Total synthesis of Cacalol

Full text of DOI:10.1021/jo9822838

J . Org. Chem. 1999, 64, 3369-3372
3369
Tota l Syn th esis of Ca ca lol†
to reproduce these published procedures, the reactions
were extremely exothermic and gave intractable mixtures
or mixtures of isomeric products. Furthermore, it became
clear that larger scale reactions required to produce the
amount of material needed would constitute a hazard,
and consequently we abandoned this approach.
Albert W. Garofalo, J oane Litvak, Lisa Wang,
Larisa G. Dubenko, Raymond Cooper, and
Donald E. Bierer*
Shaman Pharmaceuticals, Inc., 213 East Grand Avenue,
South San Francisco, California 94080
Our straightforward approach constructs the 15-carbon
furotetralin ring system in 11 steps starting with 2-bromo-
4-methylphenol (8). An alkylation/cyclization strategy is
employed to install both the furyl and cyclohexyl rings.
We envisioned using radical or palladium-catalyzed
methodology to construct the benzofuran ring system of
cacalol. Although both methods have been used exten-
sively to synthesize benzofurans originating from simple
phenols and 1,3-dihydroxybenzenes, both methods have
shown limited use in constructing benzofurans from
catechol building blocks.7
First, the synthesis of tetralin intermediate 13 required
isoxazolidide 7. Esterification of levulinic acid (2) afforded
methyl levulinate (3), which was then treated with ethyl-
ene glycol and p-toluenesulfonic acid in refluxing benzene
to give the ketal 4 (Scheme 1).8 Careful hydrolysis of the
Received November 18, 1998
Psacalium decompositum1 is a shrub native to northern
Mexico, and decoctions of the plant have been used as a
treatment for diabetes.2 As part of an ongoing effort to
develop novel antihyperglycemic agents for non-insulin-
dependent diabetes,3 the components of the root extracts
of P. decompositum were recently isolated and evaluated
for activity.4 Among the isolated components was the
sesquiterpene cacalol.5 The furotetralin ring structure of
cacalol seemed to afford reasonable opportunity for
analogue development, and as part of a medicinal chem-
istry effort, a total synthesis of cacalol was undertaken.
Sch em e 1
Resu lts a n d Discu ssion
Several previous syntheses of cacalol have been re-
ported;6 however, these syntheses suffered from low-
yielding steps or procedures which were not reproducible
in our lab. These approaches to the tetralin ring system
used a Friedel-Crafts alkylation strategy. In attempting
† Dedicated to Professor Henry Rapoport on the occasion of his 80th
birthday.
* Address correspondence to this author at Bayer Corporation,
Department of Chemistry, 400 Morgan Lane, West Haven, CT
06516-4175. Tel: (203) 812-3897. Fax: (203) 812-2650. E-mail:
donald.bierer.b@bayer.com.
(1) P. decompositum has alternatively been referred to in the
literature as Cacalia decomposita A. Gray and Odontorichum decom-
positum (Gray) Rydb.
(2) (a) Sullivan, G. Vet. Hum. Toxicol. 1980, 23, 6-7. (b) Bye, R. A.,
J r. Econ. Bot. 1986, 40, 103-124. (c) Huxtable, R. J . Proc. West.
Pharmacol. Soc. 1983, 26, 185-191. (d) Winkelman, M. Med. Anthro-
pol. 1989, 11, 255-268. (e) Pe´rez, R. M. G.; Ocegueda, A. Z.; Mun˜oz,
J . L. L.; Avila, J . G. A.; Morrow, W. W. J . Ethnopharmacol. 1984, 12,
253-262.
(3) (a) Bierer, D. E.; Dubenko, L. G.; Zhang, P.; Lu, Q.; Imbach, P.
A.; Garofalo, A. W.; Phuan, P. W.; Fort, D. M.; Litvak, J .; Gerber, R.
