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E. Bellis et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 24.3, 28.2, 30.8, 41.1, 47.2, 60.4,
13C NMR (50 MHz, CDCl3): d = 28.3, 37.8, 39.0, 40.9, 41.3, 54.9,
81.6, 156.4, 171.3.
58.2, 60.2, 69.0, 69.7, 81.4, 81.7, 154.6, 155.8, 173.5.
Anal. Calcd for C11H20N2O5S (292.35): C, 45.19; H, 6.90; N, 9.58.
Found: C, 45.05; H, 7.20; N, 9.60.
Anal. Calcd for C11H20N2O6S (308.35): C, 42.85; H, 6.54; N, 9.08.
Found: C, 42.90; H, 6.50; N, 9.20.
(S)-tert-Butyl 2-(Tosylcarbamoyl)pyrrolidine-1-carboxylate
(2S,4R)-tert-Butyl 4-Hydroxy-2-(tosylcarbamoyl)pyrrolidine-1-
(9b)
carboxylate (4b)
White solid (220 mg, 60%); mp 201–203 °C; [a]D25 –117.5 (c = 1.0,
White solid (277 mg, 72%); mp 213–215 °C; [a]D25 –91.2 (c = 1.0,
CHCl3).
CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.45 [br s, 9 H, C(CH3)3], 1.70–
2.25 (m, 4 H, CH2CH2CH), 2.40 (s, 3 H, CH3), 3.10–3.60 (m, 2 H,
CH2N), 4.10 (m, 1 H, CH), 7.30 (d, J = 8.7 Hz, 2 H, C6H4), 7.90 (d,
J = 8.7 Hz, 2 H, C6H4), 9.58 (m, 0.3 H, NH), 10.70 (m, 0.7 H, NH).
13C NMR (50 MHz, CDCl3): d = 21.5, 24.2, 24.8, 28.1, 30.5, 33.7,
47.1, 49.0, 60.2, 61.0, 81.5, 128.2, 129.3, 135.7, 144.7, 157.1,
169.3.
1H NMR (200 MHz, CDCl3): d = 1.48 [br s, 9 H, C(CH3)3], 1.70–
2.10 (m, 2 H, CH2CH), 2.43 (s, 3 H, CH3), 3.30–3.60 (m, 2 H,
CH2N), 3.71 (d, J = 2.2 Hz, 1 H, OH), 4.25–4.55 (m, 2 H, CHN,
OCH), 7.32 (d, J = 7.4 Hz, 2 H, C6H4), 7.94 (d, J = 7.8 Hz, 2 H,
C6H4).
13C NMR (50 MHz, CD3OD): d = 21.5, 28.2, 28.6, 38.9, 39.9, 55.7,
55.9, 60.2, 60.4, 69.8, 70.6, 81.8, 129.1, 129.4, 130.4, 130.6, 137.6,
146.3, 155.5, 156.1, 173.1.
Anal. Calcd for C17H24N2O5S (368.45): C, 55.42; H, 6.57; N, 7.60.
Found: C, 55.40; H, 6.72; N, 7.70.
Anal. Calcd for C17H24N2O6S (384.45): C, 53.11; H, 6.29; N, 7.29.
Found: C, 53.12; H, 6.30; N, 7.32.
(2S)-tert-Butyl 2-{[((1R,4S)-7,7-Dimethyl-2-oxobicy-
clo[2.2.1]heptan-1-yl)methylsulfonyl]carbamoyl}pyrrolidine-1-
carboxylate (9c)
(2S,4R)-tert-Butyl 4-{[(1S,4R)-7,7-Dimethyl-2-oxobicy-
clo[2.2.1]heptan-1-yl]methylsulfonyloxy}-2-(methylsulfonyl-
carbamoyl)pyrrolidine-1-carboxylate (6)
Colorless oil (262 mg, 61%); [a]D25 –91.8 (c = 1.0, CHCl3).
To a stirred solution of 4a (308 mg, 1.00 mmol) in anhyd THF (12
mL) were added NMM (0.28 mL, 2.50 mmol) and (1S)-(+)-cam-
phor-10-sulfonyl chloride (315 mg, 1.25 mmol) at 0 °C. The reac-
tion mixture was stirred at 0 °C for 30 min and at r.t. for 3 h. NMM
(75 mL, 0.67 mmol) and (1S)-(+)-camphor-10-sulfonyl chloride
(150 mg, 0.60 mmol) were then added and the stirring was contin-
ued at r.t. for 18 h. The solvent was removed, H2O (15 mL) was add-
ed and the product was then extracted with EtOAc (3 × 15 mL). The
combined organic layers were washed consecutively with 1 M
KHSO4 and H2O and dried (Na2SO4), and the solvent was evaporat-
ed. The product was purified by column chromatography using a
mixture of CHCl3–MeOH (9:1) as eluent to give 6 as a colorless oil
(464 mg, 89%); [a]D25–2.2 (c = 1.0, MeOH).
1H NMR (200 MHz, CDCl3): d = 0.75–2.80 (series of m, 24 H, 5 ×
CH3, 4 × CH2, CH), 3.00 (d, J = 16 Hz, 1 H, CHHSO2), 3.10–3.30
(m, 3 H, SO2CH3), 3.58 (d, J = 16 Hz, 1 H, CHHSO2), 3.65–4.48
(m, 3 H, CHN, CH2N), 5.29 (m, 1 H, OCH), 7.50 (m, 0.5 H, NH),
7.68 (m, 0.5 H, NH).
