Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4549
For 10b: 1H NMR (CDCl3) δ 6.89-6.86 (1 H, m), 3.85 (1 H,
4.28 (1 H, m), 4.16 (2 H, q, J ) 7.2 Hz), 3.38 (1 H, p, J ) 5.8
Hz), 2.83-2.76 (1 H, m), 2.64-2.55 (1 H, m), 2.52-2.49 (1 H,
m), 2.42-2.40 (1 H, m), 1.60-1.48 (4 H, m), 1.25 (3 H, t, J ) 7.2
Hz), 0.94 (3 H, t, J ) 7.4 Hz), 0.89 (3 H, t, J ) 7.4 Hz); 13C NMR
(CDCl3) δ 166.6, 132.9, 127.6, 82.0, 70.0, 60.5, 31.5, 28.2, 26.7,
26.6, 24.2, 14.1, 9.8, 9.5; HRMS calcd for C14H24NO3 [MH+]
254.1756, found 254.1759.
m), 3.07 (s, OMs).
Eth yl (3R,4R,5S)-4,5-Ep oxy-3-(1-eth ylp r op oxy)-1-cyclo-
h exen e-1-ca r boxyla te (11). A solution of the crude 10a :10b:
10c mixture (16.4 kg, ratio 10:1:1) in absolute ethanol (55.7 kg)
was treated with potassium hydrogen carbonate (7.3 kg, 72.9
mol) in water (45.9 kg), and the mixture was warmed to 55-65
°C, affording a clear solution. After 1 h, most of the ethanol
(ca. 43 kg) was removed by distillation in vacuo (55 °C, 75
mmHg). Water (8.2 kg) was added to dissolve the salty residue,
and the mixture was extracted twice with hexanes (52 kg, then
35 kg). The organic extracts were combined, washed with water
(2 × 4.6 kg), and concentrated in vacuo (60 °C, 175 mmHg). The
residue was coevaporated with ethyl alcohol (14.9 kg) in vacuo
(65 °C, 75 mmHg) which afforded epoxide 11 as a yellow oil that
crystallized on standing (9.6 kg, 96.7% yield, based on contained
10a in the starting mixture). TLC analysis indicated a purity
of 90-95% and this material was typically used directly in the
next step. An analytical sample was recrystallized from aqueous
ethanol to afford 11 as long white needles: mp 57-8 °C; FT IR
(KBr) 1714 cm-1; 1H NMR (CDCl3) δ 6.76-6.73 (1 H, m), 4.42-
4.39 (1 H, m), 4.26-4.18 (2 H, m), 3.55-3.46 (3 H, m), 3.13-
3.05 (1 H, m), 2.49-2.40 (1 H, m), 1.67-1.57 (4 H, m), 1.30 (3
H, t, J ) 7.1 Hz), 1.01 (3 H, t, J ) 7.3 Hz), 0.98 (3 H, t, J ) 7.3
Hz); 13C NMR (CDCl3) δ 166.1, 135.3, 126.7, 81.5, 71.3, 60.7,
53.3, 50.7, 26.7, 26.5, 24.5,14.2, 9.7, 9.6. Anal. Calcd for
Eth yl (3R,4R,5S)-4-Am in o-5-a zid o-3-(1-eth ylp r op oxy)-1-
cycloh exen e-1-ca r boxyla te (6). Caution: This procedure
should only be attempted by technically qualified persons who
are fully familiar with the safe handling of sodium azide and
ammonium azide. These reagents are highly toxic and poten-
tially explosive. A mixture of crude aziridine 19 (1.66 kg, 6.55
mol), dimethylformamide (3.3 kg), ammonium chloride (0.35 kg,
6.53 mol), and sodium azide (0.43 kg, 6.61 mol) was stirred and
heated at 70-80 °C under a nitrogen atmosphere. (Caution: do
not exceed an internal temperature of 80 °C). After 19 was
consumed (12-18 h) by TLC analysis (Merck SG 60, diethyl
ether), the reaction mixture was cooled to ambient temperature
and treated with 5% aqueous sodium bicarbonate (1.97 kg, 1.17
mol). The product 6 was extracted with hexanes (4 × 1.8 kg).
Concentration of the combined extracts in vacuo (50 °C, 75
mmHg) afforded the azidoamine 6 as a brown oil (ca. 1.95 kg)
that was used directly in the next step. An analytical sample
of 6 was prepared by column chromatography (20% EtOAc/80%
hexanes, Rf 0.35) as a pale tan oil: FT IR (film) 2089, 1711 cm-1
;
C
14H22O4 (254.3): C, 66.12; H, 8.72. Found: C, 65.94; H, 8.91.
