A short enantioselective total synthesis of (-)-linderol A

Article abstract of DOI:10.1055/s-2007-1000834

An efficient short enantioselective total synthesis of (-)-linderol A was achieved via a five-step reaction with 30% overall yield, starting from 4-methoxyphloroacetophenone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000834

94
LETTER
A Short Enantioselective Total Synthesis of (–)-Linderol A
Total
S
ynthesis of
a
(–)-Lindero
t
l
A
ice Berber,* Pierre-Olivier Delaye, Catherine Mirand
FRE 2715/CNRS, UFR Pharmacie, 51 Rue Cognacq-Jay, 51096 Reims Cedex, France
Fax +33(3)26918029; E-mail: hatice.berber@univ-reims.fr
Received 11 June 2007
reospecific intramolecular epoxide opening with pheno-
late anion (via ester hydrolysis of 2) before the
introduction of the chalcone chain.
Abstract: An efficient short enantioselective total synthesis of (–)-
linderol A was achieved via a five-step reaction with 30% overall
yield, starting from 4-methoxyphloroacetophenone.
The endocyclic epoxide 2 could be formed from acetylat-
ed 3 using an epoxidation that would be diastereoselective
because of the steric bulk on the adjacent side of the alk-
ene. Furthermore, the first key step of our strategy is a ter-
penylation of 4-methoxyphloroacetophenone (4) with an
allylic cation generated from the suitable chiral monoter-
pene (–)-a-phellandrene.
Key words: total synthesis, stereoselectivity, terpenylation, ep-
oxides, hexahydrodibenzofuran
(–)-Linderol A [(–)-1, Figure 1], a monoterpene-substitut-
ed chalcone with four successive asymmetric carbons at
the 6 (R), 5a (R), 9a (S) and 9 (R) positions, was isolated
in 1995 from the fresh bark of Lindera umbellata (Lau-
raceae) by Sashida and co-workers.1 They also reported
the potent inhibitory activity of this natural product on the
melanin biosynthesis of B-16 melanoma cells without
causing any cytotoxicity on the cultured cells.1
OMe
Me
H
O
O
HO
O
H
AcO
OAc
OH
O
Ph
OMe
H
2
O
1
9
(–)-1
9b
2
3
8
9a
5a
5
O
7
6
4a
HO
4
Me
H
OMe
7'
O
OH
O
Ph
8'
Figure 1 Structure of (–)-linderol A [(–)-1]
HO
OH
HO
OH
3
4
O
O
Its first total synthesis in racemic series was reported by
Ohta and co-workers.2 The critical step of their strategy
was a tandem reaction of a 3-ethoxycarbonylcoumarin de-
rivative with dimethylsulfoxonium methylide to give the
2-ethoxycarbonylcyclopenta[b]benzofuran-3-ol deriva-
tive. Further they applied a stereoconvergent approach to
dibenzofuran derivatives from benzo[b]cyclobuta[d]pyr-
an derivatives to the second-generation synthesis of ( )-
linderol A.3
Scheme 1 Retrosynthetic approach
Terpenylation using (–)-a-phellandrene was previously
described by Crombie and co-workers for the synthesis of
(3S,4R)-(+)-linderatin, a monoterpenylated dihydrochal-
cone.4 The procedure was slightly modified for our
reagent (Scheme 2): treatment of 4-methoxyphloroace-
tophenone (4)5 with (–)-a-phellandrene in the presence of
Although they considerably improved the synthetic route p-toluenesulfonic acid in toluene at room temperature for
to linderol A by decreasing the number of steps from one hour gave the monoterpenylated compound 3 in 76%
twenty to twelve and increasing the overall yield from yield after silica gel column chromatography. As expect-
7.64% to 25%, to the best of our knowledge, no asymmet- ed, the relative configuration between H3 and H4 is trans
ric synthesis of (–)-linderol A has ever been described.
(confirmed by 1H NMR data: J3,4 = 8.8 Hz).
To fulfill this goal, we envisaged the total synthesis of the The corresponding diacetate product 5 was prepared in
optically active natural product in a minimum of steps, good yield from 3 by acetylation in pyridine at 70 °C for
starting from an easily available commercial reagent. Our 24 hours. Compound 5 was characterized by its spectro-
retrosynthetic approach is outlined in Scheme 1. The scopic data (NMR and MS) and its optical rotation was
hexahydrodibenzofuran ring can be obtained from a ste- also determined.6
To finalize our synthesis, we have been inspired by the
works developed by Razdan et al. to build the chosen tri-
SYNLETT 2008, No. 1, pp 0094–0096
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-1000834; Art ID: D18007ST
x
x.
x
x.
2
0
0
7
cyclic system with control of asymmetric centers (see
Scheme 3).7 Diacetate compound 5 was allowed to react
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (–)-Linderol A
95
hibited a 3J5a,9a coupling constant of 5.5 Hz suggesting co-
planarity.
OMe
Me
4
O
3
Considering epoxide 2¢ as a nonproductive starting mate-
