2348 J . Org. Chem., Vol. 66, No. 7, 2001
Sefkow
two drops of DMF, was treated with 1.05 mL (1.52 g, 12 mmol)
oxalyl chloride at 0 °C. The solid disappeared slowly at room
temperature, and a clear, greenish solution was obtained after
about 4 h. The solvent and excess of oxalyl chloride were
removed in vacuo. The remaining oily acid chloride 6 was
dissolved in THF (30 mL), the solution cooled to 0 °C, and 12
mL (24 mmol) of a 2.0 M solution of dimethylamine in THF
was added. The reaction mixture was stirred at room temper-
ature for 3 h and then poured into a saturated aqueous
NH4Cl solution (20 mL). The aqueous layer was extracted with
Et2O (2 × 10 mL), and the combined organic layers were dried
over anhydrous MgSO4 and filtered. The solvents were re-
moved under reduced pressure and the remaining solid
recrystallized from EtOAc/light petroleum ether, providing
2.05 g (90%) of dimethylamide 5 as white needles. The mother
liquor was concentrated and the residue was purified by FC,
affording an additional 0.19 g (8%) of 5 as a white solid. Mp:
δ 175.31 (s), 168.32 (s), 108.73 (d), 82.90 (s), 76.02 (d), 37.77
(q), 36.50 (t), 36.06 (s), 35.74 (q), 34.48 (s), 27.54 (q), 23.64 (q).
MS m/z (%) 316 (7), 258 (8), 229 (18), 173 (18), 87 (100), 72
(54).
1
epi-9. H NMR: δ 5.37 (s, 1H, H-2); 3.72 (s, 1H, H-6); 3.21/
2.75 (AB J ) 15.3 Hz, 2H, H-9); 3.02 (s, 3H, Me); 2.91 (s, 3H,
Me); 2.60 (br s, 1H, OH); 1.12 (s, 9H, tBu); 0.95 (s, 9H, tBu).
MS m/z (%) 316 (4), 173 (26), 117 (34), 87 (57), 72 (100).
P r ep a r a tion of Diisop r op yl Ma la te 14. A solution of 1.60
g (7.34 mmol) of malate 13 and 2.99 g (9.72 mmol) of benzyl
bromide 7 in THF (50 mL) was cooled to -76 °C (internal
temperature). Then 15 mL (15.9 mmol) of a 1.06 M solution of
LHMDS in THF was added (internal temperature below -73
°C). The reaction mixture was warmed to +8 °C within 12 h;
at this time, the reaction was determined to be complete as
monitored by TLC. The reaction was quenched by the addition
of a saturated aqueous NH4Cl solution (20 mL) and acidified
(pH ∼ 1-2) using an 1 M aqueous HCl solution. The aqueous
layer was extracted with Et2O (3 × 15 mL), and the combined
organic phases dried over MgSO4. The solid was filtered off,
and the solvents were removed under reduced pressure. The
crude product was purified by FC (4 × 25 cm, 25-60% EtOAc/
light petroleum ether) to afford 2.64 g of malate 14 (80%) as
pale yellow oil. [R]24D +12.2 (c 1.68, CH2Cl2). IR (neat): ν 3500,
1733, 1263, 1107 cm-1. 1H NMR: δ 7.45-7.25 (m, 5H, H-arom);
6.82 (d, J ) 1.8 Hz, 1H, H-2′); 6.82 (d, J ) 8.1 Hz, 1H, H-5′);
6.74 (dd, J ) 8.1, 1.8 Hz, 1H, H-6′); 5.13 (s, 2H, O-CH2-aryl);
5.08 (sept, J ) 6.2 Hz, 1H, O-CH(CH3)2); 4.99 (sept, J ) 6.2
Hz, 1H, O-CH(CH3)2); 4.06 (br s, 1H, H-2); 3.88 (s, 3H, OMe);
3.25 (br s, 1H, OH); 3.14-3.03 (m, 2H, H-3, CH2-aryl); 2.90
(m, 1H, CH2-aryl); 1.27 (d, J ) 6.2 Hz, 3H, CH(CH3)2); 1.25
(d, J ) 6.2 Hz, 3H, CH(CH3)2); 1.20 (d, J ) 6.2 Hz, 3H, CH-
(CH3)2); 1.16 (d, J ) 6.2 Hz, 3H, CH(CH3)2). 13C NMR: δ 173.11
(s), 171.68 (s), 149.60 (s), 146.87 (s), 137.25 (s), 131.64 (s),
128.47 (d), 127.75 (d), 127.24 (d), 121.29 (d), 114.20 (d), 113.03
(d), 71.10 (t), 69.73 (d), 69.69 (d), 68.55 (d), 55.99 (q), 50.18
(d), 33.65 (t), 21.66 (q). MS m/z (%) 444 (100), 402 (9), 385 (20),
269 (26), 207 (35), 91 (33). Anal. Calcd for C25H32O7: C 67.55,
H 7.26. Found: C 67.66, H 7.21.
