10754
M. J. Oila et al. / Tetrahedron 61 (2005) 10748–10756
(10.57 g, 55.6 mmol, 1700 mol%), 11 ml CH2Cl2 and 21 ml
THF. The resin was filtered after 1.5 h, followed by
subsequent wash with NEt3/DMF 1:2, DMF, DMF/H2O
2:1, DMF, methanol and CH2Cl2. The resin was dried at the
aspirator pressures and finally under high vacuum. IR (KBr,
cmK1) 3385.
4 ml CH2Cl2 and 0.30 ml NEt3. The residue of 18 was
dissolved in 2 ml CH2Cl2 and this solution was added to
the solution of 6. After 15 min, ice water was added to the
mixture and it was extracted three times with CH2Cl2. The
combined organics were washed with brine and dried over
Na2SO4. The solvents were evaporated and the crude
product recrystallized from EtOAc/hexane to yield 100 mg
(0.24 mmol, 62%) of 26 as a white solid. RfZ0.15 (EtOAc/
hexane 1:1, KMnO4); [a]2D2 K25.5 (c 0.07; CHCl3); mp
165–165.5 8C; IR (KBr, cmK1) 1717, 1651; 1H NMR
(400 MHz, CDCl3) d 9.12 (dd, JZ0.9, 2.0 Hz, 1H, 6-Py-
CH), 8.44 (dd, JZ2.0, 8.0 Hz, 1H, 4-Py-CH), 8.30 (d, JZ
8.2 Hz, 1H, –NHCOAr), 8.25 (dd, JZ0.8, 8.0 Hz, 1H, 3-Py-
CH), 7.43–7.30 (m, 5H, Ar-H), 7.19 (d, JZ8.6 Hz, 2H,
Ar-H), 6.92 (d, JZ8.6 Hz, 2H, Ar-H), 5.04 (s, 2H,
PhCH2OAr), 4.32 (m, 1H, –CH2CH(NHCOAr)(CH2OH)),
3.99 (s, 3H, –CO2CH3), 3.81 (m, 1H, –R2CHCH2OH-A),
3.73 (m, 1H, –R2CHCH2OH-B) 2.96 (m, 2H, Ar-CH2-
CHR2), 2.47 (t, JZ5.4 Hz, 1H, –CH2OH); 13C NMR
4.1.5. 5-(10-tert-Butyldimethylsilyloxy-3-butynyl)methyl
picolinate 25. Bromopyridine 22 (590 mg, 2.73 mmol,
100 mol%), 18 ml dry THF, NEt3 (0.58 ml, 4.16 mmol,
150 mol%) and 24 (1003 mg, 5.44 mmol, 200 mol%) were
loaded into a Schlenk apparatus. Retaining the oxygen-free
atmosphere, Pd(PPh3)2Cl2 (100 mg, 0.14 mmol, 5 mol%)
was added to the solution. The mixture was heated to reflux
for 24 h and diluted with CH2Cl2. It was quenched with
saturated aqueous NaHCO3 and extracted three times with
CH2Cl2. The organics were washed with brine and dried
over Na2SO4 to give 1.56 g of a dark brown oil. It was
purified by FC (EtOAc/hexane 1:4) to give 25 (800 mg,
2.50 mmol, 92%) as an almost colourless oil. RfZ0.29
(100 MHz, CDCl3)
d 165.0 (Ar-CO2CH3), 163.7
1
(EtOAc/hexane 1:1, UV); H NMR (400 MHz, CDCl3) d
(–NHCOAr), 157.6 (CAr-OR), 152.6 (2-PyC-CONHR),
149.4 (6-Py-C), 138.5 (CAr–CH2OAr), 137.0 (4-Py-C),
130.2 (Ar), 129.7 (Ar), 128.5 (Ar), 128.1 (Ar), 127.9 (Ar),
127.4 (Ar), 121.8 (Ar), 115.0 (Ar), 70.0 (PhCH2OAr), 64.3
(–R2CHCH2OH), 53.5 (–R2CHCH2OH), 52.6 (–CO2CH3),
36.3 (ArCH2CHR2); HRMS (ESI) calcd for C24H24N2O5Na
443.1583, found 443.1576 (MCNa).
8.70 (dd, JZ0.8, 2.0 Hz, 1H, 6-Py-CH), 8.04 (dd, JZ0.8,
8.0 Hz, 1H, 4-Py-CH), 7.77 (dd, JZ2.0, 8.0 Hz, 1H, 3-Py-
CH), 3.98 (s, 3H, –CO2Me), 3.81 (t, JZ6.8 Hz, 2H,
–CH2CH2OSiR3), 2.65 (t, JZ6.8 Hz, 2H, –CH2CH2OSiR3),
0.89 (s, 9H, –C(CH3)3), 0.07 (s, 6H, –Si(CH3)2); 13C NMR
(100 MHz, CDCl3) d 165.2 (–CO2CH3), 152.2 (6-Py-C),
145.7 (2-Py-C–CO2Me), 139.2 (4-Py-C), 124.4
(3-Py-C), 124.3 (5-Py-C-R), 94.6 (Ar-C^C–CH2R),
77.9 (Ar-C^C–CH2R), 61.4 (–CH2CH2OSiR3), 52.8
(–CO2CH3), 25.8 (–SiR2C(CH3)3), 24.0 (–C^C–CH2CH2–),
18.3 (–SiR2C(CH3)3), K5.3 (–Si(CH3)2C(CH3)3); HRMS
(ESI) calcd for C17H25NO3Si 320.1682, found 320.1690
(MC1).
