Short asymmetric synthesis of (+)-α-curcumene and (+)-xanthorrhizol

Full text of DOI:10.1021/jo970429h

J . Org. Chem. 1997, 62, 5219-5221
5219
Sch em e 1
Sh or t Asym m etr ic Syn th esis of
(+)-r-Cu r cu m en e a n d (+)-Xa n th or r h izol
A. I. Meyers* and Diana Stoianova
Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523-1872
Received March 7, 1997
The phenolic sesquiterpenoid hydrocarbon, R-cur-
cumene, a constituent of a large number of essential oils,
was first detected in the essential oil of the rhizomes of
Curcuma aromatica Salisb. The absolute configuration
of R-curcumene ((+)-8) was determined1 to be S, and an
[R]D +45.1° was observed for pure (+)-R-curcumene.2 (-)-
Xanthorrhizol (10), a compound structurally related to
R-curcumene, was isolated from the rhizomes of Curcuma
xanthorrhiza Roxb.3 The S-configuration was assigned
to (+)-xanthorrhizol through correlation with (+)-ar-
turmerone 11 of known S-configuration.4
Sch em e 2
side product of the reaction was a polymer, arising from
subsequent addition of the initially formed anion to the
starting oxazoline. Its amount depended on the steric
bulk of R and the order of addition of the reagents with
the optimal yield obtained by slow addition of the
oxazoline to an excess of the organolithium reagent. This
sequence was employed in a short asymmetric synthesis
of (+)-ar-turmerone,9 but the yield in the key asymmetric
step (addition of p-tolyllithium to 2-propenyl-substituted
oxazoline) was only 33% due to the simultaneous produc-
tion of polymeric material.
Several syntheses of nonracemic R-curcumene have
been reported,5 while only racemic syntheses6 of xanthor-
rhizol have been described. To the best of our knowledge,
the only synthesis leading to nonracemic material is the
conversion of (+)-ar-turmerone (11) into (+)-xanthor-
rhizol ((+)-10)4 and of (-)-parvifoline (12) into (-)-
xanthorrhizol.7
We now describe a short, efficient asymmetric synthe-
sis of the title compounds, based upon highly stereose-
lective addition of organolithium reagents to chiral R,â-
unsaturated oxazolines.8 It was previously observed that
addition of organolithium reagents to alkenyl oxazolines
proceeded in a conjugated manner with a high degree of
selectivity (Scheme 1).
In the present route to the title compounds, the
starting chiral oxazoline 1 was prepared from crotonic
acid, which was converted into the mixed anhydride10
upon treatment with ClCO2Et (Scheme 2).
The chemical yields of the products were modest to
Treatment of this compound with tert-leucinol and
cyclization of the resulting amide with SOCl2 gave 1 in
54% yield. The conjugate addition was carried out by
slow addition of the oxazoline 1 in THF to a solution of
the corresponding aryllithium reagent in THF at -78 °C.
The yields of the conjugate addition relied heavily on the
method of formation of the lithium reagent. The best
yield of 2 was achieved with a solution of lithium reagent,
generated by treatment of p-bromotoluene with excess
lithium (suspension in mineral oil) in Et2O and filtered
through a plug of glass wool, which was packed in the
syringe (72% isolated yield of 2). Due to the low solubility
of (o-methoxy-p-tolyl)lithium in Et2O, this reagent was
prepared in situ by treatment of the corresponding
good depending on the substituent R and R1. A major
(1) Honwad, V. K.; Rao, A. S. Tetrahedron 1965, 21, 2593.
(2) Damodaran, N. P.; Dev, S. Tetrahedron 1968, 24, 4113.
(3) Rimpler, H.; Haensel, R.; Kochendoerfer, L. Z. Naturforsch. 1970,
25B, 995.
(4) J ohn, T. K.; Krishna Rao, G. S. Indian J . Chem. 1985, 24B, 35.
(5) (a) Asaoka, N.; Shima, K.; Fujii, N.; Takei, H. Tetrahedron 1988,
44, 4757. (b) Takano, S.; Sugihara, T.; Samizu, K.; Akiyama, M.;
Ogasawara, K. Chem. Lett. 1989, 1781. (c) Takano, S.; Yanase, M.;
Sugihara, T.; Ogasawara, K. J . Chem. Soc., Chem. Commun. 1988,
1536. (d) Honda, Y.; Sakai, M.; Tsuchihashi, G. Chem. Lett. 1985, 1153.
(e) Tamao, K.; Hayashi, T.; Matsumoto, H.; Yamamoto, H.; Kumada,
M. Tetrahedron Lett. 1979, 2155.
(6) (a) Mane, R. B.; Krishna Rao, G. S. Indian J . Chem. 1974, 12,
938. (b) Rane, R. K.; Desai, U. V.; Mane, R. B. Indian J . Chem. 1987,
26B, 572. (c) Nagumo, S.; Irie, S.; Hayashi, K.; Akita, H. Heterocycles
1996, 43, 1175.
(7) Garcia, E. G.; Mendoza, V.; Guzman, A. B. J . Nat. Prod. 1987,
50, 1055.
(8) (a) Meyers, A. I.; Smith, R. K.; Whitten, C. E. J . Org. Chem. 1979,
44, 2250. (b) Meyers, A. I.; Shipman, M. J . Org. Chem. 1991, 56, 7098.
(9) Meyers, A. I.; Smith, R. K. Tetrahedron Lett. 1979, 2749.
(10) Martin, S. F.; Benage, B.; Williamson, S. A.; Brown, S. P.
Tetrahedron 1986, 42, 2903.
S0022-3263(97)00429-5 CCC: $14.00 © 1997 American Chemical Society

5220 J . Org. Chem., Vol. 62, No. 15, 1997
Notes
bromide with 1.0 equiv of t-BuLi in THF to afford the
aryllithium and after addition to 1 gave a 61% isolated
yield of 3.
The asymmetric routes described herein represent
potential routes to other members of the bisbolane family,
using aryllithium reagents with different substitution
patterns in the benzene ring (e.g., curcuhydroquinone,
curcuquinone, curcuphenol,17 isoperezone, and perezone).7
Analysis of the chromatographed addition products 2
and 3 (1H NMR, chemical shift of the t-Bu group: 0.76/
0.82 ppm for the major/minor isomer, respectively)
revealed that the diastereomeric ratio was at least 97:3.
The purification of this product was bypassed, and the
crude oxazolines 2 and 3 were taken on to the alcohols 4
and 5. Thus, hydrolysis of 2 with 1.8 M H2SO48 gave 66%
yield of the known11 (S)-3-(4-methylphenyl)butanoic acid,
which was reduced to the alcohol 4. Hydrolysis of 3 using
TFA followed by acetylation and reduction12 furnished
the known4,6a (no rotation reported) alcohol 5 in 57% yield
from 1. These compounds were treated with 1,2-bis-
(diphenylphoshino)ethane tetrabromide (DIPHOSBr)13 to
give the bromides 6 and 714 in high yield. It should be
noted that [R]D for 6 was reported1 to be +109°. On the
basis of this value, the optical purity of our bromide
should only be 73%, which was inconsistent with the
enantiomeric purity of our products 2 and 3 (NMR, 97:
1) and the observed selectivity of the addition of aryl-
lithiums to 1. Others have also reported discrepancies
with the published optical rotation.5e
The coupling15 of (2,2-dimethylvinyl)lithium and 6 or
7 was initially attempted with the lithium reagent
generated from the corresponding vinyl bromide by
treatment with 2 equiv of t-BuLi.16 However, only traces
of the desired coupling product were obtained. Finally,
direct treatment of the vinyl bromide with excess lithium
metal (suspended in mineral oil) in Et2O produced the
vinyllithium reagent, which gave R-curcumene (8) and
xanthorrhizol methyl ether (9) in high yield (90, 94%
respectively). Cleavage of the methyl ether in 9 using
sodium ethylthiolate in DMF4 gave xanthorrhizol 10 in
92% yield. Attempts to utilize BBr3 to cleave the methyl
ether in 9 gave a mixture of products, including some
cyclized material derived from Friedel-Crafts alkyla-
tions. All the physical data for the products 8 and 10
were in satisfactory agreement with natural material
except for xanthorrhizol, whose sign of rotation was (+),
opposite to that of the material previously isolated.3
Exp er im en ta l Section
(4S)-4-ter t-Bu tyl-2-[(E)-1-p r op en yl]-2-oxa zolin e (1). To a
stirred solution of crotonic acid (1.30 g, 15.1 mmol) in dry CH2Cl2
(20 mL) containing Et3N (4.3 mL, 30.8 mmol) at -15 °C was
added ethyl chloroformate (1.5 mL, 15.7 mmol) dropwise. After
45 min of stirring at -15 °C, the solution was cooled to -78 °C,
and a solution of (S)-tert-leucinol (1.96 g, 16.7 mmol) in CH2Cl2
(50 mL) was added slowly. The mixture was allowed to warm
slowly and stirred at rt for 2 h. Water and CH2Cl2 were added
and the layers separated. The organic layer was washed with
saturated NaHCO3, dried (Na2SO4), and concentrated. The
crude amide was dissolved in dry CH2Cl2 (30 mL), and SOCl2
(1.2 mL, 16.4 mmol) was added. The mixture was stirred at rt
for 10 min and quenched with water and 10% NaOH with
cooling. After separation, the aqueous layer was extracted with
Et2O, and the combined organic layers were dried and concen-
trated. Flash chromatography (7:3 hexane/Et2O) gave 1 (1.35
g, 53.5%) as a pale yellow liquid: [R]D ) -138.5 (c 2.0, acetone);
1H NMR (CDCl3) 0.85 (9 H, s), 1.83 (3 H, dd, J ) 7.0, 1.5 Hz),
3.82-3.89 (1 H, m), 3.98-4.03 (1 H, m), 4.11-4.17 (1 H, m), 5.98
(1 H, dd, J ) 15.8, 1.6 Hz), 6.46-6.56 (1 H, m); 13C NMR (CDCl3)
18.2 (q), 25.7 (q), 33.6 (s), 68.0 (t), 75.8 (d), 119.1 (d), 138.6 (d),
162.5 (s); IR (thin film) 1680, 1650, 1617. Anal. Calcd for
C
10H17NO: C, 71.81; H, 10.24; N, 8.37. Found: C, 71.79; H,
10.22; N, 8.36.
(3S)-3-(4-Meth ylp h en yl)bu ta n oic Acid . p-Bromotoluene
(5.13 g, 30 mmol) in Et2O (10 mL) was slowly added to a large
excess of lithium (25% lithium suspension in mineral oil,
containing 0.5% sodium) in Et2O (30 mL) so as to maintain a
gentle reflux. After the addition was completed, the mixture
was stirred for 1 h at rt and allowed to settle before use. To a
stirred solution of p-tolyllithium (8.0 mL 0.67 M in Et2O, 5.36
mmol, filtered through a small plug of glass wool contained in
the syringe) in dry THF (36 mL) at -78 °C was added oxazoline
1 (430 mg, 2.57 mmol) in THF (17 mL) over 1 h. After being
stirred for an additional 15 min, the mixture was quenched with
methanol and allowed to warm, saturated sodium chloride was
added, and the mixture was extracted with ether. The combined
organic layers were dried and concentrated. The resulting crude
oxazoline 2 was refluxed with sulfuric acid8 (1.8 M, 15 mL) for
36 h. On cooling, the mixture was extracted with CH2Cl2, dried,
and concentrated. Flash chromatography (7:3 hexane/Et2O)
gave (3S)-3-(4-methylphenyl)butanoic acid (300 mg, 65.6%) as
a waxy white solid: [R]D ) +44.8 (c 2.9, acetone) (lit.11 [R]D
)
+45.0 (c 6.5, CHCl3)); distillation at 120 °C (0.05 mmHg) gave
[R]D ) +65.0 (c 4.6, benzene) as reported previously;11 1H NMR
(CDCl3) 1.30 (3 H, d, J ) 7.0 Hz), 2.33 (3 H s), 2.52-2.69 (2 H,
m), 3.21-3.28 (1 H, m), 7.12 (4 H, m), 11.50-12.00 (1 H, br s);
13C NMR (CDCl3) 21.0 (q), 22.0 (q), 35.7 (d), 42.7 (t), 126.5 (d),
129.2 (d), 136.0 (s), 142.4 (s), 179.0 (s); IR (thin film) 3500-2500,
1710.
(3S)-3-(3-Met h oxy-4-m et h ylp h en yl)b u t a n ol (5). To a
stirred solution of 3-methoxy-4-methylbromobenzene18 (724 mg,
3.60 mmol) in dry THF (30 mL) at -78 °C was added t-BuLi
(2.10 mL 1.69 M solution in hexanes, 3.55 mmol). After 40 min
of stirring, oxazoline 1 (300 mg, 1.80 mmol) in THF (15 mL) was
added over 1 h. After being stirred for additional 15 min, the
mixture was quenched with methanol and allowed to warm.
Then, saturated sodium chloride was added and the mixture
extracted with ether. The combined organic layers were dried
and concentrated. The residue was dissolved in THF (20 mL),
water (1.5 mL), and trifluoroacetic acid (2.2 mL), Na2SO4 (11 g)
was added, and the suspension was stirred at rt for 24 h. After
(11) (a) Cram, D. J . J . Am. Chem. Soc. 1952, 74, 2137. (b) Honwad,
V. K.; Rao, A. S. Tetrahedron 1964, 20, 2921.
(12) (a) Moorlag, H.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 6993.
(b) Warshawsky, A. M.; Meyers, A. I. J . Am. Chem. Soc. 1990, 112,
8090.
(13) Schmidt, S. P.; Brooks, D. W. Tetrahedron Lett. 1987, 28, 767.
(14) Crude bromide 7 was used as an intermediate in a synthesis
of racemic xanthorrhizol; see ref 6a.
(15) For an example of coupling of vinyllithiums with primary
halides, see: Millon, J .; Lorne, R.; Linstrumelle, G. Synthesis 1975,
434.
(17) McEnroe, F. J .; Fenical, W. Tetrahedron 1978, 34, 1661.
(18) This compound was prepared starting from commercially
available 4-amino-2-nitrotoluene: Rinehart, K. L.; Kobayashi, J .;
Harbour, G. C.; Gilmore, J .; Mascal, M.; Holt, T. G.; Shield, L. S.;
Lafargue, F. J . Am. Chem. Soc. 1987, 109, 3378. Newbold, G. T.;
Brown, J . J . J . Chem. Soc. 1953, 1285.
(16) Neumann, H.; Seebach, D. Chem. Ber., 1978, 2785.

Notes
J . Org. Chem., Vol. 62, No. 15, 1997 5221
filtration, the solvent was removed, and the residue was dis-
solved in CH2Cl2 (30 mL). To this solution were added dry
pyridine (2.4 mL) and acetic anhydride (3.8 mL), and the mixture
was stirred at rt for 24 h, washed with 1 N HCl and water, dried,
and concentrated. The residue was dissolved in THF, and
LiAlH4 (150 mg) was added. After 2 h, the mixture was
quenched with water, Na2SO4 was added, and the solids were
filtered off and washed with THF and Et2O. The filtrate was
dried and the solvent evaporated. Flash chromatography (7:3
hexane/Et2O) gave 5 (198 mg, 56.7%) as a pale yellow liquid:
mg, 0.44 mmol) in THF (3 mL) was added a solution of
(2-methylpropenyl)lithium (3.4 mL 0.23 M solution, 0.78 mmol,
filtered through glass wool contained in the syringe) at -78 °C.
The mixture was allowed to warm slowly and stirred overnight
at rt, saturated ammonium chloride was added, and the mixture
was extracted with Et2O. The combined organic layers were
dried and concentrated. Flash chromatography (hexane) gave
8 (80 mg, 90.0%) as a pale yellow liquid: [R]D ) +50.2 (c 4.7,
acetone) (lit.2 [R]D ) +45.1); 1H NMR (CDCl3) 1.19 (3 H, d, J )
7.0 Hz), 1.50 (3 H, s), 1.50-1.65 (2 H, m), 1.65 (3 H, s), 1.81-
1.89 (2 H, m), 2.30 (3 H, s), 2.60-2.67 (1 H, m), 5.04-5.10 (1 H,
m), 7.04 (4H, s); 13C NMR (CDCl3) 17.6 (q), 20.9 (q), 22.4 (q),
25.7 (q), 26.1 (t), 38.4 (t), 39.0 (d), 124.5 (d), 126.8 (d), 128.9 (d),
131.3 (s), 135.1 (s), 144.6 (s).
1
[R]D ) +35.0 (c 6.0, acetone); H NMR (CDCl3) 1.21 (1 H, br s),
1.25 (3 H, d, J ) 7.0 Hz), 1.80-1.86 (2 H, m), 2.17 (3 H, s), 2.80-
2.87 (1 H, m), 3.52-3.57 (2 H, m), 3.81 (3 H, s), 6.66 (1 H, s),
6.69 (1 H, d, J ) 7.6 Hz), 7.04 (1 H, d, J ) 7.3 Hz); 13C NMR
(CDCl3) 15.7 (q), 22.4 (q), 36.4 (d), 40.9 (t), 55.1 (q), 61.0 (t), 108.7
(d), 118.4 (d), 124.1 (s), 130.4 (d), 145.8 (s), 157.6 (s); IR (thin
film) 3346 (br).
(S)-(+)-Xa n th or r h izol Meth yl Eth er (9). Bromide 7 (90
mg, 0.35 mmol) in THF (3 mL) was treated with solution of (2-
methylpropenyl)lithium (2.8 mL 0.23 M solution, 0.64 mmol) as
described for 6. Flash chromatography (98:2 hexane/Et2O) gave
9 (76 mg, 93.6%) as a pale yellow liquid: [R]D ) +49.6 (c 5.0,
(1S)-1-(4-Meth ylp h en yl)-3-br om obu ta n e (6). DIPHOS-
Br13 was prepared from Ph2PCH2CH2PPh2 (400 mg, 1.00 mmol)
in CH2Cl2 (5 mL) and Br2 (0.10 mL, 1.94 mmol) in CH2Cl2 (1
mL) at 0 °C. 3-(4-Methylphenyl)butanoic acid (160 mg, 0.90
mmol) was reduced with LiAlH4 (220 mg) in THF at rt to give
alcohol 4 in quantitative yield. Crude 4 was dissolved in CH2Cl2,
and a solution of DIPHOSBr (5 mL, 0.83 mmol) was added at 0
°C. The mixture was allowed to warm to rt and stirred for 30
min. Hexane and Et2O were added, the mixture was filtered
through a pad of silica gel, the solids were washed with Et2O,
and the filtrate was concentrated. Flash chromatography (hex-
ane) gave 6 (198 mg, 96.9%) as a pale yellow liquid: [R]D ) +80.0
(c 2.0, acetone) (lit.1 [R]D ) +109.0° (c 2.27, CHCl3)); 1H NMR
(CDCl3) 1.24 (3 H, d, J ) 6.7 Hz), 2.03-2.10 (2 H, m), 2.30 (3H,
s), 2.86-2.93 (1 H, m), 3.12-3.20 (1 H, m), 3.25-3.33 (1 H, m),
7.05-7.12 (4 H, m); 13C NMR (CDCl3) 20.9 (q), 21.9 (q), 32.1 (t),
37.8 (d), 41.0 (t), 126.8 (d), 129.2 (d), 135.8 (s), 142.3 (s).
(1S)-1-(3-Meth oxy-4-m eth ylp h en yl)-3-br om obu ta n e (7).
Alcohol 5 (310 mg, 1.50 mmol) was converted into bromide 7 as
described for 4. Flash chromatography (98:2 hexane/Et2O) gave
7 (373 mg, 90.7%) as a pale yellow liquid: [R]D ) +90.0 (c 2.5,
acetone); 1H NMR (CDCl3) 1.30 (3 H, d, J ) 7.0 Hz), 2.07-2.14
(2 H, m), 2.20 (3 H, s), 2.90-2.97 (1 H, m), 3.19-3.25 (1 H, m),
3.30-3.36 (1 H, m), 3.84 (3 H, s), 6.69-6.73 (2 H, m), 7.07 (1 H,
d, J ) 7.3 Hz); 13C NMR (CDCl3) 15.7 (q), 21.8 (q), 32.3 (t), 38.1
(d), 41.0 (t), 55.1 (q), 108.8 (d), 118.3 (d), 124.4 (s), 130.5 (d),
144.2 (s), 157.6 (s).
1
acetone)(lit.4 [R]D ) +51.6); H NMR (CDCl3) 1.21 (3 H, d, J )
7.0 Hz), 1.51 (3 H, s), 1.51-1.65 (2 H, m), 1.65 (3 H, s), 1.83-
1.89 (2 H, m), 2.16 (3H, s), 2.59-2.66 (1 H, m), 3.8 (3 H, s), 5.05-
5.10 (1 H, m), 6.63 (1 H, s), 6.67 (1 H, d, J ) 7.6 Hz), 7.02 (1 H,
d, J ) 7.3 Hz); 13C NMR (CDCl3) 15.8 (q), 17.7 (q), 22.5 (q), 25.7
(q), 26.2 (t), 38.4 (t), 39.5 (d), 55.2 (q), 108.9 (d), 118.7 (d), 123.8
(s), 124.6 (d), 130.3 (d), 131.4 (s), 146.7 (s), 157.6 (s).
(S)-(+)-Xa n th or r h izol (10). To a suspension of NaH (105
mg, 60% in mineral oil, 2.6 mmol) in dry DMF (5 mL) was added
dropwise ethanethiol (0.18 mL, 2.44 mmol) at 0 °C (ice bath).
After the addition was completed, the cooling bath was removed
and the mixture stirred at rt for 15 min. Xanthorrhizol methyl
ether (9) (92 mg, 0.4 mmol) in DMF (1.5 mL) was added and
the mixture heated to reflux for 3.5 h, cooled, diluted with water,
neutralized with concentrated HCl, and extracted with Et2O.
The combined organic layers were dried and concentrated. Flash
chromatography (9:1 hexane/Et2O) gave 10 (80 mg, 91.7%) as a
pale yellow liquid: [R]D ) +52.8 (c 3.6, acetone) (lit.3 [R]D
)
-52.5); 1H NMR (CDCl3) 1.18 (3 H, d, J ) 7.0 Hz), 1.51 (3 H, s),
1.51-1.65 (2 H, m), 1.66 (3 H, s), 1.82-1.90 (2 H, m), 2.20 (3 H,
s), 2.56-2.63 (1 H, m), 4.58 (1 H, br s), 5.07 (1 H, br t, J ) 7.0
Hz), 6.59 (1 H, s), 6.66 (1 H, d, J ) 7.6 Hz), 7.01 (1 H, d, J ) 7.7
Hz); 13C NMR (CDCl3) 15.3 (q), 17.6 (q), 22.3 (q), 25.7 (q), 26.1
(t), 38.3 (t), 39.0 (d), 113.5 (d), 119.4 (d), 120.9 (s), 124.5 (d), 130.8
(d), 131.4 (s), 146.2 (s), 153.5 (s).
(S)-(+)-r-Cu r cu m en e (8). 1-Bromo-2-methylpropene (0.5
mL, 4.9 mmol) in Et2O (1 mL) was slowly added to a large excess
of lithium (25% lithium suspension in mineral oil, containing
0.5% sodium) in Et2O (3 mL) so as to maintain gentle reflux.
After the addition was completed, the mixture was stirred for 1
h at rt, diluted with 15 mL of THF at -40 °C, and allowed to
settle before use. To a stirred solution of the bromide 6 (100
Ack n ow led gm en t. The authors are grateful to the
National Institutes of Health for financial support of
this work.
J O970429H