Dondoni et al.
Å molecular sieves (100 mg), and t-BuOH (2.5 mL). The vial was
sealed with the Teflon septum and aluminum crimp by using an
appropriate crimping tool. The mixture was then vigorously stirred,
degassed under vacuum, and saturated with argon (by an Ar-filled
balloon) three times The vial was then placed in its correct position
in the Biotage Initiator cavity where irradiation for 2.5 h at 120 °C
was performed. After the full irradiation sequence was completed,
and the vial was cooled to room temperature and then opened. The
mixture was diluted with AcOEt (10 mL), filtered through a pad
of Celite, and concentrated. The residue was dissolved in CH2Cl2
(8 mL), and then Amberlyst 15 (400 mg), Ambersep 900 OH (400
mg), and aminomethylated polystyrene (185 mg, 0.50 mmol of a
2.7 mmol g-1 resin) were added. The suspension was shaken for 2
h, and then the polymers were filtered off and washed thoroughly
with CH2Cl2. The combined filtrates were concentrated to give the
corresponding crude dihydropyridine derivative. A mixture of the
above residue, pyridinium chlorochromate immobilized on silica
gel34 (1.87 g, ∼1.50 mmol of a ∼0.8 mmol g-1 resin) and anhydrous
CH2Cl2 (8 mL), was stirred at room temperature for 12 h. Then
the immobilized reagent was filtered off and washed thoroughly
with CH2Cl2. The combined filtrates were concentrated, and the
resulting residue was eluted from a column of silica gel with the
suitable elution system to give the corresponding pyridine 16.
(2′′′S)-2-(2′,3′,4′,6′-tetra-O-Benzyl-â-D-galactopyranosyl-meth-
yl)-4-(2′′′-tert-butoxycarbonylamino-2′′′-methoxycarbonylethyl)-
6-methylpyridine-3,5-dicarboxylic Acid Di-tert-butyl Esters (â-
16b). Column chromatography with 4:1 cyclohexane-AcOEt
afforded â-16b (351 mg, 68%) as a white foam: [R]D ) -17.8 (c
0.7, CHCl3); 1H NMR (DMSO-d6, 140 °C) δ ) 7.40-7.10 (m, 20
H, Ph), 6.08 (bs, 1 H, NH), 4.88 and 4.55 (2 d, 2 H, J ) 11.5 Hz,
PhCH2), 4.86 and 4.69 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.81 and
4.69 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.42-4.36 (m, 1 H, H-2′′′),
4.38 and 4.32 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.05 (dd, 1 H, J3′,4′
) 2.5 Hz, J4′,5′ ∼ 0.5 Hz, H-4′), 3.92-3.84 (m, 1 H, H-1′), 3.78-
3.72 (m, 2 H), 3.62-3.52 (m, 2 H), 3.60 (s 3 H, OCH3), 3.46-
3.40 (m, 1 H), 3.24 (dd, 1 H, J1′,1′′a ) 3.5 Hz, J1′′a,1′′b ) 14.0 Hz,
H-1′′a), 3.17 (dd, 1 H, J1′′′a,2′′′ ) 6.5 Hz, J1′′′a,1′′′b ) 14.5 Hz, H-1′′′a),
2.95 (dd, 1 H, J1′,1′′b ) 9.0 Hz, H-1′′b), 2.89 (dd, 1 H, J1′′′b,2′′′ ) 9.5
Hz, H-1′′′b), 2.42 (s, 3 H, CH3), 1.61, 1.52, and 1.30 (3 s, 27 H, 3
t-Bu); 13C NMR δ ) 172.8, 167.7, 167.3, 157.6-154.7 (5 C),
139.1-135.0 (5 C), 129.4-127.3 (20 C), 84.8, 83.9, 79.5, 79.3,
78.9, 78.4, 75.1, 74.5, 74.0, 73.3, 72.0, 68.6, 53.7, 52.2, 38.9, 31.9,
28.0 (3 C), 27.9 (6 C), 23.1; MALDI-TOF MS 1070.9 (M+ + K).