4.1.8. 5-Methoxycarbonylpicolinyl-(10-(S)-(p-benzyloxy-
phenyl)-20-mesyloxy)ethylamide 27. Amide 26 (50 mg,
0.12 mmol, 100 mol%) was dissolved in 3 ml CH2Cl2. NEt3
(0.10 ml, 0.72 mmol, 600 mol%) and DMAP (3 mg,
0.03 mmol, 20 mol%) were added, followed by MsCl
(30 ml, 0.39 mmol, 320 mol%). This caused a spontaneous
heating of the mixture. TLC monitoring showed total
conversion after 3 min. The reaction was quenched with
water 10 min later. The mixture was extracted three times
with CH2Cl2. The combined organics were washed with
brine and dried over Na2SO4. The solvents were evaporated
and the crude mixture filtered through a short pad of silica
and recrystallized from EtOAc/hexane to yield 48 mg
(0.10 mmol, 81%) of 27 as a white solid. RfZ0.15
(EtOAc/hexane 1:1, KMnO4); [a]2D2 C21.0 (c 0.07;
CH2Cl2); mp 115–117.5 8C; IR (KBr, cmK1) 1725, 1666;
1H NMR (400 MHz, CDCl3) d 9.14 (dd, JZ0.8, 2.0 Hz, 1H,
6-Py-CH), 8.44 (dd, JZ2.0, 8.0 Hz, 1H, 4-Py-CH), 8.25
(d, JZ8.2 Hz, 1H, –NHCOAr), 8.23 (dd, JZ0.8, 8.2 Hz,
1H, 3-Py-CH), 7.43–7.29 (m, 5H, Ar-H), 7.19 (d, JZ
8.6 Hz, 2H, Ar-H), 6.93 (d, JZ8.6 Hz, 2H, Ar-H), 5.03 (s,
2H, PhCH2OAr), 4.59 (m, 1H, R2CH(CH2OSO2Me)-
(NHCOAr)), 4.36 (m, 1H, R2CHCH2OSO2Me-A), 4.26
(m, 1H, R2CHCH2OSO2Me-B), 3.99 (s, 3H, 5-Py-
CO2CH3), 3.00 (m, 2H, Ar-CH2CHR2), 3.00 (s, 3H,
–CH2OSO2CH3); 13C NMR (100 MHz, CDCl3) d 165.0
(Ar-CO2CH3), 163.2 (–NHCOAr), 157.9 (CAr-OR), 152.2
(2-PyC-CONHR), 149.5 (6-Py-C), 138.6 (4-Py-C), 136.9
(Ar), 130.3 (Ar), 128.6 (Ar), 128.5 (Ar), 128.3 (Ar), 127.9
(Ar), 127.4 (Ar), 121.9 (Ar), 115.2 (Ar), 70.0 (R2CHCH2-
OSO2Me), 69.4 (PhCH2OAr), 52.7 (–CO2CH3), 50.0
(–R2CHCH2OH), 37.3 (–CH2OSO2CH3), 36.1 (ArCH2-
CHR2); HRMS (ESI) calcd for C25H27N2O7S 499.1539,
found 499.1521 (MC1).
4.1.6. 5-(10-tert-Butyldimethylsilyloxy-3-butynyl)pico-
linic acid 19. Ester 25 (620 mg, 1.94 mmol, 100 mol%)
was dissolved in 30 ml of 90% aqueous methanol. Finely
ground NaOH (82 mg, 2.05 mmol, 110 mol%) was added
and the mixture was set for reflux for 6 h. The solution was
concentrated to a small volume and acidified carefully with
1 M aqueous HCl at 0 8C. The formed solid was filtered and
dried at pump to yield 19 (380 mg, 1.24 mmol, 64%) as a
white solid; mp 104–105 8C (dec); IR (KBr, cmK1) 2229,
1703; 1H NMR (400 MHz, d6-DMSO) d 8.62 (s, 1H,
6-Py-CH), 7.97 (d, JZ7.9 Hz, 1H, 4-Py-CH), 7.90 (d, JZ
8.0 Hz, 1H, 3-Py-CH), 3.80 (t, JZ6.4 Hz, 2H, –CH2CH2-
OSiR3), 2.68 (t, JZ6.4 Hz, 2H, –CH2CH2OSiR3), 2.08
(s, 1H, –CO2H), 0.89 (s, 9H, –C(CH3)3), 0.08 (s, 6H,
–Si(CH3)2); 13C NMR (100 MHz, d6-DMSO) d 165.8
(–CO2H), 151.1 (6-Py-C), 147.9 (2-Py-C–CO2H), 139.3
(4-Py-C), 124.1 (3-Py-C), 122.7 (5-Py-C-R), 94.5
(Ar-C^C–CH2R), 77.9 (Ar-C^C–CH2R), 61.0 (–CH2-
CH2OSiR3), 25.7 (–SiR2C(CH3)3), 23.3 (–C^C–CH2CH2–),
17.9 (–SiR2C(CH3)3), K5.3 (–Si(CH3)2C(CH3)3); HRMS
(ESI) calcd for C16H23NO3SiNa 328.1345, found 328.1342
(MCNa).
4.1.7. 5-Methoxycarbonylpicolinyl-(10-(S)-(p-benzyloxy-
phenyl)-20-hydroxy)ethylamide 26. Acid 18 (70 mg,
0.39 mmol, 100 mol%) was refluxed in 3 ml SOCl2 for
2.5 h. The mixture was evaporated to dryness. Amino-
alcohol 6 (100 mg, 0.39 mmol, 100 mol%) was dissolved in