3974 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Hubschwerlen et al.
filtrate was evaporated and distilled affording 13.3 g of 7 (84%),
bp0.11 mm ) 83-85 °C. NMR (CDCl3): 1.42-1.90 (6H, m), 2.34
(2H, m), 2.54 (1H, t, J ) 5.5), 3.43 (2H, m), 3.70-3.95 (2H,
m), 4.06 (2H, b), 4.59 (1H, t, J ) 3), 5.70 (2H, m).
1:1 Mixtu r e of (2R,3S)-1-(Ben zyloxy)-4-oxo-2-[[(R)- a n d
(S)-tetr a h yd r op yr a n -2-yloxy]eth yl]a zetid in -3-ylca r ba m -
ic Acid ter t-Bu tyl Ester (12). A solution of 11 (1.74 g, 3.97
mmol) and triphenylphosphine (1.15 g, 4.37 mmol) in absolute
THF (25 mL) was reacted with diisopropyl azodicarboxylate
(0.88 g, 4.37 mmol) for 2 h at room temperature. The solvent
was evaporated; the residue was chromatographed (hexane/
Et2O/CH2Cl2, 5:4.5:0.5) affording an oil which was crystallized
from Et2O/hexane (820 mg, 50%), mp 104-08 °C. [R]D -195°
1:1 Mixtu r e of (2R,3S)-3-{2-[(R)- a n d (S)-Tetr a h yd r o-
p yr a n -2-yloxy]eth yl}oxir a n -2-ylm eth a n ol (8). Molecular
sieve (3 Å) was activated at 120 °C under high vacuum for 12
h and finely pulverized before use. A suspension of molecular
sieve (20 g) and L-(+)-diisopropyl tartrate (3.4 mL, 16.25 mmol)
in absolute CH2Cl2 (0.25 L) was reacted at -30 °C with
tetraisopropyl orthotitanate (3.8 mL, 13 mmol). After 15 min
the suspension was treated with tert-butyl hydroperoxide in
isooctane (3 M; 108 mL, 325 mmol) for 30 min. A solution of
7 (25 g, 130 mmol) in absolute CH2Cl2 (50 mL) was added at
-20 °C and further stirred for 4 h. The reaction mixture was
quenched at this temperature with a solution of NaOH (1 g)
and NaCl (1 g) in water (10 mL). After 30 min at 10 °C, the
reaction mixture was diluted with CH2Cl2. The organic
solution was worked up and chromatographed (AcOEt/hexane,
1:1) giving 18.5 g (70%) of 8. [R]D ) -22.9° (c 1, CHCl3). NMR
(CDCl3): 1.52-1.90 (6H, m), 1.85 (2H, m), 2.60 (1H, 2t, J )
6), 3.00 (1H, m), 3.10 (1H, m), 3.49-3.92 (2 × 3H, 2m), 4.60
(1H, t, J ) 3).
(c 1, CHCl3). IR: 3343, 1784, 1691, 1531 cm-1
. MS (FAB):
421.3 (M + H)+. NMR (CDCl3): 1.42 (9H, s), 1.50-1.98 (8H,
m), 3.30-4.00 (5H, m), 4.30-4.80 (2H, m), 4.90-5.1 (2H, m),
5.5-5.75 (1H, 2d, J ) 10), 7.40 (5H, s). Anal. (C22H32N2O6)
C, H, N.
(2R,3S)-1-(Ben zyloxy)-2-(2-h ydr oxyeth yl)-4-oxoazetidin -
3-ylca r ba m ic Acid ter t-Bu tyl Ester (13). A solution of 12
(5.1 g, 12.13 mmol) and p-toluenesulfonic acid (0.5 g) in EtOH
(0.1 L) was warmed to 80 °C for 2 h. The solvent was
evaporated, and the residue, dissolved in CH2Cl2, was worked
up and crystallized from Et2O/hexane (3.54 g, 87%), mp 102-
103 °C. [R]D +123.3 ° (c 1, CHCl3). IR: 3429, 3355, 1765, 1680,
1536 cm-1
.
MS (EI): 337.8 (M + H)+, 281.8 (M - (CH2d
C(Me)2)). NMR (CDCl3): 1.42 (9H, s), 1.71 (2H, dd, J ) 7 and
12), 3.67 (2H, t, J ) 7), 3.75 (1H, dt, J ) 5), 4.75 (1H, dd, J )
6 and 8), 4.99 (2H, ab, J ) 10), 5.75 (1H, bd, J ) 8), 7.40 (5H,
s). Anal. (C17H24N2O5) C, H, N.
