â-Lactone Inhibitors of Fatty Acid Synthase
colorless oil (>96% ee, chiral GC): [R]D26 -27.1 (c ) 0.5, CHCl3);
oil and a mixture of cis/trans diastereomers (dr, 6:1). Data provided
for major diastereomer: Rf (15% Et2O:hexanes) 0.64; IR (thin film)
1824 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.18 (dd (major diast.),
J ) 6.0, 8.5 Hz, 1H), 1.63-1.78 (m, 2H), 1.45-1.53 (m, 2H), 1.39
(s, 3H), 1.24-1.39 (m, 10H), 0.89-0.94 (m, 6H); 13C NMR (500
MHz, CDCl3) 14.1, 14.2, 20.0, 22.1, 25.5, 25.6, 26.5, 30.3, 31.7,
35.9, 56.8, 84.5, 175.5; ESI LRMS calcd for C13H24O2Li [M +
Li], 219; found, 219.
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Rf 0.47 (15% Et2O:hexanes); IR (thin film) 1824 cm-1; H NMR
(300 MHz, CDCl3) δ 4.54 (ddd, J ) 2.1, 3.6, 5.7 Hz, 1H), 3.59
(ddd, J ) 4.5, 5.4, 8.4 Hz, 1H), 1.46-1.84 (m, 6H), 1.31-1.44
(m, 8H), 0.88-0.94 (m, 6H); 13C NMR (500 MHz, CDCl3) δ 14.5,
14.7, 23.2, 23.2, 24.4, 26.0, 30.5, 30.9, 32.2, 53.3, 76.5, 173.1;
ESI LRMS calcd for C12H22O2 [M + Li], 205; found, 205.
The enantiomeric purity of ketene dimer 2a and â-lactone 3a
was determined to be >96% ee by chiral GC analysis. Column
type, chiral bis-OTBS-cyclodextrin; retention time, tdimer 16.96
(major) and 17.16 (minor), tâ-lactone 26.23 (major) and 26.44 (minor).
Conditions: make up flow, 25 mL/min; H2 flow, 30 mL/min; air
flow, 300 mL/min; injector temperature, 200 °C, pressure, 5 psi
(hold time 30 min); oven temperature gradient, 100 f140 °C (hold
time 30 min); detector temperature, 250 °C.
(3S,4S)-3-Benzyl-3-butyl-4-pentyloxetan-2-one (8b). To a -78
°C solution of â-lactone 3a (153 mg, 0.76 mmol) dissolved in 7.5
mL of THF was added 1.52 mL of LiHMDS (1.52 mmol, 2.0 equiv,
1.0 M solution in THF) under nitrogen atmosphere. After 1.5 h,
180 µL (1.52 mmol, 2.0 equiv) of benzyl bromide was added and
the reaction warmed to -40 °C and stirred for an additional 45
min. The reaction mixture was concentrated in vacuo and purified
by flash chromatography (0-5% Et2O:hexanes) to give â-lactone
8b (192 mg, 88%) as a mixture of cis/trans diastereomers (>19:1).
Data provided for major diastereomer: Rf 0.55(5% Et2O:hexanes);
trans-(3R,4R)-3-Butyl-4-pentyloxetan-2-one (trans-3a). To a
-78 °C solution of 100 mg (0.51 mmol) of 3a in 5 mL of THF
was added 760 µL of LiHMDS (1.5 equiv, 1.0 M in THF), and
this was allowed to stir for 1 h. Tetramethylenediamine (TMEDA,
120 µL, 1.5 equiv, 0.76 mmol) was then added at -78 °C and
allowed to stir for an additional 30 min, after which the solution
was quenched with glacial acetic acid (130 µL, 3.0 equiv, 2.27
mmol) and warmed to 22 °C. After extraction with diethyl ether
(2 × 6 mL), the combined organics were washed with 2 mL of pH
7.0 buffer and 2 mL of brine and then dried over Na2SO4.
Concentration in vacuo gave a colorless oil, which upon purification
by flash chromatography on SiO2 (15% Et2O:hexanes) gave cis-3a
and trans-3a (72 mg, 72% yield) as a 1:1 mixture of diastereomers.