Eth yl (3R,4S,5R)-5-Azid o-3-(1-eth ylp r op oxy)-4-h yd r oxy-
1H NMR (CDCl3) δ 6.79-6.77 (1 H, m), 4.20 (2 H, q, J ) 7.2
Hz), 3.89-3.83 (1 H, m), 3.48-3.39 (1 H, m), 3.37 (1 H, p, J )
5.8 Hz), 2.89-2.82 (2 H, m), 2.33-2.21 (1 H, m), 1.79 (2 H, bs),
1.65-1.40 (4 H, m), 1.28 (3 H, t, J ) 7.2 Hz), 0.91 (6 H, t, J )
7.4 Hz); 13C NMR (CDCl3) δ 165.7, 137.3, 128.0, 81.0, 78.0, 61.5,
60.8, 55.9, 29.7, 26.3, 25.5, 14.0, 9.6, 9.2; HRMS calcd for
C14H25N4 O3 [MH+] 297.1927, found 297.1926.
cycloh exen e-1-ca r boxyla te (18a ). Caution: This procedure
should only be attempted by technically qualified persons who
are fully familiar with the safe handling of sodium azide and
ammonium azide. These reagents are highly toxic and poten-
tially explosive. A solution of epoxide 11 (1.0 kg, 3.93 mol) in
ethanol (1.54 kg) and water (0.5 kg) was treated with ammonium
chloride (0.231 kg, 4.31 mol) and sodium azide (0.280 kg, 4.31
mol) and the resulting mixture was heated to 70-75 °C.
(Caution: do not exceed an internal temperature of 78 °C). When
TLC analysis (Merck SG 60, 50% EtOAc/50% hexanes) indicated
that 11 was consumed (12-18 h), the mixture was cooled to
ambient temperature and treated with 5% aqueous sodium
bicarbonate (1.23 kg, 0.73 mol). Most of the ethanol was
removed by distillation in vacuo (50 °C, 25 mmHg). The aqueous
residue was extracted with ethyl acetate (1.58 kg, then 0.81 kg),
and the combined extracts were washed with brine (1.5 kg) and
dried over anhydrous sodium sulfate (0.79 kg). Filtration and
concentration in vacuo (50 °C, 25 mmHg) afforded a ca. 10:1
mixture of isomeric azido alcohols 18a :18b as a brown oil (1.0
kg, 85.5% yield). An analytical sample of 18a was prepared by
column chromatography (20% EtOAc/ 80% hexanes) as a pale
Eth yl (3R,4R,5S)-4-Acetam ido-5-azido-3-(1-eth ylpr opoxy)-
1-cycloh exen e-1-ca r boxyla te (20). A solution of crude azi-
doamine 6 (1.95 kg, 6.56 mol) in hexanes (6 kg) and dichlo-
romethane (3.8 kg) was treated portionwise with 7.8% aqueous
sodium bicarbonate (12.4 kg, 11.51 mol) and acetic anhydride
(0.56 kg, 5.48 mol) over 1 h. (Caution: Frothing). The aqueous
layer was discarded, and the organic layer was concentrated in
vacuo (40 °C, 50 mmHg). The residue was crystallized from hot
ethyl acetate (0.51 kg) and hexanes (1.8 kg). After cooling to
0-5 °C for 3-24 h, the solid was isolated by filtration and
washed with cold (0-5 °C) 19% ethyl acetate in hexanes (2 kg).
Drying in vacuo at 25-40 °C afforded azidoacetamide 20 as a
light brown solid (1.12 kg). Recrystallization from ethyl acetate
(2.53 kg) and butyl ether (10.7 kg) afforded pure 20 as off-white
needles (0.98 kg, 44.2% yield from 19): mp 137-138 °C; FT IR
(KBr) 2100, 1717, 1656 cm-1; 1H NMR (CDCl3) δ 6.81 (1 H, dd,
J ) 2.2, 2.3 Hz), 6.01 (1 H, d, J ) 7.4 Hz), 4.60-4.57 (1 H, m),
4.34-4.27 (1 H, m), 4.23 (2 H, q, J ) 7.1 Hz), 3.40-3.31 (2 H,
m), 2.88 (1 H, dd, J ) 5.7, 17.1 Hz), 2.31-2.19 (1 H, m), 2.06 (3
H, s), 1.59-1.47 (4 H, m), 1.32 (3 H, t, J ) 7.1 Hz), 0.93 (3 H, t,
J ) 7.3 Hz), 0.92 (3 H, t, J ) 7.3 Hz); 13C NMR (CDCl3) δ 171.1,
165.8, 137.9, 128.1, 82.0, 73.4, 61.0, 58.0, 57.2, 30.5, 26.2, 25.6,
23.5, 14.2, 9.6, 9.3. Anal. Calcd for C16H26 N4O4: C, 56.79; H,
7.74; N, 16.56. Found: C, 56.55; H, 7.65; N, 16.68.
