T. Seitz et al. / Tetrahedron 62 (2006) 6155–6165
6163
a/b: 60/40) 1.30 (t, J¼7.1 Hz, 3H, a+b), 1.4–1.8 (m, 5H, a+b),
2.1–2.4 (br m, 1H, a+b), 3.7–3.9 (br m, 1H, b), 3.2–3.4 (br m,
1H, a), 3.7–3.8 (br m, 1H, a), 3.83 (s, 3H, a+b), 4.23 (q,
J¼7.1 Hz, 2H, a+b), 4.5–4.7 (br m, 2H, b), 5.45 (br s, 1H,
a), 6. 91 (d, J¼8.6 Hz, 2H, a+b), 7.40 (d, J¼8.6 Hz, 2H,
a+b); 13C NMR d (2 rotamers) 14.3 (a+b, CH3), 21.3 (a+b,
CH2), 24.7 (b, CH2), 25.6 (a, CH2), 26.8 (a, CH2), 27.3 (b,
CH2), 40.2 (b, CH2), 46.1 (a, CH2), 52.6 (a, CH), 55.4
(a+b, CH3), 58.8 (b, CH), 61.3 (a+b, CH2), 113.7 (a+b, C),
127.5 (a+b, CH), 128.0 (a+b, CH), 129.05 (a+b, C), 160.8
(a+b, C), 171.2 (a+b, C), 171.6 (a+b, C); IR (NaCl) 3455,
2940, 2243, 1731, 1632, 1512, 1422, 1003, 912, 840,
728 cmꢁ1; MS (EI) m/z (%) 291 (M+, 9), 218 (34), 135
(100), 107 (5); HRMS (ESI) calcd for C16H21NO4 [M+H]+
292.1549, found 292.1540.
134.5, 134.7, 134.8 (aromatic carbons of rotamers a, b, c,
d), 170.8–171.0–171.1 (a+b+c+d, C), 171.2 (b, C), 171.3
(d, C), 171.4 (c, C), 171.5 (a, C); IR (NaCl) 3442, 3016,
1731, 1628, 1437, 1215, 756; MS (EI) m/z (%) 311 (20),
265 (5), 238 (50), 155 (100), 127 (28); HRMS (ESI) calcd
for C19H21NO3 [M+H]+ 312.1600, found 312.1597.
4.8. Synthesis of cinchona alkaloid derivatives
4.8.1. N-(9-Deoxycinchonin-9-yl)-2-methoxybenz-
amide—CN–Amide. To (8R, 9S)-9-amino-(9-deoxy)-cin-
chonine (0.530 g, 1.83 mmol) in CH2Cl2 (5 mL) were added
Et3N (1.62 mL, 11.52 mmol) and DMAP (0.032 g, 0.26
mmol). Themixturewascooledto0 ꢀCando-anisoylchloride
(0.641 g, 3.76 mmol) in CH2Cl2 (10 mL) was added. Stirring
was continued at 0 ꢀC for 30 min then at room temperature
for three days. After addition of NaOH (2 N, 10 mL), the
aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried (MgSO4) and concentrated under
reduced pressure. Purification by flash chromatography
over silica gel (CH2Cl2/MeOH: 95/5) afforded CN–Amide
(0.703 g, 90%) as a white solid: mp 88–89 ꢀC; [a]D20 +13.2
4.7.4. (S)-1-(4-Nitrobenzoyl)piperidine-2-carboxylic acid
