10.1002/ejoc.201801241
European Journal of Organic Chemistry
FULL PAPER
4.26 (d, J = 11.5 Hz, 1H), 3.89 (dd, J = 13.5, 5.7 Hz, 1H), 3.73–3.65 (m,
3H), 3.60 (dd, J = 15.1, 10.4 Hz, 1H), 3.51 (t, J = 9.2 Hz, 1H), 2.94 (dd, J
= 13.3, 10.9 Hz, 1H), 2.29 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 149.7,
146.2, 138.4, 137.5, 137.3, 128.77, 128.74, 128.5, 128.4, 128.2, 128.19,
128.12, 128.0, 127.9, 123.9, 82.6, 79.5, 76.8, 75.4, 73.5, 73.2, 70.1, 65.4,
(2S,3R,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-1-(4-methoxy
benzyl)-1,2,3,4-tetrahydropyridine (9): To a mixture of 7 (200 mg, 0.33
mmol) in dry CH3CN (5 mL) at room temperature, K2CO3 (137 mg, 0.99
mmol) and thiophenol (40 µL, 0.39 mmol) were added. The reaction
mixture was stirred for 10 h at same temperature, and after completion of
the reaction (TLC monitoring), the mixture was extracted with ethyl
acetate (2 x 5 mL). The organic phase was washed with water (1 x 5 mL)
and brine (1 x 5 mL), dried over anhydrous Na2SO4 and concentrated
under reduced pressure to give the crude amino derivative. The crude
amino derivative was subjected to the next reaction without any further
purification. Thus, the amino derivative (160 mg, 0.38 mmol) was
dissolved in THF (4 mL), to which was added K2CO3 (106 mg, 0.77
mmol), NaI (85 mg, 0.57 mmol) and p-methoxybenzyl chloride (77 L,
0.57 mmol) and stirred the same at room temperature for 2 h. Upon
consumption of the starting material (TLC monitoring), solvent was
concentrated, and then the residue was extracted with EtOAc (2 x 5 mL)
and washed with water (2 x 5 mL). Evaporation of the organic solvent
gave a crude product which was purified by column chromatography to
55.2, 44.3; HRMS calcd for
619.2113.
C
33H35N2O8S [M+H]+ 619.2114; found
(2S,3R,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-1-((4-
nitrophenyl) sulfonyl)-1,2,3,4-tetrahydropyridine (7): Compound
6
(100 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane (3
mL) and cooled to 0 °C. Anhydrous pyridine (26 μL, 0.32 mmol) was
added to it followed by dropwise addition of trifluoromethanesulfonic
anhydride (54 μL, 0.32 mmol). The reaction mixture was stirred at 0 °C
for 15 min and after consumption of the starting material (TLC
monitoring), it was quenched with water (1 mL). The resulting mixture
was then extracted with CH2Cl2 (2 x 5 mL). The organic phase was dried
with Na2SO4, filtered and the solvent removed in vacuo to afford a
reddish crude compound. The crude triflate product (110 mg, 0.14 mmol)
was dissolved in dry THF (3 mL) and DBU (63 μL, 0.42 mmol) was added
to it, and the reaction mixture was refluxed for 1 h. After completion of
reaction (TLC monitoring), solvent was evaporated and the crude product
purified by column chromatography to give compound 7 as a solid in 71%
give compound 9 as a colorless oil in 71% (127 mg) yield; Rf = 0.8
[ ]2D8
(hexane : ethyl acetate = 4:1);
= +46.1 (c = 0.4, CH2Cl2); IR (neat)
max /cm-1: 3021, 1618, 1236, 1086; 1H NMR (500 MHz, CDCl3) δ 7.35–
7.19 (m, 17H), 6.87 (d, J = 8.6 Hz, 2H), 6.42 (d, J = 6.3 Hz, 1H), 4.89–
4.81 (m, 2H), 4.65 (d, J = 4.5 Hz, 1H), 4.62 (d, J = 4.9 Hz, 1H), 4.55 (d, J
= 11.0 Hz, 5H), 4.21 (dd, J = 4.2, 1.5 Hz, 1H), 4.06 (ddd, J = 8.2, 5.0, 2.8
Hz, 1H), 3.86 (dd, J = 8.6, 6.2 Hz, 1H), 3.81–3.76 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 159.8, 144.8, 138.4, 138.3, 138.1, 130.1, 129.8, 128.53,
128.51, 128.0, 127.9, 127.8, 127.7, 114.2, 100.0, 75.8, 74.5, 73.8, 73.6,
70.6, 68.6, 55.4, 46.4; HRMS calcd for C35H38NO4 [M + H]+ 536.2801;
found 536.2800.
