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Can. J. Chem. Vol. 78, 2000
20 h. The yellow solution was concentrated to half volume
by partial evaporation of the solvent under reduced pressure
and then poured into water (40 L). The white solid formed
was filtered and re-dissolved in Et2O (10 L). The solution
was washed with brine (3 × 1 L), treated with anhydrous
MgSO4 and charcoal, and filtered through a pad of Celite®.
The pale yellow filtrate was concentrated under reduced
pressure to give a white solid which, after drying under re-
duced pressure for 3 h, afforded B′ as an amorphous product
(1.27 kg, 100% mass recovery, containing 2.47% w/w of
1,4-dioxane): mp 124–125°C; 1H NMR (CDCl3) δ : 5.70
(broad s, 1H), 5.54 (d, J = 1.6 Hz, 1H), 4.54–4.48 (m, 1H),
4.43 (ddd, J = 7.9, 3.5, 3.2 Hz, 1H), 4.30–4.22 (m, 2H),
2.89 (dd, J = 17.4, 10.2 Hz, 1H), 2.86 (dd, J = 14.1, 5.1 Hz,
1H), 2.64 (dd, J = 17.4, 4.3 Hz, 1H), 2.53 (dd, J = 14.1,
8.6 Hz, 1H), 2.37 (sept d, J = 7.0, 3.5 Hz, 1H), 0.91 (d, J =
7.0 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H); MS (FAB) m/z:
348/350 (M+). Anal. calcd. for C13H18NO5Br (+ 2.47% w/w
1,4-dioxane): C 45.08, H 5.32, N 3.92; found: C 45.15, H
5.69, N 3.62.
concentrated under reduced pressure to remove the THF.
The aqueous extract was extracted with EtOAc (6 × 1 L) and
the combined organic extracts were extracted with saturated
NaHCO3 (8 × 500 mL). The combined aqueous extracts con-
taining the carboxylic acid sodium salt were extracted manu-
ally with ether (7 × 750 mL) and then submitted to
continuous extraction with Et2O (4 L) for 17 h. All the or-
ganic extracts were combined and evaporated to dryness al-
lowing recovery of the chiral auxiliary. The aqueous extracts
were acidified with solid citric acid to pH 3 and extracted
with EtOAc (4 × 1 L). The combined organic extracts were
washed with brine (2 × 600 mL), treated with anhydrous
MgSO4 and charcoal, filtered through Celite®, and concen-
trated under reduced pressure. The resulting gummy residue
was further dried at 45°C under reduced pressure for 8 h to
afford acid 10 as a yellow glassy solid (1.51 kg, 77%) con-
taminated with EtOAc (2.5% w/w) and residual chiral auxil-
1
iary (2.5% w/w): H NMR (CDCl3) δ : 10.00 (broad s, 1H),
8.62, 8.58, 8.55, 8.53 (4d, J = 4.4, 4.8, 5.1, 5 Hz, 1H), 7.73–
7.66 (m, 1H), 7.33–7.17 (m, 2H), 5.74, 5.69, 5.63 (3s, 1H),
5.50, 5.47, 5.45 (3 broad s, 1H), 4.09–3.85 (m, 2H), 3.77–
3.60 (m, 2H), 3.25–3.04 (m, 5H), 2.98, 2.97, 2.94, 2.90 (4s,
3H), 2.99–2.88, 2.74–2.67 and 2.51–2.30 (m, 4H), 1.76–1.44
(m, 6H), 1.27–1.13 (m, 3H), 0.95–0.85 (m, 2H); MS
(FAB) m/z: 508/510 (MH+). Homogeneity was determined
to be 97.8% (chiral auxiliary not detected by UV) by RP-
HPLC (A). This acid (10) was used directly in the subse-
quent reaction.
3-[4-Bromo-2(S)-[2-[(cyclohexylmethyl)[2-[methyl[2-(2-py-
ridinyl)ethyl]amino]-2-oxoethyl]amino]-2-oxoethyl]-1-oxo-
4-pentenyl]-4(S)-(1-methylethyl)-2-oxazolidinone (9): Et3N
(1.02 L, 7.30 mol) was added in one portion to a solution of
B′ (1.27 kg, 3.65 mol) in dry THF (5 L). The mixture was
cooled to –45°C and iso-butyl chloroformate (497 mL, 3.83
mol) was added dropwise over a 30 min period while main-
taining the temperature below –40°C. After stirring for
30 min, a solution of amine A (1.16 kg, 3.99 mol, 1.1 equiv.)
in dry THF (2 L) was added dropwise over 45 min and the
resulting mixture was stirred at room temperature for 2.5 h.