ethyl ester (2d). Purification of the crude product by flash
chromatography on silica gel (AcOEt/CH2Cl2: 6/4) afforded
2d as a colourless oil (260 mg, 85% yield). [a]2D0 ꢁ60 (c 0.45,
CHCl3); HPLC retention times: (S) 23.5 min; (R) 31.0 min;
1
(T: 35 ꢀC, l: 262 nm); H NMR d (2 rotamers a/b: 75/25)
1
1.33 (t, J¼7.1 Hz, 3H, a+b), 1.3–1.8 (m, 5H, a+b), 2.23 (d,
J¼13.2 Hz, 1H, b), 2.39 (d, J¼13.2 Hz, 1H, a), 2.86 (t,
J¼12.9 Hz, 1H, b), 3.29 (t, J¼12.9 Hz, 1H, a), 3.47 (d,
J¼12.9 Hz, 1H, a), 4.2–4.3 (m, 2H, a+b, and 1H, b), 4.65
(br d, J¼13.9 Hz, 1H, b), 5.47 (d, J¼4.8 Hz, 1H, a), 7.5–
7.6 (m, 2H, a+b), 8.2–8.3 (m, 2H, a+b); 13C NMR d (two ro-
tamers) 14.7 (a+b, CH3), 21.4 (a+b, CH2), 24.9 (b, CH2), 25.7
(a, CH2), 26.9 (a, CH2), 27.6 (b, CH2), 40.5 (b, CH2), 46.2 (a,
CH2), 52.8 (a, CH), 58.7 (b, CH), 61.9 (a, CH2), 62.3 (b,
CH2), 124.3 (a, CH), 124.4 (b, CH), 127.9 (b, CH), 128.3
(a, CH), 142.6 (a+b, C), 148.7 (a+b, C), 169.7 (a+b, C),
171.0 (a+b, C); IR (NaCl) 3445, 2933, 1734, 1640, 1522,
1430, 1347, 1173, 1021, 852 cmꢁ1; MS (EI) m/z (%) 306
(6), 233 (100), 150 (42), 120 (5), 104 (9); HRMS (ESI) calcd
for C15H19N2O5 [M+H]+ 307.1294, found 307.1278.
(c 0.26, EtOH); H NMR d 1.5–1.8 (m, 4H), 1.8–2.0 (m,
1H), 2.1–2.3 (m, 1H), 2.6–2.9 (m, 4H), 3.4–3.5 (m, 1H),
3.86 (s, 3H), 4.9–5.1 (m, 2H), 5.9–6.1 (m, 1H), 6.2–6.3 (m,
1H), 6.93 (d, J¼8.4 Hz, 1H), 7.0–7.1 (m, 1H), 7.3–7.5
(m, 2H), 7.5–7.6 (m, 1H), 7.6–7.7 (m, 1H), 8.0–8.2 (m,
2H), 8.30 (d, J¼8.5 Hz, 1H), 8.38 (d, J¼8.5 Hz, 1H), 8.90
(d, J¼4.6 Hz, 1H); 13C NMR d 25.4 (CH2), 26.6 (CH2),
28.2 (CH), 40.3 (CH), 48.4 (CH2), 49.4 (CH2), 50.2 (CH),
56.1 (CH3), 59.4 (CH) 111.4 (CH), 114.9 (CH2), 118.7
(CH), 121.2 (C), 121.5 (CH), 123.8 (CH), 126.9 (CH),
127.4 (C), 129.2 (CH), 130.3 (CH), 132.5 (CH), 133.1
(CH), 140.4 (CH), 148.0 (C), 148.9 (C), 150.1 (CH), 157.4
(C), 165.0 (C); IR (KBr) 3482, 3357, 2938, 1600, 1541,
1243, 1023, 756 cmꢁ1; MS (EI) m/z (%) 427 (M+, 48), 386
(10), 332 (16), 292 (88), 135 (100), 77 (27); HRMS (ESI)
calcd for C27H30N3O2 [M+H]+ 428.2338, found 428.2334.
