An enantioselective route to paeonilactone A via palladium- and copper- catalyzed reactions

Article abstract of DOI:10.1021/jo991787i

We herein report on a formal total synthesis of paeonilactone A involving palladium-, copper-, and enzyme-catalyzed reactions starting from 1,3-cyclohexadiene. The key step in the synthesis, a palladium(II)-catalyzed 1,4-oxylactonization of a conjugated diene, simultaneously introduces two of the oxygen substituents required for the target molecule. The synthesis also includes our recently developed copper(I)-catalyzed cross-coupling reaction between dienyltriflates with Grignard reagents, introducing one of the methyl groups present in the target molecule. This new approach toward paeonilactone A allows complete control of all four stereogenic centers and is the first enantioselective route toward paeonilactone A starting from an achiral substrate.

Full text of DOI:10.1021/jo991787i

2122
J . Org. Chem. 2000, 65, 2122-2126
An En a n tioselective Rou te to P a eon ila cton e A via P a lla d iu m - a n d
Cop p er -Ca ta lyzed Rea ction s
Catrin J onasson,† Magnus Ro¨nn,*,‡,§ and J an-E. Ba¨ckvall*,†
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden, and Department of Organic Chemistry, University of Uppsala, Box 531,
SE-751 21 Uppsala, Sweden
Received November 17, 1999
We herein report on a formal total synthesis of paeonilactone A involving palladium-, copper-, and
enzyme-catalyzed reactions starting from 1,3-cyclohexadiene. The key step in the synthesis, a
palladium(II)-catalyzed 1,4-oxylactonization of a conjugated diene, simultaneously introduces two
of the oxygen substituents required for the target molecule. The synthesis also includes our recently
developed copper(I)-catalyzed cross-coupling reaction between dienyltriflates with Grignard reagents,
introducing one of the methyl groups present in the target molecule. This new approach toward
paeonilactone A allows complete control of all four stereogenic centers and is the first enantiose-
lective route toward paeonilactone A starting from an achiral substrate.
In tr od u ction
Paeonilactone A (1), B (2), and C (3) (Figure 1) are some
of the compounds isolated from paeony root, the root of
Paeonia Albiflora Pallas.1 This root has been extensively
used in Chinese and J apanese herbal medicine for
treatment of abdominal pain and syndromes such as
stiffness of abdominal muscles.2 Moreover, paeonilactone
C has been proven to suppress both directly and indi-
rectly stimulated muscle twitching of sciatic nerve-
sartorius muscle preparations from frogs.3 Several syn-
thetic approaches toward paeonilactones have been
published in racemic3 as well as enantioselective2,4,5
forms. However, all of the enantioselective routes used
a chiral pool approach. Thus, an enantioselective route
toward paeonilactones starting from achiral substrates
would therefore be a novel contribution in this area of
research.
F igu r e 1. Paeonilactone A-C, isolated from paeony root.
previously described the use of these reactions in the
synthesis of heterocyclic natural products.7,8 Recently, we
described an application of the Pd(II)-catalyzed lacton-
ization in the formal total synthesis of paeonilactone A
(1) and B (2) using the chiral pool approach starting from
commercially available S-(+)-carvone.5
We now report a novel route toward paeonilactone A
(1), which is based on readily available (1R,4S)-4-bis-
(carbomethoxy)-2-cyclohexenol (4) as starting material.
This substrate is obtained in an enantioselective manner
from 1,3-cyclohexadiene via a combination of palladium-
and enzyme-catalyzed reactions (Scheme 1) and has
earlier been used in the synthesis of chiral lactones.9 A
similar approach has also been employed for the synthe-
sis of chiral amino alcohols.10
Our retrosynthetic analysis (Scheme 2) denotes the
usefulness of 4 as starting material in the synthesis of
paeonilactone A. Oxidation of 4, MeLi addition to the
resulting enone, acylation of the tertiary alcohol, and
subsequent Pd(0)-catalyzed allylic elimination yielding
5 would be a possible reaction sequence to introduce the
C-10 methyl group11 and the 1,3-diene necessary for the
The 1,4-oxidation of 1,3-dienes developed in our labo-
ratories has proven to be an efficient process for the
synthesis of substituted alkenes.6 These 1,4-additions are
usually highly regio- and stereoselective, and we have
† Stockholm University.
‡ University of Uppsala.
§ Present address: Dr. Magnus Ro¨nn, Roche Colorado Corporation,
2075 N 55th Street, Boulder, CO, 80301.
(1) Hayashi, T.; Shinbo, T.; Shimizu, M.; Arisawa, M.; Morita, N.;
Kimura, M.; Matsuda, S.; Kikuchi, T. Tetrahedron Lett. 1985, 26, 3699.
(2) Hatakeyama, S.; Kawamura, M.; Shimanuki, E.; Takano, S.
Tetrahedron Lett. 1992, 33, 333.
(3) (a) Richardson, D. P.; Carr, P. W.; Cumming, J . N.; Harbison,
W. G.; Raoof, N. D.; Sanders, M. S.; Shin, E.; Smith, T. E.; Wintner, T.
H. Tetrahedron Lett. 1997, 38, 3817. (b) Richardson, D. P.; Smith, T.
E.; Lin, W. W.; Kiser, C. N.; Mahon, B. R. Tetrahedron Lett. 1990, 31,
5973.
