described for the preparation of 4-tert-butyl 1-ethyl [2-oxo-4-
[(phenylmethyl)seleno]-1-azetidinyl]butanedioate (above) and
isolated as a yellow oil in 76% yield as a 7:1 mixture of
diastereomers of which the major isomer was fully characterized.
1H NMR 0.01 (m, 6H), 0.83 (s, 9H), 1.03 (d, 3H, J = 6.3 Hz), 1.25
(q, 3H, J = 6.9 Hz), 1.45, (s, 9H), 2.79 (dd, 1H, J = 7.8, 16.8 Hz),
3.00 (dd, 1H, J = 6.0, 16.8 Hz), 3.18 (dd, 1H, J = 2.1, 3.9 Hz), 3.89
(d, 1H, J = 11.7 Hz), 4.01 (d, 1H, J = 11.7 Hz), 4.3 (m, 3H), 4.39
(dd, 1H, J = 6.3, 7.8 Hz), 5.06 (d, 1H, J = 2.1 Hz), 7.1–7.4 (m, 5H).
13C NMR −4.99, −4.74, 14.01, 17.76, 25.60, 25.83, 51.76, 53.66,
60.77, 62.12, 64.91, 65.54, 82.62, 126.77, 128.46, 128.51, 128.87,
128.95,138.31, 165.98, 167.28, 170.26. 77Se NMR 299.76. IR
1.25 mmol) in THF (30 mL) at −78 °C and under nitrogen. After
15 minutes, 2-iodobenzyl bromide (1.0 g, 3.36 mmol) inTHF (5 mL)
was added and the mixture stirred for 4 hours, at which time TLC
analysis revealed an absence of starting material. Water (50 mL)
was added and the mixture extracted with ether (3 × 50 mL). The
combined organic layers were dried (MgSO4) and the solvent
removed under reduced pressure. The residue was subjected to
flash chromatography (9:1 hexane/ethyl acetate) to afford the title
compound (0.84 g, 96%) as a colourless viscous oil. []D25 = +84.52°
(c = 1.00, CHCl3). 1H NMR 0.03 (s, 3H), 0.10 (s, 3H), 0.86 (s, 9H),
1.13 (d, 3H, J = 6.3 Hz), 3.28 (dd, 1H, J = 2.1, 4.5 Hz), 3.64 (d, 1H,
J = 17.7 Hz), 3.76 (d, 1H, J = 17.7 Hz), 4.09 (d, 1H, J = 18 Hz),
4.26 (dq, 1H, J = 2.1, 6.3 Hz), 4.53 (d, 1H, J = 17.7 Hz), 4.84 (d,
1H, J = 2.1 Hz), 6.9–7.4 (m, 9H). 13C NMR −4.90, −4.58, 17.97,
21.99, 25.72, 49.05, 52.50, 64.72, 65.85, 98.38, 126.93, 128.36,
128.51, 128.82, 128.93, 129.17, 137.64, 138.01, 139.49, 166.48.
77Se NMR 295. IR 1760, 1251, 1064, 432. (ESI HRMS: found:
638.0469. C25H34NO2SiSeINa requires 638.0465).
max 1766, 1738, 1255, 1153. MS m/z (relative intensity) 600 (M+,
100), 544 (15), 500 (12), 446 (68), 442 (55). (ESI HRMS: found:
622.2082. C28H45NO6SeSiNa requires 622.2079).
3-Carbo-(tert-butoxy)-3-[(3S,4R)-3-[(R)-tert-butyldim
ethylsilyloxyethyl]-2-oxo-4-[(phenylmethyl)seleno]-1-
azetidinyl]propanoic acid (23)
(2S,2aR)-2-[(R)-tert-Butyldimethylsilyloxyethyl]-2,2a-dihydro-
1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (28)
Barium hydroxide octahydrate (291 mg, 0.9 mmol) was added
to a stirred mixture of 1-tert-butyl 4-ethyl (3S,4R)-[3-[(R)-tert-
butyldimethylsilyloxyethyl]-2-oxo-4-[(phenylmethyl)seleno]-1-
azetidinyl]butanedioate (460 mg, 0.77 mmol) in 1:1 ethanol/water
(20 mL) at 0 °C and the mixture stirred for 24 hours, at which
time TLC indicated the absence of starting material. The mixture
was acidified to pH 5 (10% HCl), and saturated by the addition
of solid sodium chloride. The solution was extracted with ether
(5 × 40 mL), the combined organic extracts dried (MgSO4) and
the solvent removed in vacuo. The residue was subjected to double
flash chromatography (1:1 ethyl acetate/dichloromethane followed
by 1:1 ethyl acetate/methanol) to afford the title compound as a
yellow semi-solid that proved to be a 3:1 mixture of diastereomers
(422 mg, 89%) of which the major isomer was fully characterized.
