RCM-Based Synthesis of â-C-Glycosides
26.9, 25.6; HRMS (EI) calcd for C38H48O10Na (M)+ 687.3140,
found 687.3151.
and allowed to stir for an additional 1 h. This mixture was
diluted with Et2O (10 mL), quenched by the addition of water
(5 mL), and extracted with EtOAc (3 × 15 mL). The combined
organic layers were washed with brine (1 × 15 mL), dried,
and concentrated. Flash chromatography of the residue over
silica using 20 f 30% EtOAc-hexanes gave the fully protected
C-glycoside (101 mg, 86%) as a pure (Rf ) 0.33, TLC, silica,
40% EtOAc-hexanes; 1H NMR (400 MHz, CDCl3), (HRMS
(FAB) calcd for C45H56O11Na (M)+ 795.3715, found 795.3761))
clear oil that was taken to the next step without further
characterization. The usual procedure for acetonide metha-
nolysis was followed using p-TsOH (5 mg), MeOH-CH2Cl2 (1:
1, 3 mL), the acetonide (65 mg, 0.084 mmol), and Et3N (1 mL)
for quench. After the usual workup, flash chromatography over
silica using 2 f 4% CH2Cl2-MeOH gave diol 15g (50 mg, 81%,
70% over two steps) as a pure (Rf ) 0.31, TLC, silica, 3% CH2-
C-Glycoside (6g). A solution of titanium tetrachloride (3.8
mL, 2 M in CH2Cl2, 7.67 mmol) was added to cool (0 °C) THF
(4 mL). The resulting mixture was stirred for 30 min at which
point TMEDA (2.23 mL, 14.8 mmol) was added in one portion.
The resulting yellow-brown suspension was allowed to warm
to ambient temperature and stirred for 30 min. At this point,
zinc dust (1.09 g, 16.65 mmol) and lead(II) chloride (13 mg,
0.045 mmol) were added in one portion, and stirring at ambient
temperature was continued for 10 min. A solution of ester 3g
(300 mg, 0.45 mmol) and dibromomethane (0.29 mL, 4.19
mmol) in THF (3 mL) was then added via cannula to the
reaction flask in one portion. The mixture was stirred at 60
°C for 1 h, cooled to 0 °C, and then quenched by the addition
of saturated potassium carbonate (1.0 mL). The resulting
mixture was stirred for 30 min (while warming to ambient
temperature), diluted with ether (20 mL), and stirred vigor-
ously for 15 min. The resulting mixture was filtered through
basic alumina using 3% triethylamine-ether as the eluent.
The greenish-blue precipitate that resulted was crushed
(mortar and pestle) and thoroughly extracted by vigorous
stirring over diethyl ether (15-20 mL) for 30 min. The
combined ethereal extracts were concentrated in vacuo, azeo-
troped with benzene (3 × 20 mL), and redissolved in dry
toluene (14 mL). After the crude enol ether was degassed
thoroughly under nitrogen atmosphere for 20 min, the first
aliquot (1/4) of catalyst 7 (134 mg, 0.158 mmol, 35 mol %) was
added and heated to 60 °C. The remaining catalyst was added
in three equivalent portions over the next 3 h, and upon
completion, the solution was cooled to 0 °C, BH3‚THF (4.5 mL,
1 M in THF, 4.5 mmol) was added, and the resulting mixture
was stirred at this temperature for 3 h until TLC indicated
the reaction was complete. NaOH (25 mL, 1 M, 25 mmol) and
hydrogen peroxide (25 mL, 30% in water, 0.20 mol) were added
