Total synthesis of five cacalol families at different oxidation stages, modified furanoeremophilane sesquiterpenes from Cacalia and Senecio species

Article abstract of DOI:10.1246/cl.2004.136

The recent findings of antihyperglycemic and antimicrobial activities for a modified furanoeremophilane sesquiterpene cacalol (1) prompted us to achieve the first total synthesis of five cacalol families (±)-2-4, 5, and 6 which might also be expected to i

Full text of DOI:10.1246/cl.2004.136

136
Chemistry Letters Vol.33, No.2 (2004)
Total Synthesis of Five Cacalol Families at Different Oxidation Stages, Modified
Furanoeremophilane Sesquiterpenes from Cacalia and Senecio Species
Yoshinori Hirai, Matsumi Doe, Takamasa Kinoshita, and Yoshiki Morimotoꢀ
Department of Chemistry, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka 558-8585
(Received November 14, 2003; CL-031102)
The recent findings of antihyperglycemic and antimicrobial
mediate 7 will be derived from tetralone 9 via the furan ring for-
mation in 8. 9 will be constructed from commercially available
ꢀ-valerolactone 10 and 4-bromoveratrole 11 by Friedel–Crafts
reaction.
activities for a modified furanoeremophilane sesquiterpene caca-
lol (1) prompted us to achieve the first total synthesis of five ca-
calol families (ꢁ)-2–4, 5, and 6 which might also be expected to
indicate such potent biological activities.
Cacalia decomposita A. Gray,1 a compositae widely distrib-
uted in the northern part of Mexico, is a shrub popularly known
as matarique and maturin. Matarique is a medicinal plant com-
plex of Mexico which includes perennial herbs with thin, fasci-
cled roots extending from a pubescent root crown, the concoc-
tion of which is drunk, alone or in combination with other
herbs, for treating diabetes, kidney pain, and rheumatism; it
can also be applied as a wash or cataplasm to treat wounds
and skin ulcers.2 Extensive chromatography of a hexane extract
from the roots of Cacalia decomposita A. Gray afforded a modi-
fied eremophilane cacalol (1), which has been shown to be the
first representative of a new class of compounds (cacalol fami-
lies) possessing the furotetralin ring system.3 The structures of
1 and related compounds4 were the subject of several structural
revisions,5 and the final structures were confirmed by chemical
synthesis6 and degradation studies.7
Scheme 1. Retrosynthetic analysis of cacalol families 2–6.
The intermolecular regioselective Friedel–Crafts alkylation
of 11 with 10 gave a mixture 12 of two carboxylic acids, which
without separation into each component was successively treat-
ed with AcCl in MeOH and subsequent Me2SO4 to afford a sin-
gle methyl ester 13 in 54% yield over 3 steps (Scheme 2).6b Sap-
onification of the ester 13 provided carboxylic acid 14, an
intramolecular Friedel–Crafts acylation of which proceeded by
(CF3CO)2O in CF3CO2H13 to furnish tetralone 9. Since it was
found that selective demethylation of the 8-MeO group in 9
was difficult, we chose to alkylate the 8-OH group with a C3 unit
required for the furan ring formation after removing both methyl
groups. Treatment of 9 with BBr3 yielded catechol 15, etherifi-
cation of which with chloroacetone could regioselectively be
achieved at the 8-OH to give ether 16 in 86% yield. After meth-
ylation of 16, the resulting 17 was subjected to reduction with
NaBH4 and CF3CO2H to afford monoketone 8 reduced only at
the benzylic carbonyl group and further reduced alcohol 18, re-
spectively, both of which were mutually convertible in high
yields by a usual manner. Cyclization of 8 with CF3SO3H result-
ed in the furan derivative 7, which could be dehydrogenated with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)14 to provide
naphthofuran 19. Debromination of 19 with LiAlH4 produced
14-nordehydrocacalohastine (5) in a quantitative yield. The
spectral characteristics of synthetic 515 were in good agreement
with those reported for the natural product.12
Next, we turned our attention to syntheses of the other caca-
lol families 2–4 and 6 with 6-substituents. First, we examined
modification at the C6 position in the furotetralin 7; however,
it has been found difficult, probably owing to steric hindrance
by the two lateral methyl groups at C4 and C11 positions. There-
fore, we adopted a C–C bond formation at C6 before construct-
ing the furan ring. After methoxymethyl (MOM) protection of
the alcohol 18, lithium–halogen exchange in the resultant bro-
mide 20 followed by formylation furnished aldehyde 21 in
90% yield (Scheme 3). Deprotection of the MOM ether in 21
and subsequent Swern oxidation16 of the alcohol 22 yielded ke-
Recently, in vivo bioassay-directed fractionation of an ex-
tract from the roots of Cacalia decomposita A. Gray revealed
that 1 exhibits antihyperglycemic8 and antimicrobial9 activities.