4.7.5. 1-(1-Naphtoyl)piperidine-2-carboxylic acid ethyl
ester (2e). Purification of the crude product by flash chroma-
tography on silica gel (AcOEt/CH2Cl2: 6/4) afforded 2e as
a colourless oil (245 mg, 79% yield). [a]2D0 ꢁ94 (c 1.3,
CHCl3); HPLC retention times: (S) 9.0 min; (R) 13.7 min;
(T: 20 ꢀC, l: in nm); 1H NMR d (four rotamers a/b/c/d in ap-
proximate ratio: 51/24/15/10, respectively) 1.16, 1.28, 1.38,
1.43 (d, c, b, a, respectively) (t, J¼7.1 Hz, 3H), 1.3–1.8 (m,
5H, a+b+c+d), 2.0–2.1 (m, 1H, c+d), 2.4–2.5 (m, 1H, a+b),
2.97 (td, J¼13.4 and 3.2 Hz, 1H, c), 3.0–3.2 (m, 1H,
a+b+d), 3.3–3.4 (m, 1H, a+b), 4.0–4.1 (m, 2H, d), 4.12 (br
d, J¼5.0 Hz, 1H, d), 4.2–4.4 (m, 2H, a+b+d and 1H, c),
4.8–4.9 (m, 1H, c+d), 5.73 (d, J¼5.0 Hz, 1H, a+b), 7.4–7.6
(m, 4H, a+b+c+d), 7.8–7.9 (m, 2.5H), 8.13 (d, J¼8.1 Hz,
0.5H); 13C NMR d (four rotamers a, b, c, d) 14.4 (d, CH3),
14.6 (c, CH3), 14.7 (b, CH3), 14.8 (a, CH3), 21.5–21.6
(a+b+c+d, CH2), 25.3 (d, CH2), 25.4 (c, CH2), 25.8 (a,
CH2), 26.2 (b, CH2), 27.1 (a, CH2), 27.2 (b, CH2), 27.8 (d,
CH2), 28.2 (c, CH2), 39.3 (d, CH2), 40.0 (c, CH2), 45.6 (a,
CH2), 46.0 (b, CH2), 52.4 (a+b, CH), 58.4 (c, CH), 58.5
(d, CH), 61.8–61.9 (a+b+c+d, CH2), 123.5, 123.8, 124.1,
124.3, 124.6, 124.8, 125.0, 125.3, 125.6, 125.7, 125.8,
126.1, 126.3, 126.8, 126.9, 127.3, 127.4, 127.5, 128.5,
128.6, 128.8, 128.9, 129.2, 129.4, 129.5, 129.7, 129.8,
129.9, 130.1, 130.2, 133.7, 133.8, 134.1, 134.46, 134.4,
4.8.2. Cinchonin-9-yl phenylcarbamate—CN–PhCarb.
Phenyl isocyanate (1.44 g, 12.10 mmol) was added to a solu-
tion of cinchonine (2.73 g, 9.26 mmol) in toluene (30 mL).
The reaction mixture was heated at 110 ꢀC for 16 h.
Toluene was removed under reduced pressure. The crude
product was purified by flash chromatography over silica
gel (CH2Cl2/MeOH: 97.5/2.5) to afford CN–PhCarb
(2.88 g, 75%) as a white solid: mp 201–202 ꢀC [lit.13 190–
191 ꢀC]; [a]D20 +51 (c 0.8, CHCl3) [lit.13 +53 (c 0.54,
1
CHCl3)]; H NMR d 1.4–1.6 (m, 2H), 1.8–2.0 (m, 2H),
2.25 (q, J¼8.2 Hz, 1H), 2.6–2.8 (m, 2H), 2.90 (d, J¼
8.9 Hz, 2H), 3.34 (q, J¼8.5 Hz, 1H), 5.0–5.2 (m, 2H), 5.9–
6.1 (m, 1H), 6.57 (d, J¼7.9 Hz, 1H), 6.79 (br s, 1H), 7.06
(t, J¼7.1 Hz, 1H), 7.2–7.4 (m, 5H), 7.44 (d, J¼4.5 Hz,
1H), 7.5–7.6 (m, 1H), 7.6–7.7 (m, 1H), 8.13 (d, J¼8.3 Hz,
1H), 8.25 (d, J¼8.4 Hz, 1H), 8.90 (d, J¼4.5 Hz, 1H); 13C
NMR d 24.4 (CH2), 26.4 (CH2), 27.8 (CH), 39.8 (CH),
49.0 (CH2), 49.7 (CH2), 59.9 (CH), 74.0 (CH), 115.1
(CH2), 119.1 (CH), 119.2 (CH) 123.8(CH), 123.9 (CH),
126.6 (C), 127.1 (CH), 129.2 (CH), 129.4 (CH), 130.4
(CH), 138.0 (C), 140.6 (CH), 146.3 (C), 148.6 (C), 150.0
(CH), 153.0 (C); IR (KBr) 3240, 3064, 2938, 1730, 1600,
1545, 1445, 1317, 1219, 1053, 758 cmꢁ1; MS (ESI) m/z
(%) 414 (M+1, 17), 295 (3), 277 (100), 246 (2), 234 (4);