yield (69 mg, over two steps); m. p = 182-184 °C; Rf = 0.6 (hexane : ethyl
[ ]2D8
acetate = 4:1);
= +32.4 (c = 0.3, CH2Cl2); IR (neat) max /cm-1:
3283, 1641, 1532, 816; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz,
2H), 7.79 (d, J = 8.7 Hz, 2H), 7.36–7.12 (m, 15H), 6.56 (d, J = 8.3 Hz,
1H), 5.05 (dd, J = 8.3, 2.1 Hz, 1H), 4.66–4.57 (m, 4H), 4.43 (d, J = 11.9
Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.24 (dd, J = 9.7, 4.8 Hz, 1H), 4.16–
4.12 (m, 1H), 3.71 (d, J = 4.7 Hz, 2H), 3.36 (dd, J = 8.3, 5.5 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 149.9, 144.6, 138.1, 137.8, 137.6, 128.6,
128.5, 128.4, 128.17, 128.11, 127.9, 127.8, 127.7, 127.4, 124.3, 124.1,
109.2, 75.4, 74.8, 73.3, 72.6, 72.2, 66.7, 56.4; HRMS calcd for
(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-(4-
methoxybenzyl)-2-vinylpiperidin-3-ol (11): To a stirred solution of 9
(300 mg, 0.56 mmol) in CH2Cl2 (4 mL), saturated aqueous NaHCO3 (4
mL) solution and acetone (0.4 mL) were added and cooled to 0 oC. to it
was added a solution of Oxone® (689 mg, 1.12 mmol) in H2O (4 mL)
dropwise over 5 min.[26] The reaction mixture was vigorously stirred at the
same temperature for 3 h. After completion of the reaction (TLC analysis),
the reaction mixture was diluted with 5 mL of CH2Cl2 then extracted with
CH2Cl2 (2 x 5 mL) and washed with water (2 x 5 mL). The combined
organic layers were dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure to give a crude product. The unstable
crude product obtained was used without purification. Thus, the crude
product (260 mg, 0.47 mmol) was dissolved in dry THF (5 mL) and
cooled to 0 oC, to which was added vinyl magnesium bromide (315 L,
2.35 mmol). The reaction mixture was allowed to stir at room temperature
C33H36N3O7S [M + NH4]+ 618.2274; found 618.2271.
(2S,3R,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-nitro-1-((4-
nitro phenyl)sulfonyl)-1,2,3,4-tetrahydropyridine (8): To stirred
a
solution of Ac2O (1 mL) at 10 oC under nitrogen, was added conc. HNO3
(27 L, 0.64 mmol) and allowed to stir at -10 °C for 15 min. The reaction
mixture was further cooled to -35 oC and compound 7 (110 mg, 0.18
mmol) in Ac2O (1 mL) was added to the reaction mixture and stirred at
same temperature for 45 min. After complete consumption of the starting
material (monitored by TLC), the mixture was poured into ice-water (2
mL) and extracted with Et2O (5 mL x 2). The combined organic layers
were dried over Na2SO4, concentrated in vacuo to give a crude product.
The crude product (106 mg, 0.15 mmol) was dissolved in CH2Cl2 (2 mL),
cooled to 0 °C and to it was added NEt3 (32 μL, 0.22 mmol).[25] After 30
min of stirring at the same temperature, the reaction mixture was
quenched with water (2 mL) and extracted with CH2Cl2 (5 mL x 2). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated to give a crude product which was purified by column
chromatography to give pure product 8 in 68% (81 mg) yield (over two
for
6 h. After complete consumption of the starting material (TLC
analysis), the reaction mixture was cooled to 0 oC and quenched with
aqueous NH4Cl solution (5 mL). The organic layer was separated and the
aqueous layer extracted with Et2O (2 x 5 mL). The combined organic
phase was dried over anhydrous Na2SO4 and the solvent evaporated
under reduced pressure to give a crude product which was purified
chromatographically to afford pure compound 11 as a syrup in 68% (221
[ ]2D8
[ ]2D8
mg) yield; Rf = 0.6 (hexane : ethyl acetate = 4:1);
= +28.4 (c = 0.6,
steps) as a colorless syrup; Rf = 0.5 (hexane : ethyl acetate = 4:1);
CH2Cl2); IR (neat) max /cm-1: 3394, 3019, 1641, 911; 1H NMR (500 MHz,
CDCl3) δ 7.34–7.19 (m, 17H), 6.80 (d, J = 8.6 Hz, 2H), 6.12–6.02 (m, 1H),
5.22 (dd, J = 9.9, 8.3 Hz, 2H), 4.70–4.59 (m, 4H), 4.51 (d, J = 11.7 Hz,
1H), 4.45 (m, 2H), 3.94 (d, J = 2.8 Hz, 1H), 3.90 (dd, J = 8.5, 5.3 Hz, 1H),
3.84 (d, J = 14.2 Hz, 1H), 3.80 (s, 3H), 3.78–3.75 (m, 1H), 3.72 (dd, J =
10.7, 3.5 Hz, 1H), 3.66–3.62 (m, 1H), 3.61–3.56 (m, 1H), 3.26 (d, J = 3.6
Hz, 1H), 2.52 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 158.5, 138.7, 138.6,
138.5, 132.2, 129.6, 128.5, 128.4, 128.3, 127.8, 127.76, 127.71, 127.63,
127.60, 113.7, 76.5, 73.3, 72.9, 72.52, 63.6, 55.3, 53.3; HRMS calcd for
= +5.6 (c = 0.1, CH2Cl2); IR (neat) max /cm-1: 2924, 1533, 1178, 742; 1
H
NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.08 (d, J = 9.1 Hz, 2H), 7.76 (d,
J = 9.1 Hz, 2H), 7.35–7.24 (m, 15H), 4.80 (d, J = 10.6 Hz, 1H), 4.71 (dd,
J = 8.0, 4.9 Hz, 2H), 4.55 (d, J = 11.5 Hz, 1H), 4.44–4.34 (m, 3H), 3.98
(dd, J = 9.6, 4.4 Hz, 1H), 3.86–3.80 (m, 2H), 3.59–3.52 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 150.5, 143.2, 137.4, 137.1, 136.8, 135.6, 132.6,
128.7, 128.67, 128.63, 128.5, 128.4, 128.2, 127.8, 124.7, 74.9, 74.6,
73.6, 73.4, 70.7, 66.0, 56.7; HRMS calcd for C34H32N3O11S [M + HCO2]-
690.1758; found 690.1755.
C
37H42NO5 [M + H]+ 580.3063; found 580.3061.
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