Total Synthesis of (R)-Dihydroactinidiolide and (R)-Actinidiolide
J . Org. Chem., Vol. 63, No. 1, 1998 121
1.0, CHCl3), 97% ee. 1H NMR δ 6.01-6.04 (m, 1H), 4.57 (d,
1H, J ) 2.2 Hz), 4.44-4.48 (m, 1H), 4.15 (q, 2H, J ) 7.2 Hz),
2.46 (t, 1H, J ) 2.2 Hz), 1.79 (d, 3H, J ) 2.2 Hz), 1.74 (dd, 1H,
J ) 13.2, 2.2 Hz), 1.24 (t, 3H, J ) 7.2 Hz), 1.18 (s, 3H), 1.09
(dd, 1H, 12.9, 1.9 Hz), 0.90 (s, 3H); 13C NMR δ 173.2, 141.2,
124.9, 70.3, 68.7, 60.7, 50.1, 42.0, 30.6, 30.0, 28.3, 22.1, 14.4.
The reaction can also be performed in a larger molar scale.
(3S ,3a R ,7a R )-4,4,7a -T r i m e t h y l-3-h y d r o x y -2-o x o -
3a ,4,5,7a -tetr a h yd r oben zofu r a n (4b). Compound 5 (1.91
g, 8.5 mmol) was added to KOH (1.0 g, 17.8 mmol) dissolved
in H2O (3 mL) and EtOH (5 mL). The solution was stirred at
rt for 6 h, partly evaporated in vacuo until total volume was
about 4 mL. Then H2O (3 mL) was added and stirred for 5-10
min, followed by the addition of 3 N HCl until the solution
became acidic (pH ) 1-2). After being stirred at rt overnight,
the solution became bright yellow with a lot of white solid in
it. The product was extracted using Et2O, and the combined
ethereal phases were washed using H2O and brine repeatedly,
dried with MgSO4, and evaporated to give 4b (1.47 g, 88%
yield) with 97% ee. The crude product contained only very
small amounts of impurities according to NMR spectroscopy.
Recrystallization from i-Pr2O gave the enantiopure 4b (only
one enantiomer could be detected by chiral GC). [R]D ) -94.4
(c ) 0.9, CHCl3). IR (KBr): 3405 (s, OH), 1756 (s, CO), 3040
µL, 0.55 mmol) was added dropwise to a stirred solution of 4b
(50 mg, 0.25 mmol) and DMAP (153 mg, 1.25 mmol) in CH2-
Cl2 (5 mL) at 0 °C. The reaction mixture was first stirred at
0 °C for 1 h and then at rt overnight. Workup as above gave
the crude product, which was purified using FC (EtOAc:
petroleum ether 20:80) to give (R)-actinidiolide (2) (5 mg, 11%
yield), 99.8% ee according to chiral GC. [R]D ) -133° (c )
1
1.0, CHCl3), H NMR δ 5.90 (dd, 1H, J ) 9.9, 2.2 Hz), 5.73-
5.75 (m, 1H), 5.71 (s, 1H), 2.27 (dd, 1H, J ) 17.3, 3.8), 2.14
(dt, 1H J ) 18, 2.8 Hz), 1.60 (s, 3H), 1.33(s, 3H), 1.29 (s, 3H);
13C NMR δ 180.9, 171.5, 128.9, 128.4, 112.7, 85.5, 44.5, 35.8,
28.2, 26.2, 26.1. The spectral data were identical with those
reported.3a
(3S,3a R,7a R)-4,4,7a -Tr im et h yl-3-(t osyloxy_-3a ,4,5,7a -
tetr a h yd r oben zofu r a n -2(3H)-on e (4d ) via Alcoh ol 4b. To
a stirred solution of 4b (196 mg, 1.0 mmol) and DMAP (367
mg, 3.0 mmol) in anhydrous CH2Cl2 (15 mL) at 0 °C was added
dropwise p-toluenesulfonyl chloride (393 mg, 2.0 mmol). After
stirring at 0 °C for 1 h and at rt for 3 h, H2O (2 mL) was added,
and the solution was stirred for another 5 min. The organic
phases were washed successively with 2 N HCl, saturated
NaHCO3, H2O, and brine, dried, and concentrated. The crude
product was purified using FC (EtOAc:petroleum ether 20:80)
to give 4d (342 mg, 98% yield). 1H NMR δ 7.89 (d, 2H, J )
8.2 Hz), 7.35 (d, 2H, J ) 8.1 Hz), 5.87-5.91 (m, 1H), 5.74 (dt,
1H, J ) 10.1, 2.2 Hz), 5.51 (d, 1H, J ) 8.2 Hz), 2.47 (d, 1H, J
) 8.2 Hz), 2.44 (s, 3H), 1.91-1.94 (m, 2H), 1.45 (s, 3H), 1.21
(s, 3H), 1.02(s, 3H); 13C NMR δ 169.8, 145.3, 133,1, 129.8,
128.2, 126.9, 81.1, 76.0, 52.6, 39.6, 31.6, 30.3, 27.9, 22.3, 21.7.
