From planning to optimization: Total synthesis of valerenic acid and some bioactive derivatives

Article abstract of DOI:10.1002/ejoc.201101834

A detailed study of the total synthesis of valerenic acid, a well known GABA_A receptor subtype modulator, is described. Both successful as well as unsuccessful attempts towards the synthesis of the title compound are presented, including four different strategies to synthesize one of the key intermediates. The first two strategies are based on epoxides provided from the chiral pool, whereas the last two approaches rest on stereocontrolled modifications of 2-cyclopentenone. The streamlined synthesis implements a new one-pot reaction, which combines the addition of a Grignard species with an acid-catalyzed isomerization of the intermediate allylic alcohol. Further highlights are a stereo- and regioselective hydroxy-directed Diels-Alder reaction, a hydroxy-directed hydrogenation, and a final Negishi coupling reaction. After optimization of our synthesis, the preparation of several easily available derivatives is also discussed. Amides obtained by functionalization of the carboxyl group are more than twice as active as valerenic acid. The development and optimization of four different approaches towards valerenic acid (1) are described. The shortest approach spans 10 steps and provides valerenic acid in 25 % overall yield by incorporating a new one-pot reaction, an extremely stereo- and regioselective metal-coordinated Diels-Alder reaction, a hydroxy-directed hydrogenation, and a final Negishi coupling reaction. Copyright

Full text of DOI:10.1002/ejoc.201101834

FULL PAPER
DOI: 10.1002/ejoc.201101834
From Planning to Optimization: Total Synthesis of Valerenic Acid and Some
Bioactive Derivatives
[a]
[a]
Juergen Ramharter and Johann Mulzer*
Keywords: Natural products / Total synthesis / Cycloaddition / Hydrogenation / Structure–activity relationships
A detailed study of the total synthesis of valerenic acid, a
one-pot reaction, which combines the addition of a Grignard
well known GABA receptor subtype modulator, is de- species with an acid-catalyzed isomerization of the interme-
A
scribed. Both successful as well as unsuccessful attempts
towards the synthesis of the title compound are presented,
including four different strategies to synthesize one of the
key intermediates. The first two strategies are based on ep-
oxides provided from the chiral pool, whereas the last two
approaches rest on stereocontrolled modifications of 2-cyclo-
pentenone. The streamlined synthesis implements a new
diate allylic alcohol. Further highlights are a stereo- and re-
gioselective hydroxy-directed Diels–Alder reaction, a hy-
droxy-directed hydrogenation, and a final Negishi coupling
reaction. After optimization of our synthesis, the preparation
of several easily available derivatives is also discussed.
Amides obtained by functionalization of the carboxyl group
are more than twice as active as valerenic acid.
Introduction
usual conformation was confirmed in 1978 by X-ray crys-
tallography.
[
6]
Valerenic acid (1) was isolated in 1957 by Stoll and See-
beck from the rhizome and roots of valerian (valeriana offi-
cinalis) and is now probably the most prominent member
[
1]
of the valerenanes. Known in ancient Greece, valerian is
one of the oldest medicinal herbs in folk medicine and has
been used for various afflictions like insomnia, anxiety, and
[
2]
pain. Because of these interesting pharmacological effects,
valerian has attracted extensive studies to identify its bioac-
tive target. Presently, it is understood that several constitu-
ents of valerian interact with the GABA neurotransmitter
receptor system, and recently, valerenic acid (1) was shown
to act as a subunit-specific allosteric modulator of GABA
A
[
3]
subtype receptors. Because of this selectivity and its over-
all activity, 1 is envisaged as a potential candidate for drug
discovery and development.
Structurally, 1 features an indanyl core with three ste-
reogenic centers and two double bonds. As a sesquiterpene,
it belongs to the class of guaianes, a group of more than
500 natural products biogenetically derived from farnesyl
pyrophosphate (2) by bond connections between C-1/C-10
and C-2/C-6 (Scheme 1).[4] After the formation of guaiane
Scheme 1. Biosynthesis of valerenic acid (1).
core 4, isomerization and oxidation lead to guaianolide 5,
which undergoes a Wagner–Meerwein type ring contraction
The challenging architecture and promising pharmaco-
[
5]
to give 1. Most interestingly, both substituents on the six- logical profile prompted us, and Altmann’s group shortly
membered ring are now fixed in axial positions. This un- thereafter, to devise a concise and flexible total synthesis
of 1, which was then extended to the syntheses of suitable
derivatives and SAR (structure–activity relationship) stud-
[
a] University of Vienna, Institute of Organic Chemistry,
Währinger Strasse 38, 1090 Vienna, Austria
Fax: +43-1-4277-52189
[
7]
ies. In this report, we also present a considerably simpli-
fied and streamlined route and discuss the preparation of
several derivatives which are more active than the natural
E-mail: johann.mulzer@univie.ac.at
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101834.