H2O (7 L) was added and the mixture was extracted with
EtOAc (6 × 1 L). The combined organic extracts were
washed successively with a 10% citric acid solution (6 ×
500 mL), H2O (2 × 1 L), saturated NaHCO3 solution (3 ×
1 L), and brine (2 × 1 L). The solution was treated with an-
hydrous MgSO4 and charcoal, filtered through a pad of
Celite®, and concentrated under reduced pressure to give
amide 9 as a yellow gum (2.27 kg, 100%): 1H NMR
(CDCl3) δ : (3:3:1:1 mixture of rotamers) 8.61, 8.55, 8.51
(3d, J = 4.1, 4.8, 3.8 Hz, 1H), 7.68–7.58 (m, 1H), 7.24–7.11
(m, 2H), 5.72, 5.67, 5.64 (3s, 1H), 5.52, 5.51, 5.48, 5.46 (4d,
J = 1.6, 1.3, 1.3, 1.6 Hz, 1H), 4.57–4.47 (m, 1H), 4.45–4.40
(m, 1H), 4.28–4.17 (m, 2H), 4.17–3.68 (m, 4H), 3.50–3.30
and 3.19–2.83 (m, 5H), 2.97, 2.95, 2.90, 2.87 (4s, 3H),
2.75–2.54 (m, 2H), 2.43–2.36 (m, 1H), 2.15–2.07 (m, 1H),
1.76–1.45 (m, 6H), 1.29–1.15 (m, 3H), 0.95–0.85 (m, 8H);
MS (FAB) m/z: 619/621 (MH+). The material was used di-
rectly in the subsequent reaction.
N4-(Cyclohexylmethyl)-N4-[2-[methyl[2-(2-pyridinyl)ethyl]amino]-
2-oxoethyl]-N1-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-
5-methylhexyl]-2(S)-(2-bromo-2-propenyl)butanediamide (1):
A mixture of acid 10 (1394 g, 2.74 mol), aminodiol C
(704.5 g, 2.89 mol), and TBTU (880.4 g, 2.74 mol, 1 equiv.)
was dissolved in MeCN (7 L) and cooled to 0–5°C under an
inert atmosphere before i-Pr2NEt (1433 mL, 8.23 mol) was
added portionwise over a 15 min period raising the tempera-
ture to 15°C. The bath was removed and the mixture was
stirred at room temperature for 2 h. Water (8 L) was added
and the mixture was extracted with EtOAc (6 × 650 mL).
The combined organic extracts were washed successively
with 10% citric acid solution (6 × 1 L), water (6 × 1 L), sat-
urated NaHCO3 solution (4 × 1 L), and brine (2 × 1 L). The
organic solution was treated with anhydrous MgSO4 and
charcoal, and filtered through a pad of Celite®. The solution
was filtered twice through a pad of silica gel and washed
with EtOAc (2 × 5 L). The combined organic filtrates were
concentrated under reduced pressure to give a 6 L solution
which was left at room temperature overnight to allow crys-
tallization. The solid was filtered, washed with hexane (3 ×
1 L), and dried overnight under reduced pressure to afford a
first crop of 1 as white micro-needles (1.20 kg, 59.9%): mp
2(S)-(2-Bromo-2-propenyl)-4-[(cyclohexylmethyl)[2-[methyl[2-
(2-pyridinyl)ethyl]amino]-2-oxo-ethyl]amino]-4-oxobutanoic acid
(10): To a mechanically stirred solution of the crude tertiary
amide 9 (2269 g, 3.65 mol) in a 6:1 THF:H2O mixture
(16 L) cooled to 0°C, was added a 30% H2O2 solution
(2042 mL, 18.31 mol). After 10 min, LiOH•H2O (384 g,
9.16 mol) was added and the mixture was stirred vigorously
for 40 min. A Na2SO3 solution (2552 g in 5.7 L of H2O) was
slowly added over 40 min while keeping the temperature be-
low 25°C. After stirring for an additional 15 min to ensure
complete neutralization of the peroxide, the solution was
1
139–141°C; H NMR (DMSO-d6) δ : (1.7:1.0:1.0 mixture of
rotamers) 8.54–8.51, 8.48 (m and d, J = 4.8 Hz, 1H), 7.75–
7.67 (m, 2H), 7.33–7.19 (m, 2H), 5.77, 5.71, 5.68 (3s, 1H),
5.42, 5.40, 5.38 (s and 2d, J = 1.5, 1.5 Hz, 1H), 4.61
(broad s, 1H), 4.51 (broad s, 1H), 4.21–3.88 (m, 3H), 3.70–
3.54 (m, 2H), 3.10–2.85, 2.84, 2.80 (m and 2 s, 10H), 2.70–
2.65 (1H), 2.52–2.05 (m, 3H), 1.76–1.10 (m, 23H), 0.92–
0.70 (m, 4H), 0.86 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.6 Hz,
3H); MS (FAB) m/z: 733/735 (MH+). Anal. calcd. for
© 2000 NRC Canada