E
Z. Zhou et al.
Letter
Synlett
(f) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y. S.; Kobayashi, S.
J. Am. Chem. Soc. 2008, 130, 13321. Gold: (g) Martín-Rodríguez,
M.; Nájera, C.; Sansano, J. M.; de Cózar, A.; Cossío, F. P. Chem.
Eur. J. 2011, 17, 14224.
(monitored by TLC), the mixture purified by column chroma-
tography to give the corresponding cycloaddition product,
which was then directly analyzed by chiral HPLC.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(Pyridin-3-yl)pyroli-
dine-2,3,4-tricarboxylate (4i)
(7) (a) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.;
Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043. (b) Nájera, C.;
de Gracia Retamosa, M.; Martin-Rodríguez, M.; Sansano, J. M.;
de Cózar, A.; Cossío, F. P. Eur. J. Org. Chem. 2009, 5622.
(8) (a) Kim, H. Y.; Shih, H.-J.; Knabe, W.-E.; Oh, K. Angew. Chem.
Int. Ed. 2009, 48, 7420. (b) Wang, C.-J.; Liang, G.; Xue, Z.-Y.;
Gao, F. J. Am. Chem. Soc. 2008, 130, 17250.
(9) (a) Oderaotoshi, Y.; Cheng, W. J.; Fujitomi, S.; Kasano, Y. Org.
Lett. 2003, 5, 5043. (b) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7,
5055. (c) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem.
Soc. 2007, 129, 750.
(10) (a) Zeng, W.; Zhou, Y.-G. Tetrahedron Lett. 2007, 48, 4619.
(b) Yamashita, Y.; Imaizumi, T.; Kobayashi, S. Angew. Chem. Int.
Ed. 2011, 50, 4893.
30
White solid, yield 89 mg (85%); mp 102–105 °C; [α]D +50.2 (c
0.90, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.60–8.52 (m, 2 H),
7.79 (d, J = 7.2 Hz, 1 H), 7.29–7.26 (m, 1 H), 4.51 (d, J = 6.4 Hz, 1
H), 4.17–4.12 (m, 3 H), 3.81 (s, 3 H), 3.78–3.63 (m, 4 H), 3.37 (br
s, 1 H), 1.25 (t, J = 7.2 Hz, 3 H), 0.84 (t, J = 7.2 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 170.7, 170.2, 170.0, 149.0, 148.9, 134.3,
133.1, 123.2, 62.8, 62.2, 61.2, 60.6, 52.4, 52.3, 50.9, 14.0, 13.6.
The ee value was 92%, tR (major) = 9.28 min, tR (minor) = 10.83
min (Chiralcel AS-H, λ = 230 nm, i-PrOH–hexanes = 50:50, flow
rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C17H22N2O6 [M + H]+
351.1551; found: 351.1554.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(3,4-Dichlorophenyl)-
pyrolidine-2,3,4-tricarboxylate (4l)
30
(11) Wang, H.-F.; Deng, Q.-F.; Zhou, Z.-P.; Hu, S.-Q.; Liu, Z.-G.; Zhou,
L.-Y. Org. Lett. 2016, 18, 404.
White solid, yield 81 mg (65%); mp 127–128 °C; [α]D +46.8 (c
1
1.00, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.38
(12) Synthesis of the Representative Ligand 1g
(d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.39 (d, J = 6.8 Hz, 1
H), 4.14–4.08 (m, 3 H), 3.79 (s, 3 H), 3.78–3.67 (m, 3 H), 3.59–
3.55 (m, 1 H), 3.27 (brs, 1 H), 1.22 (t, J = 6.8 Hz, 3 H), 0.89 (t, J =
7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.7, 170.0, 137.8,
132.3, 131.6, 130.2, 129.1, 126.3, 64.0, 61.9, 61.2, 60.6, 52.3,
52.2, 51.1, 14.0, 13.6. The ee value was 87%, tR (major) = 7.75
min, tR (minor) = 13.00 min (Chiralcel AS-H, λ = 230 nm, i-
PrOH–hexanes = 50:50, flow rate = 0.8 mL/min). ESI-HRMS: m/z
calcd for C18H21Cl2N1O6 [M + H]+: 418.0819; found: 418.0824.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(2-Chlorophenyl)-pyr-
rolidine-2,3,4-tricarboxylate (4m)
The 1g′ (334 mg, 1 mmol), which was synthesized according to
the procedure of the Supporting Information, was dissolved in
CH2Cl2 (10 mL) and TFA (1 mL) was added dropwise at 0 °C.