1H NMR (d6-DMSO) 0.03 (s, 3H), 0.09, (s, 3H), 0.87 (s, 9H), 1.15
(d, 3H, J = 6.3 Hz), 1.45 (s, 9H), 2.88 (dd, 1H, J = 11.0, 6.3 Hz),
3.05 (dd, 1H, J = 11.0, 7.5 Hz), 3.24 (m, 1H), 3.9 (m, 2H), 4.29 (t,
1H, J = 6.6 Hz), 4.38 (m, 1H), 4.97 (d, 1H, J = 2.1 Hz), 7.15–7.30
(m, 5H), 10.2 (br s, 1H). 13C NMR (d6-DMSO) −4.891, −4.604,
17.86, 21.95, 25.65, 26.72, 52.08, 53.38, 65.24, 65.51, 83.04,
126.94, 128.65, 128.93, 138.24, 166.48, 167.18, 175.28; IR 3322.1,
1737.7, 1251.7, 1153.4, 837.0. MS m/z (relative intensity) 572.2
(80, M+) 514..2 (70), 414.1 (75), 300.0, (100). (ESI HRMS: found:
594.1773. C26H41NO6SeSiNa requies 594.1766).
A solution containing (3S,4R)-3-[(R)-tert-butyldimethylsilyloxy-
ethyl]-1-[(2-iodophenyl)methyl]-4-[(phenylmethyl)seleno]-
2-azetidinone (27) (0.750 g, 1.22 mmol), triphenyltin hydride
(0.514 g, 1.4 mmol) and AIBN (10 mg) in benzene (80 mL) was
stirred at reflux for thirty hours. The solvent was removed under
reduced pressure and the residue subject to flash chromatography
(9:1 hexane/ethyl acetate) to afford the cyclised product (28) as a
pale semi-solid (0.29 g, 65%). []2D5 = +194.9° (c = 1.00, CHCl3).
1H NMR 0.05 (s, 6H), 0.85 (s, 9H), 1.22 (d, 3H, J = 6.0 Hz),
3.32 (m, 1H), 4.80 (d, 1H, J = 16.8 Hz), 4.23 (m, 1H), 4.74
(d, 1H, J = 16.8 Hz), 5.06 (s, 1H), 7.0–7.3 (m, 4H). 13C NMR
−5.18, −4.29, 17.81, 22.53, 25.58, 43.20, 46.23, 64.99, 69.27,
126.14, 126.30, 127.91, 128.63, 130.39, 131.40, 166.49. 77Se
NMR 312; IR max1766.7, 837.0. (ESI HRMS: found: 420.0873.
C18H27NO2SiSeNa requires 420.0874).
