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4.3. (3S,4S,4aS)-3-((S)-2-(Benzyloxy)-1-iodoethyl)-1-
oxohexahydro-1H-pyrrolo[1,2-c][1,3]oxazin-4-yl pivalate 5a
with hot EtOAc (100 mL in all). The organic solvents were combined
and evaporated to dryness. The resulting brownish oil was chro-
matographed (silica, 30% EtOAc/hex) to give 10a (170 mg, 74%) as
20
To a solution of 7 (1.38 g, 3.1 mmol, 100 mol %) in glacial acetic
acid (20 mL), AgOAc (1.16 g, 7.0 mmol, 225 mol %) and I2 (0.824 g,
3.25 mmol, 105 mol %), respectively, were added and the resulting
mixture was stirred at room temperature for 5 h. The mixture was
filtered and the filtrate was washed with toluene. The solution was
evaporated to dryness in rotary evaporator and dried further in
vacuo. The resulting brownish thick oil was chromatographed
a clear oil. Rf (75% EtOAc/hex)¼0.38. [
a
]
ꢁ64.8 (c 1.0, CH2Cl2). 1H
D
NMR (200 MHz, CDCl3)
d
1.20 (s, 9H), 1.50–2.25 (m, 6H), 3.35–3.76
(m, 5H), 4.54 (ddd, 1H, J¼10.2 Hz, 2.5 Hz, 7.2 Hz), 4.96 (dd, 1H,
J¼4.2 Hz, 7.2 Hz,). 13C NMR (50 MHz, CDCl3)
d 22.2, 27.0, 31.5, 32.6,
38.9, 40.4, 46.5, 57.9, 69.6, 72.8, 151.9, 177.2.
4.7. (2S,3S)-2-((S)-Pyrrolidin-2-yl)tetrahydrofuran-3-ol 11
(silica, 25% EtOAc in hexanes) to give 5a (0.714 g, 55%) as a clear oil.
20
Rf (75% EtOAc/hex)¼0.8. [
a
]
D
ꢁ5.8 (c 0.54, CH2Cl2). 1H NMR
To a solution of 10a (170 mg, 0.56 mmol, 100 mol %) in MeOH/
H2O (5 mL/5 mL) was added NaOH (174 mg, 4.46 mmol, 800 mol %).
The mixture was heated to reflux for 8 h after which it was evap-
orated to dryness. The residue was dissolved in EtOAc and filtered.
The filtrate was evaporated to give 11 as yellowish oil, which was
used in the next step without purification. Rf (50% EtOAc/
(400 MHz, CDCl3)
d
1.26 (s, 9H), 1.65–2.05 (m, 4H), 2.36 (m, 1H),
3.28 (ddd, 1H, J¼1.9 Hz, 5.4 Hz, 11.8 Hz), 3.39 (m, 1H), 3.59 (m, 1H),
3.85 (dd, 1H, J¼2.7 Hz, 10.8 Hz), 4.04 (dd, 1H, J¼4.6 Hz, 10.8 Hz),
4.33 (ddd, 1H, J¼2.7 Hz, 4.6 Hz, 10.5 Hz), 4.41 (dd, 1H, J¼2.4 Hz,
10.5 Hz), 4.65 (dd, 2H, J¼12.1 Hz, 21.2 Hz), 5.41 (t, 1H, J¼2.2 Hz),
7.28–7.36 (m, 5H). 13C NMR (100 MHz)
d
21.2, 25.2, 27.0, 27.2, 30.6,
hex)¼0.04. 1H NMR (400 MHz, d5-pyridine)
d 2.71 (ddd, 1H,
38.8, 44.6, 62.3, 70.9, 72.6, 75.6, 127.7, 128.3, 152.6, 177.6. HRMS m/z
calcd for C21H28INO5 (Mþ1) 502.1091, found 502.1109.