E.; Sloan, B.; Luo, J .; Cooper, R.; Reaven, G. M. J . Med. Chem. 1998,
41, 2754-2764. (b) Bierer, D. E.; Fort, D. M.; Mendez, C. D.; Luo, J .;
Imbach, P. A.; Dubenko, L. G.; J olad, S. D.; Gerber, R. E.; Litvak, J .;
Lu, Q.; Zhang, P.; Reed, M. J .; Waldeck, N.; Bruening, R. C.; Noamesi,
B. K.; Hector, R. F.; Carlson, T. J .; King, S. R. J . Med. Chem. 1998,
41, 894-901. (c) Bierer, D. E.; Carlson, T. J .; King, S. R. Network Sci.
1996, 2 (No. 5) (http://www.awod.com/netsci/Issues/May96/feature2.html).
(d) Oubre´, A. Y.; Carlson, T. J .; King, S. R.; Reaven, G. M. Diabetologia
1997, 40, 614-617.
(4) (a) Inman, W. D.; King, S. R.; Evan, J . L.; Luo, J . U.S. Patent
5,747,527, May 5, 1998, filed J une 6, 1995. (b) Inman, W. D.; J olad, S.
D.; Luo, J .; King, S. R.; Cooper, R. J . Nat. Prod., submitted for
publication.
(5) (a) Terabe, M.; Tada, M.; Takahashi, T. Bull. Chem. Soc. J pn.
1978, 51, 661-662. (b) Soriano-Garc´ıa, M.; Walls, F.; Barrios, H.;
Sa´nchez-Obrego´n, R.; Ortiz, B.; D´ıaz, E.; Toscano, R. A.; Yuste, F. Acta
Crystallogr. 1988, C44, 1092-1094.
(6) (a) Huffman, J . W.; Pandian, R. J . Org. Chem. 1979, 44, 1851-
1855. (b) Yuste, F.; Walls, F. Aust. J . Chem. 1976, 29, 2333-2336. (c)
Inouye, Y.; Uchida, Y.; Kakisawa, H. Chem. Lett. 1975, 1317-1318.
ester followed by mixed anhydride formation and expo-
sure to isoxazolidine hydrochloride (6) gave isoxazolidide
7.9
Next, dimethyl sulfate etherification of 2-bromo-4-
methyl phenol (8) followed by lithium-halogen exchange
using tert-butyllithium and condensation with isoxazo-
lidide 7 afforded the methylanisole 10 (Scheme 2).10 It is
noteworthy that attempted lithiation with n-butyl- or sec-
butyllithium resulted only in the recovery of unreacted
9 and 7. Benzylic decarbonylation of 10 catalyzed with
10% Pd-C in EtOH and p-toluenesulfonic acid was
accompanied by deprotection to afford pentanone 11 in
77% yield. Reduction to the pentanol and cyclization in
P2O5-MeSO3H11 completed the tetralin ring system, 13,
in high yield.
(7) Parker, K. A.; Spero, D. M.; Inman, K. C. Tetrahedron Lett. 1986,
27, 2833-2836.
(8) Herna´ndez, A.; Marcos, M.; Rapoport, H. J . Org. Chem. 1995,
60, 2683-2691.
(9) Cupps, T. L.; Boutin, R. H.; Rapoport, H. J . Org. Chem. 1985,
50, 3972-3979.
(10) Berre´e, F.; Chang, K.; Cobas, A.; Rapoport, H. J . Org. Chem.
1996, 61, 715-721.
10.1021/jo9822838 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/02/1999

3370 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
Sch em e 2
tion precursor 18. Radical cyclization using Bu3SnH and
AIBN in p-xylene completed the furotetralin ring system
but gave a mixture of exo- and endocyclic double-bond
isomers.14 The exo isomer could be isomerized to the
desired endo by exposure to p-toluenesulfonic acid in CH2-
Cl2. Demethylation with BBr3 in CH2Cl2 afforded cacalol
(1) in 7% overall yield from phenol 8.
Several alternative strategies were simultaneously
studied during the course of our synthesis. Acylation of
bromoaniline 9 with isoxazolidide 2015 followed by ben-
zylic decarbonylation16 gave butyrate 22 (Scheme 4).