sequentially dropwise, and the solution was allowed to warm
to room temperature over 2 h at which point TLC showed a
clean product spot. The solution was extracted with ether
(3 × 15 mL), and the combined ethereal extracts were washed
with brine (1 × 10 mL), dried over magnesium sulfate, filtered,
and concentrated in vacuo. Flash chromatography of the
residue over silica using 30f40% EtOAc-hexanes gave 6g
(175 mg, 60% over three steps) as a pure (Rf ) 0.36, TLC, silica,
40% EtOAc-hexanes; 1H NMR (500 MHz, CDCl3)) oil:
[R]26D ) +28.7 (c ) 1.00, CHCl3); FT-IR (neat) 3450 (br), 2915,
2853, 1612, 1513, 1246, 1173, 1078, 1033, 819 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.27-7.20 (m, 6 H, ArH), 6.88-6.86 (m,
4 H, ArH), 6.85-6.81 (m, 2 H, ArH), 4.76 (d, 1 H, J ) 11.5 Hz,
OCH2Ar), 4.63 (d, 1 H, J ) 11 Hz, OCH2Ar), 4.54 (d, 1 H, J )
12 Hz, OCH2Ar), 4.43 (d, 1 H, J ) 11 Hz, OCH2Ar), 4.37 (d, 1
H, J ) 12 Hz, OCH2Ar), 4.36 (d, 1 H, J ) 11 Hz, OCH2Ar),
4.08 (dddd, 1 H, J ) 13, 13, 6.0, 6.0 Hz, H-9), 4.00 (dd, 1 H,
J ) 8.0, 7.5 Hz, H-10), 3.96 (app d, 1 H, J ) 2.0 Hz, H-4), 3.80
(s, 6 H, 2 × OCH3), 3.77 (s, 3 H, OCH3), 3.70 (dd, 1 H, J ) 10,
10 Hz, H-2), 3.54-3.48 (m, 4 H, H-5, 2 × H-6, H-10), 3.31 (dd,
1 H, J ) 9.5, 2.0 Hz, H-3), 3.12 (dd, 1 H, J ) 8.5, 8.5, 1.5 Hz,
H-1), 2.30 (br s, 1 H, OH), 1.93-1.82 (m, 2 H, H-7, H-8), 1.63-
1.51 (m, 2 H, H-7, H-8), 1.38 (s, 3 H, C(CH3)2), 1.32 (s, 3 H,
C(CH3)2); 13C NMR (125 MHz, CDCl3) δ 159.4, 159.3, 159.1,
130.7, 129.9, 129.8, 129.7, 129.6, 129.3, 114.0, 113.8, 113.6,
108.5, 83.8, 79.6, 77.2, 75.9, 73.9, 73.1, 71.9, 71.1, 70.5, 69.4,
68.5, 55.2, 55.2, 29.4, 27.8, 26.9, 25.7; HRMS (FAB) calcd for
C37H48O10Na (M)+ 675.3140, found 675.3183.
1
Cl2-MeOH; H NMR (500 MHz, CDCl3)) white solid: mp )
100-101 °C; [R]26 ) -10.6 (c ) 1.00, CHCl3); FT-IR (neat)
D
3419 (br), 2999, 2931, 2864, 1612, 1586, 1513, 1464, 1301,
1244, 1173, 1090, 1031, 820 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.32-7.28 (m, 2 H, ArH), 7.23-7.19 (m, 6 H, ArH), 6.90-
6.82 (m, 8 H, ArH), 4.87 (d, 1 H, J ) 10 Hz, OCH2Ar), 4.84 (d,
1 H, J ) 11 Hz, OCH2Ar), 4.68 (d, 1 H, J ) 12 Hz, OCH2Ar),
4.62 (d, 1 H, J ) 11.5 Hz, OCH2Ar), 4.56 (d, 1 H, J ) 10.5 Hz,
OCH2Ar), 4.54 (d, 1 H, J ) 12.0 Hz, OCH2Ar), 4.40 (d, 1 H,
J ) 11.5 Hz, OCH2Ar), 4.32 (d, 1 H, J ) 11.5 Hz, OCH2Ar),
3.82 (dd, 1 H, J ) 3.0, 3.0 Hz, H-4), 3.81 (s, 3 H, OCH3), 3.80
(s, 6 H, 2 × OCH3), 3.79 (s, 3 H, OCH3), 3.70-3.64 (m, 1 H,
H-9), 3.61 (dd, 1 H, J ) 9.0, 9.0 Hz, H-2), 3.53 (dd, 1 H, J )
9.0, 2.5 Hz, H-3), 3.53-3.47 (m, 3 H, H-5, H-6, H-10), 3.36 (dd,
1 H, J ) 10.5, 7.5 Hz, H-10), 3.27 (dd, 1 H, J ) 8.0, 4.0 Hz,
H-6), 3.21 (ddd, 1 H, J ) 9.0, 9.0, 1.5 Hz, H-1), 3.21 (bs, 1 H,
OH), 2.16-2.02 (m, 2 H, H-7, OH), 1.64-1.52 (m, 2 H, H-7,
H-8), 1.50-1.43 (m, 1 H, H-8); 13C NMR (125 MHz, CDCl3) δ
159.3, 159.3, 159.2, 159.2, 130.5, 130.4, 130.4, 129.9, 129.8,
129.7, 129.7, 129.2, 113.8, 113.8, 113.7, 113.6, 84.4, 80.4, 78.3,
75.1, 73.8, 73.2, 72.9, 72.1, 69.2, 66.8, 55.2, 30.9, 28.5; HRMS
(FAB) calcd for C42H52O11Na (M)+ 755.3402, found 755.3354.