(4) (a) Kadota, S.; Takeshita, M.; Makino, K.; Kikuchi, T. Chem.
Pharm. Bull. 1989, 37, 843. (b) Hatakeyama, S.; Kawamura, M.;
Takano, S.; Irie, H. Tetrahedron Lett. 1994, 35, 7993. (c) Hatakeyama,
S.; Kawamura, M.; Mukugi, Y.; Irie, H. Tetrahedron Lett. 1995, 36,
267.
(5) Ro¨nn, M.; Andersson, P. G.; Ba¨ckvall, J . E. Acta Chem. Scand.
1998, 52, 524.
(6) (a) Ba¨ckvall, J . E. In The Chemistry of Functional Groups:
Polyenes and Dienes, Patai, S., Rappoport, Z., Eds. Wiley: NewYork,
1996; pp 653-682. (b) Ba¨ckvall, J . E. Palladium-Catalyzed 1,4-
Additions to Conjugated Dienes. Review in Metal-catalyzed Cross
Coupling Reactions; Stang, P., Diederich, F., Eds. VCH: Weinham,
1998; pp 339-382.
(7) (a) Tanner, D.; Selle´n, M.; Ba¨ckvall, J . E. J . Org. Chem. 1989,
54, 3374. (b) Ba¨ckvall, J . E.; Andersson, P. G.; Stone, G. B.; Gogoll, A.
J . Org. Chem. 1991, 56, 2988.
(8) Andersson, P. G.; Ba¨ckvall, J . E. Synthesis of Heterocyclic
Natural Products via Regio- and Stereocontrolled Palladium-Catalysed
Reactions. Review in Advances in Heterocyclic Natural Product
Synthesis; Pearson, W. H., Ed.; J AI Press: Greenwich, CT, 1996; Vol.
3, pp 179-215.
(9) Ba¨ckvall, J . E.; Gatti, R.; Schink, H. E. Synthesis 1993, 343.
(10) Gatti, R. G. P.; Larsson, A. L. E.; Ba¨ckvall, J . E. J . Chem. Soc.,
Perkin Trans. 1 1997, 577.
(11) Numbering taken from ref 4a.
10.1021/jo991787i CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/31/2000

Enantioselective Route to Paeonilactone A
J . Org. Chem., Vol. 65, No. 7, 2000 2123
Sch em e 1
Sch em e 3a
Sch em e 2. Retr osyn th etic An a lysis of
P a eon ila cton e A
a
E ) CO2Me. (a) CrO3/pyridine, CH2Cl2, 84%; (b) (i) 2.3 equiv
of LDA, THF, (ii) 1.4 equiv of Tf2NPh, THF, 70%; (c) CuI (cat.),
MeMgBr, THF, 96%; (d) NaCN, wet DMSO; (e) KOH, MeOH, 71%
from 5.
nation gave a mixture of three different dienes with the
desired isomer 5 only in low yield.13 Optimization of this
reaction was unsuccessful, and instead a new method for
the synthesis of 2-substituted 1,3-dienes was developed.14
Transformation of 9 to the triflate 10 was done using
standard procedures,15 and subsequent application of our
newly developed copper-catalyzed Grignard coupling
between 10 and MeMgBr smoothly furnished the desired
2-methyl-1,3-diene 5 in excellent yield. The 1,3-diene acid
11 needed for the key lactonization step was then
obtained from 5 in 71% overall yield via a Krapcho
decarboxylation16 and subsequent hydrolysis.
The lactonization of diene acid 11 was initially per-
formed using the recently developed palladium-catalyzed
cis-1,4-oxylactonization employing oxygen as a reoxidant
and o-chlorobenzoic acid as an external nucleophile.17
Unfortunately, this cis-oxylactonization did not perform
consistently using 11 as substrate, and instead we had
to revert to the trans-oxylactonization developed in our
group.18 Using this method, we were able to isolate
lactone 12a in 70% yield (Scheme 4). For the introduction
of the C-1 oxygen (vide infra), however, we now had to
invert the C-6 oxygen. This was done by hydrolysis of
the ester in 12a (95% yield) and subsequent Mitsunobu
reaction19 (80% yield) providing ester 6a . Stereoselective
introduction of a methyl group in the R-position of a
lactone via trapping of the enolate is well-known,20 and
in this way 6a was alkylated using 1.2 equiv of LDA
followed by alkylation with MeI. Alkylation of 6a pro-
ceeded with complete stereoselectivity; however, 7 was
isolated as a mixture of 7R- and 7S-isomers due to
epimerization of the methyl group during the hydrolysis
key lactonization step. After Krapcho decarboxylation
and saponification, a Pd(II)-catalyzed 1,4-oxylactoniza-
tion could be carried out providing lactone 6, which would
serve as the key step in this synthesis. In this step, the
C-3 and C-6 oxygens are simultaneously introduced, of
which the latter will serve as a directing group for the
introduction of the C-1 oxygen. We envisioned introduc-
ing the second (C-9) of the two methyl groups absent in
4 by deprotonation of the lactone 6 followed by alkylation
of the corresponding enolate using MeI. Alcohol 7 (as a
7-Me epimeric mixture) has earlier been used as an
intermediate in a route toward paeonilactone A.4a To
introduce the C-1 oxygen, Kikuchi and co-workers treated
7 with Cl3CCHO and I2 to form a trichloroacetal. Sub-
sequent reduction of the iodide, followed by hydrolysis
of the acetal, gave diol 8 as an epimeric mixture of 7R-
and 7S-methyl isomers. However, the introduction of the
C1 oxygen in that procedure was only performed in 50%
yield, which substantially lowered the overall yield. We
visualized replacing this somewhat low-yielding pathway
by a hydroxyl-directed epoxidation of the allylic alcohol
7, followed by selective opening of the epoxide by a
nucleophile (e.g., I-). Subsequent reduction of the nu-
cleophile and oxidation of the secondary alcohol would
provide paeonilactone A.
