The first total synthesis of (+/-)-linderol A, a tricyclic hexahydrodibenzofuran constituent of Lindera umbellata bark, with potent inhibitory activity on melanin biosynthesis of cultured B-16 melanoma cells.

Article abstract of DOI:10.1021/ol0157398

[reaction in text] The first total synthesis of (+/-)-linderol A, a hexahydrodibenzofuran isolated from Lindera umbellata bark, with potent inhibitory activity on melanin biosynthesis of cultured B-16 melanoma cells was achieved via a 20-step of reaction

Full text of DOI:10.1021/ol0157398

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1359-1362
The First Total Synthesis of (±)-Linderol A,
a Tricyclic Hexahydrodibenzofuran
Constituent of Lindera umbellata Bark,
with Potent Inhibitory Activity on
Melanin Biosynthesis of Cultured B-16
Melanoma Cells
Masayuki Yamashita, Nobukazu Ohta, Ikuo Kawasaki, and Shunsaku Ohta*
Kyoto Pharmaceutical UniVersity, Misasagi-Nakauchicho 5, Yamashinaku,
Kyoto 607-8414, Japan
sohta@mb.kyoto-phu.ac.jp
Received February 20, 2001
ABSTRACT
The first total synthesis of (±)-linderol A, a hexahydrodibenzofuran isolated from Lindera umbellata bark, with potent inhibitory activity on
melanin biosynthesis of cultured B-16 melanoma cells was achieved via a 20-step of reaction in 7.64% overall yield starting from
4,6-dimethoxysalicylaldehyde.
In 1995, Sashida et al. reported isolation of linderol A (1),
(5aR*,6R*,9R*,9aS*)-4-cinnamoyl-3,6-dihydroxy-1-methoxy-
6-methyl-9-(1-methylethyl)-5a,6,7,8,9,9a-hexahydrodibenzo-
furan, from the fresh bark of Lindera umbellata (Lauraceae)
(Figure 1).1,2 They also reported the potent inhibitory activity
of 1 on melanin biosynthesis of cultured B-16 melanoma
cells without causing any cytotoxicity in the cultured cells
or skin irritation in guinea pigs.1
We reported in 1995 an interesting rearrangement of the
coumarin derivatives 2, which had an electron-withdrawing
group at the 3-position, to the tricyclic 2-substituted cyclo-
penta[b]benzofuran-3-ol derivatives 3 by treatment with a
small excess over 2 equiv of dimethylsulfoxonium methylide
(Scheme 1).3
We planned the total synthesis of 1 by applying this
Scheme 1
Figure 1. Structure of the natural product 1.
10.1021/ol0157398 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/06/2001

Scheme 2a
a (a) Ethyl malonate, piperidine, acetic acid, EtOH, reflux, 97.0%; (b) Me3S(O)I, 60% NaH, DMF, rt, 78.8%; (c) i. PhSeCl, 60% NaH,
THF, 0 °C to rt; ii. NaIO4, THF-H2O, rt, 78.9%; (d) i-PrMgBr, CuI, BF3‚Et2O, Et2O-CH2Cl2, -78 °C, 65.5%.
rearrangement to an appropriately substituted coumarin
followed by a one-carbon ring expansion of the cyclopentane
portion of 3. In this Letter, we describe the first total synthesis
of (()-1 according to this strategy.
bromide in the presence of CuI and BF3 etherate to afford
the desired enolester 8 as a single product (Scheme 2). The
stereochemistry of the introduced isopropyl group of 8 was
confirmed on the basis of NOE data as shown in Figure 2.
After decarboxylation of 8 by heating in acetic acid, a one-
carbon ring enlargement of the cyclopentanone ring in the
resultant 9 was carried out by treatment with ethyl diazo-
acetate in the presence of BF3 etherate to afford successfully
the cyclohexane 10 in 85.8% yield.7 Attempts of decarboxy-
lation after acidic or alkaline hydrolysis of 10 resulted in a
complex mixture or complete recovery of 10, respectively;
therefore, it was considered that alkaline hydrolysis of the
ethoxycarbonyl group in 10 should be carried out after
protection of the enol. Thus, the enol 10 was converted to
the corresponding MOM ether 11 (84.0%), alkaline hydroly-
sis of which followed by acidification and refluxing in xylene
gave the ketone 12 in 72.2% yield from 11. Wittig olefination
of ketone 12 (97.2%) with methylenetriphenylphosphorane
followed by cis-1,2-dihydroxylation with a catalytic amount
of microencapsulated OsO4 in the presence of N-methyl-
morpholine N-oxide afforded the diol 14 as a single isomer
in quantitative yield.8,9 It was expected that OsO4 oxidation
would occur at the less hindered side (convex face) of 13
(Figure 3).
The starting material, 4,6-dimethoxysalicylaldehyde 4,4
was converted to the coumarin 5 by Knoevenagel reaction
in 97.0% yield, and the product 5 was treated with 2.2 equiv
of dimethylsulfoxonium methylide according to the previ-
ously reported procedure3 to afford the rearranged cyclo-
penta[b]benzofuran derivative 6 in 78.8% yield.5 The ben-
zofuran 6 was converted to the R,â-unsaturated ketoester 7
according to the well-known phenylselenenylation-oxidation
methodology.6 The next step is introduction of an isopropyl
group to 7. We predicted that an appropriate organometallic
reagent (RM) would attack almost exclusively from the less
hindered side (convex face) of the 5,5-rings and the adduct
would bring about the desired stereochemistry (Figure 2).
Figure 2. â-Face attack of RM to 7 (left) and observed NOEs for
8 (right).
In fact, the isopropyl group was regio- and stereoselectively
introduced by treatment of 7 with isopropylmagnesium
(1) Mimaki, Y.; Kameyama, A.; Sashida, Y.; Miyata, Y.; Fujii, A. Chem.
Pharm. Bull. 1995, 43, 893.
(2) Recently, Professor Sashida (Tokyo University of Pharmacy and Life
Science) proposed to us the name linderol A for compound 1, which was
treated as a no name natural product in the report (ref 1). In this Letter, we
will use the name of linderol A.
Figure 3. â-Face attack of OsO4 to 13.
The desired stereochemistry of the tertiary alcohol portion
was confirmed on the basis of NOE data of the corresponding
(3) Yamashita, M.; Okuyama, K.; Kawasaki, I.; Ohta, S. Tetrahedron
Lett. 1995, 36, 5603.
1360
Org. Lett., Vol. 3, No. 9, 2001