rial for ring opening, the exact yield is 87% starting from
2 (see Scheme 3).
(2 equiv)
PTSA (2 equiv)
1
2
HO
OH
RO
OR
toluene
O
(–)-Linderol A was finally obtained after introduction of
the chalcone side chain by treatment of 6 with benzalde-
hyde in the presence of NaOH in methanol at 80 °C
(66%).
4
O
76%
3: R = H
Ac2O,
py, 70 °C
5: R = Ac, 91%
The spectroscopic properties of the synthetic (–)-1 (NMR
and MS) were identical to those previously reported1,2 and
the optical rotation ([a]D –27, c = 0.833, CHCl3) was in
agreement with that reported for the natural compound
{[a]D –22.7 (CHCl3; no precise concentration given in the
literature)}.1
Scheme 2 Terpenylation reaction
at room temperature with m-chloroperbenzoic acid in
methylene chloride for 1 hour, giving a mixture of the two
diastereomeric epoxides 2 and 2¢ (94%), favoring the de-
1
sired compound 2 in a ratio of 2.6:1 (evaluated by H
Yamashita et al. have confirmed the absolute configura-
tion of (–)-1 after racemic resolution and found –32.8 (c
1.0, CHCl3) as the specific rotation.9
NMR spectrum). According to this diastereomeric ratio,
the yield for 2 is actually 68%. Epoxidation of 5 occurs
preferentially on the less substituted face; the low selec-
tivity can be explained by the presence of the isopropyl
group on the same face.
In conclusion, we have completed the first enantioselec-
tive total synthesis of (–)-linderol A after five steps in
30% overall yield. Two key reactions have been used, ter-
penylation and a stereospecific intramolecular epoxide
opening with a phenolate anion.
The nature of endocyclic epoxides (2 and 2¢) was correlat-
1
ed on the basis of the H NMR spectra: at d = 3.07 and
3.61 ppm (d, 1 H, J = 10.7 Hz, C3H) and at d = 2.82 and
2.92 ppm (s, 1 H, C2H). These data were in agreement
with the literature.7
Improvement of each reaction step, and especially the
asymmetric epoxidation, is currently under investigation
in order to optimize our synthesis.
Me
Me
4
4
O
O
Acknowledgment
MCPBA
(1.2 equiv)
O
3
5
3
We would like to thank Dr. A. Haudrechy for helpful discussions,
C. Petermann and P. Sigaut for spectroscopic recordings (NMR and
MS, respectively) and the Centre National de la Recherche Scienti-
fique (CNRS) for financial support.
+
1
1
2
CH2Cl2
94%
2
O
AcO
OAc
AcO
OAc
2'
2 (68%)
O
H
O
1:2.6
NaOH (2%)
MeOH–H2O
69%
(or 87% from 2)
References and Notes
(1) Mimaki, Y.; Kameyama, A.; Sashida, Y.; Miyata, Y.; Fujii,
A. Chem. Pharm. Bull. 1995, 43, 893.
OMe
OMe
H
H
9
NaOH (3 equiv)
PhCHO (2 equiv)
(2) (a) Yamashita, M.; Ohta, N.; Kawasaki, I.; Ohta, S. Org.
Lett. 2001, 3, 1359. (b) Yamashita, M.; Ohta, N.; Shimizu,
T.; Matsumoto, K.; Matsuura, Y.; Kawasaki, I.; Tanaka, T.;
Maezaki, N.; Ohta, S. J. Org. Chem. 2003, 68, 1216.
(3) (a) Yamashita, M.; Inaba, T.; Shimizu, T.; Kawasaki, I.;
Ohta, S. Synlett 2004, 1897. (b) Yamashita, M.; Inaba, T.;
Nagahama, M.; Shimizu, T.; Kosaka, S.; Kawasaki, I.; Ohta,
S. Org. Biomol. Chem. 2005, 3, 2296. (c) Yamashita, M.;
Shimizu, T.; Inaba, T.; Takada, A.; Takao, I.; Kawasaki, I.;
Ohta, S. Heterocycles 2005, 65, 1099.
9a
5a
6
HO
O
MeOH, 80 °C
66%
HO
O
H
OH
OH
O
Ph
O
6
(–)-1
Scheme 3 Ring closure via epoxide opening
The unseparated epoxides 2 and 2¢, in the presence of 2%
sodium hydroxide in methanol–water (1:1) at room tem-
perature for one hour, led in good yields to the hexahy-
drodibenzofuran derivative 6 after deacetylation and
resulting phenolate attack on the oxirane.
(4) Crombie, L.; Crombie, W. M. L.; Firth, D. F. J. Chem. Soc.,
Perkin Trans. 1 1988, 1251.
(5) 4-Methoxyphloroacetophenone (4) was obtained from the
commercially available phloroacetophenone and its
synthesis has been previously described: Huang, C.; Da, S.;
Li, Y.; Li, Y. J. Nat. Prod. 1997, 60, 277.
The transformation of 2 to 6 involves an intramolecular
trans opening of the epoxide at the less hindered site, fix-
ing the relative stereochemistry of the fused furan ring at
C5a and C9a protons as cis. The configuration of the C6
quaternary carbon bearing the hydroxyl group is R. Com-
pound 6 was fully characterized by its spectroscopic data
(IR, NMR, and MS).8 The two bridgehead hydrogens ex-
(6) Selected Physical Properties for 5
[a]D +14 (c 0.44, CHCl3). 1H NMR (300 MHz, CDCl3): d =
6.56 (s, 1 H, Har), 5.09 (s, 1 H, H2), 3.80 (m, 4 H, H3 and
CH3O), 2.40 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 2.12 (s, 3 H,
CH3), 2.03 (m, 2 H), 1.90 (m, 1 H), 1.78 (dt, 1 H, J = 2.3 Hz),
1.63 (s, 3 H, CH3), 1.36 (m, 2 H), 0.86 (d, 3 H, J = 6.8 Hz,
Synlett 2008, No. 1, 94–96 © Thieme Stuttgart · New York

