8258 J. Am. Chem. Soc., Vol. 123, No. 34, 2001
Co´rdoVa and Janda
[G#2]-Tetraaldol (8). Acetone (99 mg, 1.71 mmol), LDA solution
(Aldrich, 2 M, heptane/THF/ethylbenzene, 0.86 mL, 1.71 mmol) and
[G#2]-tetraaldehyde 7 (0.26 g 0.2 mmol) were reacted according to
the general aldol formation procedure to give a crude product that was
purified by column chromatography (10:80:5 hexane:EtOAc: MeOH)
) 8.8 Hz, 2H), 9.90 (s, 1H); 13C NMR (CDCl3) δ 55.85, 114.59, 130.24,
132.27, 164.91, 191.10.
[G#1.5]-Monoacetonide (15). DCC was added to a solution of 1
(2.62 g, 11.6 mmol), acetonide protected bis-MPA (2.85 g, 16 mmol),
and DMAP (0.5 g, 4.1 mmol) in CH2Cl2 at room temperature and the
reaction mixture was stirred for 24 h under argon atmosphere. The
DCC-urea was filtered off and the crude product was purified by column
chromatography (50:50 hexane:EtOAc) to give 15 as a clear oil: (78%).
1H NMR (250 MHz, CDCl3) δ 1.07 (s, 3H, -CH3), 1.24 (s, 3H, -CH3),
1.36 (s, 3H, -CH3), 1.42 (s, 3H, -CH3), 2.75 (t, H, -OH), 3.56 (d,
2H, -CH2OR), 3.64 (d, 2H, -CH2OH), 4.41 (dd, 2H, -CH2OR), 5.17
(s, 2H, ArCH2OR), 7.35 (s, 5H, ArH).13C NMR (CDCl3) δ 10.5, 11.2,
14.3, 18.8, 35.1, 41.4, 58.1, 59.0, 59.1, 59.2, 59.6, 91.1, 120.9, 121.3,
121.5, 128.5, 166.9, 167.3. HRMS calcd for C20H28O7 (M + Na+)
403.1727, found 403.1738.
[G#2]-Monoacetonide-Br2 (16). 2,2-Bis(4-butyroxymethyl)propi-
onic acid chloride 5 (2.94 g, 7.0 mmol, diluted in a small amount of
CH2Cl2), acetonide protected 15 (2.48 g, 6.54 mmol), DMAP (30 mg
0.13 mmol), and TEA (0.79 g, 7.8 mmol) were reacted according to
the general esterification procedure for 24 h to give a slightly yellow
product that was purified by column chromatography on silica gel (40:
20 hexane/EtOAc) to give 16 as a colorless oil: 3.7 g (65%). 1H NMR
(250 MHz, CDCl3) δ 1.08 (s, 3H, -CH3), 1.18 (s, 3H, -CH3), 1.30 (s,
3H, -CH3), 1.34 (s, 3H, -CH3), 1.41 (s, 3H, -CH3), 2.15 (m, 4H,
CH2CH2CH2), 2.50 (t, 4H, ROOCCH2CH2), 3.45 (t, 6H, CH2CH2Br),
3.56 (d, 2H, -CH2OR), 4.08 (d, 2H, -CH2OR), 4.13 (s, 4H, -CH2-
OR), 4.31 (d, 4H, -CH2OR), 5.16 (s, 2H, ArCH2OR), 7.35 (s, 5H,
ArH). 13C NMR (CDCl3) δ 18.07, 18.1, 18.8, 22.3, 25.7, 28.0, 32.6,
32.9, 42.4, 46.8, 47.2, 65.5, 65.6, 66.3, 67.4, 98.5, 128.7, 128.9, 129.0,
135.8, 167.8, 172.3, 172.5, 173.9. HRMS calcd for C33H46O12Br2 (M
+ Na+) 815.1248, found 815.1233.
1
to give pure 8 as a colorless viscous oil: 0.2 g (65%). H NMR (250
MHz, CDCl3) δ 1.14 (s, 6H, -CH3), 1.22 (s, 3H, -CH3), 2.10 (m, 8H,
CH2CH2CH2), 2.19 (s, 12H, COCH3), 2.49 (t, 8H, ROOCCH2CH2),
2.79 (m, 8H, CHOHCH2CO), 3.95 (t, 8H, CH2CH2OAr), 4.15 (bs, 8H,
-CH2OR), 4.21 (m, 4H, -CH2OR), 5.06 (m, 4H, ArCHOHCH2), 5.13
(s, 2H, ArCH2OR), 6.83 (d, 8H, ArH), 7.24 (d, 8H, ArH), 7.33 (s, 5H,
ArH);13C NMR (CDCl3) δ 17.73, 17.90, 24.70, 30.17, 30.98, 46.84,
52.19, 65.37, 65.88, 66.81, 67.32, 69.69, 114.68, 127.15, 128.54, 128.72,
128.89, 135.46, 135.53, 158.48, 172.17, 172.22, 172.80, 209.21. HRMS
calcd for C78H96O26 (M + Na+) 1471.6082, found 1471.6098.