[
8,9]
product.
Eur. J. Org. Chem. 2012, 2041–2053
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2041

J. Ramharter, J. Mulzer
FULL PAPER
Results and Discussion
silyl)propargylmagnesium bromide instead of the lithium
compound led only to an increased amount of the unde-
sired alcohol rac-12, whereas the use of the unsubstituted
propargyllithium or 3-methylpropargyllithium predomi-
nantly afforded the corresponding allenes. The allylic
alcohol rac-11 was protected as a TBS (t-butyldimethylsilyl)
ether, and then the TMS (trimethylsilyl) group was removed
selectively to give alkyne rac-13 which was methylated to
provide enyne rac-14 for the envisaged enyne-RCM (ring-
closing metathesis) reaction. Initially, we planned to use
Many of the previously known approaches towards the
valerenanes are based on intermediates which are moder-
ately stable and prone to epimerization of the diaxial ring
substituents and/or include low-yielding steps to install the
substituents stereoselectively.[10] The key strategy in our
synthesis rests upon the construction of a trans-fused in-
danyl core. The trans-annulated five-membered ring locks
one of two chair conformations of the cyclohexane ring
which allows us to fix both substituents in an axial position
platinum dichloride as a catalyst for the skeletal rearrange-
(see Scheme 2).
[11]
ment according to a protocol by Murai et al.
However,
though the cyclization of very similar substrates is known,
all attempts failed and led only to isolation of the starting
material under an argon atmosphere or to complete decom-
position under a carbon monoxide atmosphere. We ration-
alized that in comparison to other substrates, the missing
Thorpe–Ingold effect prevented the noble metal-catalyzed
rearrangement of our precursor. Therefore, we switched to
Grubbs I catalyst for the enyne-RCM reaction. Under an
ethylene atmosphere (Mori’s conditions), the reaction pro-
ceeded smoothly to furnish cyclopentene rac-15 in an excel-
Scheme 2. Trans-annulated indanyl core as key strategy.
[
12]
lent yield. After deprotection of the alcohol, the desired
key intermediate rac-9 for the envisaged Diels–Alder reac-
tion was obtained in six steps from vinyloxirane (rac-10).
As depicted in Scheme 3, our retrosynthetic analysis
leads back to a Diels–Alder reaction of diene 9 with an
acrylic ester to generate indanyl structure 8 stereoselectively.
Further key steps are a Wittig reaction to introduce the
side chain and a stereocontrolled hydrogenation to place
the methyl group in the desired axial position.
Scheme 3. Retrosynthetic analysis.
Scheme 4. Racemic approach. Reagents and conditions:
(
a) TMSCϵCCH
rac-12 (29%); (b) TBSCl, imidazole, DMF (dimethylformamide),
room temp.; (c) K CO , MeOH/THF, 1:1, room temp., 80% over
two steps; (d) nBuLi, MeI, THF (tetrahydrofuran), –78 °C, 89%;
2 2
Li, Et O/THF, 5:1, –25 °C, rac-11 (65%) and
2
3
Racemic Approach
(
(
e) ethylene atmosphere, Grubbs I catalyst, room temp., 86%;
f) TBAF (tetra-n-butylammonium fluoride), THF, room temp.,
To begin our project, we needed a simple strategy to get
enough material of hydroxy diene 9 to support our retro- 94%.
synthetic considerations. As depicted in Scheme 4, we de-
vised a six-step sequence starting with vinyloxirane (rac-10).
Although 10 is available in both racemic and optically
Glycidol Approach
active forms, only the racemic material of rac-10 was used.
