Integral stereocontrolled synthesis of a spiro-norlignan, sequosempervirin A: Revision of absolute configuration

Article abstract of DOI:10.1021/ol2018533

A novel synthetic path to sequosempervirin A was established by employing a samarium diiodide promoted intramolecular Barbier-type reaction of the lactonic iodide, in which the key structural feature, a spiro[4.5]decane ring system, could be constructed b

Full text of DOI:10.1021/ol2018533

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4640–4643
Integral Stereocontrolled Synthesis of a
Spiro-norlignan, Sequosempervirin A:
Revision of Absolute Configuration
Yuji Ito, Kazunori Takahashi, Hiromasa Nagase, and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received July 10, 2011
ABSTRACT
A novel synthetic path to sequosempervirin A was established by employing a samarium diiodide promoted intramolecular Barbier-type reaction
of the lactonic iodide, in which the key structural feature, a spiro[4.5]decane ring system, could be constructed by controlling the stereochemistry
of the hydroxyl group at the 8-position. The absolute configuration of natural sequosempervirin A was revised to be 4S based on this synthesis.
Sequosempervirin A 1 was isolated from dried and
powdered branches and leaves of Sequoia sempervirens
(Taxodiaceae) as the first naturally occurring norlignan
compound.
Synthesis of sequosempervirin A has been reported by
Maity and Ghosh in 2007,3 in which an orthoester Claisen
rearrangement and a ring-closing metathesis were exploited
as the key reactions to construct the basic carbon frame-
work. In their synthesis, however, deoxygenation at the
3-position (sequosempervirin A numbering) and also reduc-
tion of the ketone at the 8-position resulted in the mixture of
regio- and stereoisomeric compounds, respectively, provid-
ing the target compound in 2% overall yield in 13 steps.
The crucial step for synthesis of sequosempervirin A
obviouslyliesinthe facile construction of a spiro[4.5]dec-1-
ene system by controlling the stereochemistry of the hydro-
xyl group at the 8-position, since this stereogenic center
was located far from any functional groups in the target
compound.
Figure 1. Originally proposed structure for the natual sequo-
sempervirin A 1.
The structure of sequosemperivirin A, including its
absolute configuration, was determined to be (4R)-4-(4-
hydroxybenzyl)spiro[4.5]dec-1-en-8-ol on the basis of re-
sults obtained by using spectroscopic methods and results
of its X-ray crystallographic analysis (Figure 1).1 Acetone
extracts of S. sempervirens exhibited antifungal activities
toward Candida glabrata (IC50 = 15.98 μg/mL), and both
the acetone and MeOH extracts were found to inhibit the
proteolytic activity of cathepsin B (IC50 = 4.58 and 5.49
μg/mL, respectively).2
Our own interest in construction of this unique structur-
al feature grew out of a desire to develop an entirely new
route for the total synthesis of sequosempervirin A with
integrated stereocontrol of all of the stereogenic centers.
The retrosynthetic route to sequosempervirin A is illu-
strated in Scheme 1.
Approaching the synthesis from a retrosynthetic per-
spective, we envisioned the following scheme: the target
(2) Zhang, Y.-M.; Tan, N.-H.; Yang, Y.-B.; Lu, Y.; Cao, P.; Wu,
Y.-S. Chem. Biodivers. 2005, 2, 497–505.
(3) Maity, S.; Ghosh, S. Tetrahedron Lett. 2007, 48, 3355–3358.
(1) Zhang, Y.-M.; Tan, N.-H.; He, M.; Lu, Y.; Shang, S.-Q.; Zheng,
Q.-T. Tetrahedron Lett. 2004, 45, 4319–4321.
r
10.1021/ol2018533
Published on Web 08/01/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Route to Sequosempervilin A
Scheme 2. Preparation of Bicyclic Iodo-lactone 7
compound 1 would be derived from an alcohol A by
employing a hydroxyl group-directed hydrogenation to
control the stereochemistry at the 4-position, followed by
dehydration. A benzylidene derivative A would be ob-
tained from a cyclopentanone derivative B by installation
of a benzyl moiety. Compound B would be accessible from
a bicyclo-compound C via a samarium diiodide promoted
Barbier-type reaction. A bicyclic halide C would be pre-
pared from a 4-oxocyclohexane-1,1-dicarboxylate E, via a
bicylic lactone D, by several steps involving reduction of a
ketone, lactonization, two-carbon elongation, and so on.
A principal advantage offered by Scheme 1 is the ready
construction of the key spiro[4.5]decane ring system by
controlling the stereochemistry of the hydroxyl group at
the 8-position via a samarium diiodide promoted Barbier-
type reaction of a bicyclic compound C in one step.
Our synthesis commenced withthe synthesis of a bicyclic
lactone, which was easily accessible from 4-oxocyclohex-
anone-1,1-dicarboxylate, as follows (Scheme 2).
Reduction of 24 with NaBH4, followed by lactonization
of the resulting alcohol 3 with p-TsOH in refluxing ben-
zene, afforded the bicyclic acid 4. Treatment of 4 with
oxalyl chloride gave the acid chloride, which was then
coupled with (tributylvinyl)stannane in the presence of
tetrakis(triphenylphosphine)palladium in THF5 to pro-
vide acrylate derivative 5. After addition of hydrogen
chloride to 5, the resulting keto-chloride was reduced with
NaBH4 to give secondary alcohol 6 in 97% yield from 5.
Chloride 6 was further converted to the corresponding
iodide 7 with NaI in acetone.
First, we attempted a samarium diiodide promoted
Barbier-type reaction6,7of 7 in THF in the presence or
absence of an additive under various reaction conditions;
however, formation of a reductive dehalogenation com-
pound was observed as the major isolable product in these
reaction conditions, probably due to the presence of the
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Org. Lett., Vol. 13, No. 17, 2011
4641