Sch em e 4
The furyl ring was fused to tetralin 13 as shown in
Scheme 3. Regioselective bromination of tetralin 13 using
Sch em e 3
Cyclization as before produced the R-tetralone 23 in 86%
yield. Addition of methyllithium followed by dehydration
to the intermediate alkene and hydrogenation with PtO2
in ethanol afforded tetralin 13.6a
A second successful approach to the formation of the
furan was also examined (Scheme 5). Hydroxytetralin 15
Sch em e 5
bromine in dioxane afforded bromotetralin 14.12 Attempts
to form the aryl Grignard using magnesium shavings
were unsuccessful; however, the use of Rieke magnesium
ameliorated the problem. Transmetalation with BH3‚
THF and oxidation with alkaline hydrogen peroxide then
afforded tetralol 15.13 Bromination as before followed by
alkylation with propargyl bromide afforded the cycliza-
could be halogenated, either brominated (16) or iodinated
(25), and alkylated with either allylbromide (26) or
(11) Eaton, P. E.; Carlson, G. R.; Lee, J . T. J . Org. Chem. 1973, 38,
(14) Tsukazaki, M.; Snieckus, V. Can. J . Chem. 1992, 70, 1486-1491.
(15) The procedure described for 7 was employed for the synthesis
of 20 starting with the known mono tert-butylsuccinate; see: Guzzo,
P. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4862-4867.
(16) Klix, R. C.; Cain, M. H.; Bhatia, A. V. Tetrahedron Lett. 1995,
36, 6413-6414.
4071-4073.
(12) Schlegel, D. C.; Tipton, C. D.; Rinehart, K. L., J r. J . Org. Chem.
1970, 35, 849.
(13) Breuer, S. W.; Broster, F. A. J . Organomet. Chem. 1972, 35,
C5-C6.

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3371
allyliodide (27). Pd(OAc)2-catalyzed cyclization17 afforded
the furotetralin 19. In this case, only the endo double-
bond isomer was isolated.
acid (0.16 g, 0.84 mmol) with 10% Pd-C (0.91 g) in ethanol (45
mL) was agitated for 3 h under 50-60 psi of hydrogen. The
reaction mixture was filtered through Celite, and the solvent
was removed by rotary evaporation. Purification of the material
on a silica gel column using EtOAc-hexanes (3:7) as eluant
afforded 0.58 g (77%) of pentanone 11 as a clear, colorless oil:
1H NMR (CDCl3) δ 6.97 (d, J ) 8.1, 1H), 6.94 (s, 1H), 6.74 (d, J
) 8.3, 1H), 3.79 (s, 3H), 2.45 (dd, J ) 7.5, 7.5, 2H), 2.45 (dd, J
) 7.4, 7.4, 2H), 2.28 (s, 3H), 2.13 (s, 3H), 1.87 (dddd, J ) 7.5,
7.5, 7.5, 7.5, 2H); 13C NMR (CDCl3) δ 209.23, 155.34, 130.73,
129.66, 129.47, 127.32, 110.18, 55.33, 43.24, 29.79, 29.34, 24.00,
20.43. Anal. Calcd for C13H18O2: C, 75.69; H, 8.80. Found: C,
75.59; H, 8.87.
5-(2-Meth oxy-5-m eth yl)p h en yl-2-p en ta n ol (12). A solution
of pentanone 11 (8.25 g, 0.04 mol) in absolute MeOH (450 mL)
was stirred at room temperature as powdered NaBH4 (2.29 g,
0.06 mol) was added. After 1 h, the reaction mixture was poured
into brine, and the pH was lowered to 5 with 1 M HCl. The
solution was then extracted with EtOAc. The organic layer was
dried over MgSO4 and filtered, and the solvent was removed by
rotary evaporation. Purification of the material on a silica gel
column using EtOAc-hexanes (3:7) as eluant afforded 6.64 g
(80%) of pentanol 12 as a clear, colorless oil: 1H NMR (CDCl3)
δ 6.96 (m, 2H), 6.75 (d, J ) 8.1, 1H), 3.85 (tq, J ) 6.1, 6.1, 1H),
3.80 (s, 3H), 2.61 (m, 2H), 2.28 (s, 3H), 1.75-1.45 (m, 4H), 1.20
(d, J ) 6.1, 3H); 13C NMR (CDCl3) δ 155.25, 130.59, 130.49,
129.45, 127.10, 110.20, 67.98, 55.39, 39.00, 29.94, 26.14, 23.36,
20.45. Anal. Calcd for C13H20O2: C, 74.96; H, 9.68. Found: C,
74.66; H, 9.84.
