2748
W. J. Brouillette et al. / Bioorg. Med. Chem. 11 (2003) 2739–2749
3.81–3.70 (m, 4H), 2.66–2.52 (m, 3H), 2.20–2.13 (m, 1H)
and 1.90–1.70 (m, 1H).
2.72–2.63 (m, 2H), 2.44–2.00 (m, 4H), 2.04–2.00. Anal.
calcd for C22H23N5O5: C, 60.44; H, 5.30; N, 16.00.
Found: C, 60.56; H, 5.18; N, 15.91.
5-Benzoyloxymethyl-5-(2-bromoethyl)-N-(4-methoxy-
carbonyl-2-nitrophenyl)pyrrolidin-2-one (30). A solution
of 29 (isomers A and B combined, 2.75 g, 6.45 mmol) in
anhydrous benzene (117mL) was treated with N-bromo-
succinimide (1.60 g, 8.99 mmol) at ambient temperature
and stirred under nitrogen for 23 h. Benzene (63 mL)
was added, and stirring was continued for an additional
3 h. The reaction mixture was concentrated under
vacuum, the residue was suspended in water (50 mL)
and the product was extracted into chloroform (3 Â
50 mL). The combined organic layers were dried
(MgSO4) and concentrated to give an oily residue. This
was placed on a flash chromatography column (ether)
to give 30 (2.35 g, 72.3%) as a white powder: mp 69–
5-(2-Azidoethyl)-5-benzoyloxymethyl-N-[4-methoxy-
carbonyl-2-(3-pentylamino)phenyl]pyrrolidin-2-one (33).
A solution of 32 (0.19 g, 0.43 mmol) in 2 mLof 1,2-
dichloroethane was treated with 1 mLof acetic acid and
stirred under nitrogen. After 10 min, 3-pentanone
(0.39 g, 4.5 mmol) and NaCNBH3 (0.14 g, 2.2 mmol)
were added, and stirring was continued for 5 h. Another
portion of 3-pentanone (0.39 g, 4.5 mmol) and
NaBH3CN (0.14 g, 2.2 mmol) was added, followed by
an additional five portions, each added every 5 h. No
further progress in reaction was observed. To the reac-
tion mixture was added saturated NaHCO3 (8 mL), and
this was concentrated under high vacuum. The white
residue was triturated with ether (5 Â 25 mL). The
combined ether washes were shaken with H2O (10 Â
20 mL), brine (20 mL) and dried (MgSO4). This was
concentrated to give a green oil (180 mg), which was
placed on a flash chromatography column (ether) to
give recovered 32 (100 mg) and the desired product 33
(70 mg, 70% conversion) as an oil. This material was
carried forward without additional purification. MS
71 ꢀC. MS (ES) m/z 505 (M+H); H NMR (CDCl3) d
1
8.68 (s, 0.6H), 8.58 (s, 0.4H), 8.32–8.26 (m, 1H), 7.98–
7.96 (d, 1H), 7.66–7.26 (m, 5H), 4.73–4.41 (m, 2H), 3.98
(s, 3H), 3.51–3.46 (m, 1H), 3.36–3.33 (m, 1H), 2.71–2.24
(m, 6H). Anal. calcd for C22H21N2O7Br: C, 52.33; H,
4.19; N, 5.55. Found: C, 52.24; H, 4.31; N, 5.39.
5-(2-Azidoethyl)-5-benzoyloxymethyl-N-(4-methoxy-
carbonyl-2-nitrophenyl)pyrrolidin-2-one (31). Compound
30 (1.90 g, 3.76 mmol) was dissolved in DMF (5.7 mL),
NaN3 (0.300 g, 4.61 mmol) was added, and the mixture
was stirred at 70–75 ꢀC for 16 h. The DMF was removed
under vacuum at 40 ꢀC, the residue was diluted with
EtOAc (25 mL), and the mixture was washed with water
(4Â15 mL) followed by brine (15 mL). The organic layer
was dried (MgSO4) and concentrated. The residue was
purified by flash chromatography (ether) to give 31
(1.48 g, 85.0%) as pale yellow needles: mp 46–48 ꢀC. MS
(ES) m/z 468 (M+H); 1H NMR (CDCl3) d 8.66 (s, 1H),
8.28–8.25 (d, 1H), 7.98–7.95 (d, 1H), 7.64–7.22 (m, 5H),
4.72–4.40 (m, 2H), 3.97 (s, 3H), 3.61–3.57 (t, 1H), 3.45–
3.40 (t, 1H), 2.77–2.08 (m, 5H) and 1.94–1.84 (m, 1H).