(12) Kazlauskas, R. J .; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J . Org. Chem. 1991, 56, 2656.
(13) The two other isomers being the 1,4-substituted 1,3-diene
(major product) and the 1,3-diene having an exo cyclic double bond.
(14) Karlstro¨m, A. S. E.; Ro¨nn, M.; Thorarensen, A.; Ba¨ckvall, J . E.
J . Org. Chem. 1998, 63, 2517.
(15) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(16) Krapcho, A. P. Synthesis 1982, 805.
(17) Ro¨nn, M.; Andersson, P. G.; Ba¨ckvall, J . E. Acta Chem. Scand.
1997, 51, 773.
Resu lts a n d Discu ssion
Allylic alcohol 4 was oxidized to the corresponding
unsaturated ketone 9 in 84% yield employing CrO3/
pyridine (Scheme 3).12 Although the MeLi addition to 9
and acetylation of the corresponding tertiary alcohol was
successful, the subsequent Pd(0)-catalyzed allylic elimi-
(18) (a) Ba¨ckvall J . E.; Granberg, K. L.; Andersson, P. G.; Gatti, R.;
Gogoll, A. J . Org. Chem. 1993, 58, 5445. (b) Ba¨ckvall, J . E.; Andersson,
P. G.; Vågberg, J . O. Tetrahedron Lett. 1989, 30, 137.
(19) Mitsunobu, O. Synthesis 1981, 1.
(20) A recent example: Tanner, D.; Andersson, P. G.; Tedenborg,
L.; Somfai, P. Tetrahedron 1994, 50, 9135.

2124 J . Org. Chem., Vol. 65, No. 7, 2000
J onasson and Ro¨nn
Sch em e 4a
Sch em e 5a
a
(a) m-CPBA, CH2Cl2, -6 °C, 70%; (b) NH4I, LiClO4, CH3CN,
78%; (c) Bu3SnH, PhH, rflx, 97%.
a
(a) Pd(OAc)2 (cat.), p-benzoquinone, PhCO2H, acetone, 70%;
(b) MeOH, K2CO3, 95%; (c) PPh3, DEAD, o-ClC6H4CO2H, 80%; (d)
(i) 2.2 equiv of LDA, (ii) MeI, THF, 82%.
forded iodohydrin 14 in 78% yield. The final steps include
a tributyltin hydride reduction of 14 giving the diol 8.28
The ee of 8 was determined to be 98% by 1H NMR
analysis of the corresponding Mosher ester.29 The trans-
formation of diol 8 to paeonilactone A in more than 74%30
yield has been previously described in the literature.2
of the ester group. Unfortunately, attempts to suppress
this isomerization by modifying the conditions for the
hydrolysis proved to be unsuccessful. Because of the
problem with eperimization during the hydrolysis of the
ester group, we decided to reverse the introduction of the
R-methyl and the hydrolysis step. Thus, hydrolysis of 6a
to 6b (95% yield) followed by treatment of 6b with 2.2
equiv of LDA and subsequent alkylation of the enolate
with MeI led to the formation of methyl lactone 7 in 82%
yield (>95% of the desired isomer).
Con clu sion s
We have developed an efficient enantioselective route
toward paeonilactone A starting from commercially
available 1,3-cyclohexadiene. The synthesis utilizes a
combination of palladium-, enzyme-, and copper-cata-
lyzed reactions. The key step is the highly stereo- and
regioselective palladium (II)-catalyzed oxylactonization
reaction demonstrating its utility in the total synthesis
of natural products. Although a large body of enantiose-
lective synthetic routes toward paeonilactones is present
in the literature, all utilize the chiral pool approach. To
our knowledge an enantioselective approach based on
achiral material has not yet been reported, thus making
our organotransition metal approach both competitive
and attractive.
Epoxidation of 7 was more complicated than initially
anticipated. Employing tBuOOH in combination with
both catalytic and stoichiometric amounts of Ti(O-i-Pr)4,21
or using CF3CO3H,22 gave no or very low amounts of the
desired epoxide. The use of VO(acac)2 in combination with
tBuOOH23 gave mainly the unsaturated ketone as a
product. Using 1.5 equiv of m-CPBA in CH2Cl2 at 0 °C
gave 60% isolated yield of the desired epoxide 13 with
the remainder of the mass balance being the anti epoxide.