1H NMR (200 MHz, CDCl3): d = 0.87 (s, 3 H, CH3), 1.01 (s, 3 H,
CH3), 1.44 [br s, 9 H, C(CH3)3], 1.65–2.52 (series of m, 11 H, 5 ×
CH2, CH), 3.00–3.90 (m, 4 H, CH2SO2, CH2N), 4.38 (m, 1 H,
CHN).
13C NMR (50 MHz, CDCl3): d = 19.5, 19.8, 24.2, 24.9, 26.4, 26.9,
28.2, 30.5, 42.5, 42.9, 47.1, 48.4, 48.8, 50.0, 53.5, 58.4, 59.1, 81.4,
156.0, 172.0, 217.3.
Anal. Calcd for C20H32N2O6S (428.54): C, 56.05; H, 7.53; N, 6.54.
Found: C, 56.40; H, 7.52; N, 6.60.
(2S)-tert-Butyl 2-{[((1S,4R)-7,7-Dimethyl-2-oxobicy-
clo[2.2.1]heptan-1-yl)methylsulfonyl]carbamoyl}pyrrolidine-1-
carboxylate (9d)
Colorless oil (286 mg, 67%); [a]D25 –51.3 (c = 1.2, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.88 (s, 3 H, CH3), 1.08 (s, 3 H,
CH3), 1.47 [br s, 9 H, C(CH3)3], 1.60–2.58 (series of m, 11 H, 5 ×
CH2, CH), 3.10–3.95 (m, 4 H, CH2SO2, CH2N), 4.30 (m, 1 H,
CHN).
13C NMR (50 MHz, CDCl3): d = 19.5, 19.7, 24.4, 25.0, 26.7, 27.2,
28.4, 30.5, 42.4, 42.7, 47.1, 48.4, 48.5, 50.2, 53.5, 58.5, 59.2, 81.6,
156.3, 172.4, 217.5.
13C NMR (50 MHz, CDCl3): d = 19.5, 26.3, 26.7, 28.1, 28.4, 32.3,
34.5, 41.0, 42.3, 42.5, 46.5, 48.0, 53.0, 57.8, 60.0, 77.2, 78.9, 82.2,
155.6, 167.6, 214.4.
Anal. Calcd for C21H34N2O9S2 (522.63): C, 48.26; H, 6.56; N, 5.36.
Found: C, 48.52; H, 6.32; N, 5.60.
Anal. Calcd for C20H32N2O6S (428.54): C, 56.05; H, 7.53; N, 6.54.
Found: C, 56.35; H, 7.55; N, 6.59.
N-Boc-(S)-2-azidomethylpyrrolidine (13)
To an ice-cold solution of N-Boc-L-prolinol (12) (201 mg, 1.00
mmol) in anhyd CH2Cl2 (4 mL) were added Et3N (0.21 mL, 1.50
mmol) and methanesulfonyl chloride (116 mL, 1.50 mmol). The re-
action mixture was stirred for 3 h. The solvent was removed, H2O
(7 mL) was added and the product was then extracted with EtOAc
(3 × 5 mL). The combined organic layers were washed consecutive-
ly with 1 M KHSO4 and H2O and dried (Na2SO4), and the solvent
was evaporated. The intermediate mesylate was obtained in quanti-
tative yield as a yellowish oil (279 mg) and used without additional
purification. Thus, the mesylate was dissolved in anhyd DMF (5
mL) and NaN3 (195 mg, 3.00 mmol) was added. The reaction mix-
ture was heated to 60 °C for 18 h, allowed to cool to r.t. and the sol-
vent was removed under reduced pressure. Subsequently, H2O (10
mL) was added and the product was then extracted with EtOAc
(3 × 10 mL). The combined organic layers were dried (Na2SO4),
and the solvent was evaporated. The product was purified by col-
umn chromatography using a mixture EtOAc–petroleum ether (7:3)
Removal of Benzyl Group from the Protected Acyl Sulfon-
amides 2a,b; General Procedure
To a stirred solution of 2a,b (1.00 mmol) in anhyd 1,4-dioxane (15
mL), 10% Pd/C (50 mg) was added. The reaction mixture was
stirred under H2 for 24 h at r.t. After filtration through a pad of
Celite, the solvent was removed and the residue was purified by col-
umn chromatography using a mixture of CHCl3–MeOH (9:1) as
eluent to give 4a,b.
(2S,4R)-tert-Butyl 4-Hydroxy-2-(methylsulfonylcarbam-
oyl)pyrrolidine-1-carboxylate (4a)
White solid (foam) (274 mg, 89%); mp 92–94 °C; [a]D25 –97.0 (c =
1.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.45 [br s, 9 H, C(CH3)3], 1.95–
2.50 (m, 2 H, CH2CH), 3.10–3.75 (m, 5 H, SO2CH3, CH2N), 4.20–
4.60 (m, 2 H, CHN, OCH).
Synthesis 2005, No. 14, 2407–2413 © Thieme Stuttgart · New York