Anal. Calcd for C60H74N2O13 (1031.24): C, 69.88; H, 7.23; N, 2.72.
Found: C, 69.82; H, 7.23; N, 2.71.
16b). Column chromatography with 6:1 cyclohexane-AcOEt
afforded R-16b (320 mg, 62%) as a white foam: [R]D ) -3.6 (c
1
1.2, CHCl3); H NMR (DMSO-d6, 140 °C): δ ) 7.40-7.10 (m,
20 H, Ph), 6.18 (bs, 1 H, NH), 4.70 and 4.65 (2 d, 2 H, J ) 11.5
Hz, PhCH2), 4.69-4.62 (m, 1 H, H-2′′′), 4.68 and 4.55 (2 d, 2 H,
J ) 12.0 Hz, PhCH2), 4.62 and 4.56 (2 d, 2 H, J ) 11.0 Hz,
PhCH2), 4.42-4.34 (m, 1 H, H-1′), 4.38 and 4.31 (2 d, 2 H, J )
11.5 Hz, PhCH2), 4.11 (ddd, 1 H, J4′,5′ ) 1.5 Hz, J5′,6′a ) 4.5 Hz,
J5′,6′b ) 9.0 Hz, H-5′), 4.05 (dd, 1 H, J3′,4′ ) 2.0 Hz, H-4′), 3.94
(dd, 1 H, J2′,3′ ) 6.0 Hz, H-3′), 3.88 (dd, 1 H, J1′,2′ ) 3.5 Hz, H-2′),
3.76-3.68 (m, 2 H, 2 H-6′), 3.60 (s, 3 H, OCH3), 3.24 (dd, 1 H,
J1′,1′′a ) 6.0 Hz, J1′′a,1′′b ) 14.0 Hz, H-1′′a), 3.12 (dd, 1 H, J1′′′a,2′′′
) 8.0 Hz, J1′′′a,1′′′b ) 15.0 Hz, H-1′′′a), 3.06 (dd, 1 H, J1′′′b,2′′′ ) 6.0
Hz, H-1′′′b), 2.42 (s, 3 H, CH3), 1.61, 1.55, and 1.30 (3 s, 27 H, 3
t-Bu); 13C NMR (selected data): δ ) 172.8, 167.5, 167.2, 155.5,
155.3, 154.6, 139.0, 138.2, 138.1, 129.0-127.4 (20 C), 84.2, 84.0,
79.6, 75.6, 74.0, 73.1, 72.9, 72.5, 66.8, 53.6, 52.3, 34.0, 31.6, 28.2
(3 C), 28.0 (6 C), 23.0; MALDI-TOF MS 1032.7 (M+ + H). Anal.
Calcd for C60H74N2O13 (1031.24): C, 69.88; H, 7.23; N, 2.72.
Found: C, 69.93; H, 7.15; N, 2.70.