Increasing the amount of m-CPBA or changing the
solvent to benzene or CCl4 gave no improvement. Per-
forming the reaction at -15 °C resulted in a much
improved ratio between the syn- and anti-epoxide, but
the reaction was not complete after 72 h. Finally, a
reasonable reaction time in combination with good se-
lectivity could be achieved by using 1.3 equiv of m-CPBA
and performing the reaction at -6 °C (Scheme 5). This
protocol made it possible to isolate the desired epoxide
13 in 70% yield after 48 h. Opening of the epoxide was
equally intricate. Most of the attempts made use of I- as
the nucleophile, which renders a group that is easy to
remove after the reaction. Iodine in combination with Ti-
(O-i-Pr)4 as the Lewis acid24 gave low yield of the desired
Exp er im en ta l Section
1
Gen er a l P r oced u r es. H NMR (400 or 300 MHz) and 13C
NMR (100 or 75 MHz) spectra were recorded on a Varian
Mercury spectrometer. IR spectra were obtained using a
Perkin-Elmer 1600 FT-IR instrument, and the samples were
examined as thin films or CDCl3 solutions. Only the strongest/
structurally most important peaks (cm-1) are listed. Merck
silica gel 60 (240-400 mesh) was used for flash chromatog-
raphy, and analytical thin-layer chromatography was per-
formed on Merck precoated silica gel 60-F254 plates. Melting
points (mp) are uncorrected. Elemental analyses were per-
formed by Analytische Laboratorien, Lindlar, Germany. Ana-
lytical high-pressure liquid chromatoghraphy (HPLC) was
performed on a Waters liquid chromatograph using a Daicel
Chiracel OD-H column. Unless otherwise noted, all material
was obtained from commercial suppliers and used without
further purification. All reactions were performed at room
temperature unless otherwise noted. Tetrahydrofuran (THF)
and diethyl ether (Et2O) were freshly distilled from sodium
benzophenone ketyl prior to use. Methylene chloride (CH2Cl2)
was distilled from calcium hydride. cis-(1R,4S)-4-[Bis(methoxy-
carbonyl)methyl]-2-cyclohexanol (4)9 was prepared according
26
iodohydrin 14 as did MgI2.25 Iodine and PPh3 in CH2Cl2
gave approximately a 40% yield of 14 and even better
results were achieved using ammonium iodide in aceto-
nitrile in the presence of LiClO4.27 This procedure af-
(21) (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102,
5976. (b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(22) McKittrick, B. A.; Ganem, B. Tetrahedron Lett. 1985, 26, 4895.
(23) Lempers, H. E. B.; Ripolle`s i Garcia, A.; Sheldon, R. A. J . Org.
Chem. 1998, 63, 1408.
(27) Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. Tetrahedron 1992,
48, 3805.
(28) Kuivila, H. G. Synthesis 1970, 499.
(24) Alvarez, E.; Nun˜ez, M. T.; Martin, V. S. J . Org. Chem. 1990,
55, 3429.
(25) Bonini, C.; Righi, G. Tetrahedron 1992, 48, 1531.
(26) Palumbo, G.; Ferreri, C.; Caputo, R. Tetrahedron Lett. 1983,
24, 1307.
(29) A sample with 80% ee resulting from incomplete enzyme
hydrolysis was used as a comparison.
(30) The 75% yield also includes hydrolysis of an acetal.

Enantioselective Route to Paeonilactone A
J . Org. Chem., Vol. 65, No. 7, 2000 2125
to literature procedures and had spectral data in accordance
with those previously reported.
(MgSO4), and concentrated in vacuo to give 1.06 g (80%) of
the monoester which was used without further purification.
cis-(1R,4S)-4-[Bis(m et h oxyca r b on yl)m et h yl]-2-cyclo-
h exa n ol (4). The ee for 4 was determined to 95% by HPLC
analysis (hexane/iPrOH 95:5; retention times 33.9, 38.5 min);
The product from the Krapcho reduction (1.0 g, 6.0 mmol)
was dissolved in MeOH:H2O 5:1 (25 mL). KOH (1.0 g, 18 mmol)
was added, and the mixture was stirred for 4 h. The solvent
was evaporated, and H2O (25 mL) was added. The basic layer
was subsequently extracted with pentane:Et2O 1:1, acidified
to pH ) 1 (concentrated HCl), and extracted with EtOAc. The
combined organic layers were washed with H2O, dried (Mg-
[R]24 +23 (c ) 0.6, CHCl3).
D
(S)-4-[Bis(m et h oxyca r b on yl)m et h yl]-2-cycloh exen -1-
on e (9). Chromium trioxide (36.7 g, 0.36 mol) was added at 0
°C to a stirred solution of dry pyridine (57.9 g, 0.74 mol) in
dry CH2Cl2 (600 mL) under argon. After 30 min of stirring at
room temperature, a solution of the alcohol 4 (14.0 g, 0.061
mol) in dry CH2Cl2 (22 mL) was added to the dark red-brown
solution. A black tarry substance precipitated after a few
minutes. The flask was equipped with a drying tube, and the
mixture was stirred for 24 h at room temperature. The CH2-
Cl2 solution was decanted, and the residue was extracted with
alternating portions of ethyl ether and saturated aqueous
NaHCO3 (3 × 300 mL and 2 × 250 mL respectively). All
extracts were combined with the CH2Cl2 solution and shaken.