96
H. Berber et al.
LETTER
CH3), 0.77 (d, 3 H, J = 6.8 Hz, CH3) ppm. 13C NMR (300
MHz, CDCl3): d = 198.4 (C=O), 169.2 (C=O), 168.5 (C=O),
160.1 (Cq), 147.4 (Cq), 147.1 (Cq), 132.9 (Cq, C1), 124.9
(CH, C2), 124.3 (Cq), 102.6 (CHar), 55.9 (CH3O), 42.5 (CH),
36.0 (CH, C3), 30.8 (CH3), 30.6 (CH2), 28.0 (CH, C4), 23.4
(CH3), 22.3 (CH2), 21.5 (CH3), 21.1 (CH3), 20.8 (CH3), 15.9
(CH3) ppm. LRMS (EI): m/z (%) = 402 (0.1) [M+], 359(52),
317(99), 290(22), 248(100), 233(30). HRMS (EI): m/z calcd
for C23H30O6: 402.2042; found: 402.2041.
6 as a pale yellow solid (29 mg, 0.087 mmol, 69% or 87%
from 2); mp 146–147 °C. IR (KBr): 3430, 2947, 2921, 1625,
1433, 1363, 1293, 1211, 1150, 1054, 831, 805 cm–1. 1H
NMR (300 MHz, CDCl3): d = 13.16 (s, 1 H, OH), 6.02 (s, 1
H, H2), 4.16 (dd, 1 H, J = 5.5, J = 1.0 Hz, H5a), 3.81 (s, 3 H,
CH3O), 3.11 (dd, 1 H, J = 11.1, 5.5 Hz, H9a), 2.60 (s, 3 H,
CH3), 1.80 (m, 3 H, H7 and CHi-Pr), 1.61 (s, 1 H, OH), 1.50
(s, 3 H, CH3), 1.40 (m, 2 H, H8), 1.10 (m, 1 H, H9), 0.90 (d,
3 H, J = 6.9 Hz, CH3), 0.83 (d, 3 H, J = 6.9 Hz, CH3) ppm.
13C NMR (300 MHz, CDCl3): d = 201.8 (C=O), 165.0 (C3),
162.0 (Cqar), 161.8 (Cqar), 113.1 (C9b), 102.9 (C4), 92.5
(C2), 92.3 (C5a), 69.3 (CH, C6), 55.4 (CH3O), 46.5 (CH,
C9), 39.6 (C9a), 35.2 (CH2, C7), 31.1 (CH3C=O), 28.2
(CH3), 27.1 (CHi-Pr), 21.7 (CH3), 17.1 (C8), 15.3 (CH3).
LRMS (EI): m/z (%) = 334 (50) [M+], 318 (40), 249 (98),
233 (100), 207 (48), 195 (22). HRMS (EI): m/z calcd for
C19H26O5: 334.1780; found: 334.1788.
(7) Uliss, D. B.; Razdan, R. K.; Dalzell, H. C. J. Am. Chem. Soc.
1974, 96, 7372; and cited references.
(8) Experimental Procedure for 6
The mixture of epoxides 2 and 2¢ (52.8 mg, 0.126 mmol with
a ratio of 2.6:1) was treated at r.t. with 2 mL of a 2% NaOH
solution in MeOH–H2O (1:1). The solution was stirred at r.t.
for 1 h, then neutralized with 10% HCl. The mixture was
extracted with CH2Cl2, the organic layer was washed with
H2O and dried over MgSO4. The solvent was then removed
under reduced pressure and the residue was purified by silica
gel column chromatography (CH2Cl2–EtOAc, 90:10) to give
(9) Yamashita, M.; Shimizu, T.; Kawasaki, I.; Ohta, S.
Tetrahedron: Asymmetry 2004, 15, 2315.
Synlett 2008, No. 1, 94–96 © Thieme Stuttgart · New York

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