Eth yl (3R,4R,5S)-4-Acetam ido-5-azido-3-(1-eth ylpr opoxy)-
1-cycloh exen e-1-ca r boxyla te P h osp h a te [1:1] (2‚H3P O4). A
mixture of azidoacetamide 20 (0.33 kg, 0.98 mol) and Raney
nickel (107 g) in absolute ethanol (5.2 kg) was vigorously stirred
for 10-16 h while hydrogen (1 atm) was bubbled through the
mixture. After the starting azidoacetamide 20 was consumed
by TLC analysis (Merck SG 60, EtOAc), excess hydrogen was
removed by purging with nitrogen. The reaction mixture was
filtered through a 0.45 µm polypropylene filter cartridge, rinsed
forward with ethanol (1.0 kg), and concentrated in vacuo (45
°C, 20 mmHg) to afford free base 2 as a tan oil (ca. 0.32 kg) that
solidified on standing. The free base was dissolved in absolute
ethanol (2.1 kg) and added in one portion to a 55-65 °C solution
of 85% phosphoric acid (108 g, 0.94 mol) in absolute ethanol (4
kg). Crystallization commenced within minutes. After cooling
to 0 °C over 3-24 h with slow agitation, the precipitate was
collected by filtration and washed with acetone (3 kg) to afford
yellow oil: FT IR (film) 2100, 1717 cm-1 1H NMR (CDCl3) δ
;
6.88-6.86 (1 H, m), 4.25 (2 H, q, J ) 7.0 Hz), 4.17-4.14 (1 H,
m), 3.94-3.87 (1 H, m), 3.83-3.78 (1 H, m), 3.47 (1 H, p, J )
5.7 Hz), 2.91-2.82 (1 H, m), 2.75 (1 H, bs), 2.33-2.24 (1 H, m),
1.66-1.52 (4 H, m), 1.33 (3 H, t, J ) 7.0 Hz), 0.97 (3 H, t, J )
7.4 Hz), 0.93 (3 H, t, J ) 7.4 Hz); 13C NMR (CDCl3) δ 165.9,
135.0, 130.1, 81.9, 71.0, 70.2, 61.0, 58.9, 28.2, 26.4, 26.1, 14.2,
9.6, 9.5; HRMS calcd for C14H23 N3O4 [M+] 297.1689, found
297.1685.
Eth yl (3R,4S,5R)-4,5-Im in o-3-(1-eth ylp r op oxy)-1-cyclo-
h exen e-1-ca r boxyla te (19). A ca. 10:1 mixture of azido
alcohols 18a :18b (2.00 kg, 6.73 mol) was dissolved in anhydrous
acetonitrile (2.1 kg) and dried by azeotropic distillation of
acetonitrile in vacuo (50 °C, 100 mmHg). When the water
content was determined to be <0.1% by Karl Fischer titration,
the solution was cooled and diluted to a total volume of 5 L with
anhydrous acetonitrile. A solution of trimethylphosphine (0.52
kg, 6.83 mol) in anhydrous acetonitrile (4.7 kg) was added
dropwise over 2 h, while maintaining a temperature <38 °C.
(Caution: trimethylphosphine stench!) The mixture was con-
centrated in vacuo (50 °C, 50 mmHg), and the residue was
partitioned between ethyl acetate (6 kg) and water (3.4 kg). The
organic layer was washed with water (3.4 kg) and concentrated
in vacuo (50 °C, 50 mmHg), which afforded aziridine 19 as a
brown oil (1.66 kg, 97.3% crude yield). An analytical sample of
19 was prepared by column chromatography (45% EtOAc/45%
hexanes/10% MeOH, Rf 0.5) as a pale yellow oil: FT IR (film)
1711, 1656 cm-1; 1H NMR (CDCl3) δ 6.78-6.75 (1 H, m), 4.33-
2‚H3P O4 as long white needles (0.285 kg, 71% yield): [R]D
)
-39.9° (c 1, water); mp 203-4 °C; FT IR (KBr) 3500, 1719, 1661
1
cm-1; H NMR (500 MHz, D2O) δ 6.87 (1 H, s), 4.78 (bs, HOD),