A Synthesis of (+)-Salvadione-A

Article abstract of DOI:10.1021/ol035380i

(Matrix presented) The p-benzoquinone shown is converted to the novel hexacyclic triterpene salvadione-A in four steps.

Full text of DOI:10.1021/ol035380i

ORGANIC
LETTERS
2
003
Vol. 5, No. 21
847-3850
A Synthesis of (+)-Salvadione-A
3
George Majetich,* Yanyun Wang, Yang Li, Jason K. Vohs, and
Gregory H. Robinson†
Department of Chemistry, UniVersity of Georgia, Athens, Georgia 30602
majetich@chem.uga.edu
Received July 23, 2003
ABSTRACT
The p-benzoquinone shown is converted to the novel hexacyclic triterpene salvadione-A in four steps.
The genus SalVia, comprising more than 800 species, is the
1
largest genus of the Lamiaceae family. SalVia bucharica,
Scheme 1
popularly known in Pakistan as “sursaudah”, is found
throughout Central Asia, and is used in popular medicines
2
for liver disorders as well as for its cooling effects. In 1999,
salvadione-A (1) was isolated from sursaudah by Ahmad and
co-workers, and its structure was rigorously established by
means of 2D-NMR spectroscopy and X-ray diffraction
3
analysis (Scheme 1). Since salvadione-A possesses many
4
of the salient features of perovskone (3), we recognized that
it could be synthesized from quinone 2, a key intermediate
5
in our perovskone synthesis. A detailed discussion of our
synthesis of salvadione-A follows.
Scheme 2 summarizes our retrosynthetic analysis for
salvadione-A. We have found that dienes add to the R-face
of quinone 2.5 In addition, the presence of a Lewis acid
allows the Diels-Alder reaction to occur at temperatures as
,6
†
Author for correspondence regarding the X-ray studies.
(1) (a) Fujita, E.; Node, M. Diterpenoids of Rabdosia Species. In Prog.
Chem. Org. Nat. Prod. 1986, 46, 77-157. (b) Chopra, R. N.; Nayar, S. L.;
low as -20 °C, and also controls the regioselectivity of the
Chopra, I. C. Glossary of Indian Medicinal Plants; CSIR: New Delhi, India,
1
956; p 189. (c) Kirtikar, K. R.; Basu, B. D. Indian Medicinal Plants; Indian
Press: Allahabad, India, 1918; p 1031.
2) Nasir, E.; Ali, S. I. Flora of Pakistan; Fakhri Printing Press: Karachi,
Pakistan, 1986; Vol. 56, p 156.
3) Ahmad, V. U.; Zahid, M.; Ali, M. S.; Ali, Z.; Jassbi, A. R.; Abbas,
M.; Clardy, J.; Lobkovsky, E.; Tareen, R. B.; Iqbal, M. Z. J. Org. Chem.
999, 64, 8465-8467.
4) Parvez, A.; Choudhary, M. I.; Akhter, F.; Noorwala, M.; Mohammad,
F. V.; Hasan, N. M.; Zamir, T.; Ahmad, V. U. J. Org. Chem. 1992, 57,
339-4340.
5) For our synthesis of (()-perovskone, see: Majetich, G.; Zhang, Y.
J. Am. Chem. Soc. 1994, 116, 4979-4980.
cycloaddition when an asymmetric diene, such as isoprene,
5,6
is used.
(
The use of triene 4 as the diene substrate raises the
question of which conjugated diene moiety, the 3,5- or the
(
1
(
(6) Optically active p-benzoquinone 2 has been prepared in 11 steps and
in >50% overall yield. A manuscript detailing this work and a synthesis of
(+)-perovskone is under review. See: Majetich, G.; Zhang, Y.; Tian, X.;
Britton, J. F.; Wang, Y.; Li, Y. The Total Synthesis of (()- and
(+)-Perovskone.
4
(
1
0.1021/ol035380i CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/20/2003

