Determination of the absolute configuration and the first total synthesis of (-)- and (+)-linderol A

Article abstract of DOI:10.1016/j.tetasy.2004.06.017

Racemic triol 4-acetyl-3,6-dihydroxy-6-hydroxymethyl-1-methoxy-9-(1- methylethyl)-5a,6,7,8,9,9a-hexahydrodibenzofuran, (±)-2, an intermediate of the total synthesis of (±)-linderol A 1, was acetylated and resolved by HPLC on chiral stationary phases into

Full text of DOI:10.1016/j.tetasy.2004.06.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2315–2317
Determination of the absolute configuration and the
first total synthesis of ())- and (+)-linderol A
Masayuki Yamashita, Takashi Shimizu, Ikuo Kawasaki and Shunsaku Ohta*
Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashinaku, Kyoto 607-8414, Japan
Received 17 May 2004; accepted 11 June 2004
Abstract—Racemic triol 4-acetyl-3,6-dihydroxy-6-hydroxymethyl-1-methoxy-9-(1-methylethyl)-5a,6,7,8,9,9a-hexahydrodibenzo-
furan, ( )-2, an intermediate of the total synthesis of ( )-linderol A 1, was acetylated and resolved by HPLC on chiral stationary
phases into the respective enantiomers (ꢀ)- and (þ)-3. Enantiopure (ꢀ)-2, obtained by hydrolysis of (ꢀ)-3, was treated with (ꢀ)-
camphanic chloride to give the crystalline camphanate (ꢀ)-4, the absolute configuration of which was determined by X-ray crys-
tallography. Triols (ꢀ)- and (þ)-2 were converted to (ꢀ)- and (þ)-1 without disrupting their stereogenic centers according to the
previously reported synthesis of ( )-1. As natural (ꢀ)-linderol A 1 was derived from (ꢀ)-2, its absolute configuration was elucidated
to be 5aR,6R,9R,9aS.
ꢀ 2004Elsevier Ltd. All rights reserved.
1. Introduction
reported the first total synthesis of ( )-1.2 As the abso-
lute configuration of (ꢀ)-1 was not determined, we
planned its elucidation in terms of the medicinal chem-
istry. Herein, we report the determination of the abso-
lute configuration as well as the first total synthesis of
natural (ꢀ)-linderol A 1.
In 1995, Sashida et al. reported the isolation of (ꢀ)-
linderol A 1 from the fresh bark of Lindera umbellata
(Lauraceae) (Fig. 1). The structure and the relative
configuration of (ꢀ)-1 were unambiguously determined
on the basis of their spectral data as (5aR*,6R*,9R*,
9aS*)-4-cinnamoyl-3,6-dihydroxy-1-methoxy-6-methyl-
9-(1-methylethyl)-5a,6,7,8,9,9a-hexahydrodibenzofuran
(Fig. 1).1 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 have
taken much interest in (ꢀ)-1 in view of these structural
and biological aspects. We have already succeeded and
2. Results and discussion
We planned the resolution of an intermediate, which
appeared in the total synthesis of ( )-1. First, esterifi-
cations of the triol ( )-22 with optically active acids
followed by separation of the resulting diastereomeric
mixtures were tried. However, all attempts (including
HPLC separation and lipase-catalyzed kinetic resolu-
tion) failed. Next, monoacetate ( )-3 was subjected to
HPLC separation on chiral stationary phases. After
several experiments, HPLC with CHIRALPAKꢁ AD-H
[2 cm (/) · 25 cm (L), Daicel Chemical Industries, Ltd]
with n-hexane/ethanol (7/3) as an eluent showed good
separation of the enantiomers. Isolated (ꢀ)- and (þ)-3
were hydrolyzed by K2CO3 in methanol to give each
triol (ꢀ)- and (þ)-2 (Scheme 1).
OMe
H
9
R*
1
9b
9a
5a
S*
R*
3
R*
4a
HO
O
5
4
H 6
OH
O
Ph
Figure 1. (ꢀ)-Linderol A 1.
In order to prepare single crystals for X-ray crystallo-
graphy, (þ)- or (ꢀ)-2 was converted to several enantio-
merically pure esters with optically active acylating or
sulfonylating agents. Carboxylic acid ester (ꢀ)-4 derived
* Corresponding author. Tel.: +81-75-595-4703; fax: +81-75-595-4795;
e-mail: sohta@mb.kyoto-phu.ac.jp
0957-4166/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.017