C-Glycoglycerolipid (17j). Oleoyl chloride (271 µL, 0.82
mmol) was added in one portion to a pyridine (2 mL) solution
of diol 15g (100 mg, 0.136 mmol) and 4-DMAP (8.5 mg, 0.068
mmol). The solution was stirred for 18 h at ambient temper-
ature and then concentrated in vacuo. Flash chromatography
of the residue over silica using 25-30% EtOAc-hexanes gave
16j (121 mg, 71%) as a pure (Rf ) 0.22, TLC, silica, 25%
1
EtOAc-hexanes; H NMR (500 MHz, CDCl3)) yellow oil. The
product was then taken directly to the next step. TFA (5 drops)
was added to a solution of 16j (25 mg, 0.022 mmol) in CH2Cl2
(2.0 mL), and the reaction was stirred for 1 h at ambient
temperature. At this point TLC analysis (silica, first 30%
EtOAc-hexanes then 5% MeOH-CH2Cl2) indicated the reac-
tion was almost complete and upon concentration in vacuo the
reaction went to completion. Flash chromatography of the
residue over silica gel using 5 f 10% MeOH-CH2Cl2 gave 17j
(19 mg, 77%) as a pure (Rf ) 0.21, TLC, silica, 10% MeOH-
1
CH2Cl2; H NMR (500 MHz, CDCl3)) white solid: mp ) 41-
42 °C; [R]26 ) +3.4 (c ) 1.00, CH2Cl2); FT-IR (neat) 3600-
D
3300 (b), 2921, 2852, 1736, 1463, 1245, 1168, 1088, 1052, 722
cm-1
;
1H NMR (500 MHz, CDCl3) δ 5.38-5.27 (m, 5 H, 4 ×
CdC-H, H-9), 4.31 (dd, 1 H, J ) 12.0, 3.5 Hz, H-10), 4.08-
4.04 (m, 1 H, H-4), 3.97 (dd, 1 H, J ) 11.5, 7.0 Hz, H-10), 3.92-
3.82 (m, 2 H, 2 × H-6), 3.80-3.72 (s, 1 H, OH), 3.57 (dd, 1 H,
J ) 9.0, 9.0 Hz, H-2), 3.48-3.44 (m, 1 H, H-3), 3.42 (dd, 1 H,
J ) 4.0, 4.0 Hz, H-5), 3.24 (ddd, 1 H, J ) 9.5, 2.0, 2.0 Hz,
H-1), 3.11 (s, 1 H, OH), 3.00 (s, 1 H, OH), 2.73 (s, 1 H, OH),
2.33-2.26 (m, 4 H, 2 × C(O)CH2), 2.03-1.98 (m, 8 H, 4 × CH2),
1.97-1.88 (m, 1 H, H-7), 1.82-1.68 (m, 2 H, 2 × H-8), 1.68-
1.55 (m, 5 H, H-7, 2 × CH2), 1.35-1.24 (m, 40 H, 20 × CH2),
0.88 (t, 6 H, J ) 6.5 Hz, 2 × CH3); 13C NMR (125 MHz, CDCl3)
δ 174.0, 173.8, 130.0, 130.0, 129.7, 129.7, 79.3, 77.3, 77.1, 75.5,
Diol 15g. The hydroborated product 6g (100 mg, 0.15 mmol)
was dissolved in DMF (2 mL) and added dropwise into a
stirring solution of KH (72 mg, 0.535 mmol, 35% dispersion
in mineral oil) and DMF (2 mL) at 0 °C. After 10 min,
p-methoxybenzyl chloride (62 µL, 1.07 mmol) was added
dropwise, followed by a catalytic amount of TBAI (20 mg). The
reaction was stirred for 30 min, warmed to room temperature,
J. Org. Chem, Vol. 70, No. 3, 2005 835