Scheme 3a
a (e) AcOH, 100 °C, 98.2%; (f) N2CHCOOEt, BF3‚Et2O, Et2O, 0 °C, 85.8%; (g) 60% NaH, MOMCl, THF, rt, 84.0%; (h) i. NaOH-H2O,
rt; ii. c-HCl, 0 °C; iii. xylene, reflux, 72.2%; (i) CH3PPh3Br, n-BuLi, THF, 0 °C, 97.2%; (j) MC OsO4, NMO, rt, 100%; (k) CDI, Et3N,
DMAP, CH2Cl2, rt, 97.2%; (l) Ac2O, Sc(OTf)3, nitromethane, 50 °C, 75.9%; (m) BBr3, CH2Cl2, 0 °C, 100%; (n) 1 N NaOH-dioxane, rt,
85.9%; (o) TsCl, Et3N, DMAP, rt, THF, 84.2%; (p) NaBH3CN, HMPA, 120 °C, 84.3%; (q) t-BuOK, t-BuOH, benzaldehyde, rt, then KOH
aq-MeOH, rt, 86.7%.
cyclic carbonate 15, that is, NOEs were not observed between
5a-H and -CH2- of cyclic carbonate and 9a-H and -CH2- of
cyclic carbonate, respectively.10,11
afforded the phenol 17 in quantitative yield,13 and then
alkaline hydrolysis of the cyclic carbonate function in 17
Next, Friedel-Crafts reaction of 15 was carried out by
treatment with acetic anhydride in the presence of a catalytic
amount of Sc(OTf)3 to give regioselectively the desired
4-acetyl compound 16 as the sole product in 75.9% yield.12
The position of the introduced acetyl group was confirmed
on the basis of the HMBC spectrum as shown in Figure 4.
Selective demethylation, assisted by the adjacent acetyl
group, of the 3-methoxy group of 16 by treatment with BBr3
Figure 4. Selected HMBC correlation of 16.
(4) Tsukayama, M.; Horie, T.; Fujimoto, K.; Nakayama, M. Chem.
Pharm. Bull. 1986, 34, 2369.
(5) A plausible mechanism for the rearrangement is illustrated as follows.
gave the diol 18 in 85.9% yield. The ditosylate 19 was
prepared in the usual manner, and its NaBH3CN reduction
converted selectively only the alkyl tosylate function to the
R-methyl group in 84.3% yield. Finally, treatment of 20 with
benzaldehyde in the presence of tert-BuOK followed by
alkaline hydrolysis gave crystalline (()-1 in 86.7% yield
(Scheme 3). The spectral data of synthetic (()-1 were
identical with those of an authentic sample1 in all respects.14
(11) The stereochemistry of 15 was further supported by the following
NOE data of diastereomers I and II, which were prepared from 12/MeMgBr/
THF/0 °C and 14-monotosylate/NaBH3CN/HMPA/120 °C, respectively.
(6) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97,
5434.
(7) Ghosh, A. K.; Biswas, S.; Venkastewaran, R. V. J. Chem. Soc., Chem.
Commun. 1988, 1421.
(8) Nagayama, S.; Endo, M.; Kobayashi, S. J. Org. Chem. 1998, 63,
6094.
(9) Unfortunately, epoxidation of 13 with MCPBA afforded a complex
mixture.
(10) The numbering for the natural product 1 in ref 1 is conveniently
used for the 6,5,6-ring systems appearing in this paper (see Figure 1).
(12) Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett 1994, 545.
(13) Sca¨fer, W.; Franck, B. Chem. Ber. 1966, 99, 160.
(14) Satisfactory analytical and spectroscopic data have been obtained
for all new compounds reported herein.
Org. Lett., Vol. 3, No. 9, 2001
1361

In conclusion, the first total synthesis of (()-linderol A,
a melanin biosynthesis inhibitory active natural product 1,
was achieved in 20 steps in 7.64% overall yield from 4,6-
dimethoxysalicylaldehyde 4.
University) for his useful advice. This research was finan-
cially supported in part by the Frontier Research Program
of the Ministry of Education, Science, Sports and Culture
of Japan.
Supporting Information Available: Characterization
data for compounds 1 and 4-20. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank Professor Yutaka
Sashida (Tokyo University of Pharmacy and Life Science)
for providing the spectral data of linderol A. The authors
are also grateful to Professor Tetsuaki Tanaka (Osaka
OL0157398
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Org. Lett., Vol. 3, No. 9, 2001