Lin et al.
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procedures,25a,55 4.80 g, 22.5 mmol) in dichloromethane (70 mL)
over 7 min by cannula under positive nitrogen pressure. The
reaction was stirred at room temperature for 3 h and then
diluted with ethyl acetate. The organic phase was washed with
2 N HCl and the aqueous phase back-extracted once with ethyl
acetate. The combined organic extracts were washed with
saturated aqueous sodium bicarbonate and then brine, dried
with magnesium sulfate, filtered, and concentrated in vacuo.
The crude was purified by silica gel flash chromatography
(hexanes/ethyl acetate, 90:10 to 65:35 v/v) to give 31 (5.43 g,
65%) as a mixture of diastereomers: yellow oil; 1H NMR (600
MHz, CDCl3) δ (ppm) 0.77-0.89 (m, 6 H), 0.94-1.08 (m, 6 H),
1.14-1.19 (m, 1 H), 1.23-1.36 (m, 1 H), 1.54-1.64 (m, 1 H),
1.78-2.11 (m, 2 H), 2.43-2.51 (m, 1 H), 3.79 (s, 3 H), 4.19-4.31
(m, 1 H), 4.45-4.70 (m, 1 H), 4.91-5.00 (m, 1 H), 5.25-5.31
(m, 1 H), 7.39-7.41 (m, 5 H), 9.33-9.71 (m, broad, 1 H); 13C NMR
(150 MHz, CDCl3) δ (ppm) 10.2, 10.3, 10.4, 11.0, 11.1, 11.4,
11.7, 11.8, 15.5, 15.8, 16.0, 16.1, 16.8, 16.8, 25.4, 25.7, 25.9, 26.4,
26.4, 26.8, 27.0, 27.2, 31.7, 32.0, 32.5, 32.9, 33.0, 36.9, 37.5, 37.6,
37.9, 48.7, 48.7, 50.1, 50.3, 64.5, 64.6, 78.6, 78.7, 78.8, 78.9,
129.0, 129.0, 129.4, 129.4, 129.5, 129.5, 129.6, 129.7, 133.7,
167.5, 167.5, 171.3, 171.4, 171.5, 171.6; IR (thin film) νmax
1643, 1666, 2965, 3222 (broad) cm-1; HRMS calcd for
C20H31Br79N2O4 443.1546 [M þ H]þ, found (ESI) m/z
443.1549; calcd for C20H31Br81N2O4 445.1525 [M þ H]þ, found
(ESI) m/z 445.1523.
3,6,-Di((S)-sec-butyl)-1-hydroxy-4-methoxypiperazine-2,5-dione
(33b).28a A suspension of 33a (2.0 g, 5.52 mmol) and Pd(OH)2-
C (20% Pd, 250 mg) in THF (56 mL, degassed immediately prior
to use by bubbling through nitrogen gas for 15 min) was stirred
while hydrogen gas was bubbled through the suspension for
90 min. The solution was purged of hydrogen gas by bubbling
nitrogen gas through the suspension for 10 min and then the
solution opened to ambient atmosphere. The Pd(OH)2-C was
removed by filtration through a pad of Celite 545, washing with
ethyl acetate, and the resulting clear solution concentrated in
vacuo. The crude was purified by silica gel flash chromatogra-
phy (dichloromethane/acetone, 98:2 to 80:20 v/v) to give 33b
(1.42 g, 94%); all four possible diastereomers were isolated,
which could be partially separated into two sets of diastereo-
mers. 33b, upper diastereomers: orange amorphous solid; mp =
145-155 °C dec; 1H NMR (600 MHz, CDCl3) δ (ppm)
0.87-1.03 (m, 12 H), 1.24-1.65 (m, 4 H), 2.27-2.34 (m, 1 H),
2.41-2.49 (m, 1 H), 3.76-3.77 (m, 3 H), 4.33-4.34 (m, 1 H),
4.39-4.40 (m, 1 H); 13C NMR (150 MHz, CDCl3) δ (ppm) 12.3,
12.3, 12.4, 12.5, 14.3, 14.7, 14.7, 25.5, 25.7, 25.8, 26.4, 37.2, 37.6,
38.7, 38.8, 61.7, 61.8, 63.8, 64.2, 65.0, 65.3, 159.9, 160.7, 161.9,
162.8; IR (thin film) νmax 1625, 1670, 2964, 3121 (broad) cm-1
;
HRMS calcd for C13H24N2O4 273.1814 [M þ H]þ, found (ESI)
m/z 273.1819. 33b, lower diastereomers: orange gum; 1H NMR
(600 MHz, CDCl3) δ (ppm) 0.96-1.12 (m, 12 H), 1.29-1.76 (m,
4 H), 2.15-2.38 (m, 2 H), 3.80-3.82 (m, 3 H), 4.23-4.31 (m, 2
H); 13C NMR (150 MHz, CDCl3) δ (ppm) 12.2, 12.3, 12.4, 12.4,
14.8, 14.9, 15.4, 15.5, 25.8, 25.9, 26.5, 27.1, 37.2, 37.4, 38.0, 38.4,
61.7, 62.2, 64.9, 65.1, 65.5, 65.9, 160.5, 161.2, 162.4, 162.9; IR
(thin film) νmax 1652, 2964, 3148 (broad) cm-1; HRMS calcd for
C13H24N2O4 273.1814 [M þ H]þ, found (ESI) m/z 273.1818.
