in 2.2 L of THF. The THF solution of 2 was slowly charged to
the LDA solution while holding the temperature at -70 °C.
The resulting mixture was stirred at -70 °C for 1 h while a
light-green enolate slurry formed. Allyl bromide (0.46 kg, 3.8
mol) was added to the reactor, and the resulting mixture slowly
warmed to -40 °C and stirred for 1 h. A sample was taken for
HPLC analysis which indicated >97% conversion of 2. In a
separate vessel, an aqueous solution of dihydrogen sodium
phosphate monohydrate (0.75 kg, 5.4 mol) and water (8 L) was
prepared. The aqueous phosphate solution was charged to the
reaction mixture, allowing the reaction temperature to increase
to 20 °C. EtOAc (2.2 L) was charged to the reaction mixture,
and after mixing, the layers were allowed to separate. The lower
aqueous phase was removed, and the organic layer was washed
two times with water (2 × 6 L). Using vacuum distillation at
<40 °C, the solution was concentrated until the distillation rate
slowed substantially. EtOAc (2.2 L) was charged to the mixture,
and the vacuum distillation continued. When the distillation rate
slowed substantially, distillation was ceased and a sample of
the intermediate 2-(4-benzyloxyphenyl)-pent-4-enoic acid meth-
yl ester 3 was submitted for HPLC analysis. (The area percent
of 3 was >90%. Note: if the area percent of 3 is <90%,
crystallization of 4 becomes difficult.) The crude 2-(4-benzy-
loxyphenyl)-pent-4-enoic acid methyl ester 3 was diluted with
EtOAc (7.5 L) and the resulting mixture cooled to -50 to -55
°C. Ozone was introduced to the reaction mixture below the
surface of the liquid with rapid agitation. (Caution: the
combination of oxygen and EtOAc can present a fire hazard!
To mitigate risk, the outgas stream was diluted with nitrogen
gas.) When the solution turned light-gray/blue, a sample was
submitted for HPLC analysis which indicated >99A% conver-
sion of 3. The reaction mixture was warmed to -30 °C while
purging with nitrogen to remove excess ozone from solution.
Acetic acid (0.75 L) and water (0.75 L) were added to the
reaction mixture, followed by zinc (the zinc used was ∼325
mesh, 99.9% pure). The temperature was kept between -10
and -20 °C during the addition of four portions of zinc (total
of 0.37 kg, 5.6 mol of zinc added). Note: we waited a minimum
of 20 min between additions of zinc to avoid large exotherms).
After the zinc additions were complete, the mixture was stirred
at 0 to -10 °C for 30 min. A sample was submitted for HPLC
analysis which indicated >99.8A% conversion of the ozonide.
At 0 to -10 °C, the reaction mixture was filtered through a
3-in. bed of Celite. The Celite/zinc cake was washed with
EtOAc (3.0 L), the resulting filtrates were combined and washed
two times with water (2 × 4.5 L). Aqueous sodium bicarbonate
(4 wt %) (5 L) was combined with the organic phase and the
resulting mixture stirred for 15 min to give a pH of >7. The
aqueous layer was removed, and vacuum distillation at <30 °C
was employed to reduce the volume of the organic phase by
approximately 4 L. Heptane (6 L) was charged to the mixture,
and the vacuum distillation was continued to give an ending
volume of approximately 8 L. A sample was removed for GC
analysis, which indicated <20% EtOAc by volume when
compared to a reference solvent mixture. The mixture was
cooled to 0-10 °C and stirred for 1 h; the product was filtered
off, washed with heptane (3 L), and dried under vacuum to
constant weight at 45 °C. The title aldehyde 4 (698 g; 80%
isolated yield) was afforded as a tan solid. Mp (DSC) (10 °C/
min) onset 70.68 °C, peak 84.58 °C. IR (KBr pellet) 3441, 2952,
1
2833, 2727, 1729 cm-1. H NMR (400 MHz, CDCl3) δ 9.79
(1H, s), 7.46-7.34 (5H, m), 7.22 (2H, d, J ) 8.8 Hz), 6.96
(2H, d, J ) 8.8 Hz), 5.07 (2H, s), 4.11 (1H, dd, J ) 5.0, 9.6
Hz), 3.69 (3H, s), 3.39 (1H, dd, J ) 9.6, 18.7 Hz), 2.81 (1H,
dd, J ) 5.0, 18.7 Hz). 13C NMR (100 MHz, CDCl3) δ 199.6,
173.4, 158.1, 136.7, 129.8, 128.7, 128.5, 127.9, 127.3, 115.0,
69.8, 52.2, 47.2, 43.8. HRMS (ESI) calcd for C18 H19 O4 (M+)
299.128, found 299.128.