1:1 Mixtu r e of (2R,3S)-3-[2-[(R)- a n d (S)-Tetr a h yd r o-
p yr a n -2-yloxy]eth yl]oxir a n e-2-ca r boxylic Acid (9).
A
solution of 8 in MeCN (0.2 L) and CCl4 (0.2 L) was diluted
with water (0.4 L) and reacted with RuO2 (0.2 g) and NaIO4
(80.2 g, 0.375 mol) for 4 h. The temperature of the reaction
mixture was kept below 30 °C by occasional cooling, and the
pH was adjusted to pH 4.5 by addition of 2 N Na2CO3. The
reaction mixture was diluted with CH2Cl2. The aqueous layer
was saturated with NaCl and extracted with CH2Cl2 (3×). The
combined organic layers were worked up leaving an oil which
was dissolved in ether and filtered over Dicalite. The filtrate
was evaporated giving a foam (15.11 g, 76%). MS: 215 (M -
H). NMR (CDCl3): 1.52-2.00 (6H, m), 1.88 (2H, m), 3.33 (2H,
m), 3.40-3.53 and 3.80-3.90 (2 × 2H, 2m), 4.60 (1H, m), 7.30
(1H, b).
(2R,3S)-1-(Ben zyloxy)-2-[2-(m eth ylsu lfon yloxy)eth yl]-
4-oxoa zetid in -3-ylca r ba m ic Acid ter t-Bu tyl Ester (14). A
solution of 13 (3.44 g, 10.2 mmol) and triethylamine (1.13 g,
11.2 mmol) in CH2Cl2 (50 mL) was treated dropwise with
MeSO2Cl (1.28 g, 11.2 mmol) at 0 °C. The reaction mixture
was stirred for 1 h at room temperature, then diluted with
CH2Cl2, and washed with ice water and a cooled 10% NaCl
solution. The organic layer was dried over MgSO4, filtered,
and evaporated, leaving an oil which was crystallized from
AcOEt/hexane. The yield was 4.2 g (99%), mp 148 °C. [R]D
+83.2° (c 1, CHCl3). IR: 3324, 1777, 1683, 1533 cm-1. MS
(ISP): 437.3 (M + Na), 415.3 (M + H). NMR (CDCl3): 1.43
(9H, s), 1.87 (2H, m), 2.98 (3H, s), 3.75 (1H, dt, J ) 3 and 5),
4.19 (2H, m), 4.70 (1H, t, J ) 5), 4.95 and 5.02 (2H, ab), 5.20
(1H, d, J ) 5), 7.41 (5H, s). Anal. (C22H34N2O7) C, H, N.
(1R,5R)-6-(Ben zyloxy)-7-oxo-2,6-diazabicyclo[3.2.0]h ep-
ta n e-2-ca r boxylic Acid ter t-Bu tyl Ester (15). A solution
of 14 (4.14 g, 10 mmol) in absolute THF (40 mL) was treated
dropwise at -10 °C with 1 M lithium bis(trimethylsilyl)amide
in THF (11.5 mL, 11.5 mmol). After stirring at room temper-
ature overnight, the reaction mixture was quenched with
saturated NH4Cl solution (25 mL) and extracted with AcOEt.
The organic layer was worked up, chromatographed (hexane/
AcOEt, 6:4) and crystallized from Et2O/hexane (819 mg, 25%),
mp 88-90 °C. [R]D -195° (c 0.9, CHCl3) (lit.8 [R]D -214.9° (c
1, CHCl3)). IR: 1767, 1687, 1421 cm-1. MS (EI): 290 (M -
CO). NMR (CDCl3): 1.46 (9H, s), 1.52 (1H, m), 1.75 (1H, dd,
J ) 6 and 14), 3.10 (1H, dt, J ) 6 and 10), 3.80 (1H, bt, J )
10), 4.09 (1H, b), 4.75 and 5.00 (1H, b), 4.96 (2H, s), 7.40 (5H,
s). Anal. (C17H22N2O4) C, H, N.