J¼9.6 Hz, 6.3 Hz, 7.9 Hz,), 2.87 (m, 1H,), 3.61 (dd, 1H, J¼3.4 Hz,
6.0 Hz), 3.69 (dd, 1H, J¼7.4 Hz, 13.6 Hz,), 3.83 (ddd, 1H, J¼11.8 Hz,
7.8 Hz, 4.0 Hz,), 4.17 (ddd, 1H, J¼8.0 Hz, 7.8 Hz,), 4.61 (ddd, 1H,
4.4. (3S,4S,4aS)-3-(2-(Benzyloxy)ethyl)-1-oxohexahydro-1H-
pyrrolo[1,2-c][1,3]oxazin-4-yl pivalate 8a
J¼1.6 Hz, 3.2 Hz, 4.8 Hz). 13C NMR (100 MHz, CDCl3)
d 24.3, 27.5,
36.3, 45.3, 59.3, 66.7, 72.5, 81.4. HRMS m/z calcd for C8H15NO2
(Mþ1) 158.1181, found 158.1085.
Compound 5a (682 mg, 1.33 mmol, 100 mol %) was dissolved in
MeOH (50 mL). Air was evacuated from the reaction vessel and
replaced by argon. Triethylamine (382 mL, 2.66 mmol, 200 mol %)
and 10% Pd/C (68.2 mg, 10 wt %) were added. Argon was evacuated
from the reaction vessel and replaced with H2. The mixture was
allowed to stir under H2 pressure for 18 h. The mixture was filtered
through a short Celite pad and evaporated to dryness. The resulting
4.8. ((S)-2-((2S,3S)-3-Hydroxytetrahydrofuran-2-yl)-
pyrrolidin-1-yl)(4-nitrophenyl)methanone 12
To a solution of 11 from the previous reaction (0.56 mmol,
100 mol %) in dichloromethane (10 mL) were added pyridine
(362 mL, 4.48 mmol, 800 mol %) and p-nitrobenzoylchloride
(418 mg, 2.24 mmol, 400 mol %). The resulting mixture was stirred
at room temperature for 6 h after which 10 mL saturated NaHCO3 in
brine (50:50) was added. The layers were separated and the organic
phase was successively washed with 10 wt % citric acid (10 mL) and
brine (10 mL) and dried over Na2SO4. Filtration and evaporation
gave a yellowish oil, which was chromatographed to give 12
yellowish oil was chromatographed (silica, 50% EtOAc/hex) to give
20
8a (301 mg, 59%) as a clear oil. Rf (75% EtOAc/hex)¼0.63. [
(c 1.0, CH2Cl2). 1H NMR (200 MHz, CDCl3)
(m, 6H), 3.36–3.71 (m, 5H), 4.5 (m, 3H), 4.95 (dd, 1H, J¼6.8 Hz,
4.3 Hz), 7.3 (m, 5H). 13C NMR (50 MHz, CDCl3)
22.1, 26.9, 29.8, 31.3,
a
]
ꢁ90.4
D
d
1.21 (s, 9H), 1.52–2.20
d
38.8, 46.2, 58.0, 65.7, 69.9, 72.9, 73.1, 127.5, 127.8, 128.3, 138.0, 152.3,
177.2. HRMS m/z calcd for C21H29NO5 (Mþ1) 376.2124, found
376.2118.
(64 mg, 37%).
20
Compound 12: Rf (75% EtOAc/hex)¼0.32. [
a]
ꢁ75.6 (c 0.345,
D
CHCl3). 1H NMR (400 MHz, CDCl3)
d
1.8–2.21 (m, 6H), 3.32 (m, 1H),
4.5. (3S,4S,4aS)-3-(2-Hydroxyethyl)-1-oxohexahydro-1H-
pyrrolo[1,2-c][1,3]oxazin-4-yl pivalate 9a
3.45 (m, 1H), 3.9 (m, 1H), 4.1 (q, 1H, J¼8.4 Hz), 4.18 (s, 1H), 4.5 (ddd,
1H, J¼3.6 Hz, 6.0 Hz, 7.2 Hz), 7.63 (d, 2H, J¼8.8 Hz), 8.25 (d, 2H,
J¼8.8 Hz). 13C NMR (100 MHz, CDCl3)
d 24.1, 28.2, 34.2, 50.5, 55.7,
Compound 8a (298 mg, 0.79 mmol, 100 mol %) was dissolved in
MeOH (25 mL). Air was evacuated from the reaction vessel and
replaced by argon after which Pd(OH)2 (20%, 47 mg, 15 wt %) was
added. Argon was evacuated from the reaction vessel and replaced
with H2. The mixture was allowed to stir under H2 pressure for 18 h.
