First total synthesis of valeriananoid A

Article abstract of DOI:10.1016/S0040-4039(03)00064-9

A tricyclic sesquiterpenoid, valeriananoid A 1, has been synthesized via domino Michael reaction of oxophorone 4 and subsequent 6-endo-trig cyclization of a ketyl radical as key steps.

Full text of DOI:10.1016/S0040-4039(03)00064-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1595–1597
First total synthesis of valeriananoid A
Hisahiro Hagiwara,a,* Akihiro Morii,a Yu Yamada,a Takashi Hoshib and Toshio Suzukib
aGraduate School of Science and Technology, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
bDepartment of Chemistry and Chemical Engineering, Faculty of Engineering, Niigata University, 8050, 2-nocho, Ikarashi,
Niigata 950-2181, Japan
Received 21 November 2002; revised 27 December 2002; accepted 27 December 2002
Abstract—A tricyclic sesquiterpenoid, valeriananoid A 1, has been synthesized via domino Michael reaction of oxophorone 4 and
subsequent 6-endo-trig cyclization of a ketyl radical as key steps. © 2003 Elsevier Science Ltd. All rights reserved.
Valeriana jatamansii Jones widely distributes in south-
western China and the roots of this plant have been
utilized as a Chinese folk medicine which has hypnotic,
tranquilizing and antiviral activities. In 1997, De Quan
Yu and co-workers reported the isolation from ethyl
acetate extracts of the roots and the structure determi-
nation of three new sesquiterpenoids, valeriananoids A
1, B 2 and C 3 having a unique tricyclic carbon
framework (Fig. 1).1 The structure of valeriananoid A 1
was established by single crystal X-ray analysis and was
revealed to be the same carbon framework as that of
seychellene2 or patchouli alcohol.3
Our ongoing interest toward the total synthesis of
natural products via the domino Michael process4
prompted us to investigate the synthesis of this unique
sesquiterpenoid 1.
The synthetic design is outlined in Scheme 1. The
bicyclic domino Michael product 5, prepared according
Scheme 1.
to our previous procedure5 from oxophorone 4, would
enable mono-protection of the less hindered carbonyl
group to give a mono-ketal whose ester group would be
equilibrated to the same side as the carbonyl group to
provide keto-ester 6. After introduction of an allyl-
alkoxy unit and subsequent ring closure by electron
transfer reaction by the 6-endo-trig mode, the tricyclic
valeriananoid framework would be obtained.
Figure 1.
Keywords: bicyclic aliphatic compounds; domino Michael reactions;
sesquiterpenenoid; valeriananoid.
* Corresponding author. Tel./fax: +81-25-262-7368; e-mail:
hagiwara@gs.niigata-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00064-9