[G#1]-Monoaldol (9). To a solution of 3 (1.5 g, 1.23 mmol) in
acetone (60 mL) was added 1% aqueous NaOH solution (6 mL) at 0
°C. After stirring at 0 °C for 10 min the solution was neutralized with
3 drops of 1 N HCl, and concentrated under reduced pressure. The
residue was dissolved in H2O (10 mL) and extracted with EtOAc (2 ×
30 mL). The organic phase was washed with citric acid and brine, dried
(MgSO4), concentrated, and purified by column chromatography (10:
20 hexane:EtOAc) to give 9 as a colorless viscous oil: 0.4 g (50%).1H
NMR (250 MHz, CDCl3) δ 1.22 (s, 3H, -CH3), 2.10 (m, 4H, CH2CH2-
CH2), 2.19 (s, 3H, COCH3), 2.49 (m, 4H, ROOCCH2CH2), 2.79 (m,
2H, CHOHCH2CO), 3.94 (t, 2H, CH2CH2OAr), 4.05 (t, 2H, CH2CH2-
OAr), 4.21 (bs, 4H, -CH2OR), 5.06 (m, 1H, ArCHOHCH2), 5.13 (s,
2H, ArCH2OR), 6.83 (d, 2H, ArH), 6.96 (d, 2H, ArH), 7.24 (d, 2H,
ArH), 7.33 (s, 5H, ArH), 7.81 (d, 2H, ArH), 9.87 (s, 1H, ArCHO);13C
NMR (CDCl3) δ 18.12, 24.57, 24.79, 30.65, 30.85, 31.08, 46.68, 52.23,
65.72, 66.90, 67.13, 67.25, 69.81, 114.80, 115.04, 127.25, 128.44,
128.67, 128.88, 130.31, 132.30, 135.42, 135.85, 158.60, 164.09, 172.70,
172.79, 172.91, 191.09, 209.36. HRMS calcd for C37H42O11 (M + Na+)
685.2619, found 685.2634.
[G#2]-Monoacetonide-Dialdehyde (17). 4-Hydroxybenzaldehyde
(0.5 g, 4.2 mmol), [G#2]-monoacetonide-Br2 16 (1.7 g, 2.1 mmol), K2-
CO3 (0.9 g, 6.3 mmol), and NaI (0.2 g, 1.1 mmol) were reacted
according to the general alkylation procedure for 28 h to give a crude
product that was purified by column chromatography (30:20 hexane:
[G#2]-Trialdol (10). To a solution of 7 (0.1 g, 82 µmol) in acetone
(60 mL) was added 1% aqueous NaOH solution (6 mL) at 0 °C. After
stirring at 0 °C for 10 min the solution was neutralized with 3 drops of
1 N HCl and concentrated under reduced pressure. The residue was
dissolved in H2O (5 mL) and extracted with EtOAc (2 × 30 mL). The
organic phase was washed with citric acid and brine, dried (MgSO4),
concentrated, and purified by column chromatography (10:30 hexane:
1
EtOAc) to give 17 as a colorless viscous oil: 1.6 g (85%). H NMR
(250 MHz, CDCl3) δ 1.06 (s, 3H, -CH3), 1.17 (s, 3H, -CH3), 1.27 (s,
3H, -CH3), 1.33 (s, 3H, -CH3), 1.40 (s, 3H, -CH3), 2.07 (m, 4H,
CH2CH2CH2), 2.50 (t, 4H, ROOCCH2CH2), 3.56 (d, 2H, -CH2OR),
4.07 (m, 6H), 4.19 (s, 4H, -CH2OR), 4.31 (bs, 4H, -CH2OR), 5.15
(s, 2H, ArCH2OR), 6.96 (d, 4H, ArH), 7.34 (s, 5H, ArH), 7.81 (d, 4H,
ArH), 9.87, (s, 2H, ArCHO).13C NMR (CDCl3) δ 17.9, 18.0, 18.7, 22.1,
24.6, 25.6, 30.6, 42.3, 46.7, 47.0, 65.4, 65.5, 66.1, 66.2, 67.2, 67.3,
98.4, 115.0, 128.5, 128.8, 128.9, 130.3, 132.3, 135.7, 163.9, 172.2,
172.7, 191.0. HRMS calcd for C47H56O16 (M + Na+) 899.3461, found
899.3471.