The mixture was filtered through a short Celite pad and evaporated
66.3, 70.4, 83.8, 123.7, 128.0, 142.1, 148.5, 169.6, HRMS m/z calcd for
C15H18N2O5 (Mþ1) 307.1294, found 307.1321.
4.9. (3R,4S,4aS)-3-((S)-2-(Benzyloxy)-1-iodoethyl)-4-
hydroxyhexahydro-1H-pyrrolo[1,2-c][1,3]oxazin-1-one 5b
to dryness to give 9a (216 mg, 95%) as a clear oil. Rf (75% EtOAc/
To a solution of alcohol 4 (1.3 g, 3.76 mmol, 100 mol %) in glacial
acetic acid (55 mL) was added AgOAc (4.13 g, 24.75 mmol,
450 mol %) and then I2 (2.93 g, 11.55 mmol, 210 mol %) in portions.
The resulting mixture was stirred at room temperature for 2 h after
which NaCl was added and the solids were filtered off. The filtrate
was evaporated to dryness and the residue was dissolved in EtOAc
(20 mL). The organic phase was washed with water (20 mL) and
brine (20 mL) and dried over anhydrous Na2SO4. Filtration and
evaporation gave the crude product, which was purified by flash
20
hex)¼0.1. [
a
]
ꢁ81.6 (c 1.0, CH2Cl2). 1H NMR (200 MHz, CDCl3)
D
d
1.19 (s, 9H), 1.54–2.18 (m, 6H), 2.85 (br s, 1H), 3.35–3.64 (m, 3H),
3.8 (m, 2H), 4.52, (ddd, 1H, J¼4.7 Hz, 4.7, 9.0 Hz), 4.94, (dd, 1H,
J¼3.8 Hz, 6.8 Hz). 13C (50 MHz, CDCl3)
d 22.1, 26.9, 31.3, 31.9, 38.8,
46.3, 58.1, 58.2, 70.0, 73.2, 152.6, 177.3. HRMS m/z calcd for
C14H23NO5 (Mþ1) 286.1654, found 286.1640.
4.6. (3S,4S,4aS)-3-(2-Chloroethyl)-1-oxohexahydro-1H-
pyrrolo[1,2-c][1,3]oxazin-4-yl pivalate 10a
chromatography (15% i-PrOH/hex) to give 5b (855 mg, 55%) as
20
a yellowish oil. Rf (i-PrOH/hex)¼0.31. [
a]
ꢁ35.4 (c 1.0, CH2Cl2). 1H
D
To a solution of 9a (216 mg, 0.75 mmol, 100 mol %) in MeCN
(10 mL) were successively added K2CO3 (207 mg, 1.5 mmol,
200 mol %), PPh3 (492 mg, 1.88 mmol, 250 mol %) and CCl4 (342 mg,
2.25 mmol, 300 mol %). The resulting mixture was stirred at 40 ꢂC
for 3 h after which the reaction mixture was evaporated to dryness.
The brownish thick residue was washed thoroughly several times
NMR (400 MHz, CDCl3) d 1.58 (m, 1H), 1.83 (m, 1H), 2.0 (m, 1H), 2.19
(m, 1H), 3.01 (broad d, 1H, J¼8.0 Hz) 3.40 (ddd, 1H, J¼4.0 Hz, 9.9 Hz,
11.3 Hz), 3.46 (ddd, 1H, J¼3.7 Hz, 5.5 Hz, 11.2 Hz), 3.61 (dt,
1H, J¼8.1 Hz, 11.3 Hz), 3.91 (dd, 1H, J¼4.6 Hz, 10.6 Hz), 3.98 (dd, 1H,
J¼4.6 Hz, 10.6 Hz), 4.35 (ddd, 1H, J¼3.3 Hz, 7.7 Hz), 4.39 (dd,
1H, J¼3.0 Hz, 8.5 Hz), 4.40 (dt, 1H, J¼4.6 Hz, 8.4 Hz), 4.65 (m, 2H).