Therefore, other known cacalol families, such as 14-oxocacalol
methyl ether (2),10 14-oxo-1,2-dehydrocacalol methyl ether
(3),10,11 14-hydroxy-1,2-dehydrocacalol methyl ether (4),11 and
14-nordehydrocacalohastine (5)12 isolated from Senecio species
and maturinin (6)4,11b isolated from Cacalia decomposita A.
Gray, might also be expected to possess similar biological activ-
ities. We took an interest in biological activities of the furano-
eremophilanes 2–6, the oxidation stages of which were different
from those of 1 at the C-ring and C14 position. In this paper,
we report the first total synthesis of these cacalol families (ꢁ)-
2–4, 5, and 6 via stepwise regioselective dehydrogenation of
the C-ring.
The retrosynthetic analysis of 2–6 is depicted in Scheme 1.
These compounds 2–6 possess a variety of oxidation states and
substituents at the C-ring and C6 position, respectively; there-
fore, we envisaged tetralin 7 as a possible intermediate, because
7 will allow stepwise regioselective dehydrogenation of the C-
ring and introduction of various substituents at C6. The inter-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.2 (2004)
137
plication of this synthetic strategy to many other cacalol families
are in progress.
M. Doe thanks Osaka City University for the OCU Grant for
Graduate Course Students.
References and Notes
1
Synonyms for Cacalia decomposita A. Gray include Psacalium
decompositum and Odontorichum decompositum (Gray) Rydb.
E. Linares and R. A. Bye, J. Ethnopharmacol., 19, 153 (1987).
J. Romo and P. Joseph-Nathan, Tetrahedron, 20, 2331 (1964).
J. Correa and J. Romo, Tetrahedron, 22, 685 (1966).
P. M. Brown and R. H. Thomson, J. Chem. Soc. C, 1969, 1184; H.
Kakisawa and Y. Inouye, Tetrahedron Lett., 1969, 1929; R. M. Ruiz,
J. Correa, and L. A. Maldonado, Bull. Soc. Chim. Fr., 1969, 3612.
a) F. Yuste and F. Walls, Aust. J. Chem., 29, 2333 (1976). b) Y.
Inouye, Y. Uchida, and H. Kakisawa, Bull. Chem. Soc. Jpn., 50,
961 (1977). c) J. W. Huffman and R. Pandian, J. Org. Chem., 44,
1851 (1979). d) A. W. Garofalo, J. Litvak, L. Wang, L. G. Dubenko,
R. Cooper, and D. E. Bierer, J. Org. Chem., 64, 3369 (1999).
M. Terabe, M. Tada, and T. Takahashi, Bull. Chem. Soc. Jpn., 51,
661 (1978).
2
3
4
5
6
Scheme 2. Reaction conditions: a) 10, AlCl3, (CHCl2)2, 70 ꢃC;
b) AcCl, MeOH, rt, 14 h; c) Me2SO4, K2CO3, acetone, reflux,
46 h, 54% (3 steps); d) NaOH, MeOH, 40 ꢃC, 24 h, 97%; e)
(CF3CO)2O, CF3CO2H, 40 ꢃC, 3 h, 64%; f) BBr3, CH2Cl2,
ꢂ78 to ꢂ40 ꢃC, 18 h, 98%; g) chloroacetone, Li2CO3, 70 ꢃC,
17 h, 86%; h) Me2SO4, K2CO3, acetone, reflux, 14 h, 77%; i)
NaBH4, CF3CO2H, 0 ꢃC to rt, 4 h; j) NaBH4, MeOH, rt, 14 h,
96%; k) Jones oxidation, 92%; l) CF3SO3H, CH2Cl2, 0 ꢃC,
30 min, 57%; m) DDQ, CH2Cl2, 0 ꢃC, 5 h, 41%; n) LiAlH4,
THF, 0 ꢃC, 4 h, 100%.