Scheme 2
5
,7-system, should preferentially take part in the Diels-Alder
a synthesis of salvadione-A (i.e., 6 f 7 f 1). Since each of
these transformations can in principle be carried out by using
Lewis acid catalysis, the judicious choice of catalyst and
reaction conditions should permit the Diels-Alder reaction,
addition. Scrutiny of triene 4 indicates that the presence of
a Z-methyl substitutent as part of the 3,5-butadiene moiety
reduces its reactivity by hindering the likelihood of the s-cis
form (cf. 4i, Scheme 3), whereas the 5,7-diene readily adopts
N
the intramolecular S 2′-alkylation, and the sequential hydra-
tion of the C(11)-carbonyl and tetrahydrofuran formation to
proceed in a tandem cascade fashion (Scheme 4). While the
Scheme 3
Scheme 4
an s-cis conformation (cf. 4ii). Hence, the cycloaddition of
2
with 4 will produce only adduct 5, which has the correct
stereochemistry at C(8), C(9), and C(24).
Protection of the C(2) hydroxyl of triene 4 as an acetate
permits the subsequent formation of the C(13),C(25)-bond
N
by means of an intramolecular S 2′-alkylation of the latent
7
1
,3-dione present in the C-ring. We predicted that simple
conformational biasing, prior to the S 2′-alkylation, would
N
control the C(25) stereochemistry. In particular, nonbonded
steric interactions between the C(24) side chain and the C(13)
isopropyl unit would disfavor conformer 5i, thus causing the
less sterically congested conformation 5ii to predominate,
leading to the formation of pentacycle 6. Examination of a
Dreiding molecular model of triketone 6 reveals that the
C(11) carbonyl oxygen is situated almost directly above the
C(10) carbon atom, which should faciliate hydration of the
C(1),C(10)-trisubstituted double bond, thereby completing
synthesis of salvadione-A via this cascade-based process is
our ultimate goal, we decided to first synthesize 1 in a
stepwise fashion.
Triene 4 was synthesized from trans-â-ocimene (8) in
8
three simple steps (Scheme 5). The reaction of 8 with 1
equiv of mCPBA in cold methylene chloride gave a high
9
yield of epoxide 9, which produced octa-3(E),5(E)-trien-2-
ol (10) when treated with excess LDA at 0 °C.
Unfortunately, acetate 4, derived from tertiary alcohol 10,
was shown to undergo rapid elimination at ambient temper-
(
7) For the alkylation of 1,3-diones with allylic carbonates and allylic
acetates, see: Trost, B. M.; Tometzki, G. B.; Hung, M.-H. J. Am. Chem.
Soc. 1987, 109, 2176-2177.
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Org. Lett., Vol. 5, No. 21, 2003

Treatment of adduct 12 with excess boron trifluoride
etherate in CH Cl at 0 °C rapidly gave the S 2′-alkylation
2
2
N
Scheme 5
1
product in 54% yield. H NMR data suggested that the 2.7-
Hz coupling constant between the C(24) and C(25) methines
was indicative of a dihederal angle of almost 120°, indicating
that C(25) had the desired stereochemistry; molecular models
indicated that the wrong stereochemistry at C(25) would
produce a dihedral angle of about 30° and a coupling constant
of >6 Hz.
A fundamental tenet in organic chemistry is that carbonyl
groups with electron-withdrawing subsitutents are easily
hydrated. Indeed, in 1963 Bakule and Long demonstrated
that 1,2-cyclohexandiones which cannot enolize, such as 6,
are completely and rapidly hydrated when exposured to
1
1
dilute aqueous acid. While the reaction of triketone 6
under various aqueous acidic conditions or with water-sol-
uble Lewis acids produced a geminal diol, hydration of the
C(1),C(10)-double bond was not observed. These observa-
tions suggest that the C(12) carbonyl, which is geometrically
unable to assist in the hydration of the C(1),C(10)-double
bond, is preferentially hydrated. Fortunately, the observation
that the C(11) carbonyl oxygen was near the C(10) carbon
atom of the trisubstituted double bond of 6 offered a solution
to our hydration difficulties. We speculated that the bromo-
nium ion intermediate generated from the C(1),C(10)-double
bond would be opened by the oxygen atom of the C(11)
carbonyl to form the desired tetrahydrofuran ring. Treatment
of 6 with NBS and 1 N perchloric acid gave bromide 13 in
ature, upon attempted purification, or upon exposure to mild
Lewis acid catalysts (even at low temperatures). Methyl ether
11 was prepared in the hope that the methoxyl group would
be less prone to elimination, thereby permitting the Diels-
Alder reaction to occur. Triene ether 11 was thermally stable
and reacted over a 72-h period with quinone 2 at 80 °C to
afford adduct 12 in 76% yield (Scheme 6); an X-ray analysis
1
2,13
Scheme 6
88% yield (Scheme 7).
Note that triketone 6 contains
Scheme 7
of adduct 12 confirmed the predicted facial and regioselec-
tivity of this cycloaddition.10,13
(
8) Ocimene is sold by International Flavors & Fragrances as a mixture
two other trisubstituted double bonds which might also react
with bromine. However, the steric influence of the C-ring
of triketone 6 prevents the bromonium ions derived from
of the C(3),C(4)-E and -Z isomers. Treatment of this mixture with gaseous
SO2 selectively forms an adduct with the C(3),C(4)-E isomer, which is easily
separated from the unreacted C(3),C(4)-Z isomer by chromatography on
silica gel. Extrusion of SO2 from the adduct provides pure trans-R-ocimene
(
8). For the total synthesis of trans-R-ocimene from the SO2 adduct of
isoprene, see: Chou, T.; Tso, H.-H.; Chang, L.-J. J. Chem. Soc., Chem.
Commun. 1984, 1323-1324.
(10) Crystal data for C31H44O4 (12): MW ) 480.66, orthorhombic, Pbca,
a ) 12.679(5) Å, b ) 20.791(10) Å, c ) 21.054(10) Å, R, â, γ ) 90°, V
3
(
9) Conjugation diminishes the reactivity of an alkene in epoxidations;
) 5550(4) Å , Z ) 8, T ) 293(2) K, µ(Mo KR) ) 0.71073 Å, Dcalcd )
3
thus, isolated alkenes are usually epoxidized before a conjugated alkene,
see: Hiyama, T.; Kanakura, A.; Yamamoto, H.; Nozaki, H. Tetrahedron
Lett. 1978, 3051-3054.
1.151 Mg/m , R(1) ) 8.49% for 6642 observed independent reflections
(I > 2σ(I)). All non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were treated as idealized contributions.
Org. Lett., Vol. 5, No. 21, 2003
3849