In the first step, oxirane rac-10 was opened with 3-(trimeth-
To obtain key compound 9 in optically pure form, we
ylsilyl)propargyllithium to furnish a separable mixture of decided to avoid beginning with expensive enantioenriched
the desired allylic alcohol rac-11 and the undesired primary vinyloxirane (10). Therefore, our first enantioselective ap-
alcohol rac-12 in a 2:1 ratio and in a combined yield of proach was based on (R)-glycidol (16), which can be used
94%. It is noteworthy that all attempts to use 3-(trimethyl- without the protecting group in the first step (see
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Total Synthesis of Valerenic Acid and Some Bioactive Derivatives
Scheme 5). Regioselective opening of the epoxide with un-
substituted propargylmagnesium bromide led to diol 17
whose primary alcohol was selectively tosylated in the next
[
13]
step by using catalytic amounts of dibutyltin oxide.
Treatment of tosylate 18 with an excess amount of the basic
Corey–Chaykovsky reagent afforded epoxide 19 which was
immediately opened by an additional equivalent of dimeth-
ylsulfonium methylide to furnish the slightly volatile allylic
[
14]
alcohol 20.
Without purification, the crude alcohol was
protected as TBS ether 13 in enantiopure form. The last
three steps were the same as in the racemic series and pro-
vided optically active key intermediate 9 in seven steps from
(R)-glycidol.
Scheme 6. Oxidative rearrangement approach. Reagents and condi-
tions: (a) isopropenyllithium, Et O, –78 °C; (b) PDC (pyridinium
dichromate), DCM, room temp., 49% over two steps; (c) DIBALH
diisobutylaluminum hydride), DCM, –78 °C, 99%; (d) vinyl acet-
ate, Amano lipase PS, MTBE (methyl tert-butyl ether), room temp.,
(45%, ee Ն 95%) and 24 (46%); (e) silica gel, THF, H O, room
temp., 95%.
2
(
9
2
ium oxide, because the acetate was hydrolyzed on silica gel.
This observation proved useful in the end, as simple treat-
ment of the acetate with aqueous silica gel in THF recon-
verted it into the racemic hydroxy diene which was then
recycled through another chiral resolution procedure.
One-Pot Reaction Approach
Scheme 5. Glycidol approach. Reagents and conditions:
a) HCϵCCH MgBr, Et O, –78 °C, 94%; (b) TsCl, NEt , cat.
Bu SnO, DCM (dichloromethane), room temp., 80%; (c) Me SI,
nBuLi then 19, THF, –20 °C; (d) TBSOTf, NEt
(
2
2
3
The final and by far shortest method to provide sufficient
, DCM, 0 °C, 58% amounts of 9 incorporated a new one-pot reaction, which
over two steps; (e) nBuLi, MeI, THF, –78 °C, 89%; (f) ethylene at- was recently devised by our group (see Scheme 7).
mosphere, Grubbs I catalyst, room temp., 86%; (g) TBAF, THF,
room temp., 95%.
2
3
3
[
8]
Oxidative Rearrangement Approach
The third approach towards compound 9 was developed
to shorten our synthesis and avoid costly starting materials
Scheme 7. One-pot reaction approach. Reagents and conditions:
a) (i) isopropenyllithium, Et O, –78 °C; then (ii) TFA (trifluoro-
acetic acid), H O, 0 °C, 81% (72% on gram scale).
and metathesis catalysts. As depicted in Scheme 6, this ap-
proach started with inexpensive cyclopentenone (21).
It is noteworthy that the 1,2-addition of the appropriate
isopropenyl nucleophile proved more difficult than we had
(
2
2
The idea is based on the above-mentioned acid lability
envisaged. In most cases the yield was low, and the compet- of allylic alcohol 22. We rationalized that this compound
ing 1,4-addition was observed. After screening different should be able to undergo an acid-induced [1,3]-isomeriza-
conditions, using diethyl ether as the solvent and isopropen- tion which would lead to the formation of the thermody-
[
17]
yllithium as the nucleophile was found to provide allylic namically more stable product. To confirm this hypothe-
alcohol 22 in a satisfying yield. However, this compound sis, the initially formed tertiary alkoxide 25 was protonated
turned out to be very sensitive to acids and, therefore, only with aqueous acid to form an alcohol which isomerized to
of moderate stability and slightly volatile. Therefore, with- the more stable secondary hydroxy diene rac-9. If an inor-
out further purification, an oxidative rearrangement with ganic acid such as sulfuric acid or hydrochloric acid was
PDC was performed to furnish dienone 23 in a reasonable added, low yields were obtained, indicating that decomposi-
[
15]
yield. The reduction to the alcohol proceeded smoothly, tion and side reactions were competing with the [1,3]-isom-
and chiral resolution with Amano lipase PS and vinyl acet- erization. However, when acetic acid or trifluoroacetic acid
ate gave enantiomerically enriched hydroxy diene 9 along was used, the yields increased considerably, but isomeriza-
[
16]
with acetate 24.