(2′′′S)-4-(2′,3′,4′,6′-Tetra-O-benzyl-R-D-glucopyranosylmethyl)-
2-(2′′′-tert-butoxycarbonylamino-2′′′-methoxycarbonylethyl)-6-
methylpyridine-3,5-dicarboxylic Acid Di-tert-butyl Esters (R-
16a). Column chromatography with 4:1 cyclohexane-AcOEt
afforded R-16a (299 mg, 58%) as a white foam: [R]D ) 16.8 (c
0.8, CHCl3); 1H NMR (DMSO-d6, 120 °C) δ ) 7.40-7.10 (m, 20
H, Ph), 6.24 (bs, 1 H, NH), 4.81 and 4.73 (2 d, 2 H, J ) 11.0 Hz,
PhCH2), 4.80-4.70 (m, 1 H, H-1′), 4.72 and 4.57 (2 d, 2 H, J )
11.5 Hz, PhCH2), 4.68 and 4.64 (2 d, 2 H, J ) 10.8 Hz, PhCH2),
4.42 and 4.35 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.40-4.30 (m, 1 H,
H-2′′′), 3.92-3.82 (m, 2 H), 3.76 (dd, 1 H, J ) 4.5 Hz, J ) 7.5
Hz), 3.64-3.50 (m, 3 H), 3.60 (s, 3 H, OCH3), 3.23 (dd, 1 H, J1′′′a,2′′′
) 6.5 Hz, J1′′′a,1′′′b ) 14.0 Hz, H-1′′′a), 3.18 (dd, 1 H, J1′,1′′a ) 6.5
Hz, J1′′a,1′′b ) 14.5 Hz, H-1′′a), 3.12 (dd, 1 H, J1′,1′′b ) 5.0 Hz,
H-1′′b), 2.87 (dd, 1 H, J1′′′b,2′′′ ) 8.0 Hz, H-1′′′b), 2.44 (s, 3 H,
CH3), 1.62, 1.56, and 1.31 (3 s, 27 H, 3 t-Bu); 13C NMR δ ) 172.7,
167.5, 167.2, 155.5-154.9 (5 C), 139.0-138.2 (5 C), 128.8-127.5
(20 C), 84.5, 84.1, 82.4, 79.7, 78.0, 75.2, 74.7, 73.7, 73.3, 72.8,
71.8, 68.5, 53.7, 52.3, 32.0, 31.7, 28.2 (3 C), 28.0 (6 C), 23.1;
MALDI-TOF MS 1054.3 (M+ + Na). Anal. Calcd for C60H74N2O13
(1031.24): C, 69.88; H, 7.23; N, 2.72. Found: C, 69.81; H, 7.18;
N, 2.86.
(2′′′S)-4-(2′,3′,4′,6′-Tetra-O-benzyl-â-D-galactopyranosylmethyl)-
2-(2′′′-tert-butoxycarbonylamino-2′′′-carboxyethyl)-6-methylpy-
ridine-3,5-dicarboxylic Acid Di-tert-butyl Esters (17). To a cooled
(0 °C) stirred solution of methyl ester â-15b (103 mg, 0.10 mmol)
in THF (2 mL) was added dropwise a pre-cooled 0.2 M aqueous
solution of LiOH (0.60 mL, 0.12 mmol). The mixture was stirred
at 0 °C until the complete disappearance of the starting material
was detected (TLC analysis, ∼1 h). The mixture was then acidified
with 5% aqueous HCl to pH ) 2, warmed to room temperature,
diluted with CH2Cl2 (80 mL), and washed with H2O (2 × 10 mL).
The organic phase was dried (Na2SO4) and concentrated to give
the crude acid 17 in almost quantitative yield: 1H NMR δ ) 7.40-
7.10 (m, 20 H, Ph), 5.93 (bd, 1 H, J ) 6.0 Hz, NH), 4.98 and 4.52
(2 d, 2 H, J ) 10.5 Hz, PhCH2), 4.93 and 4.71 (2 d, 2 H, J ) 11.0
Hz, PhCH2), 4.80 and 4.68 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.47
and 4.38 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.38 (ddd, 1 H, J1′′′a,2′′′
) 8.5 Hz, J1′′′b,2′′′ ) 8.5 Hz, H-2′′′), 4.03 (dd, 1 H, J3′,4′ ) 3.5 Hz,
J4′,5′ ∼ 0.5 Hz, H-4′), 3.72-3.60 (m, 2 H, H-2′, H-6′a), 3.57 (dd,
1 H, J2′,3′ ) 9.0 Hz, H-3′), 3.50-3.30 (m, 4 H, H-1′′a, H-1′, H-5′,
H-6′b), 3.22 (dd, 1 H, J1′,1′b ) 9.5 Hz, J1′′a,1′′b ) 16.5 Hz, H-1′’b),
3.10 (d, 2 H, 2 H-1′′′), 2.52 (s, 3 H, CH3), 1.44, 1.42, and 1.28 (3
s, 27 H, 3 t-Bu). Anal. Calcd for C59H72N2O13 (1017.21): C, 69.66;
H, 7.13; N, 2.75. Found: C, 69.75; H, 7.10; N, 2.70.