5-Met h oxy-1,8-d im et h ylt et r a lin (13). A solution of P2O5
(17.18 g, 60.5 mmol) in methanesulfonic acid (110 mL) was
stirred at room temperature as pentanol 12 (6.30 g, 30.2 mmol)
was added. The reaction mixture was stirred for 2 h, poured into
water, and extracted with EtOAc. The organic layer was washed
with saturated aqueous NaHCO3, dried over MgSO4, and
filtered, and the solvent was removed by rotary evaporation.
Purification of the material on a silica gel column using hexanes
as eluant afforded 5.25 g (91%) of tetralin 13 as a clear, colorless
oil: 1H NMR (CDCl3) δ 6.98 (d, J ) 8.3, 1H), 6.62 (d, J ) 8.3,
1H), 3.81 (s, 3H), 3.07 (m, 1H), 2.88 (dd, J ) 18.1, 5.3, 1H), 2.48
(ddd, J ) 18.1, 10.6, 7.5, 1H), 2.29 (s, 3H), 1.92-1.74 (m, 4H),
1.21 (d, J ) 7.1, 3H); 13C NMR (CDCl3) δ 155.59, 141.76, 127.64,
127.54, 124.99, 106.66, 55.19, 29.59, 29.33, 23.14, 20.58, 18.30,
16.65. Anal. Calcd for C13H18O: C, 82.06; H, 9.54. Found: C,
82.00; H, 9.76.
6-Br om o-5-m eth oxy-1,8-d im eth yltetr a lin (14). A solution
of tetralin 13 (2.3 g, 12.1 mmol) in dry ether (50 mL) was added
to a solution of dioxane dibromide (3.2 g, 12.9 mmol) in ether
(40 mL) at -15 °C. The reaction mixture was stirred for 20 min
and then allowed to warm to room temperature overnight. The
reaction mixture was poured into brine and extracted with ether.
The organic layer was dried over MgSO4 and filtered, and the
solvent was removed by rotary evaporation. Purification of the
material on a silica gel column using hexanes as eluant afforded
2.62 g (81%) of bromotetralin 14 as a clear, colorless oil: 1H NMR
(CDCl3) δ 7.19 (s, 1H), 3.79 (s, 3H), 3.03-2.95 (m, 2H), 2.61 (ddd,
J ) 18.0, 10.4, 7.2, 1H), 2.26 (s, 3H), 1.85-1.73 (m, 4H), 1.16 (d,
J ) 7.1, 3H); 13C NMR (CDCl3) δ 152.87, 141.66, 133.31, 131.77,
131.61, 113.25, 59.77, 29.48, 29.28, 24.07, 20.63, 18.31, 16.80.
Anal. Calcd for C13H17BrO: C, 58.01; H, 6.37. Found: C, 58.25;
H, 6.43.
As shown above, we have presented the total synthesis
of cacalol along with tangent approaches to the tetralin
ring system and two methods for the incorporation of the
furan moiety. Both approaches to the tetralin ring system
provide regiochemically pure product free of isolation
difficulty. Although the approach shown in Scheme 2
offers the best overall yield of tetralin 13, the approach
shown in Scheme 4 offers the possibility for an asym-
metric synthesis of cacalol via intermediate 23. Incorpo-
ration of the furan onto tetralin 15 was achieved using
two well-known approaches that have not been widely
reported for the construction of benzofurans from catechol
building blocks.
Exp er im en ta l Section
Gen er a l Meth od s. THF was distilled from sodium/benzophe-
none. Moisture- and air-sensitive reactions were performed
under a nitrogen atmosphere. Analytical TLC was performed
on E. Merck silica gel 60 F254 precoated plates (250 µm
thickness). Plates were analyzed by either UV light or by
staining with a solution of phosphomolybdic acid (PMA) in
EtOH. Flash chromatography was performed on E. Merck silica
gel 60 (230-400 mesh) using nitrogen pressure. Combustion
microanalysis was performed at the University of California,
1
Berkeley. H and 13C NMR were recorded at 400 and 100 MHz
respectively, with NMR shifts being expressed in ppm downfield
from TMS. NMR coupling constants (J ) are reported in hertz.