1-((R)-2-Amino-4-methylpentanoic acid)-3-(4-benzyloxyphe-
nyl)pyrrolidin-2-one (5). Under a nitrogen atmosphere, aldehyde
4 (628 g; 2.1 mol) was dissolved in diethoxymethane (DEM)
(6 L), and D-leucine methyl ester hydrochloride (419 g; 2.31
mol) was added, followed by diisopropylethylamine (320 g;
2.48 mol). The resulting mixture was stirred at 20 °C for 30
min and treated with sodium triacetoxyborohydride (540 g; 2.55
mol), giving a temperature rise to 31 °C. After 1 h, HPLC
indicated complete consumption of the starting material. The
resulting mixture was washed with water (2 × 4 L) and heated
to reflux. Distillate (2 L) was removed, and at a pot temperature
of 82 °C the reaction was held for 14 h giving complete
lactamization by HPLC. The reaction mixture was cooled to 5
°C, and aqueous LiOH (60 g; 2.5 mol in 1 L water) and MeOH
(1.5 L) were charged to the reaction. The resulting mixture was
warmed to 20 °C, and held for 4 h. HPLC indicated >95A%
conversion to γ-lactam 5. The pH was adjusted to between 2
to 3 with 1 N HCl and EtOAc (2 L) was charged. The aqueous
layer was removed, and the organic layer was washed with
water (2 × 3 L), concentrated Via distillation to 3.5 L, and held
at 65 °C. Heptane (3 L) was slowly added while holding at 65
°C. After 1 h, the resulting slurry was slowly cooled to 20 °C
and held for 4 h. The solids were filtered and washed with 30%
EtOAc/heptane (1 L) and finally with heptane (2 × 1 L). The
product was dried to constant weight at 50 °C giving γ-lactam
5 (692 g: 86% isolated yield) with a purity of >99.5A% by
HPLC analysis as a tan powder. Mp (DSC) (10 °C/min) onset
129.52 °C, peak 131.55 °C. IR (KBr pellet) 3449, 2958, 2873,
1
2583, 1735, 1632 cm-1. Mixture of diastereomers: H NMR
(400 MHz, CDCl3) δ 9.40 (1H, bs), 7.46-7.33 (5H, m), 7.22
(1H, d, J ) 8.6 Hz), 7.17 (1H, d, J ) 8.6 Hz), 6.96 (2H, d, J
) 8.6 Hz), 5.07 (1H, s), 5.05 (1H, s), 4.92 (1H, dd, J ) 8.0,
15.6 Hz), 3.75 (1H, m), 3.62 (1H, m), 3.42, (1H, m), 2.54 (1H,
m), 2.12 (1H, m), 1.81 (2H, m), 1.55 (1H, m), 0.99 (6H, m).
13C NMR (100 MHz, CDCl3) δ 176.8, 174.7, 174.4, 157.7,
136.8, 131.9, 131.5, 129.1, 128.8, 128.4, 127.7, 127.3, 114.9,
69.8, 52.4, 47.4, 42.3, 42.0, 37.3, 36.8, 28.5, 28.3, 24.9, 23.0,
21.1, 20.9. HRMS (ESI) calcd for C23 H28 NO4 (M+) 382.201,
found 382.202.
1-Chloro-1-nitrosocyclopentane (6). Under a nitrogen at-
mosphere, cyclopentanone oxime (600 g, 6.06 mols), and
MTBE (4.0 L) were combined. The reaction vessel was marked
at the solvent line for later reference, and the agitation was
started. After obtaining a solution, the mixture was held at
20-25 °C. Safety Note: The following addition was exothermic,
and the reactor was vented to an aqueous NaOH scrubber. The
NaOH charge to the scrubber was 5 times the excess of chlorine
gas (1 equiv of the chlorine was consumed by the cyclopen-
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