Enantiopure Piperazine Scaffolds
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129.3, 128.2 (2C), 127.9, 127.4 (2C), 127.2, 126.2, 125.2, 125.0 (2C), 122.0,
120.2 (2C), 71.9, 46.6 ppm.
*signals corresponding to
a
minor rotamer; HRMS: m/z: calcd for
C17H25N3O7S: 416.14915; found: 416.14858 [M+H]+.
Allyl
(2S,5S)-2-ethyl-5-hydroxymethyl-4-(4-nitrophenylsulfonyl)pipera-
Allyl 2,4-dinitrophenyl carbonate: The reaction was performed according
to GP C using allyl chloroformate (0.88 mL, 8.30 mmol). Recrystalliza-
tion from Et2O afforded 1.69 g (89%) of yellow crystals. M.p. 54–578C;
1H NMR (300 MHz, CDCl3): d=8.99 (d, J=3.0 Hz, 1H), 8.54 (dd, J=
3.0, 9.0 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 6.07–5.94 (m, 1H), 5.51–5.37
(m, 2H), 4.81 ppm (dt, J=1.5, 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=151.2, 148.4, 145.2, 130.1, 129.3 (2C), 126.3, 122.0, 120.7, 70.9 ppm; el-
emental analysis calcd (%) for C10H8N2O7: C 44.79, H 3.01, N 10.45;
found: C 44.57, H 2.78, N 10.34.
zine-1-carboxylate (12b): The reaction was performed according to GP D
using allyl 2,4-dinitrophenyl carbonate (83 mg, 0.31 mmol) and N-nosyl-
protected diamino alcohol resin 6b (100 mg; 0.77 mmolgÀ1). Yield: 22 mg
(69%; two steps) of a colorless oil. [a]2D0 =À4.2 (c=0.52 in methanol);
1H NMR (300 MHz, CDCl3): d=8.36–8.33 (m, 2H), 8.02–7.99 (m, 2H),
5.95–5.82 (m, 1H), 5.30–5.20 (m, 2H), 4.65–4.53 (m, 2H), 4.18–4.05 (m,
3H), 3.66–3.40 (m, 3H), 3.26–3.04 (m, 2H), 2.39 (brs, 1H), 1.71–1.42 (m,
2H), 0.87–0.81 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=156.3,
155.3*, 149.9, 146.2, 132.4*, 132.3, 128.3 (2C)*, 128.3 (2C), 124.4 (2C),
124.3 (2C)*, 118.2, 66.8, 66.6*, 58.6*, 58.1, 53.9, 52.4, 51.6*, 43.4, 43.0*,
39.0*, 38.3, 22.0, 21.6*, 10.4 ppm; *signals corresponding to a minor rota-
mer; HRMS: m/z: calcd for C17H23N3O7S: 414.13350; found: 414.13292
[M+H]+.
N-Protection of N-nosylated diamino alcohol resin and subsequent Fu-
kuyama–Mitsunobu cyclization (General procedure D): The appropriate
carbamoylating agent (4 equiv) in dry DCE (1 mL) was added to the ap-
propriate N-nosyl-protected diamino alcohol resin (1 equiv) in a micro-
wave reactor (0.5–2.0 mL), which then was sealed. The mixture was
heated to 1208C for 30 min under MW irradiation. The resin was trans-
ferred to a Teflon reactor, drained and washed with DMF (3ꢂ5 mL, each
for 5 min), MeOH (3ꢂ5 mL) and CH2Cl2 (3ꢂ5 mL). Et3P (0.50 mL,
0.50 mmol; 1m in THF) was added to the N,N’-diprotected diamino alco-
hol resin pre-swollen in dry CH2Cl2 (1 mL). DEAD (63 mL, 0.40 mmol)
in dry CH2Cl2 (1 mL) was added and the resin was agitated at RT for
16 h under N2. The resin was drained, and then washed with DMF (3ꢂ
5 mL, each for 5 min), MeOH (3ꢂ5 mL) and CH2Cl2 (3ꢂ5 mL). The
product was cleaved with TFA/CH2Cl2 2:98 (1.5 mL for 30 min, then
1.5 mL for 15 min), and finally the resin was washed with CH2Cl2 (2 mL).
The eluates were pooled and the solvents were removed in vacuo. The
crude material was purified by preparative reversed-phase HPLC.
Allyl (2R,5S)-2-ethyl-5-hydroxymethyl-4-(4-nitrophenylsulfonyl)pipera-
zine-1-carboxylate (12c): The reaction was performed according to GP D
using allyl 2,4-dinitrophenyl carbonate (96 mg, 0.36 mmol) and N-nosyl-
protected diamino alcohol resin 6c (100 mg; 0.90 mmolgÀ1). Yield: 17 mg
(46%; two steps) of a colorless oil. [a]2D0 =À167.0 (c=0.52 in methanol);
1H NMR (300 MHz, CDCl3): d=8.35–8.32 (m, 2H), 8.03–8.00 (m, 2H),
5.76–5.67 (m, 1H), 5.18–5.12 (m, 2H), 4.31–4.29 (m, 1H), 4.02–3.83 (m,
5H), 3.73–3.67 (m, 1H), 3.59–3.50 (m, 1H), 3.15 (dd, J=11.0, 15.0 Hz,
1H), 2.96 (dd, J=10.0, 14.0 Hz, 1H), 2.77 (brs, 1H), 1.51–1.34 (m, 2H),
0.82 ppm (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=154.8,
150.2, 145.0, 131.9, 128.3 (2C), 124.7 (2C), 117.7, 66.3, 63.7, 57.1, 52.8,
45.3, 38.2, 24.9, 9.9 ppm; HRMS: m/z: calcd for C17H23N3O7S: 414.13350;
found: 414.13290 [M+H]+.