3,6,-Di((S)-sec-butyl)-1,4-dihydroxypiperazine-2,5-dione (33c).28b
To a solution of 33b (30 mg, 0.110 mmol, dried azeotropically by
dissolving in benzene and concentrating in vacuo) in dichloro-
methane (1.1 mL) under nitrogen atmosphere at room tem-
perature was added boron tribromide (1.0 M in dichloro-
methane, 0.33 mL, 0.330 mmol). The reaction was stirred at
room temperature for 30 min, and then the reaction was
quenched by the addition of saturated aqueous sodium bicar-
bonate until the pH of the aqueous phase was 8-9 as measured
by pH paper. The mixture was extracted with ethyl acetate and
the organic extract dried with magnesium sulfate, filtered, and
concentrated in vacuo to give 33c (26 mg, 92%) as an insepara-
ble mixture of diastereomers: yellow-white solid; mp =145-
155 °C dec; 1H NMR (600 MHz, CD3OD) δ (ppm) 0.92-1.08
(m, 12 H), 1.39-1.73 (m, 4 H), 2.27-2.40 (m, 2 H), 4.22-4.28
(m, 2 H); 13C NMR (150 MHz, CD3OD) δ (ppm) 12.5, 12.6,
14.6, 15.0, 15.5, 15.6, 26.9, 26.9, 27.5, 27.7, 28.0, 38.4, 38.5,
39.4, 39.9, 67.3, 67.7, 67.8, 67.9, 68.0, 163.4, 164.2, 164.4, 165.0;
IR (thin film) νmax 1622, 2963, 3140 (broad) cm-1; HRMS
calcd for C12H22N2O4 259.1658 [M þ H]þ, found (ESI) m/z
259.1645.
Cyclization to 32 and 33a.26 To a solution of 31 (4.40 g, 9.92
mmol) in toluene (220 mL) were added 2 M aqueous NaOH (100
mL, 200 mmol) and 15-crown-5 (2.2 mL, 9.92 mmol) under
ambient atmosphere. The reaction was heated to 95 °C for 2 h
and then diluted with ethyl acetate. The organic phase was
washed with water and then brine, dried with magnesium
sulfate, filtered, and concentrated. The crude was purified by
silica gel flash chromatography (benzene/acetone, 98:2 to 95:5 v/v)
to give both 32 (1.72 g, 50%) and 33a (1.25 g, 35%), each as
inseparable mixtures of diastereomers.
