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Arch. Pharm. Chem. Life Sci. 2007, 340, 530–537
4.25 (m, 5H), 4.46–4.58 (m, 4H), 4.70 (dd, 1H, J = 5.7 and 5.3 Hz),
4.82 (dd, 1H, J = 5.3 and 5.3 Hz), 5.19–5.34 (m, 3H), 5.42 and 5.47
(2s, 1H), 5.87–6.04 (m, 2H).
(2S,4S)-2-[7-(t-Butyloxycarbonylamino-5-aza-
spiro[2.4]heptane)carbonyl]-4-tritylthio-1-(allyloxy-
carbonyl)pyrrolidine 20
The syntheses of compounds IIb-h were carried out by the
same procedure as described for the preparation of IIa.
IIb: Yield 39%. 1H-NMR (CDCl3): d 0.61–0.77 (m, 2H), 0.88–0.94
(m, 2H), 1.21–1.29 (m, 3H), 1.34–1.37 (m, 3H), 2.02–2.13 (m, 2H),
2.64–2.68 (m, 1H), 3.24–3.26 (m, 1H), 3.37–3.50 (m, 2H), 3.60–
3.64 (m, 2H), 3.72–3.79 (m, 2H), 4.02–4.05 (m, 1H), 4.12–4.14
(m, 1H), 4.23–4.26 (m, 2H), 4.51–4.58 (m, 3H), 4.69 (dd, 1H, J =
5.4 and 5.6 Hz), 4.82 (dd, 1H, J = 5.4 and 5.5 Hz), 5.17–5.34 (m,
3H), 5.42 and 5.48 (2s, 1H), 5.90–6.02 (m, 2H).
The synthesis of compound 12 was carried out by the same pro-
cedure as described for the preparation of 9. The synthesis of
compound 20 was carried out by the same procedure as
described for the preparation of 14. 1H-NMR (300 MHz, CDCl3): d
0.56–0.95 (m, 4H), 1.40–1.50 (m, 9H), 1.73–1.91 (m, 2H), 2.72–
2.75 (m, 1H), 3.04–3.21 (m, 3H), 3.45–3.82 (m, 4H), 4.01–4.05
(m, 1H), 4.40–4.56 (m, 2H), 5.13–5.29 (m, 2H), 5.13–5.29 (m, 2H),
5.81–5.86 (m, 1H), 7.20–7.47 (m, 15H). 13C-NMR (300 MHz,
CDCl3): d 5.65, 13.34, 24.10, 24.93, 28.33, 36.21, 41.12, 41.65,
52.42, 53.02, 56.91, 65.83, 67.21, 80.06, 117.23, 126.87, 128.08,
129.50, 130.09, 132.72, 144.61, 154.05, 155.31, 169.92.
1
IIc: Yield 33%. H-NMR (CDCl3): d 0.93 (s, 2H), 1.11–1.28 (m,
8H), 1.98–2.02 (m, 2H), 2.67–2.69 (m, 1H), 3.37–3.42 (m, 3H),
3.56–3.64 (m, 1H), 3.72–3.74 (m, 3H), 3.98–4.06 (m, 3H), 4.08–
4.19 (m, 1H), 4.26–4.32 (m, 1H), 4.38–4.51 (m, 4H), 4.62 (dd, 1H, J
= 5.5 and 5.6 Hz), 4.74 (dd, 1H, J = 4.0 and 5.3 Hz), 5.10–5.27 (m,
3H) 5.34 and 5.40 (2s, 1H), 5.71–5.96 (m, 2H).
