4
5 min, the mixture was gradually warmed to 35-40 °C
in a vacuum tumble drier at 40-50 °C, 379 lbs (52.5%) of
the alcohol 13 was obtained.
and held for 1 h to afford the vinylborane intermediate 17.
Preparation of Alkene 7. The vinylborane solution from
the previous step was cooled to 20-25 °C and 4 M aqueous
KOH (33 mL, 0.132 mol) added slowly as hydrogen
evolution occurred. The solution was then treated with
Preparation of Epoxone (10). The alcohol 13 (220 lbs),
TBAB (3 lbs), K
stirred in DEM (556 lbs) and H
NaIO (268 lbs) in H O (224 gal) was mixed separately and
2
CO
3
3 2
(27 lbs), and RuCl ‚H O (5.5 lbs) were
2
O (26 gal). A solution of
4
2
3
-fluorobenzyl chloride (12 mL, 0.099 mol), Ph
3
P (0.700 g,
added slowly to the alcohol intermediate at <40 °C. The
reaction was then held for 1 h at 25-35 °C, at which point
it was checked for completion by GC (<1% starting
material). When complete, IPA (7 gal) and celite (2 lbs) were
added, and the mixture was stirred for an additional 1 h.
The solution was then filtered and the product extracted into
EtOAc (598 lbs followed by 3 × 198 lbs). The combined
2.67 mmol), and Pd(OAc) (0.150 g, 0.667 mmol). The
2
resultant olive-green mixture was heated to 65-70 °C for 1
h. After atmospherically stripping the THF and hexanes,
MTBE (133 mL) and water (67 mL) were added. The layers
were separated, and the aqueous layer was acidified with
2 4
25% H SO . The acidified aqueous layer was extracted with
toluene (133 mL) at 50-55 °C. The toluene layer was
extracted with KOH solution [from water (93 mL) and 45%
KOH (7 mL)] to generate the aqueous potassium trans-
alkenoate solution required for the epoxidation step. The
concentration of the solution of 7 was determined by HPLC.
Epoxidation of Alkene 7. The potassium trans-alkenoate
solution from the Suzuki cross-coupling was adjusted to pH
extracts were washed with 10% Na
2
SO
3
(22 lbs in 26 gal
H O) followed by 10% brine (22 lbs NaCl in 26 gal H O)
2 2
and then distilled under vacuum to a volume of ap-
proximately 86 gallons. Heptane (102 gal) was added and
approximately the same volume of solvent removed by
vacuum distillation. Additional heptane was then added to
bring the pot volume up to 185 gallons, whereupon the
temperature was adjusted to 50-60 °C. The batch was then
filtered and slowly cooled to crystallise the product. When
a slurry had formed, it was cooled to 0 °C and centrifuged.
The crude product was then recrystallised from IPA (300
gal) by dissolution at 70-75 °C, filtering, and slowly cooling
to 0 °C. The resultant slurry was centrifuged and the solid
washed with IPA (10 gal). After drying in a vacuum tumble
drier at 40-50 °C, 157 lbs (71.9%) of Epoxone (10) was
obtained.
2 4
10.5 with 25% aqueous H SO . The solution was cooled to
between -5 to 5 °C and D-Epoxone (10) (4.3 g, 0.017 mol),
as a solution in acetonitrile (20 mL) was added. While the
mixture was stirred with vigorous agitation, Oxone (45.3 g,
0
.074 mol) in water (160 mL) was added to the mixture.
The temperature was maintained below 10 °C by control of
the Oxone solution charge rate, and the pH was maintained
at 10.0-11.0 by the addition of 20% KOH as necessary.
After the addition was complete, the mixture was held at
1
2
0-15 °C for 1 h. The mixture was adjusted to pH 2 with
5% H SO . Toluene (233 mL) was added, the mixture was
Preparation of the Lithium-4-pentynoate Salt (15). 4-Pen-
tynoic acid (41 lb) was charged to a dry reactor, dissolved
in THF (76 gal), cooled to -10 to 0 °C, and treated with
1.01 equiv of 24% n-butyllithium (113 lb). The resultant
thick, white slurry was held at -10 to 0 °C until the
disiamylborane reagent was prepared.
Preparation of Disiamylborane Reagent. In a precooled
vessel, 1 M borane-THF was charged (557 lb), cooled to
-5 to -15 °C, and treated with isoamylene (88 lb) while
maintaining the temperature below 10 °C. The solution was
maintained at -5 to 5 °C for approximately 30 min to ensure
complete conversion to the disiamylborane reagent.
Preparation of the Vinylborane (17). The disiamylborane
solution prepared above was transferred to the lithium-4-
pentynoate slurry over approximately 30 min while main-
taining the temperature below 0 °C. The mixture was
gradually warmed to 35-40 °C to afford a homogeneous
solution of the desired vinylborane.
Suzuki Coupling. The vinylborane (17) solution, prepared
as described above, was treated with 4 M aqueous KOH (243
lb), and vigorous hydrogen evolution was observed. Next,
3-fluorobenzyl chloride (90 lb) was added, followed by
triphenylphosphine (5 lb) and palladium (II) acetate (1 lb).
The mixture was heated under reflux at approximately 60
°C for 3-6 h. THF was stripped from the mixture by
atmospheric distillation, MTBE was added (621 lb), and the
mixture was circulated through a bag filter. The phases were
separated, and the product was contained in the aqueous
layer, which was then acidified to pH 2 with 25% sulphuric
2
4
heated to 75-80 °C, and the layers were separated. The
organic layer was filtered and concentrated until the pot
volume was approximately 100 mL. The solution was cooled
to 20-30 °C, and heptane (67 mL) was added over
approximately 1 h to crystallise the product. The solids were
filtered, washed with cold heptane (∼15 mL), and dried at
35-40 °C to afford a 55% yield of hydroxylactone 5 in 86%
1
ee; H NMR (300 MHz, CDCl
H), 4.43 (m, 1H), 4.11 (m, 1H), 2.83-2.17 (m, 7H).
Pilot-Plant Scale Experiments. Preparation of Bis-
3
) δ 7.28 (m, 1H), 6.98 (m,
3
acetonide (13). D-Fructose (12) (500 lbs) and 2,2-dimethoxy-
propane (648 lbs) were stirred with acetone (314 gal), and
the mixture was cooled to 0-5 °C. p-Toluenesulphonic acid
(26 lbs) was added and the mixture held at 0-5 °C. for 24
h. When the reaction was complete (>65% 13 as indicated
by GC), water (20 gal) and 50% NaOH solution (12 lbs)
were added. The acetone and methanol were removed by
vacuum distillation. Toluene (66 gal) was added. The mixture
was distilled under vacuum to remove the last traces of
acetone. Additional toluene (266 gal) was then added and
the resultant solution washed with brine (70 lbs of NaCl in
8
2
4 gal of H O) and then water (16 gal). The volume was
then reduced to approximately 120 gallons by vacuum
distillation and the product crystallised by slow addition of
heptane (334 gal) at 50-60 °C followed by slow cooling.
The resultant slurry was cooled to <5°, isolated on the
centrifuge, and washed with heptane (∼10 gal). After drying
50
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Vol. 11, No. 1, 2007 / Organic Process Research & Development