Mass spectrometry was performed on a Kratos MS 50 spectrom-
eter. Melting points are uncorrected.
1-[4-(Eth ylen ed ioxy)p en ta n oyl]isoxa zolid in e (7). A solu-
tion of pentanoic acid 5 (18.98 g, 0.12 mol) in dry THF (250 mL)
was stirred at -20 °C as N-methylmorpholine (13.0 mL, 0.12
mol) was added, followed by isobutyl chloroformate (15.5 mL,
0.12 mol). After 5 min, a slurry of isoxazolidine hydrochloride9
(14.3 g, 0.13 mol) and Et3N (18.5 mL, 0.13 mol) in dry DMF (190
mL) was added. The reaction mixture was stirred for 30 min,
warmed to room temperature, and stirred for an additional 2 h.
The reaction mixture was quenched with 1 M NaH2PO4 and
extracted with EtOAc. The organic layer was dried over MgSO4
and filtered, and the solvent was removed by rotary evaporation.
Purification of the material on a silica gel column using EtOAc
as eluant afforded 24.72 g (97%) of 7 as a clear, colorless oil: 1H
NMR (CDCl3) δ 3.94 (m, 6H), 3.70 (dd, J ) 7.4, 7.4, 2H), 2.53
(dd, J ) 8.0, 8.0, 2H), 2.30 (m, 2H), 2.01 (dd, J ) 8.0, 8.0, 2H),
1.34 (s, 3H); 13C NMR (CDCl3) δ 207.52, 109.36, 69.08, 64.62,
43.12, 33.23, 27.51, 27.44, 23.82. Anal. Calcd for C10H17NO4: C,
55.80; H, 7.96; N, 6.51. Found: C, 55.57; H, 7.99; N, 6.65.
2-[(4-Eth ylen ed ioxy)p en ta n oyl]-4-m eth yla n isole (10). A
solution of anisole 9 (20.26 g, 0.10 mol) in dry THF (400 mL)
was stirred at -78 °C as a 1.2 M solution of tert-butyllithium
(140 mL, 0.17 mol) was added dropwise. After 1 h, a solution of
isoxazolidide 7 (14.59 g, 0.07 mol) in THF (100 mL) was added
using a cannula. The reaction mixture was allowed to warm to
room temperature. After 20 h, the reaction mixture was quenched
with saturated aqueous NH4Cl and extracted with EtOAc. The
organic layer was dried over MgSO4 and filtered, and the solvent
was removed by rotary evaporation. Purification of the material
on a silica gel column using EtOAc-hexanes (3:7) as eluant
afforded 12.14 g (68%) of methylanisole 10 as a pale-yellow oil:
1H NMR (CDCl3) δ 7.46 (d, J ) 2.4, 1H), 7.25 (dd, J ) 8.5, 2.4,
1H), 6.85 (d, J ) 8.5, 1H), 3.93 (m, 4H), 3.87 (s, 3H), 3.06 (dd, J
) 7.7, 7.7, 2H), 2.30 (s, 3H), 2.08 (dd, J ) 7.7, 7.7, 2H), 1.36 (s,
3H); 13C NMR (CDCl3) δ 202.42, 156.36, 133.49, 130.47, 129.94,
111.59, 109.71, 64.67, 55.61, 38.55, 33.45, 24.00, 20.19. Anal.
Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.36; H, 7.65.
5-(2-Meth oxy-5-m eth yl)p h en yl-2-p en ta n on e (11). A solu-
tion of methylanisole 10 (0.97 g, 3.7 mmol) and p-toluenesulfonic
6-Hyd r oxy-5-m eth oxy-1,8-d im eth yltetr a lin (15). A solu-
tion of tetralin 14 (0.48 g, 1.8 mmol) in dry THF (5.0 mL) was
stirred at room temperature as a 5% w/v suspension of Rieke
Mg in THF (2.10 mL, 4.3 mmol) was added, followed by a 1 M
solution of BH3‚THF (2.30 mL, 2.3 mmol). The mixture was
refluxed for 1 h and cooled to room temperature, and water was
then carefully added dropwise until H2 gas evolution ceased.
