Concise asymmetric synthesis of (-)-herbertenediol

Article abstract of DOI:10.1016/S0040-4039(02)02440-1

The rearrangement of the optically active 3-aryl-2-methyl-2,3-epoxy tosylate (>98% ee) afforded the α-keto tosylate with a chiral quaternary carbon center and without loss of chirality. Reductive removal of the tosyloxy group gave the keto compound with a chiral quaternary carbon center, which was converted to (-)-herbertenediol (>98% ee).

Full text of DOI:10.1016/S0040-4039(02)02440-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 411–413
Concise asymmetric synthesis of (−)-herbertenediol
Yasuyuki Kita,* Junko Futamura, Yusuke Ohba, Yoshinari Sawama, Jnaneshuwara K. Ganesh and
Hiromichi Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 10 October 2002; revised 26 October 2002; accepted 30 October 2002
Abstract—The rearrangement of the optically active 3-aryl-2-methyl-2,3-epoxy tosylate (>98% ee) afforded the a-keto tosylate
with a chiral quaternary carbon center and without loss of chirality. Reductive removal of the tosyloxy group gave the keto
compound with a chiral quaternary carbon center, which was converted to (−)-herbertenediol (>98% ee). © 2002 Elsevier Science
Ltd. All rights reserved.
(−)-Herbertenediol ((−)-1),1 isolated from liverwort Her-
berta adunca, is a herbertane-type sesquiterpene. Pheno-
lic coupling of two (−)-1 is supposed to presumably
biosynthesize the dimer, mastigophorenes A (2) and B
(3), since both co-occur in the same source as (−)-1.2
Indeed, compounds 2 and 3 were synthesized by pheno-
lic coupling of the two (−)-1.3 Promising biological
activity of (−)-1 itself, anti-lipid peroxidation activity,4a
and the activities of its dimer 2 and 3, intriguing
neurotrophic properties, i.e. promote neuronal out-
rearrangements of epoxy acylates depends on the elec-
growth and enhance choline acetyltransferase activity,5
make (−)-1 an attractive synthetic target. In addition to
the racemic syntheses of ( )-1,4 a few groups, Meyers et
al.,3b Bringmann et al.,3c and Fukuyama et al.,3d have
reported the asymmetric syntheses of (−)-1. Compound
(−)-1 is composed of a cyclopentane ring with three
methyl groups and the methylated dihydroxyphenyl
group. The benzylic quaternary carbon center of (−)-1
becomes chiral, and only its center makes the (−)-1
chiral, non-racemic one. The most important point in
an asymmetric synthesis of (−)-1 is then how to con-
struct the chiral benzylic quaternary carbon center in
the optically active form. We present here our synthetic
study leading to the concise asymmetric synthesis of
(−)-1.
tron-withdrawing nature of the acyloxy groups6 sug-
gested that the epoxy derivatives with a similar
electron-withdrawing group would proceed with the
same type of rearrangement. For the epoxy sulfonates,
a-keto sulfonates would be obtained. Second, the sul-
fonyloxy groups are widely recognized not only as
strong electron-withdrawing groups, but also as good
leaving groups. The reductive removal of the sulfony-
loxy group of the a-keto sulfonates would then proceed
without any problem. Third, since the rearrangement of
the epoxy sulfonates with a Lewis acid is unknown, the
study of their reactivity will provide new information.
Scheme 1 shows the retrosynthetic analysis of (−)-1.
Optically active epoxy tosylate 7 would be prepared
from the corresponding enone 5 by a method similar to
our previously reported synthesis of the optically active
epoxy acylates.6g If the rearrangement reaction of 7
would proceed in a manner similar to that of the epoxy
acylates, b-cleavage of the oxirane ring, the a-keto
tosylate 8 would be obtained, which would be con-
verted to the optically active 9 by reductive removal of
the tosyloxy group. Further transformation and
dimethylation of the ketone of 9 followed by cleavage
of the methyl ether, would give 1.
For the asymmetric synthesis of (−)-1, we planned the
rearrangement of an epoxy sulfonate as the key reac-
tion for the asymmetric construction of the chiral qua-
ternary carbon center for the following reasons. First,
the fact that the success of our recently developed
* Corresponding author. E-mail: kita@phs.osaka-u.ac.jp
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02440-1

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Y. Kita et al. / Tetrahedron Letters 44 (2003) 411–413
attack of the reagent was controlled by chelation
between the reagent and the oxygen atom of the
methoxy group. The treatment of 10 with Burgess’
reagent13 gave the dehydrated product 11 in a high
yield. The cyclopropanation of 11 under the usual
Simmons–Smith condition afforded the cyclo-
propanated product 12 as a diastereomeric mixture (ca.
3 to 1). The reductive opening of the cyclopropane ring
of 12 gave the trimethyl compound 13, whose ee value
was determined to be >98% by HPLC analysis.10 The
acidic cleavage of the methyl ether bond of 13 with
BBr3 furnished the formation of (−)-1 (>98% ee by
HPLC analysis),10 whose physical data were in good
agreement with the reported ones: [h]2D8 −57 (c 0.78,
CHCl3) {lit. [h]D −47;1 [h]D −53.8 (c 1.0, CHCl3);3b [h]2D8
−47.1 (c 1.0, CHCl3)3d}.
Scheme 1.
The nucleophilic 1,2-addition of 2,3-dimethoxy-5-
methylphenyl lithium7 to the iso-butyl ether8 of 2-
methylcyclopentane-1,3-dione
4 followed by acidic
work-up afforded the enone 5. Asymmetric reduction
of the enone 5 with Corey’s reagent9 gave the highly
enantiomeric allyl alcohol 6, whose enantiomeric excess
(ee) was determined to be >98% ee by HPLC analysis.10
The stereoselective epoxidation11 of 6 followed by tosyl-
ation gave the cis-epoxy tosylate 7. As our expectation,
the treatment of 7 with aluminum reagent (EtAlCl2)
proceeded in the same manner as that of epoxy acylates
to give the desired rearranged product 8 in a high yield.
The treatment of 8 with Zn powder in AcOH removed
the tosyloxyl group without any problem to give the
ketone 9 in a one-step operation (Scheme 2).
Scheme 3.
In conclusion, we have succeeded in the asymmetric
synthesis of (−)-herbertenediol (−)-1 from the commer-
cially available 4 in 12 steps with 44% total yield. The
method described here is short compared to the other
asymmetric syntheses, and the yield of the each step is
very high. In addition, during the synthesis we have
developed a reliable way to construct the optically pure
chiral quaternary carbon center in the herbertane
sesquiterpenes. The method here would open the way
for the asymmetric synthesis of other simple herbertane
sesquiterpenes.14
Scheme 2.
References
Although Me2TiCl2-treatment, the usual condition for
the dimethylation of carbonyl compounds, of 9 did not
give the dimethylated compound,12 it was transformed
to (−)-1 through a cyclopropane compound as shown in
Scheme 3. The methylation of 9 with MeCeCl2 gave the
single product 10 in a high yield. Its stereochemistry
was determined by an NOE experiment. Maybe the
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413
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The absolute configuration of the secondary alcohol was