(2S,4S)-2-[(7-Fluoro-5-aza-spiro[2.4]heptane)-car-
bonyl]-4-tritylthio-1-(allyloxycarbonyl)pyrrolidine 21
To a suspension of compound 15 (1.11 g, 1.95 mmol) in CH2Cl2
was added DAST (0.35 g, 2.15 mmol) at –708C. The mixture was
stirred at –708C for 45 min and then allowed to warm to room
temperature. At this time, 4 mL of methanol were added to
quench the reaction. The solvent was evaporated in vacuo and
the resulting oil dissolved in ethyl acetate, neutralized (pH = 7-8)
by addition of a 32% ammonia solution, and extracted with
ethyl acetate. The organic phase was washed with brine, dried
over MgSO4, and then evaporated. The crude residue was puri-
fied by silica gel column chromatography (EtOAc : n-hexane;
1 : 3) to give 21 (0.7 g, 58%) as a pale yellow oil. 1H-NMR
(300 MHz, CDCl3): d 1.15–1.40 (m, 2H), 1.67–1.86 (m, 2H), 2.24
(bs, 1H), 2.35–2.47 (m, 1H), 2.77 (bs, 1H), 3.02–3.27 (m, 3H),
3.44–3.50 (m, 1H), 3.58–3.81 (m, 2H), 4.00–4.21 (m, 2H), 4.11–
4.57 (m, 2H), 5.10–5.28 (m, 2H), 5.77–5.91 (m, 1H), 7.22–7.41
(m, 15H). 13C-NMR (300 MHz, CDCl3): d 16.00, 30.98, 36.29, 37.24,
41.10, 41.70, 50.88, 52.04, 57.21, 65.88, 67.23, 117.03, 126.86,
128.08, 129.52, 132.76, 144.61, 153.30, 154.10.
IId: Yield 34%. 1H-NMR (CDCl3): d 0.93 (bs, 1H), 1.03–1.23 (m,
6H), 1.27–1.29 (m, 2H), 1.89–1.98 (m, 2H), 2.56–2.67 (m, 1H),
3.18–3.20 (m, 1H), 3.54–3.65 (m, 2H), 4.02–4.11 (m, 2H), 4.16–
4.20 (m, 2H), 4.29–4.34 (m, 1H), 4.40–4.55 (m, 4H), 4.59–4.64
(m, 1H), 4.74 (dd, 1H, J = 5.3 and 5.4 Hz), 5.10–5.27 (m, 3H), 5.35–
5.40 (2s, 1H) 5.75–5.96 (m, 1H), 8.20–8.50 (m, 1H).
IIe: Yield 29%. 1H-NMR (CDCl3): d 0.81–0.94 (m, 2H), 1.11–1.22
(m, 6H), 1.28–1.30 (m, 2H), 1.92–2.13 (m, 2H), 2.52–2.64 (m, 1H),
3.18–3.19 (m, 1H), 3.32–3.37 (m, 2H), 3.40–3.44 (m, 2H), 3.55–
3.65 (m, 1H), 3.94–4.09 (m, 2H), 4.17–4.19 (m, 2H), 4.27–4.32
(m, 1H), 4.37–4.44 (m, 4H), 4.50–4.52 (m, 2H), 4.65 (dd, 1H, J =
4.2 and 6.8 Hz), 4.75 (dd, 1H, J = 5.4 and 5.3 Hz), 5.12–5.27 (m,
5H), 5.35 and 5.41 (2s, 1H), 5.72–5.95 (m, 3H).
IIf: Yield 31%. 1H-NMR (CDCl3): d 0.99–1.00 (m, 2H), 1.17–1.23
(m, 3H), 1.26–1.32 (m, 6H), 1.35–1.37 (m, 2H), 1.99–1.53 (m, 2H),
2.60–2.72 (m, 1H), 3.24–3.25 (m, 1H), 3.38–3.51 (m, 2H), 3.60–
3.82 (m, 2H), 3.99–4.09 (m, 2H), 4.14–4.19 (m, 1H), 4.21–4.27
(m, 2H), 4.31–4.37 (m, 1H), 4.48–4.59 (m, 4H), 4.67–4.73 (m, 1H),
4.82 (dd, 1H, J = 5.4 and 5.4 Hz), 5.17–5.38 (m, 3H), 5.42 and 5.48
(2s, 1H), 5.79–6.03 (m, 2H).