1:1 Mixtu r e of (1S,2S)-1-Ca r boxy-2-h yd r oxy-4-[(R)- a n d
(S)-tetr a h yd r op yr a n -2-yloxy]bu tylca r ba m ic Acid ter t-
Bu tyl Ester (10). A solution of 9 (2.58 g, 11.9 mmol) in MeOH
(10 mL) was treated with KHCO3 (1.31 g, 13.1 mmol) in water
(20 mL). The solvents were evaporated. The residue was
taken up in concentrated NH4OH (40 mL), placed in a sealed
tube, and warmed to 50 °C for 20 h. Excess ammonia was
evaporated, and the residue was dried under high vacuum. It
was dissolved in dioxane/water (60 mL; 2:1) and treated with
(BOC)2O. After stirring for 3 h, the organic solvent was
evaporated and the aqueous layer was extracted twice with
AcOEt. The combined organic extracts were discarded. The
pH of the aqueous layer was adjusted to pH 3.5 with 1 N HCl
and extracted with AcOEt (3×). The combined organic phases
were worked up affording 2.62 g (66%) of 10. NMR (CDCl3):
1.45 (9H, s), 1.50-1.98 (8H, m), 3.50-4.05 (4H, m), 4.13 (1H,
m), 4.36 (1H, m), 4.55 (1H, m), 5.65 (1H, d, J ) 9).
1:1 Mixtu r e of (1S,2S)-1-(Ben zyloxyca r ba m oyl)-2-h y-
d r oxy-4-[(R)- a n d (S)-tetr a h yd r op yr a n -2-yloxy]bu tylca r -
ba m ic Acid ter t-Bu tyl Ester (11). The pH of a solution of
10 (2.62 g, 7.85 mmol) and BnONH2‚HCl (1.63 g, 10.2 mmol)
in THF/water (0.1 L; 1:1) was adjusted to pH 4.5 with 1 N
NaOH. The solution was reacted with a solution of 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.85
g, 15.71 mmol) in water (10 mL) at pH 4.5 (kept by the addition
of 1 N HCl). After the mixture stirred for 4 h, the pH was
adjusted to 6.7, and the reaction mixture was diluted with
AcOEt, the organic phase separated, and the aqueous layer
extracted with AcOEt. The combined organic phases were
worked up and chromatographed (hexane/ethyl acetate, 3:7)
affording 1.74 g (51%) of 11, mp 87-88 °C (hexane). [R]D
-9.4°(c 1, CHCl3). MS (ISP): 461.4 (M + Na), 439.4 (M + H).
NMR (CDCl3): 1.43 (9H, s), 1.50-1.98 (9H, m), 3.45-4.10 (6H,
m), 4.55 (1H, m), 4.91 (2H, 2m), 5.5-5.7 (1H, m), 7.35 (5H, s),
9.50 (1H, 2s). Anal. (C22H34N2O7) C, H, N.
(1R,5R)-6-Hydr oxy-7-oxo-2,6-diazabicyclo[3.2.0]h eptan e-
2-ca r boxylic Acid ter t-Bu tyl Ester (16). A solution of 15
(769 mg, 2.41 mmol) in EtOH (15 mL) was hydrogenated over
10% Pd/C. The catalyst was filtered off, and the filtrate was
evaporated under reduced pressure and crystallized giving 0.48
g (87%) of 15, mp 150-52 °C (AcOEt/n-hexane). IR: 3437,
1754, 1721, 1697, 1404 cm-1. MS (EI): 211 (M - OH). NMR
(DMSO-d6): 1.40 (9H, s), 1.68 (1H, m), 2.0 (1H, dd, J ) 6 and
12), 3.09 (1H, m), 3.81 (1H, dd, J ) 9 and 12), 4.39 (1H, t, J )
4.5), 4.8 (1H, broad), 10.32 (1H, s). Anal. (C10H16N2O4) C, H,
N.
Sod iu m [(1S,5R)-2-(ter t-Bu t oxyca r b on yl)-7-oxo-2,6-
d ia za bicyclo[3.2.0]h ep ta n -6-yl]su lfa te (2a ). A solution of
16 (114 mg, 0.5 mmol) in pyridine (2 mL) was reacted with
C5H5N‚SO3 complex (95 mg, 0.6 mmol) and molecular sieve (4
Å). The reaction mixture was filtered, and the filtrate was
evaporated. The residue was dissolved in EtOH (3 mL) and
precipitated by the addition of Et2O. The first oily crystals