Next, a 1 M aqueous solution of NaOH was added (10 mL, 10.0
mmol), followed by 30% H2O2 (1.0 mL, 8.8 mmol). After 62 h,
the reaction mixture was poured into water and extracted with
EtOAc. The organic layer was dried over MgSO4 and filtered,
and the solvent was removed by rotary evaporation. Purification
of the material on a silica gel column using EtOAc-hexanes (2:
8) as eluant afforded 0.29 g (79%) of tetralol 15 as a clear,
colorless oil: 1H NMR (CDCl3) δ 6.66 (s, 1H), 5.35 (s, 1H), 3.76
(s, 3H), 3.02 (m, 1H), 2.93 (m, 1H), 2.59 (ddd, J ) 17.6, 10.4,
(17) Larock, R. C.; Stinn, D. E. Tetrahedron Lett. 1988, 29, 4687-
4690.

3372 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
6.4, 1H), 2.26 (s, 3H), 1.90-1.74 (m, 4H), 1.16 (d, J ) 7.1, 3H);
13C NMR (CDCl3) δ 145.77, 142.64, 133.17, 132.56, 129.63,
115.00, 60.17, 30.03, 28.87, 23.61, 21.09, 18.69, 16.93. Anal.
Calcd for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.46; H, 8.96.
7-Br om o-6-h yd r oxy-5-m eth oxy-1,8-d im eth yltetr a lin (16).
A solution of bromine (0.03 mL, 0.58 mmol) in dioxane (4.0 mL)
was stirred at 0 °C for 15 min after which a solution of tetralol
15 (0.10 g, 0.48 mmol) in dioxane (1.0 mL) was added. After 5
h, the solvent was removed by rotary evaporation. Purification
of the material on a silica gel column using EtOAc-hexanes (2:
8) as eluant afforded 0.12 g (85%) of tetralol 16 as a clear,
colorless oil: 1H NMR (CDCl3) δ 5.65 (s, 1H), 3.80 (s, 3H), 3.11
(m, 1H), 2.92 (m, 1H), 2.54 (ddd, J ) 18.0, 10.4, 7.6, 1H), 2.37
(s, 3H), 1.79 (m, 4H), 1.15 (d, J ) 7.1, 3H); 13C NMR (CDCl3) δ
143.45, 142.98, 133.92, 131.27, 129.32, 111.25, 60.05, 30.11,
29.96, 23.52, 21.32, 18.68, 16.77. Anal. Calcd for C13H17BrO2:
C, 54.75; H, 6.01. Found: C, 54.76; H, 6.08.
7-Br om o-5-m eth oxy-6-p r op a r gyloxy-1,8-d im eth yltetr a -
lin (18). A solution of tetralol 16 (0.85 g, 3.0 mmol) in dry
acetone (30 mL) was stirred at room temperature as K2CO3 (2.10
g, 15.2 mmol) was added, followed by an 80% w/w solution of
propargyl bromide in toluene (0.67 g, 4.5 mmol). The reaction
mixture was refluxed for 2 h, cooled to room temperature, and
filtered through Celite. The filtrate was concentrated, and the
residue was dissolved in CH2Cl2. The solution was dried over
MgSO4 and filtered, and the solvent was removed by rotary
evaporation. Purification of the material on a silica gel column
using EtOAc-hexanes (1:9) as eluant afforded 0.86 g (89%) of
tetralin 18 as a clear, colorless oil: 1H NMR (CDCl3) δ 4.68 (dd,
J ) 2.4, 0.8, 2H), 3.85 (s, 3H), 3.11 (m, 1H), 2.89 (m, 1H), 2.55
(dd, J ) 2.4, 2.4, 1H), 2.49 (ddd, J ) 18.0, 9.0, 9.0, 1H), 2.38 (s,
3H), 1.80 (m, 4H), 1.16 (d, J ) 6.9, 3H); 13C NMR (CDCl3) δ
149.46, 145.66, 138.82, 131.67, 130.05, 118.79, 79.10, 75.13,
60.13, 30.27, 29.89, 29.68, 23.49, 21.03, 18.80, 16.66. Anal. Calcd
for C16H19BrO2: C, 59.45, H; 5.93. Found: C, 59.44; H, 5.95.