86-87 °C. [R]25 -6.5 (c 1.02, CH2Cl2). IR (KBr) ν 2960, 1803,
D
1652, 1196 cm-1
.
1H NMR: δ 5.20 (d, J ) 0.9 Hz, 1H, H-2);
4.89 (ddd, J ) 8.2, 2.7, 0.9 Hz, 1H, H-5); 3.04 (s, 3H, Me); 3.00
(s, 3H, Me); 2.92 (dd, J ) 16.6, 2.7 Hz, 1H, H-1′); 2.74 (dd, J
) 16.6, 8.2 Hz, 1H, H-1′); 0.98 (s, 9H, tBu). 13C NMR: δ 173.40
(s), 167.96 (s), 109.56 (d), 72.13 (d), 37.01 (q), 35.56 (q), 34.86
(t), 34.06 (s), 23.41 (q). MS m/z (%) 230 (58), 172 (35), 126 (33),
116 (28), 87 (84), 72 (100).
P r ep a r a tion of Sp ir ola cton e 8. To a cold (-78 °C)
solution of 129 mg (0.50 mmol) of dioxolanone 4 in THF (10
mL) was added 1.05 mL (1.1 mmol) of LHMDS (1.06 M in THF)
dropwise (internal temperature below -75 °C). After 20 min
all starting material was consumed and the pale orange
reaction mixture was quenched with 20% DCl in D2O (0.2 mL).
The solution was poured into brine (10 mL) and the aqueous
layer extracted with Et2O (2 × 5 mL). The combined organic
extracts were dried over MgSO4 and filtered, and the solvents
were removed under reduced pressure. The crude product was
purified by FC (2 × 14 cm, 15% EtOAc/light petroleum ether),
affording 27 mg (20%) spirolactone 8 (diastereoselectivity 8:11
) 97:3) as a white solid. Mp: 127-129 °C [lit.14 mp 129 °C].
[R]28D +33.8 (c 0.35, CH2Cl2) [lit.14 -31 for the enantiomer (!)].
1
IR (neat): ν 3433, 1801, 1784, 1199 cm-1. H NMR: δ 5.34 (s,
P r ep a r a tion of Dia cid 16. Diisopropyl ester 14 (3.00 g,
6.75 mmol) was dissolved in a 1 M ethanolic KOH solution
(30 mL). The pale yellow solution was stirred for 72 h at room
temperature, during which a white precipitate formed. EtOH
was removed under reduced pressure, and the residue was
dissolved in water (50 mL). Et2O (50 mL) was added. The
aqueous layer was acidified with a 2 M aqueous HCl solution
and saturated with solid NaCl. The aqueous solution was
extracted with Et2O (3 × 50 mL) and the combined organic
extracts were dried over MgSO4. After filtration and removal
of the solvent in vacuo, diacid 16 was obtained in quantitative
yield. The crude material was recrystallized from CHCl3
containing small amounts of MeOH to afford diastereoisomeri-
cally pure 16 (2.16 g, 87%) as a white solid. Mp: 153-154 °C.
1H, H-2); 4.29 (s, 1H, H-6); 3.14/2.79 (AB, J ) 17.7 Hz, 2H,
H-9); 1.08 (s, 9H, tBu); 0.97 (s, 9H, tBu). 13C NMR: δ 171.71
(s), 171.21 (s), 110.18 (d), 90.34 (d), 83.23 (s), 42.63 (t), 35.18
(s), 34.07 (s), 26.09 (q), 23.20 (q). MS m/z (%) 271 (4), 184 (8),
156 (37), 128 (19), 87 (19), 57 (100), 41 (48).
Alternatively, spirolactone 8 was prepared as described
previously,14 along with two other isomers 11 and 12, in ratios
of (8:11:12) 5:1:1 (LDA) or 5:2:1 (LHMDS).