Interestingly, chromatographic separa- tion induced by acetic acid took much longer and led to
tion of both compounds had to be performed on alumin- considerable amounts of 1-acetoxy-3-isopropenylcyclopent-
Eur. J. Org. Chem. 2012, 2041–2053
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2043

J. Ramharter, J. Mulzer
FULL PAPER
2
-ene (rac-24) as a byproduct, whereas treatment of 25 with Table 1. Selected examples of the conversion of different sub-
strates.[
a]
trifluoroacetic acid resulted in the selective formation of
2,4-dienol rac-9. Finally, with this scalable and high-yield-
ing one-pot reaction, we were able to synthesize gram quan-
tities of hydroxy diene rac-9 in a single step. In combination
with the chiral resolution step, 9 was now accessible in just
two steps.
To test the usefulness of this one-pot reaction, we suc-
cessfully expanded the scope of this approach.[ Fortu-
nately, the same principle could be applied to several other
cycloalkenones, although slight alterations of the reaction
conditions were sometimes necessary depending on the sub-
strate. As is depicted in Table 1, the reaction was not restric-
ted to the use of isopropenyllithium, and smooth conver-
sion was also observed with vinylmagnesium bromide
8]
(Table 1, Entries 1–5). In addition, substrates with a larger
ring size (Table 1, Entries 2 and 3) and substituted cycloalk-
enones (Table 1, Entries 4 and 5) underwent the selective
isomerization. It is noteworthy that the conversion of sub-
strate 32 was much more acid-sensitive than the other sub-
strates (Table 1, Entry 4). Therefore, the corresponding in-
termediate was treated with aqueous acetic acid instead of
trifluoroacetic acid to provide the expected alcohol as the
sole product. Interestingly, with the isomerization of this
substrate, no other products were obtained. Finally, a clean
and selective isomerization was also observed with phenyl-
magnesium bromide (Table 1, Entry 6).
[a] (i) 0.1 m in Et
2
O at 0 °C, 2.0 equiv. nucleophile; (ii) 0 °C or room
Hydroxy-Directed Diels–Alder Reaction
temp., H O, 2.5 equiv. acid. [b] Conducted on gram scale.
2
With both racemic as well as optically pure substrates in
our hands, we proceeded with the remaining steps of our
planned synthesis (see Scheme 8). Ester 38 was prepared by
treatment of alcohol 9 with acryloyl chloride to obtain the
precursor of the envisaged IMDA (intramolecular Diels–
Alder) reaction. However, all attempts failed, as either no
conversion or decomposition was observed. According to
literature precedents, the IMDA reaction of ester 38 should
lead exclusively to exo product 8b.[ The electronically pre-
ferred endo transition state 39a is highly strained and
should be disfavored relative to exo transition state 39b.
However, closer inspection and calculation of the predicted
exo product 8b revealed that such a compound would be
extremely distorted, which made its formation unlikely. In
conclusion, the endo product 8a was not accessible, because
of kinetic reasons, whereas the exo product was not formed,
because of thermodynamic instability.
18]
To solve this problem, a hydroxy-directed Diels–Alder
HDDA) reaction was chosen,[ as the esterification oc-
19]
(
curred after the Diels–Alder reaction. Therefore, the endo
transition state 39c would lack the distortion described
above. The hydroxy function served as an anchoring group
for the metal and allowed the enantio- and regioselective
cyclization (see Table 2). All attempts to use phenylmagne-
sium bromide either with or without a scavenger alcohol
Scheme 8. Attempted IMDA reaction. Reagents and conditions:
a) pyridine, acryloyl chloride, dichloromethane, 0 °C, 32%.