[G#2]-Monoacetonide-Diacetonealdol (18). Acetone (87 mg, 1.5
mmol), LDA solution (Aldrich, 2 M, heptane/THF/ethylbenzene, 0.75
mL, 1.5 mmol), and [G#2]-monoacetonide-dialdehyde 17 (0.3 g 0.3
mmol) were reacted according to the general aldol formation procedure
to give a crude product that was purified by column chromatography
(10:30 hexane:EtOAc) to give pure 18 as a colorless viscous oil: 0.2
g (65%).1H NMR (250 MHz, CDCl3) δ 1.06 (s, 3H, -CH3), 1.15 (s,
3H, -CH3), 1.26 (s, 3H, -CH3), 1.33 (s, 3H, -CH3), 1.39 (s, 3H,
-CH3), 2.07 (m, 4H, CH2CH2CH2), 2.18 (s, 6H, COCH3), 2.50 (t, 4H,
ROOCCH2CH2), 2.79 (m, 4H, CHOHCH2CO), 3.21 (s, 2H, -OH) 3.56
(d, 2H, -CH2OR), 3.95 (t, 4H, CH2CH2OAr), 4.07 (d, 2H, -CH2OR),
4.19 (s, 4H, -CH2OR), 4.31 (s, 4H, -CH2OR), 5.06 (m, 2H,
ArCHOHCH2), 5.14 (s, 2H, ArCH2OR), 6.83 (d, 4H, ArH), 7.24 (d,
2H, ArH), 7.33 (s, 5H, ArH). 13C NMR (CDCl3) δ 17.9, 18.0, 18.7,
22.3, 24.8, 25.4, 30.7, 31.0, 42.3, 46.6, 47.0, 52.2, 65.5, 66.1, 66.2,
66.9, 67.3, 69.8, 98.4, 114.8, 127.2, 128.5, 128.7, 128.9, 135.4, 135.7,
158.6, 172.3, 172.4, 172.8, 173.8, 209.2. HRMS calcd for C53H68O18
(M + Na+) 1015.4298, found 1015.4316.
1
EtOAc) to give 9 as a colorless viscous oil: 34 mg (30%). H NMR
(250 MHz, CDCl3) δ 1.14 (s, 6H, -CH3), 1.22 (s, 3H, -CH3), 2.10
(m, 8H, CH2CH2CH2), 2.19 (s, 9H, COCH3), 2.49 (m, 8H, ROOCCH2-
CH2), 2.79 (m, 6H, CHOHCH2CO), 3.94 (t, 6H, CH2CH2OAr), 4.05
(t, 2H, CH2CH2OAr), 4.15 (bs, 8H, -CH2OR), 4.21 (m, 4H, -CH2-
OR), 5.06 (m, 3H, ArCHOHCH2), 5.13 (s, 2H, ArCH2OR), 6.83 (d,
6H, ArH), 6.96 (d, 2H, ArH), 7.24 (d, 6H, ArH), 7.33 (s, 5H, ArH),
7.81 (d, 2H, ArH), 9.87 (s, 1H, ArCHO);13C NMR (CDCl3) δ 17.83,
18.00, 24.57, 24.79, 30.59, 30.79, 46.67, 46.93, 52.22, 65.43, 65.50,
65.99, 66.90, 67.27, 67.42, 69.80, 114.78, 115.04, 127.25, 128.61,
128.82, 128.98, 130.30, 132.28, 135.47, 135.60, 158.59, 164.09, 172.23,
172.26, 172.30, 172.67, 172.86, 191.08, 209.33. HRMS calcd for
C75H90O25 (M + Na+) 1413.5663, found 1413.5608.
(4R,4S)-Hydroxy-4-(4′-methoxyphenyl)butan-2-one (11). Acetone
(0.64 g, 11 mmol), LDA solution (Aldrich, 2 M, heptane/THF/
ethylbenzene, 5.5 mL, 11 mmol), and 4-methoxybenzaldehyde 12 (0.5
g, 3.7 mmol) were reacted according to the general aldol formation
procedure to give a crude product that was purified by column
chromatography (55:45 hexane:EtOAc) to give pure 11 as a colorless
oil: 0.5 g (70%). 1H NMR (500 MHz, CDCl3) δ 2.19 (s, 3H), 2.86 (m,
2H), 3.81 (s, 3H), 5.10 (m, 1H), 6.88 (d, J ) 8.8 Hz, 2H), 7.27 (d, J
) 8.8 Hz, 2H). 13C NMR (CDCl3) δ 31.06, 52.24, 55.59, 69.81, 114.23,
127.21, 135.20, 159.45, 209.41. HRMS calcd for C11H14O3 (M + Na+)
217.0835, found 217.0844.
4-Methoxybenzaldehyde (12). 4-Hydroxybenzaldehyde (1.0 g, 8.2
mmol), K2CO3 (3.14 g, 12.3 mmol), and iodomethane (1.2 g, 8.2 mmol)
were reacted according to the general etherification procedure to give
a crude product that was purified by column chromatography (30:20
hexane:EtOAc) to give pure 12 as a white solid: 1.1 g (97%). 1H NMR
(500 MHz, CDCl3) δ 3.9 (s, 3H), 7.01 (d, J ) 8.8 Hz, 2H), 7.85 (d, J
[G#2]-Monoacetonide-Monoacetone Aldol (19). Acetone (35 mg,
0.6 mmol), LDA solution (Aldrich, 2 M, heptane/THF/ethylbenzene,
0.30 mL, 0.6 mmol), and [G#2]-monoacetonide-dialdehyde 17 (106
mg, 0.12 mmol) were reacted according to the general aldol formation
procedure to give a crude product that was purified by column
chromatography (20:30 hexane:EtOAc) to give pure 19 as a colorless