Further purification by gravity column chromatography (2×, 5%
Et2O:hexanes) delivered 34 mg (34%) of trans-3a and 38 mg of
cis-3a (38%): Rf 0.38 (10% Et2O:hexanes; cis-3a Rf 0.29); IR (thin
1
IR (thin film) 1813 cm-1; H NMR (500 MHz, CDCl3) δ 7.30-
7.34 (m, 2H), 7.25-7.28 (m, 1H),7.16-7.17 (m, 2H), 4.34 (dd,
J ) 4.5, 9.5 Hz, 1H), 3.13, 2.88 (AB q, J ) 14.5 Hz, 2H), 1.68-
1.78 (m, 2H), 1.45-1.61 (m, 4H), 1.18-1.39 (m, 8H), 0.94 (t, J )
3.5, 3H), 0.87 (t, J ) 3.5, 3H); 13C NMR (500 MHz, CDCl3) 13.87,
13.89, 22.4, 23.2, 25.2, 26.3, 28.7, 29.7, 31.4, 38.2, 61.3, 80.3,
127.1(2C), 128.7(2C), 129.8, 135.8, 174.2; ESI LRMS calcd for
C19H28O2 [M + Li], 295; found, 295.
(3S,4S)-Benzyl 3-butyl-2-oxo-4-pentyloxetane-3-carboxylate
(8c). To a -78 °C solution of NaHMDS (1.2 equiv, 0.91 mmol,
45 µL, 2M in THF) in 5 mL of THF was added 150 mg (0.73
mmol) of â-lactone 3a dissolved in 2.5 mL of THF. After 1.5 h,
benzylchloroformate (1.1 equiv, 0.833 mmol, 120 µL) was added
at one time and stirred for an additional 3 h. This solution was
warmed to 23 °C over 1 h and worked up as described above for
â-lactone 8b. Flash chromatography on SiO2 (5% Et2O:hexanes)
gave â-lactone 8c (185 mg, 74% yield) as a colorless oil: Rf 0.48
1
film) 1824 cm-1; H NMR (500 MHz, CDCl3) δ 4.22 (ddd, J )
4.2, 6.0, 7.5 Hz, 1H), 3.16 (ddd, J ) 3.9, 6.6, 9.0 Hz, 1H), 1.67-
1.93 (m, 4H), 1.26-1.49 (m, 10H), 0.91 (bs, 6H); 13C NMR (300
MHz, CDCl3) 14.5, 14.7, 23.1, 23.2, 25.4, 28.3, 29.9, 32.1, 35.2,
56.9, 78.9, 172.5; ESI LRMS calcd for C12H22O2 [M + Li], 205;
found, 205.
1
(15% Et2O:hexanes); IR (thin film) 1824, 1757, 1716 cm-1; H
NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 5.27, 5.22 (AB q, J )
12.0, 2H), 4.52 (dd, J ) 4.8, 8.4 Hz, 1H), 2.50-2.56 (m, 1H),
2.22-2.30 (m, 2H), 1.71-1.85 (m, 1H), 1.44-1.60 (m, 4H), 1.15-
1.39 (m, 8H), 0.81-0.92 (m, 6H); 13C NMR (500 MHz, CDCl3)
14, 14.6, 14.7, 23.1, 23.3, 23.6, 24.9, 25.8, 26.9, 29.4, 30.4, 31.1,
31.9, 32.3, 40.4, 71.6, 79.8, 121.7, 129.2, 129.4, 129.5, 129.8, 133.1,
152.7, 163.7, 167.3; ESI LRMS calcd for C20H28LiO4+ [M + Li],
339; found, 338.
General Experimental Procedure for in Situ Mid-IR Spec-
troscopy with a RemSpec ReactionView System. A RemSpec
Reaction View system was fitted with a double-pass liquid
transmission head that was placed into a flame-dried two-necked
20 × 2.3 cm reaction tube equipped with a spin vane stir bar, and
the reaction flask was placed under a nitrogen atmosphere.
Following addition of 30 mL of CH2Cl2, a background spectrum
was obtained for 15 min and then automatic data collection was
initiated and provided 45 scans/min for both experiments at 23 °C.
The data collected for hydrocinnamoyl chloride, ketene, and ketene
dimer for both experiments were peak fitted with a Lorentzian
function on Grams/AI software and normalized on Microsoft Excel
to obtain absorbance versus time curves.
Reaction Condition I. Sequential addition of hydrocinnamoyl
chloride (0.45 mL, 2.97 mmol; t ) 14.5 min) and 565 µL of Hu¨nig’s
base (2.97 mmol; t ) 30 min) gave rise to expected acid chloride
and ketene absorbances. After complete consumption of acid
chloride, 5 mol % TMS-QN (22 mg) was added as a solution in 1
mL of CH2Cl2 in one portion at t ) 35 min, and data was collected
for an additional 540 min.
Reaction Condition II. In this procedure 5 mol % TMS-QN
(22 mg) and 565 µL of Hu¨nig’s base was added to 30 mL of CH2-
Cl2. At t ) 18.3 min, hydrocinnamoyl chloride (0.45 mL, 2.97
mmol) was added over a period of 5 min and data was collected
for an additional 230 min.
trans-(3S,4S)-4-(2-Cyclohexylethyl)-3-(cyclohexylmethyl)oxe-
tan-2-one (trans-3c). To a -78 °C solution of 30 mg (0.108 mmol)
of cis-â-lactone 3c in 3 mL of THF was added 162 µL of LiHMDS
(1.5 equiv, 1.0 M in THF), and this was stirred for 1 h.
Tetramethylenediamine (TMEDA, 25 µL, 1.5 equiv, 0.162 mmol)
was then added at -78 °C and allowed to stir for an additional 30
min, after which the solution was quenched with glacial acetic acid
(18 µL, 3.0 equiv, 0.323 mmol) and warmed to 22 °C. After
extraction with diethyl ether (2 × 3 mL), the combined organics
were washed with 2 mL of pH 7.0 buffer and 2 mL of brine and
then dried over Na2SO4. Concentration in vacuo gave a colorless
oil that was purified by flash chromatography on SiO2 (10% Et2O:
hexanes) to give a mixture of cis- and trans-3c (19.8 mg, 66%
yield). Further purification by gravity column chromatography (10%
Et2O:hexanes) delivered 12 mg (40%) of trans-3c and 7.6 mg of
cis-3c (25%): Rf 0.47 (10% Et2O:hexanes; cis-3c, Rf 0.40); IR (thin
1
film) 1824 cm-1; H NMR (500 MHz, CDCl3) δ 4.17 (ddd, J )
4.2, 6.0, 7.4 Hz, 1H), 3.24 (ddd, J ) 4.0, 6.5, 9.0 Hz, 1H), 1.79-
1.89 (m, 1H), 1.59-1.78 (m, 12H), 1.30-1.39 (m, 1H), 1.07-
1.30 (m, 10H), 0.82-0.99 (m, 4H); 13C NMR (300 MHz, CDCl3)
15.4, 26.1, 26.2, 26.3, 26.4, 26.6, 29.8, 31.9, 32.6, 32.9, 33.2, 33.3,
35.9, 37.4, 54.2, 66.0, 79.4, 172.3; ESI LRMS calcd for C18H30O2
[M + Li], 285; found, 285.
(3R,4S)-3-Butyl-3-methyl-4-pentyloxetan-2-one (8a). A solu-
tion of â-lactone 3a (36.3 mg, 0.1835 mmol) in 1.9 mL of THF
was cooled to -78 °C, and 370 µL of LiHMDS (0.367 mmol, 2.0
equiv, 1.0 M solution in THF) was added under a nitrogen
atmosphere. After 1.5 h, 23 µL (0.367 mmol, 2.0 equiv) of
iodomethane was added and the reaction warmed to -40 °C and
stirred for an additional 45 min. The reaction mixture was
concentrated in vacuo and purified by flash chromatography (0-
15% Et2O:hexanes) to give â-lactone 8a (28 mg, 73%) as a colorless
J. Org. Chem, Vol. 71, No. 12, 2006 4557