(
to generate the alkoxide led to no conversion or complete tonation with triethylamine in the presence of magnesium
decomposition (Table 2, Entries 1 and 2), whereas depro- dibromide etherate and the addition of the dienophile, ac-
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Total Synthesis of Valerenic Acid and Some Bioactive Derivatives
cording to a protocol of Barriault and co-workers, provided
lactone 8a in 45% yield (Table 2, Entry 3).[ Gratifyingly,
the use of Huenig’s base (DIPEA), instead of triethylamine,
increased the yield to 81% (Table 2, Entry 4). Unfortu-
nately, all attempts to deprotect diene rac-15 with boron
trifluoride and use the in situ formed boronate failed, prob-
ably because of the instability of rac-15 under the applied
conditions.
20]
Table 2. Optimization of the HDDA.
Entry
R
Conditions
Yield
[
a]
1
2
3
4
5
H
H
H
H
TBS
PhMgBr, toluene, room temp. to 50 °C
0%
[b]
0.5 equiv. PhMgBr, C
MgBr ·Et O, NEt
MgBr ·Et O, DIPEA, DCM, room temp.
BF ·Et O, DCM or CH CN, –15 °C
5
H11OH, toluene, room temp. 0%
Scheme 9. Envisaged endgame. Reagents and conditions: (a) Li-
AlH , Et O, 0 °C to room temp., 90%; (b) cat. Ir(cod)(py)PCy , H
DCM, room temp., 91%; (c) IBX (2-iodoxybenzoic acid), DMSO
dimethyl sulfoxide), room temp., 80%; (d) Ph P=CMeCO Et,
DCM, reflux, 6a (14%) and 6b (65%).
2
2
3
, DCM, room temp.
45%
81%
4
2
3
2
,
2
2
[a]
3
2
3
0%
(
3
2
[a] Decomposition. [b] No conversion of 9 observed.
Small amounts of the undesired regioisomer were removed
by column chromatography on silica gel (conditioned with
silver nitrate) or by HPLC. Finally, saponification furnished
Unsuccessful Attempts
To introduce the trans-fused ring in the hydroindanyl
core and, hence, the two missing stereogenic centers of val-
erenic acid, lactone 8a was reduced to diol 40 in which both
hydroxy groups could serve as anchors for a substrate-di-
rectable hydrogenation (see Scheme 9). Indeed, Crabtree’s
catalyst furnished diol 41 stereoselectively in excellent
(–)-valerenic acid (1) in an overall yield of 13% (25% if
compound 24 was fully recycled) over 10 steps (7 isolated
intermediates) starting from commercially available cyclo-
pentenone (21).
[
21]
yield.
After oxidation to ketoaldehyde 42, a Wittig ole-
Synthesis of Derivatives
fination was used to introduce the enoate side chain. Al-
though the desired compound 6a was obtained, the major
product of this reaction was 6b, resulting from epimeriz-
ation of 6a to its cis-fused diastereomer. Unfortunately, the
consequences of this epimerization were crucial, because
both ring substituents in 6b were in equatorial positions on
the six-membered ring. Therefore, all attempts to convert
After the completion and optimization of our synthesis,
we turned our attention to the preparation of suitable deriv-
atives. Recently, Rudolph and Altmann demonstrated that
functionalization of the carboxyl group has drastic conse-
[24,25]
quences on the activity of valerenic acid.
Therefore, we
identified synthetic valerenic amides as potential targets. In
an effort to learn more about the structure–activity relation-
ship of these compounds and their interaction with the GA-
BAA receptor, six simple amides with different substituents
were chosen for a first series of derivatives. (see Table 3).
Although activation of valerenic acid with chloro-
formates or other coupling reagents and treatment with am-
6b into desired enol triflate 43 failed, as this placed both
substituents in axial positions. Only the formation of the
less substituted enol triflate was observed.
