7290 J. Am. Chem. Soc., Vol. 121, No. 32, 1999
List et al.
1H NMR (400 MHz, CDCl3): δ 9.86 (t, J ) 1.8 Hz, 1H), 7.38 (d,
J ) 8.5 Hz, 2H), 7.35 (br, 1H), 7.10 (d, J ) 8.5 Hz, 2H), 2.65 (m,
4H), 2.14 (s, 3H), 1.82 (m, 2H), 1.34 (s, 3H).
1H NMR (500 MHz, CDCl3): δ 8.26 (br, 1H), 7.46 (d, J ) 8.5 Hz,
2H), 7.18 (d, J ) 8.5 Hz, 2H), 6.77 (m, 1H), 5.99 (d, J ) 16.0 Hz,
1H), 4.43 (s, 2H), 3.25 (s, 2H), 2.42 (m, 1H), 2.31 (m, 1H), 2.15 (s,
3H), 2.09 (s, 3H), 1.11 (s, 3H).
Compound 12 (18 mg, 0.059 mmol) was hydrogenated with a
catalytic amount of Pd(OH)2/C in methanol for 2 h. The reaction mixture
was filtered through Celite, and the solvent was removed under reduced
pressure to give a 12-mg mixture of (+)-Frontalin along with
p-acetamidotoluene, [R]23D +48.3 (lit.13 [R]23D +54.4). Due to the small
amount and the volatile nature of Frontalin (13), we were unable to
purify it to get an accurate reading of the optical rotation.
(4-Nitrophenyl)methylcarbamic Acid 3-Hydroxy-3-methyl-5-oxo-
pentyl Ester (11). To 4-hydroxy-2-butanone (2 mL, 23.2 mmol) and
Sc(OTf)3 (570 mg, 1.3 mmol) in CH2Cl2 (8 mL) was added tetraallyltin
(2.8 mL, 11.6 mmol). The mixture was stirred for 16 h at room
temperature. After evaporation and column chromatography (50-66%
ethyl acetate/hexane), 3-methyl-5-hexene-1,3-diol32 was isolated (2.6
g, 20 mmol, 86%).
1H NMR (300 MHz, CDCl3): δ 5.75-5.85 (m, 1H), 5.15 (m, 2H),
3.88 (br, 2H), 3.49 (br, 1H), 3.19 (br, 1H), 2.25 (d, J ) 7.4 Hz, 2H),
1.60-1.82 (m, 2H), 1.19 (s, 3H).
To a stirred solution of phosgene (0.7 mL, 1.93 M toluene, 1.4 mmol)
in 6 mL of dry THF was added a mixture of N-methyl-4-nitroaniline
(200 mg, 1.3 mmol) and triethylamine (0.18 mL, 1.3 mmol) in 3 mL
of dry THF. The mixture was stirred for 15 min at 0 °C under argon
and was warmed to room temperature. To this mixture were added at
room temperature 3-methyl-5-hexene-1,3-diol (170 mg, 1.3 mmol),
triethylamine (0.18 mL, 1.3 mmol), and DMAP (15 mg) in 2 mL of
dry THF. The mixture was stirred at room temperature under argon
for 90 h and was worked up with ether/saturated aqueous ammonium
chloride. The organic layer was dried (Na2SO4), filtered, concentrated
in vacuo, and purified by column chromatography (33% ethyl acetate/
hexane) to give carbamate 14 (285 mg, 0.93 mmol, 71%).
1H NMR (300 MHz, CDCl3): δ 8.22 (m, 2H), 7.49 (m, 2H), 5.75-
5.89 (m, 1H), 5.18 (m, 2H), 4.38 (m, 2H), 3.40 (s, 3H), 2.25 (m, 2H),
1.64-1.89 (m, 2H), 1.21 (s, 3H). 13C NMR (300 MHz, CDCl3): δ
221, 155, 148.5, 133, 124.5, 124, 119, 71, 63, 47, 40.5, 37, 26. HRMS
(FAB): M + H+ 309.1450 (expected), 309.1456 (observed).
To a solution of carbamate 14 (471.2 mg, 1.5 mmol) in 9 mL of dry
methylene chloride were added OsO4 (2.5% solution in 2-methyl-2-
propanol, 0.8 mL) and NMO (50% aqueous, 0.38 mL, 1.8 mmol). The
resulting mixture was stirred for 45 min, and then Pb(OAc)4 was added.