(R)-4,4,7a -Tr im et h yl-5,7a -d ih yd r ob en zofu r a n -2(4H )-
on e, (R)-Actin id iolid e (2) via Tosyla te 4d . To a dry flask
were added 4d (330 mg, 0.94 mmol), DMAP (488 mg, 4 mmol),
and anhydrous Cl(CH2)2Cl (10 mL). After gently refluxing for
24 h, the reaction mixture was diluted with Et2O, washed
repeatedly using H2O and brine, dried with MgSO4, filtered,
and concentrated. Purification by FC (EtOAc:petroleum ether
20:80) gave (R)-actinidiolide (2) (28 mg, 17% yield) with 99.5%
ee and 4c (154 mg, 77% yield). 4c: 1H NMR δ 5.77-5.82 (m,
1H), 5.66 (d, 1H, J ) 11 Hz), 4.30 (br d, 1H, J ) 9.9 Hz), 2.37
(br d, 1H, J ) 9.3 Hz), 2.09 (d, 1H, J ) 18.1 Hz), 1.90 (dd, 1H,
J ) 4.9, 18.7), 1.63 (s, 3H), 1.17 (s, 3H), 1.09 (s, 3H); 13C NMR
δ 171.3, 128.2, 128.1, 83.1, 59.2, 54.2, 34.6, 32.2, 28.9, 28.8,
27.7; MS m/e (relative intensity) 216 ((M + 2)+, 4), 214 (M+,
12), 199(100), 135(82), 103(60), 93(99).
(w, HCd)cm-1 1H NMR δ 5.87-5.93 (m, 1H), 5.74-5.79 (m,
.
1H), 4.90 (d, 1H, J ) 8.6 Hz), 3.23 (br s, 1H), 2.31 (d, 1H, J )
8.6 Hz), 1.90 (t, 2H, J ) 3.0), 1.44 (s, 3H), 1.19 (s, 3H), 1.02 (s,
3H); 13C NMR δ 177.7, 129.8, 127.3, 81.7, 71.0, 52.7, 39.9, 31.6,
30.3, 27.7, 22.2.
(3S ,3a R ,7a R )-4,4,7a -T r i m e t h y l-3-h y d r o x y -2-o x o -
3a ,4,5,6,7,7a -h exa h yd r ob en zofu r a n (4a ). To a dry flask
which had been evacuated and filled with H2 several times
were added (Ph3P)3RhCl (100 mg, 0.11 mmol) and freshly
distilled benzene (22 mL). The resulting suspension was
stirred for several minutes under an atmosphere of H2.
Compound 4b (196 mg, 1.0 mmol) was added under H2, and
the solution was stirred at rt under H2 overnight. After
evaporation of the solvent, the residue was purified using
PTLC (EtOAc:petroleum ether 20:80), giving 4a (188 mg, 95%
yield) with 99.8% ee as established by chiral GC. 1H NMR δ
4.47 (dd, 1H, J ) 2.8, 6.6 Hz), 2.81 (d, 1H, J ) 2.8 Hz), 1.96
(dt, 1H, J ) 12.4, 3.8 Hz), 1.89-1.63 (m, 4H), 1.55-1.43 (m,
1H), 1.50 (s, 3H), 1.25-1.20 (m, 1H), 1.18 (s, 3H), 1.08 (s, 3H);
13C NMR δ 176.7, 87.4, 72.3, 54.8, 36.9, 36.2, 32.9, 30.6, 27.6,
27.3, 19.3.
(R)-4,4,7a -Tr im eth yl-5,6,7,7a -tetr a h yd r oben zofu r a n -2-
on e, (R)-Dih yd r oa ctin id iolid e (1). (CF3SO2)2O (184 µL, 1.1
mmol) was added dropwise to a stirred solution of the bicyclic
lactone 4a (100 mg, 0.5 mmol) and 4-(N,N-dimethylamino)-
pyridine (DMAP) (305 mg, 2.5 mmol) dissolved in anhydrous
CH2Cl2 (8 mL) at 0 °C. The resulting solution was stirred at
0 °C for 1 h before being warmed to rt and left overnight. Then
H2O (3 mL) was added, the product was extracted using Et2O,
the collected extracts were washed repeatedly using H2O and
brine and dried, and the solvent was evaporated. The crude
product was purified using FC (EtOAc:petroleum ether 30:70)
to afford (R)-dihydroactinidiolide (1) (80 mg, 82% yield) with
99.8% ee according to chiral GC. [R]D ) -105° (c ) 1.0, in
CHCl3), 1H NMR δ 5.64 (s, 1H), 2.23 (dq, 1H, J ) 2.5, 12.1
Hz), 1.62-1.77 (m, 3H), 1.53 (s, 3H), 1.46 (m, 1H), 1.33-1.22
(m, 1H), 1.25 (s, 3H), 1.20 (s, 3H); 13C NMR δ 182.5, 171.9,
112.4, 87.2, 41.6, 40.1, 36.5, 29.8, 24.3, 24.2, 19.6. The spectral
data were similar with those reported.3a
Cr ysta llogr a p h ic Da ta for 4d . X-ray diffraction analysis
on 4d was carried out on a Siemens SMART CCD diffracto-
meter at 120 K. The structure of 4d (C18H22O5S, MW 350.44
amu) was determined from an orthorhombic crystal of dimen-
sions 0.4 × 0.3 × 0.2 mm3 (space group P212121), with unit
cell a ) 8.6904(2) Å, b ) 9.7113(2) Å, c ) 21.2082(4) Å, V )
1789.87 Å.3 It has four molecules per cell, Dx ) 1.30 g cm-3
,
µ ) 0.20 mm-1
reflections with I > 3σ(I), Rw ) 0.035.
. Mo KR radiation (λ ) 0.71073 Å). 4335
Ack n ow led gm en t. Thanks are expressed to Danish
National Science Foundation for support.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR and
IR spectra, chiral GC data, and X-ray materials (31 pages).
This material is contained in libraries on microfiche, im-
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(R)-4,4,7a -Tr im et h yl-5,7a -d ih yd r ob en zofu r a n -2(4H )-
on e, (R)-Actin id iolid e (2) via Alcoh ol 4b. (CF3SO2)2O (92
J O971528Y