(9H-Fluoren-9-yl)methyl
(2S,5S)-5-hydroxymethyl-2-methyl-4-(4-nitro-
Allyl
(2S,5S)-5-hydroxymethyl-2-isopropyl-4-(4-nitrophenylsulfonyl)pi-
phenylsulfonyl)piperazine-1-carboxylate (11a): The reaction was per-
formed according to GP D using (9H-fluoren-9-yl)methyl 2,4-dinitro-
phenyl carbonate (163 mg, 0.40 mmol) and N-nosyl-protected diamino al-
cohol resin 6a (100 mg; 0.96 mmolgÀ1). Yield: 11 mg (22%; two steps) of
a colorless oil. [a]2D0 =+2.1 (c=0.38 in methanol); 1H NMR (300 MHz,
CDCl3): d=8.37–8.30 (m, 2H), 7.97–7.94 (m, 2H), 7.77–7.71 (m, 2H),
7.55–7.52 (m, 2H), 7.43–7.29 (m, 4H), 4.83–4.67 (m, 1H), 4.57–4.52 (m,
1H), 4.21–4.18 (m, 1H), 4.02–3.80 (m, 2H), 3.54–3.44 (m, 1H), 3.30–3.08
(m, 3H), 3.03–2.84 (m, 2H), 2.36 (brs, 1H), 1.06–0.92 ppm (m, 3H);
13C NMR (75 MHz, CDCl3): d=156.0, 155.0*, 150.0, 146.2*, 146.0, 143.7
(2C), 143.5 (2C)*, 141.5 (2C), 141.3*, 128.3 (2C), 127.9 (2C), 127.3
(2C), 124.9 (2C), 124.6 (2C), 124.4 (2C)*, 120.1 (2C), 67.0, 66.8*, 58.6*,
57.9, 54.0, 53.8*, 47.8, 47.5*, 46.9, 45.9*, 45.1*, 44.8, 38.5*, 37.9, 15.6,
15.0* ppm; *signals corresponding to a minor rotamer; HRMS: m/z:
calcd for C27H27N3O7S: 538.16480; found: 538.16423 [M+H]+.
perazine-1-carboxylate (12d): The reaction was performed according to
GP D using allyl 2,4-dinitrophenyl carbonate (96 mg, 0.36 mmol) and N-
nosyl-protected diamino alcohol resin 6d (100 mg; 0.75 mmolgÀ1). Yield:
15 mg (45%; two steps) of a colorless oil. [a]2D0 =À9.5 (c=0.38 in metha-
nol); 1H NMR (300 MHz, CDCl3): d=8.36–8.33 (m, 2H), 8.03–7.99 (m,
2H), 5.96–5.82 (m, 1H), 5.32–5.21 (m, 2H), 4.66–4.53 (m, 2H), 4.24–4.00
(m, 2H), 3.86–3.80 (m, 1H), 3.71–3.48 (m, 2H), 3.40 (dd, J=7.0, 11.5 Hz,
1H), 3.17–3.09 (m, 1H), 3.04 (dd, J=4.0, 14.5 Hz, 1H), 2.62 (brs, 1H),
2.08–1.94 (m, 1H), 0.96 (t, J=7.0 Hz, 3H), 0.83 ppm (t, J=6.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=156.5, 155.4*, 150.0, 146.3*, 146.2, 132.4*,
132.3, 128.4*, 128.3 (2C), 124.5 (2C), 124.4*, 118.3*, 118.2, 67.0, 66.7*,
58.6*, 57.9, 57.7, 56.6*, 54.0*, 53.7, 41.5, 39.6*, 38.8, 25.2, 25.1*, 20.0, 18.8,
18.4* ppm; *signals corresponding to a minor rotamer; HRMS: m/z:
calcd for C18H25N3O7S: 428.14915; found: 428.14856 [M+H]+.