After 10 min, it was filtered over Celite, evaporated in vacuo, and
purified by column chromatography on silica gel using hexane/ethyl
acetate (1:1) to afford aldehyde 11 (409.1 mg, 1.3 mmol, 90%).
1H NMR (300 MHz, CDCl3): δ 9.82 (s, 1H), 8.23 (m, 2H), 7.49
(m, 2H), 4.42 (m, 2H), 3.40 (s, 3H), 2.73 (m, 2H), 1.90-2.10 (m, 2H),
1.37 (s, 3H). 13C NMR (300 MHz, CDCl3): δ 222, 220, 162, 142,
134, 125, 124, 71, 63, 53.5, 41, 37.5, 27.5, 20. MS (FAB): M + Na+
333 (expected), 333 (observed).
Mevalonolactone. To a solution of aldehyde 11 (340 mg, 1.1 mmol)
in 4 mL of anhydrous MeOH was added NaBH4 (46 mg, 1.2 mmol) at
0 °C under argon. The mixture was stirred at room temperature for 30
min and worked up with ether/saturated ammonium chloride. The
organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and
purified by column chromatography (75% ethyl acetate/hexane) to yield
(4-nitrophenyl)methylcarbamic acid 3,5-dihydroxy-3-methylpentyl ester
(241 mg, 0.77 mmol, 70%).
1H NMR (300 MHz, CDCl3): δ 8.25 (m, 2H), 7.49 (m, 2H), 4.41
(m, 2H), 4.05-4.20 (m, 2H), 3.91 (br, 2H), 3.40 (s, 3H), 1.60-2.10
(m, 4H), 1.30 (s, 3H). 13C NMR (300 MHz, CDCl3): δ 224, 129, 125,
124, 123.5, 119, 73, 59.5, 44, 41.5, 35, 28, 20. MS (FAB): M + Na+
335 (expected), 335 (observed).
N-[4-(2-Hydroxy-2-methyl-4-oxobutoxymethyl)phenyl]acet-
amide (10). Sodium hydride (480 mg, 12.0 mmol) was added to a
stirred solution of 2-methyl-2-propen-1-ol (925 µL, 11.0 mmol) in 10
mL of DMF at 0 °C. After 10 min, N-(4-chloromethylphenyl)acetamide
(1.0 g, 5.4 mmol) was added, and the reaction mixture was stirred for
1 h. Then, the mixture was worked up with water and ether. The organic
layer was washed with brine and dried (Na2SO4), and the solvent was
removed under reduced pressure. The crude product was purified by
column chromatography on silica gel (40% ethyl acetate/hexane) to
give N-[4-(2-methylallyloxymethyl)phenyl]acetamide (670 mg, 56%).
1H NMR (500 MHz, CDCl3): δ 7.48 (d, J ) 8.5 Hz, 2H), 7.26 (d,
J ) 8.5 Hz, 2H), 7.21 (br, 1H), 4.95 (d, J ) 20.4 Hz, 2H), 4.46 (s,
2H), 3.90 (s, 2H), 2.16 (s, 3H), 1.78 (s, 3H).
To a stirred solution of N-[4-(2-methylallyloxymethyl)phenyl]acet-
amide (657 mg, 3.0 mmol) in 10 mL of acetone was added 4-meth-
ylmorpholine N-oxide (50% solution in water, 684 µL, 3.3 mmol),
followed by osmium tetraoxide (2.5% solution in 2-methyl-2-propanol,
1.25 mL, 0.1 mmol). The reaction mixture was stirred for 1 h. After it
was confirmed that no more starting material was left according to
TLC, sodium periodate (1.28 g, 6.0 mmol) was added, and the mixture
was stirred for another hour. Then it was worked up with water and
methylene chloride. The organic phase was dried (Na2SO4), and the
solvent was removed under reduced pressure. The crude product was
purified by column chromatography on silica gel (50% ethyl acetate/
hexane) to give N-[4-(2-oxopropoxymethyl)phenyl]acetamide (625 mg,
94%).