2316
M. Yamashita et al. / Tetrahedron: Asymmetry 15 (2004) 2315–2317
OMe
H
iii
(-)-2 (94%)
[α]D33
HO
O
OH
H
= -97.2
O
OMe
OAc
H
H
HPLC
(-)-3
= -97.8
separation
[α]D33
HO
i
O
OH
OR
ii
OMe
O
H
( )-2 : R = H
( )-3 : R = Ac (96%)
iii
(+)-2 (99%)
[α]D32
HO
O
H
OH
= +99.8
O
OAc
(+)-3
33 = +101.0
[α]D
Scheme 1. Reagents and conditions: (i) Ac2O, Et3N, DMAP, CH2Cl2, rt; (ii) CHIRALPAKꢁ AD-H, n-hexane/ethanol ¼ 7/3; (iii) K2CO3, MeOH, rt.
Scheme 2. Reagents and conditions: (i) (ꢀ)-camphanic chloride, Et3N, DMAP, CH2Cl2, rt.
from (ꢀ)-2 and (ꢀ)-camphanic chloride3 as a chiral
OMe
auxiliary, gave good crystals and hence was subjected to
X-ray crystallographic analysis (CCDC No. 241976).
The obtained result is shown in Scheme 2. On the basis
of the stereochemistry of the (ꢀ)-camphanoyl group, the
stereochemistry of (ꢀ)-4 was determined to be
5aR,6S,9R,9aS (Scheme 2).
H
H
i
ii
(-)-2
(87%)
(58%)
TsO
O
OH
O
OTs
(-)-5
[α]D30
= -54.8
According to the reported total synthesis of ( )-1,1 (ꢀ)-
and (þ)-2 were converted to (ꢀ)- and (þ)-1, respectively,
by use of reactions, which occurred only on the achiral
substituents (Scheme 3). Bistosylate (ꢀ)-5 (87%) was
prepared in the usual manner, and its treatment with
NaBH3CN reduced only the C6–CH2–OTs portion to
the product having a C6-a-methyl group (ꢀ)-6 in 58%
yield.4 Finally, crossed aldol condensation of (ꢀ)-6 with
benzaldehyde in the presence of t-BuOK followed by
alkaline hydrolysis gave (ꢀ)-1 in 88% yield (Scheme 3).
Compound (þ)-2 was treated by the same procedure as
mentioned above to give (þ)-1 (Scheme 3). Spectral data
(NMR, IR, and MS) of synthetic (ꢀ)- and (þ)-1 were
identical with those of an authentic sample [natural (ꢀ)-
11 and synthetic ( )-12]. As the specific rotation of (ꢀ)-1
derived from (ꢀ)-2 was ꢀ32:8 (c 1.0, CHCl3)
(lit.1 ¼ ꢀ22:7, CHCl3),5 the undefined absolute config-
uration of natural (ꢀ)-1 could be determined to be
5aR,6R,9R,9aS.
OMe
H
iii
(-)-1
6
[α]D29
[α]D
(88%)
TsO
O
OH
= -32.8
= -22.7}
H
{lit.1
O
(-)-6
[α]D29
= -46.6
i
ii
(+)-2
(+)-5
(82%)
(65%)
28 = +55.7
[α]D
iii
(+)-1
[α]D29
(+)-6
[α]D28
(84%)
= +48.0
= +33.0
Scheme 3. Reagents and conditions: (i) TsCl, Et3N, DMAP, CH2Cl2,
rt; (ii) NaBH3CN, HMPA, 120 ꢂC; (iii) PhCHO, t-BuOK, t-BuOH;
then KOH, MeOH, rt.

M. Yamashita et al. / Tetrahedron: Asymmetry 15 (2004) 2315–2317
2317
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In conclusion, we have separated racemic acetate ( )-3
by HPLC on chiral stationary phases to each acetate
(ꢀ)- and (þ)-3. The absolute configuration of the crys-
talline (ꢀ)-4 derived from the enantiopure (ꢀ)-2 with
(ꢀ)-camphanic chloride was determined by X-ray
crystallography (CCDC No. 241976). The triols
(ꢀ)- and (þ)-2 were derived to optically active (ꢀ)- and
(þ)-linderol A 1, respectively, without affecting their
stereogenic centers. As natural (ꢀ)-1 was derived from
(ꢀ)-2, its absolute configuration was elucidated to be
5aR,6R,9R,9aS.
Acknowledgements
The authors thank Professor Yutaka Sashida (Tokyo
University of Pharmacy and Life Science) for providing
the spectral data of natural linderol A. This research was
financially supported in part by the Frontier Research
Program of the Ministry of Education, Culture, Sports,
Science and Technology of Japan, and a Grant-in-Aid
for the promotion of the advancement of education and
research in graduate schools in Subsidies for ordinary
expenses of private schools from the Promotion and
Mutual Aid Corporation for Private Schools of Japan.
References and notes
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A. Chem. Pharm. Bull. 1995, 43, 893–895.
2. (a) Yamashita, M.; Ohta, N.; Kawasaki, I.; Ohta, S. Org.
Lett. 2001, 3, 1359–1362; (b) Yamashita, M.; Ohta, N.;
Shimizu, T.; Matsumoto, K.; Matsuura, Y.; Kawasaki, I.;
5. Concentration did not appear in lit.1