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H. Hagiwara et al. / Tetrahedron Letters 44 (2003) 1595–1597
esters 6 and 10. Fortunately, treatment of the keto-ester
10 with sodium methoxide in methanol resulted in
complete isomerization of the ester group into the same
side as the carbonyl group in 96% yield. The relative
stereochemistry of the keto-ester 6 was confirmed by
NOE enhancement between the two protons as
depicted in Scheme 2, as well as disappearance of the
W-type long-range coupling of the proton endo to the
carbonyl group.
Trimethylsilylenol ether 9 prepared under specific reac-
tion conditions was treated with methyl acrylate in the
presence of diethylaluminum chloride to provide
bicyclic compound 55 (Scheme 2). The orientation of
the ester group was determined by the observed W-type
long-range coupling of the proton indicated. Conven-
tional ketalization allowed selective protection of the
less hindered ketone to provide ketal 10. The overall
yield in three steps from oxophorone 4 was 79%. Pre-
liminary MM2 and PM3 calculations revealed a subtle
difference in thermodynamic stability between keto-
In order to construct the tricyclic carbon framework, a
two-carbon unit must be introduced. Reduction of the
keto-ester 6 followed by PCC oxidation provided keto-
aldehyde 11 in 90% overall yield (two steps). Addition
of vinylmagnesium bromide gave in 85% yield allyl-
alcohol 12 which was oxidized by Jones reagent to
furnish vinyl-ketone 13 in 98% yield.
When vinyl-ketone 13 was treated with samarium diio-
dide in the presence of t-BuOH and HMPA, the desired
ring closure did not proceed. Instead, intermolecular
coupling of the vinyl moiety proceeded to give dimeric
compound 14 in 73% yield. This result is understood by
the preferential reduction of the unsaturated carbonyl
moiety due to lower reduction potential and intermolec-
ular CꢀC bond coupling reaction due to steric reason.
Actually, MM2 calculation of 13 revealed that s-cis
conformation of the vinyl-ketone moiety is thermody-
namically more stable than s-trans conformation.
One solution to solve this problem is to prevent reduc-
tion of the side chain by raising the reduction potential
and to facilitate preferential formation of the ketyl
radical in the bicyclic framework. To this end, electron
transfer cyclization of the substrate having an alkoxy-
allyl unit was investigated. Thus, allyl-alcohol 12 was
protected as an MOM ether in 75% yield. Treatment of
ether 15 with sodium6 in refluxing THF closed the third
ring to give tricyclic compound 16 in 61% yield having
the valeriananoid carbon framework (Scheme 3). It is
worthy of note that 6-endo-trig cyclization predomi-
nated rather than 5-exo-trig cyclization in this radical
process, different from the common mode of radical
cyclization.7
Encouraged by this result, a precursor having the requi-
site methyl group was prepared (Scheme 4). Addition of
Scheme 2. Reagents conditions and yields: (i) (TMS)2NH/
TMSI/(CH2Cl)2; (ii) methyl acrylate, Et2AlCl/CH2Cl2, rt; (iii)
(CH2OH)2/PTSA, benzene, 79% (three steps); (iv) MeONa/
MeOH, reflux, 96%; (v) LAH/Et2O, 95%; (vi) PCC/AcONa/4
,
A MS, 95%; (vii) vinylmagnesium bromide, 0°C, THF, 85%;
(viii) Jones reagent, 98%; (ix) SmI2 (3 equiv.)/t-BuOH (1.5
equiv.), HMPA/THF, −78°C, 73%; (x) NaH (2 equiv.),
MOMBr (1.5 equiv.), THF, 0°C, 75%.
Scheme 3. Reagents conditions and yields: (i) Na/THF, reflux,
16 61%, 17 35%; (ii) Na/HMPA/THF, reflux, 8 44%.

H. Hagiwara et al. / Tetrahedron Letters 44 (2003) 1595–1597
1597
Catalytic hydrogenation of olefin 8 proceeded selec-
tively from the less hindered outer face of 8 to give in
65% yield 21 which was deprotected in 99% yield to
furnish valeriananoid A 1 (Scheme 5). The spectral data
were identical with those kindly provided by Professor
Yu.
In summary, we have completed the first total synthesis
of valeriananoid A 1 via domino Michael reaction of
oxophorone 4 to construct the bicyclic framework and
subsequent ketyl radical cyclization to close the tricyclic
ring. Synthetic study toward optically active valeri-
ananoids is now in progress and will be reported in due
course.
Scheme 4. Reagents conditions and yields: (i) MeLi (2 equiv.),
Acknowledgements
,
Et2O, −78°C, 72%; (ii) PDC/AcONa/4 A MS, 93%; (iii)
vinylmagnesium bromide (5 equiv.), THF, rt, 99%; (iv)
MOMBr (10 equiv.), t-C4H9OK (10 equiv.), THF, 0°C, 75%.
We thank Professor De Quan Yu, Peking Union Medi-
cal College, for providing spectral data of valeriananoid
A 1 and Shorai Foundation for Science and Technol-
ogy for partial financial support.
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Scheme 5. Reagents conditions and yields: (i) H2/Pd–C,
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THF, rt, 99%
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After several attempts, the desired cyclization product 8
was obtained in 44% yield. The presence of HMPA was
crucial to the present cyclization (Scheme 3).