secondary hydroxyl group which might act as a proton
donor. Therefore, triethylsilyl derivative 8 was employed
to find the best conditions for a samarium diiodide pro-
moted Barbier-type reaction, and we found that nickel(II)
iodide was the best additive8 for this conversion to furnish
the desired product 9 in high yield (Scheme 3).
The stereochemistry at the 4-position was successfully
controlled by a hydroxyl group directed hydrogenation with
Crabtree’s catalyst10 to give 14 as a single stereoisomer.
Scheme 5. Stereochemical Determination of 14
Scheme 3. SmI2-Promoted Barbier-Type Reaction of 8
The stereochemistry of 14 was determined by NOE
experiments by comparison with its diastereoisomeric
derivative 15 obtained from 14 and 4-nitrobenzoic acid
by a Mitsunobu reaction,11 as depicted in Scheme 5.
By establishing a synthetic route to the basic skeleton of
the natural product with the desired stereochemistries, we
completed the synthesis of racemic sequosempervirin A as
follows.
It is noteworthy that the samarium diiodide promoted
Barbier-type reaction of 8 led to the construction of a spiro-
[4.5]decane ring system, in which the hydroxyl group at the
8-position was fixed as only one diastereoisomeric form.
To synthesize the target compound, a stereoselective in-
stallation of a benzyl moiety at the carbonyl carbon of 10,
derived from 9 by methoxymethylation, would be required.
The attempted preparation of a benzylidene-type deri-
vative (A in Scheme 1) by Wittig reaction of 10 with p-
methoxybenzyltriphenylphosphonium bromide in the
presence of a base gave none of the desired product,
unfortunately. Treatment of 10 with p-methoxybenzyl-
magnesium bromide provided a small amount of an
addition product. A samarium diiodide promoted Barb-
ier-type reaction of 10 with p-methoxybenzyl bromide also
unfortunately gave the addition product in low yield.
To our delight, a coupling reaction of triflate 11 derived
from 10 with p-methoxybenzylmagnesium chloride in the
presence of a palladium catalyst9 afforded cyclopentene
derivative 12, in good yield, which was further transformed
to alcohol 13 upon treatment with TBAF (Scheme 4).
Scheme 6. Synthesis of Sequosempervirin A 1
Dehydration of the secondary hydroxyl group was
achieved in two steps involving mesylation of 14, followed
by elimination of the mesylate to provide cyclopentene
derivative 16 in 84% yield from 14 (Scheme 6). Finally,
sequential removal of the protecting groups of 16 upon
treatment with conc. hydrochloric acid and potassium
1-dodecanethiolate12 withtheresultingalcohol17afforded
racemic sequosempervirin A, mp 141ꢀ144 °C [lit.,1 172ꢀ
174 °C (optically active); lit.,3 169ꢀ170 °C (racemic)] in 18
steps in 28.9% overall yield. The spectroscopic data of the
Scheme 4. Preparation of Homoallyl Alcohol 13
(8) Machrouhi, F.; Hamann, B.; Namy, J. L.; Kagan, H. B. Synlett
1996, 633–634.
(9) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc.
1972, 94, 4374–4376. (b) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc.,
Chem. Commun. 1972, 144a–144a.
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2661.
(11) (a) Mitsunobu, O. Synthesis 1981, 1–28. (b) Dodge, J. A.; Nissen,
J. S.; Presnell, M. Org. Synth. 1996, 73, 110–115.
(12) Yamamoto, N.; Fujii, H.; Imaide, S.; Hirayama, S.; Nemoto, T.;
Inokoshi, J.; Tomoda, H.; Nagase, H. J. Org. Chem. 2011, 76, 2257–
2260.
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Org. Lett., Vol. 13, No. 17, 2011