Then the reaction mixture was stirred for 18 h at r.t. All volatile
compounds were removed in vacuo, and the residue was dis-
solved in water and treated with the sat. Na2CO3 solution. The
resulting mixture was extracted with CH2Cl2 (3×), and the com-
bined organic layers were dried over Na2SO4. After filtration and
then evaporation of the solvent, the crude free amine was
obtained without purification for the next step. To the solution
of the free amine in CH2Cl2 (8 mL) was added O-benztriazole-1-
N,N,N′,N′-tetraethyluronium hexafluorophosphate (HBTU, 417
mg, 1.1 mmol), followed by the addition of diisopropylethyl-
amine (367 μL, 2.2 mmol) and 2-(diphenylphosphino)benzoic
acid (306 mg, 1 mmol), The reaction mixture was then stirred
for 18 h at r.t. The mixture was combined with CH2Cl2 and
water, and the organic layer was separated, washed with sat.
NaHCO3 (2×), and dried over Na2SO4. The solvent was removed
in vacuo to afford the crude product as colorless oil, which was
purified by flash chromatography (15% EtOAc in hexane) yield-
ing the ligand 1g. White solid (407 mg, 78%); mp 77–79 °C;
Colorless oil, yield 100 mg (87%); [α]D30 +60.1 (c 1.02, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.48 (dd, J = 7.6, 1.6 Hz, 1 H), 7.35
(dd, J = 7.6, 1.6 Hz, 1 H), 7.28–7.20 (m, 2 H), 4.72 (d, J = 6.8 Hz, 1
H), 4.14–4.08 (m, 3 H), 3.92 (dd, J = 8.4, 6.8 Hz, 1 H), 3.83 (s, 3
H), 3.77 (dd, J = 8.8, 8.8 Hz, 1 H), 3.70–3.60 (m, 2 H), 3.40 (br s, 1
H), 1.21 (t, J = 7.2 Hz, 3 H), 0.78 (t, J = 7.2 Hz, 3 H). 13C NMR (100
MHz, CDCl3): δ = 171.1, 170.3, 169.9, 134.5, 133.3, 129.1, 128.8,
127.4, 126.7, 62.0, 61.1, 61.0, 60.3, 52.3, 51.0, 50.2, 14.0, 13.5.
The ee value was 90%, tR (major) = 8.22 min, tR (minor) = 16.46
min (Chiralcel AS-H, λ = 230 nm, i-PrOH–hexanes = 50:50, flow
rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C18H22Cl1NO6 [M +
H]+: 384.1208; found: 384.1212.
30
[α]D –25.6 (c 0.88, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ =
7.63–7.62 (m, 1 H), 7.40–7.20 (m, 17 H), 7.02–6.95 (m, 1 H),
6.71–6.70 (m, 1 H), 6.62 (br s, 1 H), 5.12–5.08 (m, 1 H), 4.38–
4.35 (m, 1 H), 1.44 (d, J = 6.8 Hz, 3 H), 0.84 (s, 9 H). 13C NMR (100
MHz, CDCl3; C–P coupling not removed): δ = 169.3, 168.9, 143.0,
136.7, 134.5, 133.9, 133.8, 133.7, 133.6, 130.5, 129.1, 128.8,
128.6, 128.6, 128.6, 128.5, 127.8, 127.8, 127.3, 126.3, 61.3, 49.1,
34.7, 26.6, 21.8. 31P NMR (162 MHz, CDCl3) δ = –10.4. ESI-HRMS:
m/z calcd for C33H35N2O2P [M + H]+: 523.2509; found: 523.2511.
(13) General Procedure of 1,3-Dipole Cycloaddition
(2R,3R,4S,5R)-3,4-Diethyl 2-Methyl 2,5-Diphenylpyrrolidine-
2,3,4-tricarboxylate (4s)
Colorless oil, yield 60 mg (47%); [α]D30 +15.1 (c 0.90, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.6 Hz, 2 H), 7.45–7.37
(m, 4 H), 7.35–7.25 (m, 4 H), 4.49 (d, J = 7.2 Hz, 1 H), 4.36–4.22
(m, 2 H), 4.05 (br s, 1 H), 3.91 (d, J = 8.0 Hz, 1 H), 3.70 (s, 3 H),
3.69–3.64 (m, 1 H), 3.55–3.44 (m, 2 H), 1.35 (t, J = 7.2 Hz, 3 H),
0.75 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 172.7,
171.5, 170.2, 139.4, 137.8, 128.7, 128.6, 128.2, 128.1, 128.1,
127.8, 127.8, 126.6, 126.4, 76.0, 63.9, 61.2, 60.3, 57.2, 53.6, 52.7,
14.0, 13.5. The ee value was 82%, tR (minor) = 9.13 min, tR
(major) = 10.87 min (Chiralcel AD-H, λ = 210 nm, i-PrOH–
hexanes = 15:85, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd
for C24H27N1O6 [M + H]+: 426.1911; found: 426.1914.
Ligand of 1g (3.132 mg, 0.006 mmol) and Ag2CO3 (0.83 mg,
0.003 mmol) were dissolved in toluene (1.4 mL). The reaction
mixture was stirred for 1 h at r.t., followed by the addition of the
activated olefins (0.33 mmol), Et3N (0.015 mmol), and imine
substrate (0.3 mmol). Once starting material was consumed
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E