Anal. calcd for C22H21N5O7: C, 56.53; H, 4.53; N,
14.98. Found: C, 56.32; H, 4.53; N, 14.75.
1
(ES) m/z 508 (M+H); H NMR (CDCl3) d 8.02–7.99
(d, 1H), 7.78–7.76 (d, 1H), 7.63–7.56 (m, 1H), 7.50–7.27
(m, 4H), 7.03–6.99 (m, 1H), 4.66–4.62 (d, 0.5H), 4.53–
4.49 (d, 0.5H), 4.38 (s, 1H), 4.28–4.18 (m, 1H),
4.01–3.98 (d, 0.5H), 3.90 (s, 3H), 3.85–3.82 (d, 0.5H),
3.52–3.29 (m, 2H), 2.86–2.57 (m, 2H), 2.34–2.27 (m,
2H), 2.10–2.07 (t, 1H), 1.98–1.90 (t, 1H), 1.66–1.40 (m,
4H), 1.01–0.95 (m, 3H), 0.83–0.77 (m, 3H).
5-(2-Azidoethyl)-N-[4-carboxy-2-(3-pentylamino)phenyl]-
5-(hydroxymethyl)pyrrolidin-2-one (34). A solution of 33
(0.047 g, 0.093 mmol) in 1 N NaOH (1 mL) and metha-
nol (1 mL) was stirred at ambient temperature for 12 h.
The mixture was acidified to pH 3 with acetic acid and
concentrated to dryness under high vacuum. The white
solid residue was triturated with EtOAc (2Â10 mL), and
the combined organic washes were extracted with water
(10 mL) and brine (10 mL). The organic layer was con-
centrated to give a white solid, which was triturated
with ether (5 mL) followed by hexane (5 mL). The inso-
luble residue was purified by flash chromatography (4%
ethanol in ether) to give 34 (25 mg, 70%) as a solid: mp
164–166 ꢀC; MS (ES) m/z 390 (M+H); 1H NMR
(CH3OD) d 7.39 (d, 0.4H), 7.33–7.32 (d, 0.6H), 7.30–
7.27 (m, 0.4H), 7.23–7.19 (dd, 1H), 6.99–6.96 (d, 0.6H),
3.64–3.60 (t, 1H), 3.52–3.35 (m, 3H), 3.27–3.16 (m, 1H),
2.81–2.64 (m, 1H), 2.57–2.29 (m, 2H), 2.27–2.12 (m,
1H), 1.99–1.88 (m, 1H), 1.82–1.73 (m, 1H), 1.68–1.41
(m, 4H), 0.99–0.88 (m, 6H). Anal. calcd for
C19H27N5O5: C, 57.27; H, 7.08; N, 17.57. Found: C,
57.60; H, 6.96; N, 17.22.
N-(2-Amino-4-methoxycarbonylphenyl)-5-(2-azidoethyl)-
5-(benzoyloxymethyl)pyrrolidin-2-one (32). Compound
31 (1.50 g, 3.21 mmol) was dissolved in THF (22 mL)
and water (9.6 mL), and to this was added Na2S2O7
(2.14 g, 12.2 mmol). After stirring under nitrogen for
20 h, more Na2S2O7 (0.197 mg, 1.13 mmol) was added,
and the mixture was stirred for an additional 5 h at
room temperature. The THF was removed under
vacuum and the aqueous residue was extracted with
EtOAc (5 Â 25 mL). The aqueous layer was con-
centrated to dryness and the residue was triturated with
EtOAc (25 mL) and filtered. The combined organic lay-
ers were dried (MgSO4) and concentrated to give an oil
(1.31 g). This was purified by flash chromatography (8%
ethanol in ether) to give 32 (1.20 g, 86.0%) as a white
solid: mp 65–68 ꢀC; MS (ES) m/z 438 (M+H); 1H
NMR (CD3OD) d 8.01–7.98 (m, 1H), 7.68–7.63 (m,
0.5H), 7.54–7.45 (m, 3H), 7.39–7.36 (m, 0.5H), 7.31–
7.24 (m, 2H), 7.13–7.10 (d, 0.5H), 7.02–7.00 (d, 0.5H),
4.72–4.56 (dd, 1H), 4.36–4.35 (dd, 1H), 3.90 (s, 3H),
3.88–3.87 (d, 1H), 3.66–3.48 (m, 1H), 3.46–3.39 (q, 1H),
5-(2-Aminoethyl)-N-[4-carboxy-2-(3-pentylamino)phe-
nyl]-5-(hydroxymethyl)pyrrolidin-2-one (11). A suspen-
sion of 34 (0.065 g, 0.167 mmol), 10% Pd/C (0 073g), and
methanol (15 mL) was reacted on a Parr shaker for 3 h at
40 psi H2. The reaction mixture was diluted with MeOH
(50 mL), and the mixture was filtered and concentrated to