The aqueous phase was removed and extracted twice with
ethyl ether. The combined organic extracts were washed with
saturated aqueous sodium bicarbonate, 2% aqueous sulfuric
acid, saturated aqueous sodium bicarbonate, and brine. The
resulting organic phase was dried over MgSO4 and concen-
trated, yielding 11.6 g (84%) of a colorless oil. The ee was
determined by HPLC analysis (hexane/iPrOH 98.5:1.5; reten-
SO4), and evaporated to give 0.86 g (95%) of 11 as a colorless
1
oil. [R]22 -185 (c ) 0.9, CHCl3). H NMR (400 MHz, CDCl3):
D
δ 10.32 (br s, COOH), 5.82 (app dt, J ) 9.7, 1.6 Hz, 1H), 5.74
(dd, J ) 9.7, 4.0 Hz, 1H), 5.44 (m, 1H), 2.70 (m, 1H), 2.44 (dd,
J ) 15.6, 7.2 Hz, 1H), 2.38 (dd, J ) 15.6, 7.8 Hz, 1H), 2.31 (m,
1H), 2.00 (m, 1H), 1.73 (app q, J ) 1.9 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 178.9, 131.2, 129.1, 128.6, 119.3, 38.1, 29.6,
28.5, 21.0. IR (CHCl3): 1703 cm-1
.
Ben zoic Acid (3a R,5S,7a R)-6-Meth yl-2-oxo-2,3,3a ,4,5,-
7a -h exa h yd r oben zofu r a n -5-yl Ester (12a ). Diene 11 (2.0
g, 13.2 mmol) was added over a 16 h period to a stirred solution
of Pd(OAc)2 (0.21 g 0.92 mmol), p-benzoquinone (3.12 g, 28.9
mmol), and benzoic acid (2.84 g, 105.2 mmol) in acetone (83
mL). After an additional reaction time of 24 h, the solvent was
evaporated and Et2O (150 mL) was added. The organic fraction
was washed with 2 M NaOH (5 × 50 mL) (until the organic
phase was light yellow) and brine. Evaporation of the solvent
and flash chromatography using Et2O/pentane (3:1) as eluent
afforded lactone 12a (2.51 g, 70%) as white crystals. The ee
was determined by HPLC analysis (hexane/iPrOH 75:25;
retention times 24.6, 28.4 min) to be 92%. Recrystallization
tion times 120.7 and 127.3 min) to be 95%; [R]24 -52 (c )
D
1.1, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.89 (ddd, J ) 10.4,
2.6, 1.7 Hz, 1H), 6.02 (ddd, J ) 10.4, 2.7, 0.8 Hz, 1H), 3.77 (s,
3H), 3.76 (s, 3H), 3.49 (d, J ) 7.8 Hz, 1H), 3.22 (m, 1H), 2.52
(dt, J ) 17.0, 4.7 Hz, 1H), 2.41 (ddd, J ) 17.0, 12.6, 4.9 Hz,
1H), 2.11 (m, 1H), 1.84 (ddt, J ) 12.6, 10.2, 4.7 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 198.3, 168.0, 167.9, 150.2, 130.1,
from EtOAc/ hexane gave 99% ee. [R]22 -213 (c ) 0.53,
D
CHCl3). mp 90-92 °C. 1H NMR (300 MHz, CDCl3): δ 8.02 (m,
2H), 7.58 (m, 1H), 7.45 (m, 2H), 5.92 (dq, J ) 4.2, 1.5 Hz, 1H),
5.52 (t, J ) 3.9 Hz, 1H), 4.90 (m, 1H), 2.90-2.76 (m, 2H), 2.34
(m, 1H), 2.07 (dt, J ) 14.4, 3.9 Hz, 1H), 1.79-1.90 (m, 1H),
1.88 (app t, J ) 1.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
175.7, 165.9, 139.4, 133.2, 129.8, 129.5, 128.4, 122.5, 75.5, 68.6,
35.3, 29.8, 29.4, 21.2. IR (CHCl3): 1771, 1716 cm-1. Anal. Calcd
for C16H16O4: C, 70.56; H, 5.93; Found: C, 70.40; H, 5.84.
55.0, 52.8, 52.7, 36.8, 36.0, 27.0. IR (CDCl3): 1734, 1681 cm-1
.
(S)-5-Dim eth ylm a lon a te-1,3-cycloh exa d ien e-2-yl Tr i-
fla te (10). A solution of LDA (77.9 mmol) was prepared by
adding n-butyllithium (48.6 mL of a 1.6 M solution in hexane,
77.9 mmol) to diisopropylamine (10.8 mL, 82.4 mmol) in THF
(94 mL) at 0 °C under argon. The resulting solution was cooled
to -78 °C, and ketone 9 (8.10 g, 35.8 mmol) in THF (10 mL)
was added dropwise. The resulting suspension was rapidly
stirred for 3 h at -78 °C, and then Tf2NPh (17.9 g, 50.2 mmol)
in THF (60 mL) was added. The mixture was allowed to warm
to 0 °C over 2 h, and the reaction was completed after stirring
at 4 °C for 16 h. The solvent was evaporated, and the crude
material was dissolved in CH2Cl2 and washed with water. The
organic layer was dried (MgSO4) and concentrated in vacuo.
The crude product was purified by flash chromatography
(pentane:Et2O 4:1) to give 9.06 g (71%) of 10 as a pale yellow
unstable oil. 1H NMR (300 MHz, CDCl3): δ 5.99 (ddd, J ) 10.2,
4.1, 0.8 Hz, 1H), 5.90 (app dt, J ) 10.2, 2.0 Hz, 1H), 5.68 (ddt,
J ) 4.8, 2.0, 0.8 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.52, (d, J
) 8.7 Hz, 1H), 3.15 (dddt, J ) 9.7, 8.7, 4.1, 1.7, 1 H), 2.56
(ddd, J ) 17.7, 8.7, 4.8 Hz, 1H), 2.34 (ddd, J ) 17.7, 9.7, 4.8
Hz, 1H). 13C NMR (75.4 MHz, CDCl3): δ 168.0, 167.9, 145.2,
132.0, 122.0, 118.5 (q, J (13C,19F) ) 320 Hz), 114.0, 53.6, 52.8,
52.7, 32.1, 25.6.
(3aR,5S,7aR)-5-Hydr oxy-6-m eth yl-3a,4,5,7a-tetr ah ydr o-
3H-ben zofu r a n -2-on e (12b). To 12a (1.41 g, 5.18 mmol) in
MeOH (32 mL) was added a catalytic amount of K2CO3 (0.073
g, 0.53 mmol). After 12 h, the solvent was removed in vacuo,
and the crude product was purified by flash chromatography
using Et2O/MeOH (gradient 100:0 to 95:5). The product was
isolated as white crystals (0.83 g, 95%). [R]22 -51 (c ) 1.0,
D
1
CHCl3); mp 70.5-72 °C; H NMR (300 MHz, CDCl3): δ 5.73
(app dq J ) 5.8, 1.5 Hz, 1H), 4.79 (m, 1 H), 4.10 (t, J ) 3.9 Hz,
1 H), 2.76-2.90 (m, 2H), 2.29 (m, 1H), 2.0 (br s OH), 1.91 (app
t, J ) 1,5 Hz, 3 H), 1.85 (dt, J ) 13.9, 3.9 Hz, 1H), 1.69 (m,
1H); 13C NMR (75.4 MHz, CDCl3): δ 176.3, 142.6, 119.9, 75.8,
66.3, 35.5, 32.8, 28.8, 21.2. IR (CHCl3): 3478, 1770 cm-1. Anal.
Calcd for C9H12O3: C, 64.25; H, 7.19; Found: C,64.01; H, 7.03.
2-Ch lor oben zoic Acid (3a R,5R,7a R)-6-Meth yl-2-oxo-
2,3,3a ,4,5,7a -h exa h yd r oben zofu r a n -5-yl Ester (6a ). To a
solution of 12b (0.38 g, 2.27 mmol), triphenylphosphine (1.19
g, 4.55 mmol), and o-chlorobenzoic acid (0.71 g, 4.55 mmol) in
THF (4.2 mL) under argon was added DEAD (0.79 g, 4.55
mmol) over a period of 30 min. The reaction mixture was then
stirred for 12 h and concentrated in vacuo. The residue was
dissolved in Et2O (20 mL) and washed with water and aqueous
NaHCO3. Drying (MgSO4) and evaporation gave an oily
residue. Purification by flash chromatography (1:4 pentane/
EtOAc) gave 6a as white crystals (0.55 g, 80%). The ee was
determined by HPLC analysis (hexane/i-PrOH 98:2; retention
(S )-5-Dim e t h ylm a lon a t e -2-m e t h yl-1,3-cycloh e xa d i-
en e (5). To a stirred solution of CuI (0.033 g, 0.17 mmol) and
10 (2.5 g, 6.98 mmol) in THF (23 mL) at 0 °C was added
MeMgBr in Et2O (6.98 mL 20.9 mmol). After 20 min, the
reaction was quenched by addition of saturated aqueous NH4-
Cl. Et2O was added, the layers were separated, and the
aqueous layer was extracted with Et2O. The combined organic
layers were subsequently washed with brine, dried (MgSO4),
and evaporated. The crude mixture was purified by flash
chromatography using pentane:Et2O 4:1 as eluent to give 1.51
g (96%) of 5 as a colorless oil. Spectral data are consistent with
times 164.0, 170.9 min) to be 99%. [R]22 +25.2 (c ) 0.76,
D
MeOH). mp 64.5-67.5 °C. 1H NMR (400 MHz, CDCl3): δ 7.80
(ddd, J ) 7.8, 1.5, 0.6 Hz, 1H), 7.46 (m, 2H), 7.33 (ddd, J )
7.8, 6.7, 2.0 Hz, 1H), 5.81 (dq, J ) 3.9, 1.5 Hz, 1H), 5.62 (m,
1H), 4.83 (m, 1H), 2.77 (m, 2H), 2.51 (m, 1H), 2.22 (ddd, J )
13.2, 5.1, 4.3 Hz, 1H), 1.87 (app q, J ) 1.5 Hz, 3,H,), 1.82 (ddd,
J ) 13.2, 10.7, 8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
175.7, 165.2, 141.0, 133.8, 132.8, 131.21, 131.22, 129.6, 126.7,
121.5, 75.3, 70.3, 35.6, 31.7, 29.5, 19.5. IR (CHCl3): 1774,
those previously reported.14 [R]24 -150 (c ) 0.64, CHCl3).
D
((R)-4-Meth ylcycloh exa -2,4-d ien yl)a cetic Acid (11). A
mixture of 5 (1.8 g, 8.0 mmol), NaCN (1.97 g, 40 mmol), and
H2O (0.72 g, 40 mmol) in DMSO (25 mL) was heated to 60 °C
for 48 h. The solution was cooled, water (150 mL) was added,
and the aqueous layer was extracted with pentane:Et2O 7:3.
The combined organic layers were washed with water, dried

2126 J . Org. Chem., Vol. 65, No. 7, 2000
J onasson and Ro¨nn
1728.cm-1. Anal. Calcd for C16ClH15O4: C, 62.63; H, 4.933.
Found: C, 62.50; H, 4.93.
epoxide 13 (15 mg, 0.076 mmol) in acetonitrile (75 µL) was
treated with LiClO4 (12.1 mg, 0.11 mmol) and NH4I (16.4 mg,
0.11 mmol), and the resulting reaction mixture was stirred at
65 °C for 48 h under argon. The solution was bubbled with
argon a few times during the reaction time to get rid of NH3
that formed during the reaction. The solvent was evaporated,
and the crude material was purified by flash chromatography
using EtOAc:pentane (3:1) as eluent yielding 14 as a white
(3aR,5R,7aR)-5-Hydr oxy-6-m eth yl-3a,4,5,7a-tetr ah ydr o-
3H-ben zofu r a n -2-on e (6b). To 6a (0.21 g, 0.69 mmol) in
MeOH (1.32 mL) was added a catalytic amount of K2CO3 (9.5
mg, 0.069 mmol). After stirring 12 h at room temperature, the
solvent was removed and the crude product was purified by
flash chromatography using Et2O/MeOH (gradient 100:0 to 95:
5). The product was isolated as white crystals (0.10 g, 88%).
solid in 78% yield (19.2 mg). [R]21 +42.6 (c ) 0.38, MeOH).
D
1
1
[R]22 +7.9 (c ) 1.0, MeOH). mp 143.5-146 °C. H NMR (400
mp 152-156 °C. H NMR (400 MHz, CDCl3 + drops of CD3-
D
MHz, CDCl3): δ 5.66 (dq, J ) 4.2, 1.5 Hz, 1H), 4.73 (m, 1H),
4.13 (m, 1H), 2.78 (dd, J ) 17.4, 8.2 Hz, 1H), 2.61 (m, 1H),
2.45 (dd, J ) 17.4, 2.5 Hz, 1H), 2.03 (d, J ) 7.05 Hz, 1H), 2.02
(app dt, J ) 12.7, 4.8 Hz, 1H) 1.89 (app q, J ) 1.5 Hz, 3H),
1.52 (dt, J ) 12.7, 9.3 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 176.0, 145.6, 118.6, 76.0, 67.8, 36.4, 33.7, 32.4, 19.2. IR
(CHCl3): 3474, 1770 cm-1. Anal. Calcd for C9H12O3: C, 64.25;
H, 7.19. Found: C, 64.04; H, 7.20.
OD): δ 4.68 (dd, J ) 10.7, 7.6 Hz, 1H), 4.53 (d, J ) 10.7 Hz,
1H), 3.93 (app t, J ) 3.3 Hz, 1H), 3.19 (dq, J ) 12.6, 7.1 Hz,
1H), 2.07-2.17 (m, 2H), 1.88 (ddd, J ) 15.9, 6.8, 3.3 Hz, 1H),
1.27 (s, 3H), 1.19 (d, J ) 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3 + drops of CD3OD): δ 178.2, 82.7, 73.8, 71.9, 43.4, 41.7,
37.9, 26.3, 23.8, 13.1. IR (CDCl3): 3557, 1776 cm-1. Anal. Calcd
for C10H15IO4: C, 36.83 H, 4.63. Found: C, 36.75; H, 4.47.
(3R,3aR,5R,6S,7aR)-5,6-Dih ydr oxy-3,6-dim eth ylh exah y-
d r oben zofu r a n -2-on e (8). A solution of iodohydrin 14 (28 mg,
0.086 mmol), AIBN (0.5 mg, 3 `ımol) and tributyltin hydride
(0.030 mL, 0.11 mmol) in degassed benzene (1.5 mL) was
heated at reflux under argon for 4 h. The solvent was
evaporated and the crude material was purified by flash
chromatography (EtOAc:hexane, gradient 1:1 to 4:1) to give
compound 8 (16.7 mg, 97%) as white crystals. About 4% of an
isomeric byproduct contaminated the product. An analytical
pure sample was obtained after an additional flash chroma-
(3R,3a R,5R,7a R)-5-Hyd r oxy-3,6-d im eth yl-3a ,4,5,7a -tet-
r a h yd r o-3H-ben zofu r a n -2-on e (7). A solution of LDA (0.92
mmol) was prepared by adding n-butyllithium (0.57 mL of a
1.6 M solution in hexanes, 0.92 mmol) to diisopropylamine
(96.9 mg, 0.96 mmol) in THF (5.3 mL) at 0 °C under argon.
The resulting solution was cooled to -78 °C, and lactone 6b
(70.0 mg, 0.41 mmol) in THF (3 mL) was added dropwise. The
resulting suspension was rapidly stirred for 1.5 h. Freshly
distilled MeI (70.9 mg, 0.50 mmol) was added, and the solution
was stirred at -78 °C for 5 h. TsOH (95.1 mg, 0.50 mmol) was
then added, and the solution was allowed to warm to -30 °C.
Water was added, the aqueous phase was extracted with
EtOAc, and the combined organic layers were washed with
brine and dried (MgSO4). Evaporation followed by flash
chromatography (pentane:Et2O, 1:5) gave 7 (61.6 mg, 82%) as
white crystals. Conversion to the corresponding Mosher ester
and subsequent 1H NMR analysis showed that 7 was >98%
ee by comparison with a racemic sample. No traces of the other
isomer could be seen. Spectral data are consistent with those
tography (CH2Cl2:EtOH, 98:2). [R]21 +44 (c ) 0.22, CHCl3).
D
mp 144-148 °C (amorphous material). 1H NMR spectral data
are consistent with those previously reported.4a 1H NMR (400
MHz, CDCl3): δ 4.58 (ddd, J ) 7.8, 6.1, 5.6 Hz, 1H), 3.57 (app
q, J ) 4.9 Hz, 1H), 2.88 (app quintet, J ) 7.3 Hz, 1H), 2.32 (d,
J ) 4.9, OH), 2.20 (dd, J ) 14.2, 7.8 Hz, 1H), 2.17 (ddd, J )
12.3, 7.8, 6.1 Hz, 1H), 2.02 (br s, OH), 1.86 (m, 3H), 1.28 (s,
3H), 1.26 (d, J ) 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
179.0, 76.0, 72.8, 71.5, 40.6, 40.5, 37.1, 29.0, 25.3, 13.7.
Conversion to the corresponding Mosher ester and subse-
previously reported.5 [R]27 +58 (c ) 0.69, MeOH).
quent 1H NMR analysis showed that 8 was 98% ee by
D
(1a R,2R,3a R,4R,6a S)-2-Hyd r oxy-1r,4-d im eth ylh exa h y-
d r o-1,6-d ioxa cyclop r op a [e]in d en -5-on e (13). To a stirred
solution of 7 (100 mg, 0.55 mmol) in CH2Cl2 (1.45 mL) at -6
°C was added m-CPBA (123.2 mg, 0.71 mmol) in small
portions. The reaction was stirred for 48 h at -6 °C. The
solvent was evaporated, and the crude mixture was purified
by flash chromatography using EtOAc:pentane (gradient 3:1
to 1:0) to give 13 (74.8 mg, 70%) as white crystals. [R]21D +33.6
1
comparison with a sample that was ca. 80% ee. The H NMR
for the enantiopure ester revealed a triplet at 4.99, a broad
quartet at 3.52, and a quintet at 2.46 ppm whereas the ca.
80% ee ester had these signals and in addition a triplet at 5.02,
a broad quartet at 3.56, and a quintet at 2.35 ppm.
Ackn owledgm en t. Financial support from the Swed-
ish Natural Research Council and the Swedish Research
Council for Engineering Sciences is gratefully acknowl-
edged.
1
(c ) 0.45, CHCl3). mp 127 °C. H NMR (400 MHz, CDCl3): δ
4.77 (dd, J ) 7.6, 3.3 Hz, 1H), 3.94 (ddd, J ) 10.1, 8.8, 4.9 Hz,
1H), 3.38 (d, J ) 3.3 Hz, 1H), 2.46 (dq, J ) 7.5, 4.2 Hz, 1H),
2.16 (m, 1H), 1.83 (ddd, J ) 13.0, 6.2, 4.9 Hz, 1H), 1.66 (ddd,
J ) 13.0, 11.4, 10.1 Hz, 1H), 1.63 (br d, J ) 8.8 Hz, OH), 1.48
(s, 3H), 1.26 (d, J ) 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 178.7, 74.4, 69.2, 61.9, 59.8, 41.8, 40.1, 31.9, 18.5, 15.9. IR
(CHCl3): 3578, 1772 cm-1. Anal. Calcd for C10H14O4: C, 60.59;
H, 7.11. Found: C, 60.34; H, 6.97.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
1
spectra for compounds 9 to 11. H NMR for pertinent regions
of the spectra for the Mosher ester of enantiopure and 80% ee
diol 8. This material is available free of charge via the Internet
at http://pubs.acs.org.
(3R ,3a R ,5R ,6R ,7R ,7a S )-5,6-Dih yd r oxy-7-iod o-3,6-d i-
m et h ylh exa h yd r ob en zofu r a n -2-on e (14). A solution of
J O991787I