IIg: Yield 28%. 1H-NMR (CDCl3): d 0.63–0.95 (m, 4H), 1.26–1.38
(m, 6H), 1.90–2.28 (m, 2H), 2.30–2.64 (m, 2H), 2.87–2.95 (m, 1H),
2.97–3.14 (m, 1H), 3.19–3.49 (m, 2H), 3.54–3.85 (m, 3H), 3.96–
4.08 (m, 2H), 4.16–4.25 (m, 1H), 4.39–4.56 (m, 5H), 4.68 (dd, 1H, J
= 5.3 and 4.6 Hz), 4.83 (dd, 1H, J = 5.7 and 3.8 Hz), 5.18–5.37 (m,
5H), 5.42 and 5.48 (2s, 1H), 5.67–5.98 (m, 3H).
Allyl(1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-[[5-(7-oxo-5-
aza-spiro[2.4]heptane) carbonyl]-1-(allyloxy-
carbonyl)pyrrolidin-3-ylthio]-1-methylcarbapen-2-
em-3-carboxylate IIa
To a solution of 14 (0.6 g, 1.0 mmol) in CH2Cl2 (3 mL) was added
dropwise triethylsilane (0.20 mL, 1.2 mmol) at 58C, and then TFA
(1.2 mL). After stirring for 30 min at room temperature, the mix-
ture was evaporated under reduced pressure. The residue was
dissolved with ethyl acetate and washed with 10% NaHCO3,
brine. The organic layer was concentrated in vacuo to give a resi-
due Ia, which was used without further purification. A solution
IIh: Yield 30%. 1H-NMR (CDCl3): d 0.71–0.88 (m, 4H), 1.07–1.51
(m, 6H), 2.04–2.09 (m, 1H), 2.52–2.60 (m, 1H), 3.26–3.49 (m, 3H),
3.54–3.67 (m, 1H), 3.76–3.80 (m, 1H), 3.84–3.90 (m, 2H), 3.95–
4.10 (m, 2H), 4.17–4.30 (m, 1H), 4.41–4.60 (m, 5H), 4.69 (dd, 1H, J
= 5.52 and 5.88 Hz), 4.82 (dd, 1H, J = 5.4 and 5.6 Hz) 5.12–5.34 (m,
3H), 5.42 and 5.48 (2s, 1H), 5.88–6.00 (m, 2H).
of
allyl-(1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydrox-
(22, 0.60 g,
yethyl]-1-methylcarbapen-2-em-3-carb-oxylate
(1R,5S,6S)-6-[(1R)-Hydroxyethyl]-2-[5-(7-oxo-5-aza-
spiro[2.4]heptane)carbonyl]-pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylic acid IIIa
To a stirred solution of IIa (0.1 g, 0.2 mmol) and Pd(PPh3)4
(30 mg) in CH2Cl2 (10 mL) was added dropwise n-tributyltin
hydride (0.1 mL, 0.25 mmol) at 08C and was stirred for 1 h at
same temperature. To the resulting solution was diluted with
water (10 mL) and the organic layers was washed with water
(2610 mL). The combined aqueous layers were washed with
ethyl ether (2610 mL) and lyophilized to give a yellow powder
which was purified on a Diaion HP-20 column, eluting with 2%
1.2 mmol) in CH3CN (10 mL) was cooled to 08C under N2. To this
solution was added diisopropylethyl amine (0.13 g, 1.0 mmol)
and a solution of the mercapto compound Ia in CH3CN (5 mL).
After stirring for 5 h, the mixture was diluted with ethyl acetate,
washed with 10% NaHCO3, brine, and dried over anhydrous
MgSO4. Evaporation in vacuo gave a foam, which was purified by
silica gel chromatography (EtOAc : n-hexane; 3 : 1) to give IIa
1
(0.15 g, 31%) as a yellow amorphous solid. H-NMR (300 MHz,
CDCl3): d 1.25–1.31 (m, 6H), 1.36 (d, 3H, J = 4.3 Hz), 1.95–2.05 (m,
1H), 2.60–2.65 (bs, 1H), 2.95–3.06 (m, 1H), 3.24–3.28 (bs, 1H),
3.48–3.65 (m, 3H), 3.69–3.78 (m, 2H), 3.88–4.02 (m, 2H), 4.12–
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim