Meth yl (2R,5S,10S)-10-Meth yl-6-oxo-sp ir o[4.5]d eca n e-2-
ca r boxyla te ((2R,5S,10S)-14). tert-Butyl ester 13 (309 mg, 1.16
mmol) was directly converted to the methyl ester by ester
exchange in refluxing methanol (2.5 mL) in the presence of a
catalytic amount of concentrated H2SO4. After 24 h, the resulting
mixture was concentrated under reduced pressure and the
residue was purified by column chromatography on silica gel
affording (2R,5S,10S)-14 as a colorless oil. Yield 93%. Oil. IR
(neat) ν 2955, 1735, 1705, 1214, 1170 cm-1. 1H NMR (300 MHz,
CDCl3) δ 3.68 (s, 3H), 2.74 (m, 1H), 2.42 (t, J ) 6.8 Hz, 2H),
2.34 (ddd, J ) 12.9, 7.6, 3.0 Hz, 1H), 2.12 (dd, J ) 13.5, 7.9 Hz,
1H), 2.00-1.65 (m, 7H), 1.60-1.47 (m, 2H), 0.96 (d, J ) 7.1 Hz,
3H). MS (m/z) 224 (M+), 147, 125 (100), 108, 93, 79, 67, 55, 41.
catalyzed [3+2] cycloaddition reaction was developed.
The utility of this method was exemplified by the first
total synthesis of natural product (-)-hinesol (1), which
features a rapid and efficient construction of the spiro
carbocyclic skeleton.
Exp er im en ta l Section
The detailed procedures in the synthesis of (()-hinesol are
described in the Supporting Information.
(S)-2-((2′-(Meth oxym eth yl)-1′-p yr r olid in yl)m eth yl)cyclo-
h ex-2-en -1-on e ((S)-11).17 To compound 10 in acetonitrile (10
mL) was added (S)-2-(methoxymethyl)pyrrolidine (10.5 mmol)
at 25 °C. The reaction mixture was stirred for 1 h and
concentrated in vacuo. The oily residue was diluted with ethyl
acetate (30 mL) and washed with water (30 mL). The aqueous
layer was extracted with ethyl acetate (3 × 30 mL). The
combined organic layer was dried over MgSO4 and concentrated
in vacuo to give compound 11 in nearly quantitative yield.
(S)-3-Meth yl-2-m eth ylen ecycloh exen on e ((S)-5).17 (S)-3-
Methyl-2-methylenecyclohexenone ((S)-5) was prepared by the
reported method.17 Oil; yield 67%. 1H NMR (300 MHz, CDCl3) δ
5.79 (br s, 1H), 5.13 (br s, 1H), 2.60-2.46 (m, 2H), 2.35 (m, 1H),
2.03-1.73 (m, 4H), 1.15 (d, J ) 6.7 Hz, 3H). 94.6% ee (lit.17 95%
ee). The ee value of (S)-5 was determined by first converting
(S)-5 to cis-2-benzyl-3-methylcyclohexanone and by HPLC analy-
sis of the cyclohexanone derivative (crude product) with the same
method as that of the literature.17 HPLC: column, CHIRALCEL
OJ (4.6 mm i.d. × 250 mm, Daicel Chemical Industries); eluent,
95:5 hexane:2-propanol; flow rate, 0.7 mL/min; detecting, 214-
nm light.
[R]20 +10 (c 0.156, CHCl3).
D
Meth yl (2R,5S,10S)-10-Meth yl-6-m eth ylen esp ir o[4.5]d e-
ca n e-2-ca r boxyla te ((2R,5S,10S)-15). CH2I2 (0.32 mL) was
added at 25 °C to a stirring suspension of zinc (freshly activated,
0.48 g, 7.2 mmol) in THF (8 mL) under an argon atmosphere.
After 0.5 h, a solution of TiCl4 (1 M solution in CH2Cl2, 0.74
mL) was added at 0 °C and the resulting brown mixture was
stirred at room temperature for 30 min. Ester (2R,5S,10S)-14
(80 mg, 0.36 mmol) in THF (2 mL) was added dropwise to the
above mixture at room temperature. After 15 min, the reaction
mixture was diluted with Et2O and the reaction was quenched
by saturated NH4Cl solution. Then, the resulting mixture was
separated and the organic layer was concentrated under reduced
pressure. The product was purified by column chromatography
on silica gel affording (2R,5S,10S)-15 as a colorless oil in an 82%
yield. Oil. IR (neat) ν 2935, 1737, 1639, 1201, 1170 cm-1. 1H NMR
(300 MHz, CDCl3) δ 4.75 (s, 1H), 4.63 (s, 1H), 3.67 (s, 3H), 2.80
(m, 1H), 2.22-2.14 (m, 2H), 2.10-1.30 (m, 11H), 0.86 (d, J )
7.3 Hz, 3H). MS (m/z) 222 (M+), 162, 107, 95 (100), 91, 82, 81,
79, 67. [R]20 +30.9 (c 0.547, CHCl3).
D
(-)-Hin esol ((-)-1). Compound 15 (28 mg, 0.13 mmol) was
added to a mixture of TsOH (4 mg) in benzene (4 mL) at room
temperature. After 10 h of refluxing, the resulting mixture was
chromatographed on silica gel, affording endo-olefin (26 mg) as
a colorless oil in a 93% yield. The endo-olefin (18 mg) in Et2O (2
mL) was added dropwise to an ice-cold solution of methylmag-
nesium iodide (16 equiv) in dry ether (16 mL). The mixture was
stirred for 30 min at 0 °C and then at room temperature for 3
h. A few drops of water were added to the reaction mixture to
quench the reaction. After the mixture was stirred for 15 min,
the resulting mixture was dried (MgSO4) and concentrated under
vacuum. The residue was chromatographed on silica gel (elu-
ent: n-hexane/ethyl acetate 10/1) to afford 1 (17 mg) as a
ter t-Bu tyl (5S,10S)-10-Meth yl-6-oxo-sp ir o[4.5]d ec-2-en e-
2-ca r boxyla te ((5S,10S)-6). A solution of (S)-5 (1.2 mmol), 3
(1.0 mmol), and PBu3 (0.1 mmol) in dry toluene (10 mL) was
stirred at room temperature for 23 h. The resulting mixture was
concentrated under reduced pressure and the residue was
purified by column chromatography on silica gel to give 166 mg
of a mixture of compounds 6 and 7 in a 63% total yield (6/7 94/
6). Compound (5S,10S)-6 was isolated by further column chro-
matography on silica gel with petroleum ether and ethyl acetate
as the eluent. Oil. IR (neat) ν 2975, 2934, 1706, 1639, 1172 cm-1
.
1H NMR (300 MHz, CDCl3) δ 6.57-6.54 (m, 1H), 3.47 (d, J )
19.3 Hz, 1H), 2.76 (d, J ) 17.1 Hz, 1H), 2.52-2.38 (m, 3H), 2.19
(d, J ) 19.3 Hz, 1H), 2.00-1.97 (m, 1H), 1.75-1.60 (m, 4H), 1.47
(s, 9H), 0.91 (d, J ) 6.1 Hz, 3H). MS (m/z) 208 (M+ - C4H8), 191
(M+ - OtBu), 190, 124, 91, 77, 65, 57 (100), 41. [R]D -29.7 (c
0.750, CHCl3). 93.6% ee. HPLC (crude product): column,
CHIRALPAK AD (4.6 mm i.d. x 250 mm, Daicel Chemical
Industries); eluent, 100:1 hexane:2-propanol; flow rate, 0.5 mL/
min; detecting, 214-nm light.
1
colorless oil in a 94% yield. Oil. IR (ref 10f), H NMR (refs 10n
and 10o), and 13C NMR (ref 10k) data were identical with those
of the literature. IR (neat) ν 3399, 2964, 2926, 2877, 1660, 1468,
1457, 1378, 1134, 937, 917, 799. 1H NMR (300 MHz, CDCl3) δ
5.32 (br s, 1H), 2.10-1.91 (m, 3H), 1.79-1.26 (m, 13H), 1.21 (s,
6H), 0.92 (d, J ) 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 140.0,
121.6, 72.0, 51.4, 48.7, 36.7, 35.6, 33.2, 28.4, 28.0, 27.9, 27.6,
24.2, 19.9, 16.2. MS (m/z) 222 (M+), 161 (100), 147, 119, 107,
93, 91, 59, 43. [R]20D -40 (c 0.25, CHCl3) (lit.6a [R]D -40.2 (c 10.0,
CHCl3); lit.6b [R]D -47.8 (c 5.104, CHCl3)). The ee value of
(2R,5S,10S)-1 was determined by GC analysis. GC:column,
CHIRALCEL DEX B-PH (astec), 0.25 mm i.d. × 20 m, PE
Autosystem X L; carrier gas, N2 (8.0 psi); column temperature,
250 °C; detector temperature, 250 °C.
ter t-Bu tyl (2S,5S,10S)-10-Meth yl-6-oxo-sp ir o[4.5]d eca n e-
2-ca r boxyla te ((2S,5S,10S)-12) a n d ter t-Bu tyl (2R,5S,10S)-
10-Meth yl-6-oxo-spir o[4.5]decan e-2-car boxylate ((2R,5S,6S)-
13). The spiro olefin 6 (214 mg, 0.81 mmol) was hydrogenated
over Pd/C (5%, 40 mg) in 5 mL of MeOH at room temperature.
The resulting mixture was filtered on silica gel and washed with
ethyl acetate three times, and the filtrate was concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (ethyl acetate/petroleum ether (60-
90 °C) 1/50) affording a minor product (12) (25 mg, 12%) and a
major product (13) (188 mg, 87%). (2S,5S,10S)-12: Oil. IR (neat)
Ack n ow led gm en t. We thank the Major State Basic
Research Program (Grant G20000077502-A). We also
thank the National Natural Sciences Foundation of
China (29972048, 20072045) and Chinese Academy of
Sciences for financial support.
ν 2972, 1726, 1704, 1154 cm-1 1H NMR (300 MHz, CDCl3) δ
.
2.71-2.66 (m, 1H), 2.54-2.46 (m, 1H), 2.38-2.31 (m, 2H), 2.15-
2.10 (m, 1H), 2.00-1.80 (m, 3H), 1.78-1.73 (m, 4H), 1.57-1.37
(m, 11H), 0.92 (d, J ) 7.0 Hz, 3H). MS (m/z) 210 (M+ - C4H8),
193 (M+ - OtBu), 192, 165, 164, 147, 57 (100), 41. [R]20 +25.3
D
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for all new compounds; copies of 1H NMR
spectra, 13C NMR spectra, and chiral HPLC of (-)-hinesol
synthesized; X-ray crystallography of 6. This material is
(c 0.55, CHCl3). (2R,5S,10S)-3: Oil. IR (neat) ν 2968, 2937, 1728,
1706, 1155 cm-1 1H NMR (300 MHz, CDCl3) δ 2.69-2.58 (m,
.
1H), 2.48-2.39 (m, 2H), 2.36-2.29 (m, 1H), 2.07-1.65 (m, 8H),
1.58-1.44 (m, 2H), 1.43 (s, 9H), 0.94 (d, J ) 6.9 Hz, 3H). MS
(m/z) 210 (M+ - C4H8), 193 (2), 147, 125, 57 (100), 55, 41. [R]20
+11.3 (c 0.42, CHCl3).
D
J O034281F
J . Org. Chem, Vol. 68, No. 16, 2003 6465