Allyl (2S,5S)-2-sec-butyl-5-hydroxymethyl-4-(4-nitrophenylsulfonyl)piper-
azine-1-carboxylate (12e): The reaction was performed according to
GP D using allyl 2,4-dinitrophenyl carbonate (85 mg, 0.32 mmol) and N-
nosyl-protected diamino alcohol resin 6e (100 mg; 0.74 mmolgÀ1). Yield:
19 mg (56%; two steps) of a colorless oil. [a]2D0 =À9.6 (c=0.48 in metha-
nol); 1H NMR (300 MHz, CDCl3): d=8.36–8.33 (m, 2H), 8.03–7.97 (m,
2H), 5.96–5.81 (m, 1H), 5.32–5.21 (m, 2H), 4.65–4.53 (m, 2H), 4.25–4.03
(m, 2H), 3.89–3.74 (m, 2H), 3.63–3.47 (m, 1H), 3.41–3.31 (m, 2H), 3.19–
2.99 (m, 2H), 1.84–1.69 (m, 1H), 1.40–1.23 (m, 1H), 1.07–0.97 (m, 1H),
0.91 (t, J=6.5 Hz, 3H), 0.87–0.80 ppm (m, 3H); 13C NMR (75 MHz,
CDCl3): d=156.7, 155.4*, 150.0, 146.3*, 146.1, 132.3*, 132.1, 128.4 (2C)*,
128.3 (2C), 124.5 (2C), 124.4 (2C)*, 118.8*, 118.4, 67.2, 66.8*, 58.5*, 57.7,
56.4, 55.5*, 54.0*, 53.6, 41.7, 39.6*, 38.8, 31.0, 24.5, 24.3*, 16.0, 11.1*,
10.8 ppm; *signals corresponding to a minor rotamer; HRMS: m/z: calcd
for C19H27N3O7S: 442.16480; found: 442.16418 [M+H]+.
Allyl (2S,5S)-5-hydroxymethyl-2-methyl-4-(4-nitrophenylsulfonyl)pipera-
zine-1-carboxylate (11b): The reaction was performed according to GP D
using allyl 2,4-dinitrophenyl carbonate (106 mg, 0.40 mmol) and N-nosyl-
protected diamino alcohol resin 6a (100 mg; 0.96 mmolgÀ1). Yield: 22 mg
(55%; two steps) of a colorless oil. 1H NMR (300 MHz, CDCl3): d=
8.36–8.33 (m, 2H), 8.03–8.00 (m, 2H), 5.96–5.83 (m, 1H), 5.31–5.21 (m,
2H), 4.60–4.58 (m, 2H), 4.41–4.35 (m, 1H), 4.14–4.02 (m, 2H), 3.58–3.44
(m, 3H), 3.29 (dd, J=4.5, 13.5 Hz, 1H), 3.18–3.14 (m, 1H), 2.22 (brs,
1H), 1.18–1.16 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=156.2,
155.3*, 150.3, 146.5*, 146.3, 132.7, 128.7 (2C), 124.8 (2C), 118.6, 67.2,
67.0*, 59.1*, 58.8, 54.6, 47.2, 46.3*, 45.5, 39.1*, 38.5, 16.2, 15.4* ppm; *sig-
nals corresponding to
a minor rotamer; HRMS: m/z: calcd for
C16H21N3O7S: 400.11785; found: 400.11732 [M+H]+.
tert-Butyl (2S,5S)-5-hydroxymethyl-2-methyl-4-(4-nitrophenylsulfonyl)-pi-
perazine-1-carboxylate (11c): The reaction was performed according to
GP D using Boc2O (87 mg, 0.40 mmol) and N-nosyl-protected diamino
alcohol resin 6a (100 mg; 0.96 mmolgÀ1). Yield: 22 mg (55%; two steps)
Allyl (2S,5S)-5-hydroxymethyl-4-(4-nitrophenylsulfonyl)-2-phenylpipera-
zine-1-carboxylate (12g): The reaction was performed according to GP D
using allyl 2,4-dinitrophenyl carbonate (95 mg, 0.37 mmol) and N-nosyl-
protected diamino alcohol resin 6g (100 mg; 0.81 mmolgÀ1). Yield: 16 mg
(41%; two steps) of a colorless oil. [a]2D0 =À40.0 (c=0.54 in methanol);
1H NMR (300 MHz, CDCl3): d=8.26–8.12 (m, 2H), 7.79–7.67 (m, 2H),
7.31–7.03 (m, 5H), 5.93–5.70 (m, 1H), 5.47–5.08 (m, 2H), 4.62–4.46 (m,
3H), 4.36–4.17 (m, 2H), 4.01–3.64 (m, 5H), 3.24–3.08 (m, 1H); 13C NMR
(75 MHz, CDCl3): d=156.7, 150.0, 144.6, 137.2, 132.0, 129.0 (2C), 128.4
1
of a colorless oil. [a]2D0 =+4.4 (c=0.70 in methanol); H NMR (300 MHz,
CDCl3): d=8.36–8.33 (m, 2H), 8.02–7.99 (m, 2H), 4.39–4.23 (m, 1H),
4.10–3.98 (m, 2H), 3.51–3.72 (m, 3H), 3.28 (dd, J=4.0, 13.0 Hz, 1H),
3.09–3.05 (m, 1H), 2.05 (brs, 1H), 1.44 (s, 9H), 1.16–1.10 ppm (m, 3H);
13C NMR (75 MHz, CDCl3): d=156.0, 150.0, 145.8, 128.3 (2C), 124.4
(2C), 81.2, 58.7, 54.5, 47.4, 45.3, 39.0*, 37.4, 28.5 (3C), 16.0, 15.3* ppm;
Chem. Eur. J. 2009, 15, 2966 – 2978
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2975