1H NMR (400 MHz, CDCl3): δ 7.48 (d, J ) 8.5 Hz, 2H), 7.30 (br,
1H), 7.26 (d, J ) 8.5 Hz, 2H), 4.53 (s, 2H), 4.03 (s, 2H), 2.16 (s, 3H),
2.14 (s, 3H).
To a stirred solution of N-[4-(2-oxopropoxymethyl)phenyl]acetamide
(625 mg, 2.8 mmol) in 10 mL of methylene chloride was added
scandium trifluoromethanesulfonate (100 mg, 0.2 mmol), followed by
tetraallyl tin (340 µL, 1.5 mmol), and the mixture was stirred for 1 h.
Then it was worked up with water and methylene chloride. The organic
layer was dried (Na2SO4), and the solvent was removed under reduced
pressure. The crude product was purified by column chromatography
on silica gel (50% ethyl acetate/hexane) to give N-[4-(2-hydroxy-2-
methylpent-4-enyloxymethyl)phenyl]acetamide (605 mg, 82%).
1H NMR (500 MHz, CDCl3): δ 7.47 (d, J ) 8.5 Hz, 2H), 7.45 (br,
1H), 7.25 (d, J ) 8.5 Hz, 2H), 6.81 (m, 1H), 5.07 (m, 2H), 4.49 (s,
2H), 3.30 (d, J ) 9.0 Hz, 1H), 3.25 (d, J ) 9.0 Hz, 1H), 2.33 (s, 1H),
2.25 (m, 2H), 2.16 (s, 3H), 1.16 (s, 3H).
Aldol 10 (90%) was prepared from N-[4-(2-hydroxy-2-methylpent-
4-enyloxymethyl)phenyl]acetamide via dihydroxylation/periodate cleav-
age as described in the synthesis of N-[4-(2-oxopropoxymethyl)phen-
yl]acetamide.
1H NMR (400 MHz, CDCl3): δ 9.83 (t, J ) 2.4 Hz, 1H), 7.47 (d,
J ) 8.5 Hz, 2H), 7.33 (br, 1H), 7.24 (d, J ) 8.5 Hz, 2H), 4.49 (s, 2H),
3.34 (s, 2H), 2.91 (s, 1H), 2.68 (d, J ) 18.2 Hz, 1H), 2.49 (d, J ) 18.2
Hz, 1H), 2.19 (s, 3H), 1.25 (s, 3H).
(+)-Frontalin (13). Racemic aldol 10 (50 mg, 0.19 mmol) was
incubated with antibody 38C2 (100 mg, 0.00067 mmol) in 50 mL of
PBS (pH 7.4). The reaction was followed by HPLC, and after 7 days
(kcat ) 0.0034 min-1) it reached 50% conversion and stopped. The
reaction mixture was saturated with NaCl and extracted with ethyl
acetate. The organic layer was dried (Na2SO4), and the solvent was
removed under reduced pressure. The crude product was purified by
column chromatography on silica gel (70% ethyl acetate/hexane) to
give aldol (R)-10 (22 mg, 44%) in 95% ee.
To a stirred solution of aldol (R)-10 (22 mg, 0.083 mmol) in 2 mL
of THF was added diethyl (2-oxopropyl)phosphonate (48 mg, 0.25
mmol), followed by lithium hydroxide monohydrate (6.0 mg, 0.25
mmol). The reaction mixture was stirred for 2 h. Then it was worked
up with water and ethyl acetate. The organic layer was dried (Na2-
SO4), filtered, concentrated in vacuo, and purified by column chroma-
tography on silica gel (70% ethyl acetate/hexane) to give enone 12
(18 mg, 71%).
(4-Nitrophenyl)methylcarbamic acid 3,5-dihydroxy-3-methylpentyl
ester (46.3 mg, 0.15 mmol), TPSCl (80 µL, 0.29 mmol), and imidazole
(31 mg, 0.46 mmol) were stirred in DMF (2 mL) at room temperature
for 24 h. The reaction was then partitioned between ether and 10%
HCl. The organic layer was washed with saturated NaHCO3 and water,
(32) Ferraboschi, P.; Caevotti, R.; Grisenti, P.; Santaniello, E. J. Chem.
Soc., Perkin Trans. 1 1987, 2301-2303.