7
8
9
W. D. Inman, J. Luo, S. D. Jolad, S. R. King, and R. Cooper, J. Nat.
Prod., 62, 1088 (1999) and references cited therein.
´
M. L. Gardun˜o-Ramırez, A. Trejo, V. Navarro, R. Bye, E. Linares,
and G. Delgado, J. Nat. Prod., 64, 432 (2001).
´
10 F. Bohlmann, S. Dupre, and B. Nordenstam, Phytochemistry, 29,
3163 (1990).
11 a) F. Bohlmann, K.-H. Knoll, C. Zdero, P. K. Mahanta, M. Grenz, A.
Suwita, D. Ehlers, N. L. Van, W.-R. Abraham, and A. A. Natu, Phy-
tochemistry, 16, 965 (1977). b) F. Bohlmann and C. Zdero, Phyto-
chemistry, 17, 1161 (1978).
12 P. Torres, R. Chinchilla, M. C. Asensi, and M. Grande, Phytochem-
istry, 28, 3093 (1989).
13 S. P. Chavan, V. D. Dhondge, S. S. Patil, Y. T. S. Rao, and C. A.
Govande, Tetrahedron: Asymmetry, 8, 2517 (1997).
14 E. A. Braude, A. G. Brook, and R. P. Linstead, J. Chem. Soc., 1954,
3569.
15 5: ꢁH (300 MHz, CDCl3) 8.21 (1H, d, J ¼ 8:4 Hz), 7.72 (1H, s), 7.47
(1H, q, J ¼ 1:3 Hz), 7.33 (1H, dd, J ¼ 8:4, 6.8 Hz), 7.27 (1H, d,
J ¼ 6:6 Hz), 4.35 (3H, s), 2.75 (3H, s), 2.33 (3H, d, J ¼ 1:3 Hz);
ꢁC (75 MHz, CDCl3) 143.1, 142.3, 138.5, 133.8, 131.8, 130.4,
125.0, 124.5, 123.8, 120.3, 115.7, 107.1, 60.8, 20.3, 8.0. (ꢁ)-2: ꢁH
(400 MHz, CDCl3) 10.68 (1H, s), 7.42 (1H, q, J ¼ 1:0 Hz), 4.28
(3H, s), 4.03 (1H, qt, J ¼ 7:0, 3.5 Hz), 2.97 (1H, ddd, J ¼ 18:0,
5.9, 2.0 Hz), 2.59 (1H, ddd, J ¼ 18:1, 11.0, 7.2 Hz), 2.37 (3H, d,
J ¼ 1:2 Hz), 1.95–1.71 (4H, m), 1.27 (3H, d, J ¼ 7:1 Hz); ꢁC
(100 MHz, CDCl3) 190.4, 146.6, 144.4, 143.8, 143.2, 131.4, 123.5,
121.8, 116.0, 60.1, 29.3, 28.7, 23.7, 23.5, 16.5, 12.8. (ꢁ)-3: ꢁH
(300 MHz, CDCl3) 10.70 (1H, s), 7.47 (1H, q, J ¼ 1:1 Hz), 6.90
(1H, dd, J ¼ 9:9, 3.1 Hz), 6.00 (1H, dddd, J ¼ 9:7, 6.5, 2.4,
0.6 Hz), 4.27 (3H, s), 4.09 (1H, quintet, J ¼ 6:8 Hz), 2.51 (1H, ddt,
J ¼ 17:3, 6.7, 2.9 Hz), 2.38 (3H, d, J ¼ 1:3 Hz), 2.22 (1H, ddd,
J ¼ 17:3, 6.5, 1.5 Hz), 1.17 (3H, d, J ¼ 7:1 Hz); ꢁC (75 MHz,
CDCl3) 190.4, 145.1, 144.21, 144.18, 141.7, 131.4, 126.1, 121.7,
120.5, 120.1, 116.3, 60.6, 29.9, 27.3, 20.3, 12.7. 6: ꢁH (400 MHz,
CDCl3) 11.08 (1H, s), 8.28 (1H, t, J ¼ 4:9 Hz), 7.56 (1H, q,