these alkenes from opening. Removal of the bromine atom
via free radical reduction completed our stepwise synthesis
of (()-salvadione-A. The use of optically active p-benzo-
respectively. The C(11) carbonyl was resistant to hydration.
A synthesis of salvadione-A was completed by means of an
intramolecular bromohydrin reaction, followed by free radical
reduction. Our quest to develop conditions to synthesize
salvadione-A via a cascade-based process, while perhaps
unlikely in light of our many observations, continues.
6
24
quinone 2 produced salvadione-A with [R]
.36, CHCl ); the reported value is +37.92 (c 0.37, CHCl
In summary, salvadione-A, which has six rings and eight
D
+37.61 (c
0
3
3
).
chiral centers, was synthesized from quinone 2 in only four
steps. The first two steps feature a stereo- and regiospecific
Diels-Alder reaction and an intramolecular alkylation,
Acknowledgment. Appreciation is extended to the Na-
tional Science Foundation (GFM: CHE-0010128; G.H.R.:
CHE-0209857) for support of this research.
(
11) (a) Bakule, R.; Long, F. A. J. Am. Chem. Soc. 1963, 85, 2309-
312. (b) Sandris, C.; Ourisson, G. Bull. Soc. Chim. Fr. 1958, 338-344.
c) Sandris, C.; Ourisson, G. Bull. Soc. Chim. Fr. 1958, 1524-1526.
OL035380I
2
(
(
12) Crystal data for C30H41O4Br (13): MW ) 545.54, monoclinic, P21/
(13) Crystal data and other details for compound 12, the adduct of
quinone 2, and triene 11 have been deposited at the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK (Tel +44
1223 336408, Fax +44 1223 336033, E-mail http://www.ccdc.cam.ac.uk);
see CCDC 213664. For crystal data and other details for bromide 13, see
CCDC 209551.
c, a ) 13.308(4) Å, b ) 15.807(5) Å, c ) 13.969(4) Å, â ) 110.223(5)°,
3
V ) 2757.2(14) Å , Z ) 4, T ) 293(2) K, µ(Mo KR) ) 0.71073 Å, Dcalcd
3
)
(
1.314 Mg/m , R(1) ) 7.62% for 5595 observed independent reflections
I > 2σ(I)). All non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were treated as idealized contributions.
3850
Org. Lett., Vol. 5, No. 21, 2003