9-Meth oxyca ca lol (19). A solution of tetralin 18 (0.51 g, 1.6
mmol) in dry p-xylene (16 mL) was stirred at room temperature
as tributyltin hydride (0.50 mL, 1.9 mmol) was added, followed
by 2,2′-azobisisobutyronitrile (0.51 g, 0.03 mmol). The reaction
mixture was then heated to reflux for 2 h. Solvent was then
removed from the reaction mixture by rotary evaporation. The
residual oil was then chromatographed on a silica gel column
using EtOAc-hexanes (1:19) as eluant to give a coeluting
mixture of exo and endo double-bond isomers.
sulfonic acid (0.15 g, 0.8 mmol) was added. After 1 h, the solvent
was removed from the mixture by rotary evaporation. Purifica-
tion of the material on a silica gel column using EtOAc-hexanes
(1:19) as eluant afforded 0.20 g (53%) of methoxycacalol 19 as a
clear, colorless oil: 1H NMR (CDCl3) δ 7.27 (m, 1H), 4.06 (s, 3H),
3.25 (m, 1H), 3.05 (m, 1H), 2.64 (ddd, J ) 18.0, 10.8, 7.2, 1H),
2.56 (s, 3H), 2.40 (s, 3H), 1.83 (m, 4H), 1.20 (d, J ) 7.1, 3H); 13
C
NMR (CDCl3) δ 145.31, 140.91, 140.41, 135.52, 127.25, 124.29,
123.05, 116.48, 60.05, 30.18, 28.99, 23.53, 21.51, 16.97, 14.03,
11.41. Anal. Calcd for C16H20O2: C, 78.65; H, 8.25. Found: C,
78.30; H, 8.36.
Ca ca lol (1). A solution of methoxycacalol 19 (0.090 g, 0.4
mmol) in dry CH2Cl2 (4.0 mL) was stirred at -78 °C as a 1.0 M
solution of BBr3 in CH2Cl2 (0.41 mL, 0.4 mmol) was added
dropwise. The reaction mixture was allowed to slowly warm to
room temperature. After 4 h, the reaction mixture was poured
into saturated aqueous NH4Cl and extracted with CH2Cl2. The
organic layer was dried over MgSO4 and filtered, and the solvent
was removed by rotary evaporation. Purification of the material
on a silica gel column using EtOAc-hexanes (1:9) as eluant
afforded 0.060 g (71%) of cacalol (1) as a clear, colorless oil, which
could be recrystallized from hexanes to give white crystals, mp
87 °C (lit.18 89-91 °C): 1H NMR (CDCl3) δ 7.26 (m, 1H), 4.98
(s, 1H), 3.25 (m, 1H), 3.00 (m, 1H), 2.63 (ddd, J ) 17.6, 11.2,
7.3, 1H), 2.53 (s, 3H), 2.39 (s, 3H), 1.95-1.75 (m, 4H), 1.20 (d, J
) 6.9, 3H); 13C NMR (CDCl3) δ 142.12, 140.85, 136.29, 135.57,
126.13, 120.21, 118.65, 117.12, 30.08, 28.93, 22.90, 21.35, 16.63,
13.80, 11.30. Anal. Calcd for C15H18O2: C, 78.23; H, 7.88.
Found: C, 78.18; H, 7.90.
Ack n ow led gm en t. The authors thank ZhiJ un Ye,
J ian Lu Chen, and Nigel Parkinson for their assistance
in obtaining NMR and mass spectral data, the ethno-
botany, biology, and natural product chemistry groups
at Shaman for the isolation of cacalol and discovery of
its antihyperglycemic properties, and Professor Henry
Rapoport for valuable consulting.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 3-5 and 9, and 1H NMR spectra of
compounds 3-5, 9, and 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O9822838
The mixture of double-bond isomers was then dissolved in
CH2Cl2 (25 mL) and stirred at room temperature as p-toluene-
(18) Romo, J .; J oseph-Nathan, P. Tetrahedron 1964, 20, 2331-2337.