synthesized compound were comparable with those re-
ported in the literatures.1,2
the synthesized compound was depicted in Figure 2. These
results clearly indicated that the original assignment1 for
the absolute configuration of the natural product was not
correct, and it should be revised to (4S)-4-(4-hydro-
xybenzyl)spiro[4.5]dec-1-en-8-ol, an enantiomer of 1.16
Scheme 7. Preparation and Asymmetric Reduction of
Homoallyl Alcohol 18
Figure 2. ORTEP drawing of (ꢀ)-1.
To accomplish the total synthesis of natural sequosem-
pervirin A, the requisite chirality was constructed by an
asymmetric reduction of the prochiral ketone 18, derived
from alcohol 13 by DessꢀMartin periodinane oxidation.
Treatment of 18 with (R)-Me-CBS and a BH3ꢀTHF
complex13 in THF at ꢀ20 °C afforded chiral 13 with
91% ee14 (Scheme 7).
Although the absolute configuration of the newly gen-
erated chiral center could not be determined, it was
assumed to be (R) on the basis of the previous systematic
work.13 Conversion of chiral 13 to the natural 1 was
achieved by adopting the same procedures as those de-
scribed for the synthesis of racemic 1. The spectroscopic
data of the chiral compound 1, mp 180ꢀ181 °C [lit.,1
172ꢀ174 °C], were similar to those of the natural 1;
however, the sign of the optical rotation, [R]D ꢀ39.4
(c 0.6, MeOH), was opposite to the reported value for
the natural product {lit.,1 [R]D þ24.7 (c 0.6, MeOH)}.
To solve this confusion stemming from the different
optical rotation values, we decided to determine the abso-
lute configuration of our synthesized compound by X-ray
crystallographic analysis, and the results of X-ray analysis
clearly showed that the synthesized compound has an (R)-
configuration at the 4-position.15 The ORTEP drawing of
In summary, we were able to establish an entirely new
and stereocontrolled route for construction of a spiro-
[4.5]decane ring skeleton with a reasonably high yield, in
which a samarium diiodide promoted intramolecular
Barbier-type reaction was involved as the key step. By
exploiting this strategy, we succeeded in a concise stereo-
controlled synthesis of a norlignan, (ꢀ)-sequosempervirin
A, starting from the known cyclohexanone derivative 2 in
20 steps in 26.6% overall yield. This synthesis also proved
that the natural compound is an enantiomer of the origin-
ally proposed structure 1 and should be revised to (4S)-
4-(4-hydroxybenzyl)spiro[4.5]-dec-1-en-8-ol.
Acknowledgment. This research was supported finan-
cially in part by a grant for The Open Research Center
Project and a Grant-in-Aid from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
Supporting Information Available. Experimental de-
tails, compound characterization, and cif file for com-
pound (ꢀ)-1. This material is available free of charge via
the Internet at http://pubs.acs.org
(15) The absolute structure was deduced based on the Flack para-
meter, ꢀ0.2(3), using 1102 Friedel pairs. X-ray crystallographic data for
compound 1 have been deposited to the Cambridge Crystallographic
Data Centre and assigned the deposition number CCDC 831216 for 1.
(16) Careful reading of the original reference led to the conclusion
that the absolute configuration of the natural product has not been
determined by its X-ray analysis, unfortunately.
(13) For recent reviews of CBS reduction, see: (a) Corey, E. J.; Heral,
C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012. (b) Deloux, L.;
Srebnik, M. Chem. Rev. 1993, 93, 763–784.
(14) The enantiomeric excess was determined to be 91% by HPLC
analysis with the chiral column CHIRALPAK OD-3 (Daicel Chemical
Industries, Ltd.).
Org. Lett., Vol. 13, No. 17, 2011
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