11. 1H NMR: δ 5.17 (s, 1H, H-2); 4.29 (s, 1H, H-6); 3.15/
2.70 (AB J ) 18.3 Hz, 2H, H-9); 1.03 (s, 9H, tBu); 0.94 (s, 9H,
tBu). 13C NMR: δ 171.84 (s), 107.73 (d), 94.15 (d), 82.65 (s),
39.18 (t), 34.20 (s), 34.06 (s), 25.23 (q).
12. 1H NMR: δ 5.02 (s, 1H, H-2); 4.46 (s, 1H, H-6); 2.90/
2.85 (AB J ) 17.6 Hz, 2H, H-9); 1.09 (s, 9H, tBu); 1.05 (s, 9H,
tBu). 13C NMR: δ 171.32 (s), 171.29 (s), 108.66 (d), 88.91 (d),
83.70 (s), 37.37 (t), 34.19 (s), 33.90 (s), 25.77 (q), 24.09 (q). MS
m/z (%) 271 (3), 213 (3), 185 (8), 184 (8), 156 (12), 87 (12), 57
(100), 41 (29).
[R]25 -4.2 (c 0.56, MeOH). IR (KBr): ν 3450-2300, 1740,
D
1690, 1267 cm-1
.
1H NMR (CD3OD): δ 7.44-7.25 (m, 5H,
H-arom); 6.89 (d, J ) 8.1 Hz, 1H, H-5′); 6.89 (d, J ) 1.7 Hz,
1H, H-2′); 6.75 (dd, J ) 8.1, 1.7 Hz, 1H, H-6′); 5.04 (s, 2H,
O-CH2-aryl); 4.95 (br s, 3H, OH, CO2H); 4.12 (d, J ) 4.1 Hz,
1H, H-2); 3.83 (s, 3H, OMe); 3.14 (ddd, J ) 8.2, 7.2, 4.1 Hz,
1H, H-3); 3.04 (dd, J ) 13.6, 7.2 Hz, 1H, CH2-aryl); 2.85 (dd,
J ) 13.6, 8.2 Hz, 1H, CH2-aryl). 13C NMR (CD3OD): δ 177.05
(s), 176.09 (s), 151.64 (s), 148.64 (s), 139.31 (s), 134.44 (s),
129.91 (d), 129.34 (d), 129.22 (d), 122.93 (d), 116.51 (d), 114.98
(d), 72.91 (t), 71.68 (d), 56.97 (q), 52.64 (d), 35.07 (t). MS m/z
(%) 361 (100), 343 (29), 342 (30), 324 (29), 228 (14), 181 (13).
Anal. Calcd for C19H20O7: C 63.33, H 5.59. Found: C 63.13, H
5.66.
P r ep a r a tion of Dim eth yla m id e 9. To a cold (-78 °C)
solution of 115 mg (0.50 mmol) of dioxolanone 5 in THF (10
mL) was added 1.05 mL (1.1 mmol) of LHMDS (1.06 M in THF)
dropwise (internal temperature below -75 °C). After 30 min,
all starting material was consumed (TLC) and the reaction
mixture was quenched with 20% DCl in D2O (0.2 mL). Brine
(10 mL) was added, and the aqueous layer was extracted with
Et2O (2 × 5 mL). The combined organic extracts were dried
over MgSO4 and filtered, and the solvents were removed in
vacuo. The crude product was purified by FC (2 × 14 cm, 10-
20% EtOAc/light petroleum ether), affording 60 mg (38%) of
dimethylamide 9 and 5 mg (3%) of its epimer (ratio 12:1) as
P r ep a r a tion of Dioxola n on e 20. Recrystallized, dry
TsOH (100 mg) and 2 mL (1.57 g, 18 mmol) of pivalaldehyde
were added to a suspension of 1.80 g (5.00 mmol) of diacid 16
in benzene (100 mL). The suspension was refluxed for 8 h
using a Soxhlet apparatus, filled with activated 4 Å molecular
sieves. After 4 h, additional pivalaldehyde (2 mL) was added,
and the refluxing was continued until all starting material had
been consumed. Benzene and excess pivalaldehyde were
white solids. Mp: 112-114 °C. [R]30 +10.6 (c 1.13, CH2Cl2).
D
IR (neat): ν 3434, 1795, 1648, 1190, 1149, 1063 cm-1
.
1H
NMR: δ 5.24 (s, 1H, H-2); 4.20 (br s, 1H, OH); 3.62 (s, 1H,
H-6); 3.14/2.98 (AB J ) 15.5 Hz, 2H, H-9); 3.01 (s, 3H, Me);
2.96 (s, 3H, Me); 1.07 (s, 9H, tBu); 0.98 (s, 9H, tBu). 13C NMR: