A concise synthesis of (±)-cacalol

Article abstract of DOI:10.1021/jo800324c

(Chemical Equation Presented) A simple synthesis of the natural product cacalol has been developed that proceeds in seven steps and 21-25% overall yield. Ortho-lithiation of 4-methylanisole and alkylation with 5-iodo-1-pentene, followed by intramolecular

Full text of DOI:10.1021/jo800324c

SCHEME 1. Synthesis of Cacalol
A Concise Synthesis of (()-Cacalol
Brant L. Kedrowski* and Robert W. Hoppe
Department of Chemistry, UniVersity of Wisconsin, Oshkosh,
Oshkosh, Wisconsin 54901
kedrowsk@uwosh.edu
ReceiVed February 7, 2008
A simple synthesis of the natural product cacalol has been
developed that proceeds in seven steps and 21-25% overall
yield. Ortho-lithiation of 4-methylanisole and alkylation with
5-iodo-1-pentene, followed by intramolecular Friedel-Crafts
alkylation, gave 5-methoxy-1,8-dimethyltetralin. This com-
pound was then formylated in the 6-position. Baeyer-Villiger
oxidation and hydrolysis of the resulting formate gave
6-hydroxy-5-methoxy-1,8-dimethyltetralin. Alkylation of the
phenolic hydroxyl group with chloroacetone followed by
cyclodehydration gave cacalol methyl ether. Deprotection of
this aryl methyl ether yielded cacalol.
Cacalol (1) is a sesquiterpene natural product isolated from
the roots of the shrub Psacalium decompositum in northern
Mexico.1 It has antihyperglycemic,2a anti-inflammatory,2b
antimicrobial,2b and antioxidant2c activities, which have made
it an attractive target for synthesis. A number of syntheses of
this molecule have been reported.3a–f The method described
herein offers a number of improvements in synthetic efficiency,
providing a shorter, higher yielding route to 1.
the alkene 3. This molecule was then cyclized in an intramo-
lecular Friedel-Crafts alkylation by treatment with aluminum
chloride in methylene chloride to give the tetralin 4. Compound
4 has been a key intermediate in several previous syntheses of
cacalol. These routes have required four or more steps from
commercially available starting materials and proceeded in
overall yields of between 39% and 80%.3a,c,d The annulation
of 2 described here provides a new route to 4 that proceeds in
two steps and 83% overall yield.
A two-step procedure next installed a hydroxyl group in the
6-position of tetralin 4. Formylation of 4 with R,R-dichlorom-
ethyl methyl ether and titanium tetrachloride6 at 0 °C gave a
96% combined yield of the regioisomeric aldehydes 5a and 5b
in a 14:1 mixture as determined by 1H NMR and GCMS
analyses. Aldehydes 5a and 5b had the same mobility on silica
gel and were inseparable by flash chromatography at this point.
The mixture of aldehydes 5a and 5b was subjected to
Baeyer-Villiger oxidation with m-chloroperoxybenzoic acid (m-
CPBA) in methylene chloride. Workup with aqueous HCl and
methanol hydrolyzed the resulting mixture of aryl formates to
The synthesis of 1 is described in Scheme 1. It began with
ortho-lithiation4a,b of 4-methylanisole (2) by n-butyllithium in
THF. This anion was alkylated with 5-iodo-1-pentene5 to give
(1) (a) Romo, J.; Joseph-Nathan, P. Tetrahedron 1964, 20, 2331-2337. (b)
Kakisawa, Y.; Inouye, Y.; Romo, J. Tetrahedron Lett. 1969, 10, 1929.
(2) (a) Inman, W. D.; Luo, J.; Jolad, S. D.; King, S. R.; Cooper, R. J. Nat.
Prod. 1999, 62, 1088. (b) Jiminez-Estrada, M.; Chilpa, R. R.; Apan, T. R.;
Lledias, F.; Hansberg, W.; Arrieta, D.; Aguilar, F. J. A. J. Ethnopharm. 2006,
105, 34. (c) Shindo, K.; Kimura, M.; Iga, M. Biosci. Biotechnol. Biochem. 2004,
68, 1393.
(3) (a) Banerjee, A. K.; Melean, C. E.; Mora, H. D.; Cabrera, E. V.; Laya,
M. S. J. Chem. Res. 2007, 109. (b) Tanikawa, S.; Ono, M.; Akita, H. Heterocycles
2005, 65, 319–327. (c) Garofalo, A. W.; Litvak, J.; Wang, L.; Dubenko, L. G.;
Cooper, R.; Bierer, D. E. J. Org. Chem. 1999, 64, 3369. (d) Huffman, J. W.;
Pandian, R. J. Org. Chem. 1979, 44, 1851. (e) Yuste, F.; Walls, F. Aust. J. Chem.
1976, 29, 2333. (f) Inouye, Y.; Uchida, Y.; Kakisawa, H. Chem. Lett. 1975,
1317.
(4) For reviews of ortho-lithiation see: (a) Gschwend, H. W.; Rodriguez,
H. R. Org. React. 1979, 26, 1. (b) Snieckus, V. Chem. ReV. 1990, 90, 879.
(5) Prepared from commercially available 5-bromo-1-pentene according to:
Padwa, A.; Kamigata, N. J. Am. Chem. Soc. 1977, 99, 1871.
(6) Rieche, A.; Gross, H.; Ho¨ft, E. Ber. 1960, 93, 88.
J. Org. Chem. 2008, 73, 5177–5179 5177
10.1021/jo800324c CCC: $40.75
Published on Web 05/29/2008
2008 American Chemical Society

(3.521 g, 26.41 mmol, 1.1 equiv) was added at once, with stirring.
After 15 min, the cooling bath was removed and the mixture
warmed to rt. A cherry red solution formed, and stirring was
continued for 4 h. The solution was then cooled to 0 °C, and 1.6
N HCl was added with vigorous stirring, giving a pale yellow
emulsion. The mixture was warmed to rt and extracted with ether
(275 mL). The organic layer was washed with satd aq NaHCO3,
washed with brine, dried over MgSO4, and filtered and solvent
evaporated under reduced pressure. The crude product was purified
by flash chromatography (silica gel, hexane) giving the product as
a clear colorless liquid (4.449 g, 97%): TLC Rf 0.25 (100:1 hexane/
ether); IR (thin film, cm-1) 2930, 2869, 2832, 1587, 1477, 1439,
1301, 1253, 1242, 1089, 1055, 796; 1H NMR (CDCl3, δ ppm) 6.96
(d, J ) 8.2 Hz, 1 H), 6.60 (d, J ) 8.2 Hz, 1 H), 3.79 (s, 3 H),
3.10-3.00 (m, 1 H), 2.91-2.81 (m, 1 H), 2.52-2.37 (m, 1 H),
2.27 (s, 3 H), 1.96-1.71 (m, 4 H), 1.19 (d, J ) 7.2 Hz, 3 H); 13C
NMR (CDCl3, δ ppm) 156.0, 142.0, 127.95, 127.85, 125.3, 106.9,
55.4, 30.0, 29.8, 23.6, 20.9, 18.7, 17.1; EI MS m/z 190 (M+, 59),
175 (100). Anal. Calcd for C13H18O: C, 82.06; H, 9.53. Found: C,
82.21; H, 9.57.
give a mixture of regioisomeric phenols, which were easily
separated by flash chromatography on silica gel. Thus, the
hydroxytetralin 6 was produced. In previous syntheses that
proceeded through intermediate 4, oxygenation to 6 was
accomplished by first brominating 4 selectively ortho to the
methoxy group.3a,c,d The resulting aryl bromide was then
converted to an aryl anion that was quenched with a variety of
electrophiles including nitrobenzene,3d borane · THF,3c or
dimethylformamide3a to either install the oxygen directly or
generate it in one additional step.
The phenol 6 was alkylated on oxygen with chloroacetone
using anhydrous potassium carbonate and potassium iodide in
acetone, which gave the ketone 7. Cyclodehydration of 7 in
concentrated sulfuric acid then gave cacalol methyl ether (8).
A similar alkylation/cyclodehydration strategy has been used
previously to construct the furan ring of two cacalol analogs.7
The approach was also attempted in a previous synthesis of 1.
However, the cyclodehydration step was reported to be unsuc-
cessful in that study.3e
5-Methoxy-1,8-dimethyltetralin-6-carboxaldehyde (5a).3a Te-
tralin 4 (1.745 g, 9.172 mmol) was dissolved in dichloromethane
(18.3 mL) and cooled to 0 °C under an argon atmosphere. A 1 M
solution of titanium tetrachloride in CH2Cl2 (18.30 mL, 18.30 mmol,
2 equiv) was added dropwise, with stirring, followed by R,R-
dichloromethyl methyl ether (1.65 mL, 18.30 mmol, 2 equiv)
dropwise, with stirring.6 After 30 min at 0 °C, the inky black
solution was warmed to rt and stirred for 1 h. The dark solution
was poured into a separatory funnel filled with 10 g of ice and
shaken thoroughly. The layers were separated, and the aqueous
phase was diluted with water (10 mL) and extracted with CH2Cl2.
The combined organic layers were washed with water and satd aq
NaHCO3, diluted with ether (75 mL), and washed with brine. The
solution was dried over MgSO4, filtered, and evaporated under
reduced pressure to give the crude product as a dark oil. Purification
by flash chromatography (silica gel, 20:1 hexane/EtOAc) gave a
clear colorless liquid, which was an inseparable mixture of product
5a and regioisomeric aldehyde 5b in a 14:1 ratio (1.929 g, 90%
Finally, cleavage of the methyl aryl ether of 8 using boron
tribromide in methylene chloride according to a literature
method gave cacalol.3b,c In one literature preparation, (()-
cacalol is reported to be a crystalline solid.3c However, others
report that the product does not crystallize even after chromato-
graphic purification,3d–f which was also true in this study.
Derivatization of cacalol as its acetate is commonly used to
generate a crystalline product.3b,d–f
In summary, a new synthesis of 1 has been developed which
proceeded from 2 in seven steps and 21-25% overall yield.
Key features include a two-step annulation of 2 to give 4, a
two-step oxygenation of 4 to give 6, and a two-step annulation
of 6 to give 8.
Experimental Section
2-(4-Pentenyl)-4-methylanisole (3). A round-bottom flask was
charged with 4-methylanisole (3.414 g, 27.95 mmol) and THF (37
mL) and cooled to 0 °C under an argon atmosphere. A freshly
titrated 1.6 M solution of n-butyllithium in hexane (23.3 mL, 37.2
mmol, 1.3 equiv) was added dropwise, with stirring. After 15 min,
the yellow solution was warmed to rt and was stirred for an
additional 3 h. The solution was cooled to 0 °C, and a solution of
5-iodo-1-pentene (7.122 g, 36.34 mmol, 1.3 equiv) in THF (24 mL)
was added dropwise, with stirring. After 1 h at 0 °C, the reaction
was warmed to rt and stirred 48 h. It was quenched with water (30
mL) and the resulting mixture extracted twice with ether. The
combined ether extracts were washed with brine, dried over MgSO4,
and filtered, and volatile components were evaporated under reduced
pressure. The crude product was purified by flash chromatography
(silica gel, pentane) giving the product as a clear colorless liquid
(4.57 g, 86%): TLC Rf 0.17 (hexane); IR (thin film, cm-1) 3075,
2998, 2926, 2859, 2833, 1640, 1612, 1504, 1464, 1441, 1251, 1229,
5a, 6% 5b): TLC Rf 0.30 (8:1 hexane/EtOAc); IR (thin film, cm-1
)
1
2935, 2869, 1685, 1600, 1456, 1411, 1388, 1223, 1049, 998; H
NMR (CDCl3, δ ppm) 10.37 (s, 1/14 × 1 H, 5b), 10.28 (s, 1 H,
5a), 7.45 (s, 1 H, 5a), 7.15 (s, 1/14 × 1 H, 5b), 3.83 (s, 3H),
3.14-2.88 (m, 2 H), 2.66-2.47 (m, 1 H), 2.30 (s, 3 H), 1.90-1.70
(m, 4 H), 1.17 (d, J ) 7.2 Hz, 3 H); 13C NMR (CDCl3, δ ppm)
190.2, 160.0, 150.3, 132.4, 130.7, 127.2, 126.1, 63.2, 30.1, 29.5,
23.0, 20.6, 18.6, 16.8; EI MS m/z 218 (M+, 81), 203 (100). Anal.
Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 77.18; H, 8.44.
5-Methoxy-1,8-dimethyltetralin-6-ol (6).3a,c,d A 14:1 mixture
of aldehydes 5a and 5b (1.082 g, 4.956 mmol) was dissolved in
CH2Cl2, and 100% m-chloroperoxybenzoic acid (1.026 g, 5.947
mmol, 1.2 equiv) was added, with stirring. The resulting solution
was refluxed for 7 h and then cooled to rt. Methanol (10 mL) was
added followed by concd aq HCl (10 mL), and the mixture was
stirred rapidly for 16 h at rt as a red color developed. The CH2Cl2
layer was then separated and washed with aq Na2S2O3 and satd aq
NaHCO3 twice and then dried over MgSO4. Filtration and evapora-
tion under reduced pressure gave a yellow oil. At this point, it was
straightforward to separate the desired phenol 6 from the regioi-
someric phenol produced from reaction of 5b. Flash chromatog-
raphy (silica gel, 10:1 hexane/EtOAc) gave pure phenol 6 as a clear
colorless liquid, which slowly solidified to a white solid (0.832 g,
87%): TLC Rf 0.24 (hexane/EtOAc); mp 43-45 °C; IR (thin film,
cm-1) 3415 br, 2930, 2869, 1593, 1478, 1319, 1248, 1180, 1120,
1
1038, 910, 804; H NMR (CDCl3, δ ppm) 6.98-6.92 (m, 2 H),
6.73 (d, J ) 7.7 Hz, 1 H), 5.85 (ddt, J ) 16.8, 10.1, 6.7 Hz, 1 H),
5.07-4.92 (m, 2 H), 3.78 (s, 3 H), 2.57 (t, J ) 7.6 Hz, 2 H), 2.26
(s, 3 H), 2.14-2.05 (m, 2 H), 1.71-1.60 (m, 2 H); 13C NMR
(CD3OD, δ ppm) 155.5, 138.7, 130.4, 130.2, 129.0, 127.0, 113.7,
110.0, 54.5, 33.5, 29.6, 29.3, 19.6; EI MS m/z 190 (M+, 39), 148
(58), 135 (100), 105 (85). Anal. Calcd for C13H18O: C, 82.06; H,
9.53. Found: C, 82.00; H, 9.44.
5-Methoxy-1,8-dimethyltetralin (4).3a,c,d Alkene 3 (4.568 g,
24.00 mmol) was dissolved in dichloromethane (240 mL) and
cooled to 0 °C under an argon atmosphere. Aluminum chloride
1
995, 909, 734; H NMR (CDCl3, δ ppm) 6.66 (s, 1 H), 5.7-5.1
(br s, 1 H), 3.76 (s, 3 H), 3.06-2.88 (m, 2 H), 2.66-2.48 (m, 1
H), 2.25 (s, 3 H), 1.90-1.71 (m, 4 H), 1.16 (d, J ) 6.9 Hz, 3 H);
13C NMR (CDCl3, δ ppm) 145.9, 142.8, 133.3, 132.7, 129.8, 115.2,
60.3, 30.2, 29.0, 23.7, 21.2, 18.8, 17.1; EI MS m/z 206 (M+, 37),
(7) Hirai, Y.; Doe, M.; Kinoshita, T.; Morimoto, Y. Chem. Lett. 2004, 33,
136.
5178 J. Org. Chem. Vol. 73, No. 13, 2008

191 (100), 159 (31), 131 (19). Anal. Calcd for C13H18O2: C, 75.69;
H, 8.80. Found: C, 76.03; H, 8.87.
oil. Purification by flash chromatography (silica gel, 40:1 hexane/
ether) gave 8 as a white crystalline solid (32.8 mg, 60%): TLC Rf
0.35 (20:1 hexane/EtOAc); mp 66-67 °C; IR (neat, cm-1) 2957,
2935, 2859, 1468, 1445, 1337, 1111, 1066, 1000; 1H NMR (CDCl3,
δ ppm) 7.26 (s, 1 H), 4.06 (s, 3 H), 3.31-3.18 (m, 1 H), 3.11-2.99
(m, 1 H), 2.72-2.57 (m, 1 H), 2.56 (s, 3 H), 2.35 (d, J ) 1.0 Hz,
3 H), 1.94-1.74 (m, 4 H), 1.20 (d, J ) 7.2 Hz, 3 H); 13C NMR
(CDCl3, δ ppm) 145.2, 141.0, 140.5, 135.6, 127.4, 124.4, 123.1,
116.6, 60.1, 30.3, 29.1, 23.7, 21.6, 17.1, 14.1, 11.5; EI MS m/z
244 (M+, 83), 229 (100). Anal. Calcd for C16H20O2: C, 78.65; H,
8.25. Found: C, 78.62; H, 8.30.
1-(5-Methoxy-1,8-dimethyltetralin-6-yloxy)propan-2-one (7).
Phenol 6 (0.832 g, 4.03 mmol) was dissolved in acetone (25 mL),
and chloroacetone (0.67 mL, 8.4 mmol, 2.1 equiv) was added. The
solution was placed under an atmosphere of argon, and KI (1.392
g, 8.39 mmol, 2.1 equiv) was added, followed by anhydrous K2CO3
(1.159 g, 8.39 mmol, 2.1 equiv). The mixture was stirred vigorously
for 20 h at rt. Volatile components were evaporated under reduced
pressure, and the resulting residue was partitioned between water
and CH2Cl2. The layers were separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined CH2Cl2 layers were
washed with 5% aq Na2S2O3 solution, dried over MgSO4, and
filtered, and the solvent was removed under reduced pressure to
give a yellow oil. Purification by flash chromatography (silica gel,
8:1 hexane/EtOAc) gave ketone 7 as a pale yellow oil (0.943 g,
89%): TLC Rf 0.16 (8:1 hexane/EtOAc); IR (neat, cm-1) 2930,
Cacalol (1). Compound 8 was treated with boron tribromide
giving 1 as a clear colorless oil, as described in the literature
(60-71%):3b–d TLC Rf 0.22 (10:1 hexane/EtOAc); IR (neat, cm-1
)
1
3500, 2930, 2886, 1629, 1452, 1406, 1223, 1112, 908, 734; H
NMR (CDCl3, δ ppm) 7.24-7.22 (m, 1 H), 4.95 (br s, 1 H),
3.29-3.17 (m, 1 H), 3.03-2.92 (m, 1 H), 2.61 (ddd, J ) 17.8,
10.1, 7.9 Hz, 1 H), 2.51 (s, 3 H), 2.36 (d, J ) 1.0 Hz, 3 H),
1.95-1.72 (m, 4 H), 1.18 (d, J ) 7.2, 3 H); 13C NMR (CDCl3, δ
ppm) 142.2, 140.9, 136.4, 135.6, 126.2, 120.3, 118.7, 117.2, 30.2,
29.0, 23.0, 21.4, 16.7, 13.9, 11.4; EI MS m/z 230 (M+, 58), 215
(100).
1
2870, 1722, 1484, 1315, 1128; H NMR (CDCl3, δ ppm) 6.46 (s,
1 H), 4.52 (s, 2 H), 3.81 (s, 3 H), 3.04-2.88 (m, 2 H), 2.54 (ddd,
J ) 18.0, 10.8, 8.1 Hz, 1 H), 2.30, s, 3 H), 2.24 (s, 3 H), 1.86-1.64
(m, 4 H), 1.13 (d, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, δ ppm)
206.3, 148.0, 145.2, 135.2, 131.6, 131.2, 114.1, 74.2, 60.0, 29.9,
29.1, 26.7, 23.6, 20.9, 18.9, 16.9; EI MS m/z 262 (M+, 68), 247
(100). Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.45;
H, 8.53.
Acknowledgment. is made to the Donors of the American
Chemical Society Petroleum Research Fund (no. 39525-GB1)
and the UW Oshkosh Faculty Development Program (no. R305)
for support of this research.
Cacalol Methyl Ether (8).3b–d Ketone 7 (59.0 mg, 0.225 mmol)
was placed in a 5 mL point bottom flask and cooled to 0 °C.
Concentrated sulfuric acid at 0 °C (1 mL) was added dropwise to
7 with magnetic stirring. The dark red mixture was stirred at 0 °C
for 1 h. Ice was added with shaking, which gave a milky-white
emulsion. The mixture was extracted three times with ether, and
the combined fractions were washed successively with water, satd
aq NaHCO3, and brine and dried over MgSO4. The mixture was
filtered and solvent evaporated under reduced pressure giving an
Supporting Information Available: General experimental
methods, copies of 1H and 13C NMR spectra, as well as
chromatograms and MS spectra for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO800324C
J. Org. Chem. Vol. 73, No. 13, 2008 5179