.83 (d, J ) 4.2, 1H), 4.85 (s, 1H), 6.62 (s, 1H); IR (nujol)
3351 (s), 3194 (s), 2924 (s), 2871 (s), 1722 (s), 1658 (m),
1464 (m), 1371 (m), 1237 (s), 1093 (s); MS (EI) 202 (M+,
2.2), 185 (4.3), 173 (7.2), 156 (32), 143 (37), 138 (23), 110
(20), 97 (100). Anal. Calcd for C9H14O5 (202.206): C, 53.46;
H, 6.98. Found: C, 53.18; H 7.03.
Ethyl (3aR,7R,7aS)-2,2-Dimethyl-7-hydroxy-3a,6,7,7a-
tetrahydro-benzo[1,3]dioxole-5-carboxylate (Ethyl 3,4-O-
Isopropylidene Shikimate) (26). To the crude ethyl shiki-
mate 24, EtOAc (13.6 L), 2,2-dimethoxypropane (1.070 kg,
10.3 mol) and TsOH‚H2O (0.020 kg, 0.105 mol) were added.
At a vacuum of 150-200 mbar the reaction mixture was
heated to boiling temperature (30-35 °C) applying a jacket
temperature of 50 °C. The solvents (a mixture of EtOAc,
2,2-dimethoxypropane, MeOH and EtOH) were removed by
distillation, and after about 2 h the initial volume was reduced
by half. A second equivalent of 2,2-dimethoxypropane (1.070
kg, 10.3 mol) was added and the distillation at 30-35 °C
was continued for further 2 h. The reaction mixture was then
evaporated to dryness at 20 mbar. Acetonide 26 was obtained
as a dark brown oil (assay by GC: 86.1% area) and was
used in the next step without further purification. For
spectroscopic characterization a sample of 26 was purified
by column chromatography on SiO2 using CH2Cl2 as eluent.
Data for 26: 1H NMR (250 MHz, CDCl3) 1.30 (t, J ) 7.2,
Ethyl (3R,4R,5R)-3-(1-Ethyl-propoxy)-4-hydroxy-5-
methanesulfonyloxy-cyclohex-1-ene-1-carboxylate (9). To
a cold (-32 to -36 °C) solution of pentylidene ketal 8 (2.63
kg, 7.55 mol) in CH2Cl2 (21.0 L, H2O content 0.02%),
Et3SiH (1.18 kg, 10.2 mol) was added. A solution of TiCl4
(1.60 kg, 8.47 mol) in CH2Cl2 (1.95 L) was added at a rate
such that the temperature of the reaction mixture did not
exceed -32 °C. The addition of TiCl4 was completed after
90 min. Stirring at -36 to -32 °C was then continued for
another 2 h. To monitor the reaction progress, a 30-mL
sample of the reaction mixture was drawn and quenched as
described below. HPLC analysis of the organic layer
indicated that all of the starting material 8 had been
consumed (0.20%). The reaction mixture was rapidly added
to a stirred ice/H2O mixture (9.4 kg, 17.0 L) and the
connecting lines were washed with CH2Cl2 (2.5 L). The
resulting biphasic mixture had a temperature of -3 °C and
was warmed to 5 °C applying a maximum jacket temperature
of 35 °C. The organic layer was washed with aqueous
NaHCO3 (7.5%, 18.4 kg) and concentrated under reduced
pressure (400-200 mbar, 35 °C). Hydroxyether 9, a beige
solid, was dissolved in EtOH (10.6 L) and used in the next
step. Optional crystallization: Traces of CH2Cl2 were
evaporated at reduced pressure (50 mbar, 35 °C), the dry
crystalline residue was suspended in hexane (6.9 L), and the
solvent was evaporated. The solid was dissolved in EtOAc
(1.25 L) at 30 °C, and hexane (19.3 L) was added to the
solution over 60 min. Crystallization set in spontaneously
after about 5 L hexane had been added. The suspension was
cooled to -20 °C in 2 h and stirred for 1 h at this
temperature. The product was collected by centrifugation and
washed once with cold (-20 °C) hexane (5.75 L). It was
dried (35 °C, 20 mbar, 4 h) to constant weight to yield 2.32
kg hydroxyether 9 (HPLC assay 98% w/w, 6.49 mol, 87%
yield) as an off-white solid.
Ethyl (3R,4S,5S)-4,5-Epoxy-3-(1-ethyl-propoxy)-cyclo-
hex-1-ene-1-carboxylate (10). To the stirred solution of
crude hydroxyether 9 in EtOH was added aqueous NaHCO3
(7.5%, 14.0 kg). The reaction mixture was heated to 60-65
°C in 60 min, and stirring at this temperature was continued
for 1.5 h. After this time HPLC showed that all of the starting
material had been consumed (9 < 0.10%). The reaction
mixture was cooled to 35 °C in 30 min and extracted with
n-hexane (4 × 17.3 L). The combined organic layers were
washed once with H2O (10.2 L) at 35 °C and concentrated
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