J ¼ 1:2 Hz), 7.40 (2H, d, J ¼ 5:9 Hz), 4.43 (3H, s), 2.69 (3H, s),
2.33 (3H, d, J ¼ 1:2 Hz). (ꢁ)-4: ꢁH (400 MHz, CDCl3) 7.36 (1H,
q, J ¼ 1:2 Hz), 6.93 (1H, dd, J ¼ 9:8, 3.2 Hz), 5.94 (1H, dddd,
J ¼ 9:8, 6.4, 2.4, 0.9 Hz), 4.92 (2H, s), 4.11 (3H, s), 3.43 (1H, quin-
tet, J ¼ 6:9 Hz), 2.55 (1H, ddt, J ¼ 17:1, 6.3, 2.9 Hz), 2.42 (3H, d,
J ¼ 1:2 Hz), 2.24 (1H, ddd, J ¼ 17:1, 6.3, 1.2 Hz), 1.46 (1H, br s),
1.14 (3H, d, J ¼ 7:1 Hz); ꢁC (100 MHz, CDCl3) 145.8, 142.3,
140.5, 136.0, 128.7, 124.9, 123.7, 121.2, 121.0, 116.2, 60.8, 57.3,
30.6, 27.7, 21.2, 10.2.
Scheme 3. Reaction conditions: a) MOMCl, i-Pr2NEt, CH2Cl2,
97%; b) n-BuLi, THF, ꢂ78 ꢃC, then DMF, 1 h, 90%; c) 3 N HCl,
THF, 40 ꢃC, 100%; d) Swern oxidation, 84%; e) CF3SO3H,
CH2Cl2, 0 ꢃC to rt, 5 h, 99%; f) DDQ, benzene, 0 ꢃC to rt, 3 h;
g) Burgess reagent, benzene, rt, 37%; h) o-chloranil, CH2Cl2,
rt, 20 h, 54%; i) LiAlH4, THF, 0 ꢃC, 5 min, 69%.
tone 23, which was cyclized with CF3SO3H to give (ꢁ)-14-ox-
ocacalol methyl ether (2) in 99% yield. The spectral characteris-
tics of synthetic (ꢁ)-2 were also consistent with those reported
for the natural product.10 After many experimentations, oxida-
tion of 2 employing 1.85 equiv. of DDQ afforded regioselective-
ly 1,2-dehydrogenated (ꢁ)-14-oxo-1,2-dehydrocacalol methyl
ether (3)11a and maturinin (6),4 respectively, along with 1-hy-
droxylated compound 24, which could be transformed into 3
by dehydration with Burgess reagent.17 6 was also able to be de-
rived from (ꢁ)-3 by dehydrogenation with o-chloranil. LiAlH4
reduction of 3 gave (ꢁ)-14-hydroxy-1,2-dehydrocacalol methyl
ether (4)11a as well.
In conclusion, we have accomplished the first total synthesis
of five cacalol families (ꢁ)-2–4, 5, and 6, which might be ex-
pected to exhibit such antihyperglycemic and antimicrobial ac-
tivities as those of cacalol (1). Bioassay for synthetic 2–6 and ap-
16 A. J. Mancuso, S.-L. Huang, and D. Swern, J. Org. Chem., 43, 2480
(1978).
17 E. M. Burgess, H. R. Penton, and E. A. Taylor, Jr., J. Org. Chem., 38,
26 (1973).
Published on the web (Advance View) January 9, 2004; DOI 10.1246/cl.2004.136