2-[(Phenylmethyl)seleno]nitrobenzene
Sodium borohydride was added, in portions, to a stirred suspen-
sion of dibenzyl diselenide (2.63 g, 7.73 mmol), in absolute ethanol
(150 mL), under nitrogen until the characteristic yellow color of
the diselenide had disappeared. 2-Fluoronitrobenzene (1.63 mL,
15.5 mmol) was added and the resulting solution was stirred for
1.5 hours at ambient temperature. The solvent was removed in
vacuo, water (100 mL) added and the mixture extracted with ether
(3 × 70 mL). The combined organic extracts were dried (MgSO4)
and the solvent removed in vacuo to give the crude product which
was recrystallized from ethanol to give the title selenide as bright
tert-Butyl (2S,5R,6S)-1-aza-6-[(R)-tert-butyldimethylsilyloxy-
ethyl]-7-oxo-4-selenabicyclo[3.2.0]heptane-2-carboxylate (25)
3-Carbo-(tert-butoxy)-3-[(3S,4R)-3-[(R)-tert-butyldimethyl-
silyloxyethyl]-2-oxo-4-[(phenylmethyl)seleno]-1-azetidinyl]-
propanoic acid (23) was converted into the dithiocarbamate (Kim
ester) derivative in the manner described during the prepara-
tion of ethyl anti-1-aza-7-oxo-4-selenabicyclo[3.2.0]heptane-
2-carboxylate (18). The crude Kim ester was dissolved in benzene
and photolysed under reflux for 2 hours. The solvent was removed
in vacuo and the residue subjected to flash chromatography (3:1
hexane/ethyl acetate) to afford the title selenapenam as a pale solid
1
yellow needles (3.37 g, 75%). mp 98–99 °C. H NMR 4.14 (s,
2H), 7.21–7.57 (m, 8H), 8.23 (d, 1H, J = 8 Hz); 13C NMR 31.11,
125.56, 126.39, 127.46, 128.85, 129.14, 129.30, 133.78, 135.49.
77Se NMR 399. MS m/z (relative intensity) 292 (M+, 33), 186
(43), 93 (45), 91(100), 65 (51). (Found: C, 53.68; H, 3.94; N, 4.77.
C13H11NO2Se requires C, 53.44; H, 3.79; N, 4.79%).
1
(51%). mp 62–64 °C. H NMR 0.05 (s, 6H), 0.86 (s, 9H), 1.21
2-[(Phenylmethyl)seleno]aniline
(d, 3H, J = 6.4 Hz), 1.44 (s, 9H), 3.28 (d, 1H, J = 4.8 Hz), 3.51 (m,
2H), 4.20 (m, 1H), 4.98 (t, 1H, J = 4.8 Hz), 5.30 (s, 1H). 13C NMR
−5.06, −4.38, 17.88, 22.32, 25.66, 27.77, 56.31, 60.94, 65.48,
70.22, 82.51, 167.37, 171.77. 77Se NMR 280. IR max1755.1,
1732.0, 1367.4, 1141.8, 1062.7. MS m/z (relative intensity) 458 (15,
M+), 392 (57), 336 (81), 278 (100). (ESI HRMS: found: 458.1248.
C18H33NO4SeSiNa requires 458.1242).
Concentrated HCl (30 mL) was slowly added to a mixture of
2-[(phenylmethyl)seleno]nitrobenzene (2.83 g, 9.70 mmol) and
finely-divided tin (5.76 g, 48.5 mmol). The suspension was heated
at 50 °C for 2 days. After cooling, the mixture was washed with
ether (3 × 30 mL), basified with 10% NaOH and the product
extracted with ether (4 × 50 mL). The combined organic extracts
were dried (MgSO4) and concentrated in vacuo to give the crude
product which was purified by flash chromatography (20%
EtOAc/petroleum spirits) to give the title compound as pale plates
(1.92 g, 75%). mp 50–51.5 °C. 1H NMR 3.93 (s, 2H), 4.23 (s (br),
2H), 6.58 (t, 1H, J = 7.1 Hz), 6.72 (d, 1H, J = 8.1 Hz), 7.08–7.23
(m, 6H,), 7.34 (dd, 1H, J = 7.7, 1.8 Hz). 13C NMR 31.50, 114.53,
118.60, 126.65, 128.27, 128.65, 130.27, 138.19, 139.16. 77Se NMR
(3S,4R)-3-[(R)-tert-Butyldimethylsilyloxyethyl]-1-[(2-iodo-
phenyl)methyl]-4-[(phenylmethyl)seleno]-2-azetidinone (27)
Lithium hexamethyldisilazide (1.4 mL of a 1.0 M soln in THF) was
added to a stirred solution of (3S,4R)-3-[(R)-tert-butyldimethyl-
silyloxyethyl]-4-[(phenylmethyl)seleno]-2-azetidinone (21) (0.50 g,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 6 1 2 – 2 6 1 8
2 6 1 7