4-(Benzyloxy)-2,5-di((S)-sec-butyl)-6-(methoxyimino)morpholin-
3-one (32): colorless oil; 1H NMR (600 MHz, CDCl3) δ (ppm)
0.85-1.11 (m, 12 H), 1.20-1.56 (m, 3 H), 1.58-1.64 (m, 1 H),
1.93-2.08 (m, 1 H), 2.17-2.32 (m, 1 H), 3.79-3.81 (m, 3 H),
3.93-4.01 (m, 1 H), 4.40-4.66 (m, 1 H), 4.87-5.03 (m, 2 H),
7.35-7.43 (m, 5 H); 13C NMR (150 MHz, CDCl3) δ (ppm) 11.6,
11.7, 11.8, 12.0, 12.1, 12.8, 14.1, 14.7, 15.5, 15.5, 15.5, 23.0, 24.6,
24.9, 25.9, 26.0, 26.1, 37.1, 37.7, 38.3, 38.8, 38.8, 39.0, 62.6, 62.6,
62.8, 63.5, 64.2, 64.7, 76.5, 76.9, 77.1, 81.2, 81.6, 82.8, 83.1,
128.5, 128.8, 128.8, 129.2, 129.6, 134.5, 147.8, 148.2, 148.3,
164.5, 164.6, 165.0; IR (thin film) νmax 1645, 1680, 2963 cm-1
;
HRMS calcd for C20H30N2O4 363.2284 [M þ H]þ, found (ESI)
m/z 363.2282. The structure of the dibenzyl analogue 320 was
determined by X-ray crystallography; see the Supporting Infor-
mation for the corresponding CIF and for the preparation of 320.
1-(Benzyloxy)-3,6-di((S )-sec-butyl)-4-methoxypiperazine-2,5-
dione (33a): colorless oil; 1H NMR (400 MHz, CDCl3) δ (ppm)
0.88-1.01 (m, 9 H), 1.07-1.13 (m, 3 H), 1.21-1.82 (m, 4 H),
2.11-2.40 (m, 2 H), 3.72-3.79 (m, 3 H), 4.02-4.06 (m, 1 H),
4.17-4.29 (m, 1 H), 4.83-4.90 (m, 1 H), 4.98-5.07 (m, 1 H),
7.36-7.43 (m, 5 H); 13C NMR (150 MHz, CDCl3) δ (ppm) 12.1,
12.2, 12.2, 12.3, 12.3, 12.4, 12.4, 12.5, 14.4, 14.8, 14.8, 14.9, 15.0,
15.1, 15.7, 15.8, 25.6, 25.8, 25.9, 26.0, 26.0, 26.2, 26.6, 26.6, 37.3,
37.5, 37.6, 37.6, 38.3, 38.4, 38.8, 38.9, 61.4, 61.5, 62.1, 64.4, 64.9,
65.4, 65.4, 65.6, 65.9, 66.1, 66.3, 66.8, 76.0, 76.4, 76.5, 127.1,
127.7, 128.6, 128.7, 128.8, 129.2, 129.2, 129.3, 129.5, 129.6,
129.7, 134.2, 134.3, 134.7, 134.7, 161.9, 162.6, 162.8, 163.0,
163.3, 163.4, 163.4; IR (thin film) νmax 1671, 2964 cm-1; HRMS
calcd for C20H30N2O4 363.2284 [M þ H]þ, found (ESI) m/z
363.2280. The structure of the dibenzyl analogue 33a0 was deter-
mined by X-ray crystallography; see the Supporting Information
for the corresponding CIF and for the preparation of 33a0.
Manganese(III) Acetate Oxidations. Representative Method
A. To a solution of 33b (50 mg, 0.184 mmol) in acetonitrile
(HPLC grade, “wet”, ∼5% water, 5.0 mL) under ambient
atmosphere was added solid potassium carbonate (63 mg,
0.459 mmol) and then manganese(III) acetate dihydrate (98
mg, 0.367 mmol). The reaction was sonicated to ensure a fine
suspension and then stirred rapidly for 2.5 h at room tempera-
ture. The reaction was quenched by adding first 2 N HCl and
then 30% aqueous ethylenediaminetetraacetic acid (EDTA), tetra-
sodium salt, in a ratio of 5:3 HCl/EDTA (v/v) and then extracting
with ethyl acetate. The organic extract was dried with magnesium
sulfate, filtered, and concentrated in vacuo. The crude was purified
by silica gel flash chromatography (dichloromethane/acetone, 98:2
to 90:10 v/v, then dichloromethane/acetone/methanol, 90:10:1 to
75:25:1 v/v/v) to give 34c (24 mg, 45%) as two major diastereo-
meric products as an inseparable mixture.
J. Org. Chem. Vol. 76, No. 4, 2011 1025