(2′′′S)-2-(2′,3′,4′,6′-Tetra-O-benzyl-â-D-glucopyranosylmethyl)-
4-(2′′′-tert-butoxycarbonylamino-2′′′-methoxycarbonylethyl)-6-
methylpyridine-3,5-dicarboxylic Acid Di-tert-butyl Esters (â-
16a). Column chromatography with 4:1 cyclohexane-AcOEt
afforded â-16a (320 mg, 62%) as a white foam: [R]D ) -23 (c
1
0.5, CHCl3); H NMR (DMSO-d6, 120 °C): δ ) 7.40-7.10 (m,
20 H, Ph), 6.25 (bs, 1 H, NH), 4.84 and 4.72 (2 d, 2 H, J ) 12.0
Hz, PhCH2), 4.83 (s, 2 H, PhCH2), 4.73 and 4.60 (2 d, 2 H, J )
11.2 Hz, PhCH2), 4.41-4.30 (m, 1 H, H-2′′′), 4.40 and 4.33 (2 d,
2 H, J ) 11.8 Hz, PhCH2), 3.97 (ddd, 1 H, J1′,1′′a ) 3.5 Hz, J1′,1′′b
) 8.5 Hz, J1′,2′ ) 9.0 Hz, H-1′), 3.74 (dd, 1 H, J ) 8.8 Hz, J ) 9.0
Hz), 3.64-3.51 (m, 2 H, 2 H-6′), 3.59 (s, 3 H, OCH3), 3.51 (dd, 1
H, J ) 8.0 Hz, J ) 8.5 Hz), 3.44 (dd, 1 H, J ) 8.8 Hz, J ) 9.0
Hz), 3.39 (m, 1 H, H-5′), 3.27 (dd, 1 H, J1′′a,1′′b ) 14.5 Hz, H-1′′a),
3.19 (dd, 1 H, J1′′′a,2′′′ ) 8.0 Hz, J1′′′a,1′′′b ) 14.0 Hz, H-1′′′a), 3.26
(dd, 1 H, H-1′′b), 2.88 (dd, 1 H, H-1′′′b), 2.40 (s, 3 H, CH3), 1.59,
1.56, and 1.28 (3 s, 27 H, 3 t-Bu); 13C NMR (selected data) δ )
172.7, 87.4, 84.0, 82.1, 79.4, 78.7, 75.6, 74.9, 73.2, 68.9, 52.7, 52.4,
38.5, 31.7, 28.2, 28.0, 23.0; MALDI-TOF MS 1032.4 (M+ + H),
1054.2 (M+ + Na). Anal. Calcd for C60H74N2O13 (1031.24): C,
69.88; H, 7.23; N, 2.72. Found: C, 69.82; H, 7.28; N, 2.71.
(2′′′S)-4-(2′,3′,4′,6′-Tetra-O-benzyl-R-D-galactopyranosylmethyl)-
2-(2′′′-tert-butoxycarbonylamino-2′′′-methoxycarbonylethyl)-6-
methylpyridine-3,5-dicarboxylic Acid Di-tert-butyl Esters (R-
(2′S,2′′S,1′′′S)-4-(2,3,4,6-Tetra-O-benzyl-â-D-galactopyrano-
sylmethyl)-2-[2′-(2′′-tert-butoxycarbonylamino-3′′-methylpropio-
nylamino)-2′-(1′′′-ethoxycarbonyl-2′′′-phenylethylcarbamoyl)-
ethyl]-6-methylpyridine-3,5-dicarboxylic Acid Di-tert-butyl Ester
7686 J. Org. Chem., Vol. 72, No. 20, 2007