Completion of the Synthesis
To prevent the detrimental epimerization, lactone 8a was monia furnished the desired unsubstituted amide 47, the
reduced instead to lactol 44 (see Scheme 10). Gratifyingly, yields unfortunately decreased when bulkier amines were
subsequent Wittig olefination led to chain-elongated prod- used as nucleophiles. After eventually testing several pro-
uct 7 without epimerization. Again, the secondary alcohol cedures, the use of Ghosez’s reagent to form valerenic acid
was used to direct the chemo- and stereoselective Crabtree chloride under very mild conditions and subsequent ad-
hydrogenation which produced compound 45 in satisfying dition of the corresponding amine provided the best
[
26]
yield. A mild oxidation allowed us to isolate 6a as the sole yields.
product
In cooperation with the Department of Pharma-
[
22]
which was then converted regioselectively into cology and Toxicology at the University of Vienna, these
tetrasubstituted enol triflate 43. A Negishi coupling reac- substrates were tested both in vitro and in vivo. To our
[
9]
[
23]
tion with dimethylzinc furnished ethyl valerenate (46).
delight, all the substances were highly active GABA recep-
A
Eur. J. Org. Chem. 2012, 2041–2053
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2045

J. Ramharter, J. Mulzer
FULL PAPER
acid. Four different approaches to provide key intermediate
9
are described, leading to gradual improvements. Both suc-
cessful strategies as well as unsuccessful attempts are dis-
cussed to outline the difficulty in synthesizing compounds
with thermodynamically unstable axial substituents and
preventing irreversible epimerization. The final route incor-
porates a new one-pot reaction which allows the formation
of key intermediate 9 in gram quantities. Further extension
of this reaction emphasizes the scope and applicability of
this reaction. The number of steps was reduced from 15 to
10, which makes this route suitable for synthesizing a vari-
ety of derivatives and provides the basis for extensive SAR
studies. In a first effort, a series of amide derivatives were
prepared. Interestingly, easily available valerenic amides dis-
play a higher activity than valerenic acid both in vitro and
in vivo.
Experimental Section
Scheme 10. Final steps towards valerenic acid (1). Reagents and
General Comments: All reactions were carried out in oven-dried
glassware under an argon atmosphere unless stated otherwise. Un-
der an argon atmosphere, anhydrous CH Cl was distilled from
conditions: (a) DIBALH, DCM, –78 °C; (b) Ph
3
P=CMeCO
, H
DCM, room temp., 72%; (d) IBX, DMSO, room temp., 93%;
e) Tf O, pyridine, DCM, room temp.; (f) cat. Pd(PPh , Me Zn,
O,
2
Et,
benzene, reflux, 83% over two steps; (c) cat. Ir(cod)(py)PCy
3
2
,
2
2
P
2
O
5
, and diethyl ether, methanol, and benzene were distilled from
sodium. DMSO, triethylamine, and diisopropylethylamine were
distilled under argon from CaH , and anhydrous THF, DMF, and
(
2
3
)
4
2
THF, room temp., 78% over two steps; (g) LiOH, THF, H
MeOH, room temp., 99%.
2
2
MTBE were purchased from Aldrich. All other solvents were
HPLC grade. Commercially available reagents were used without
further purification unless stated otherwise. Reactions were mag-
netically stirred and monitored by thin layer chromatography. Flash
column chromatography was performed with silica gel (0.04–
Table 3. Preparation of derivatives.
0.063 mm, 240–400 mesh) under pressure unless stated otherwise.
Yields refer to chromatographically and spectroscopically pure
1
compounds unless stated otherwise. H NMR spectroscopic data
1
3
were recorded with either a 400 or 600 MHz spectrometer.
NMR spectroscopic data were recorded with either a 100 or
50 MHz spectrometer. Unless stated otherwise, all NMR spectra
were measured in CDCl solutions. The chemical shifts (δ) are re-
ported relative to the residual solvent peaks. All H and C NMR
shifts are given in ppm (s = singlet, d = doublet, t = triplet, q =
quadruplet, m = multiplet, br. = broad). If possible, assignments
of proton resonances were confirmed with correlated spectroscopy.
Optical rotations were measured at 20 °C. IR spectra were recorded
with samples prepared as films on silicium plates. MS spectra were
measured with a resolution of 10000.
C
1
Entry
RH
NH
NH Me
NH Et
NHEt
Product
Yield
3
1
13
1
2
3
4
5
6
3
47
48
49
50
51
52
96%
95%
94%
94%
91%
90%
2
2
2
piperidine
morpholine
tor modulators. Depending on the degree of substitution, 7-(Trimethylsilyl)hept-1-en-6-yn-3-ol (rac-11): 1-(Trimethylsilyl)
prop-1-yne (98%, 0.94 mL, 6.221 mmol, 2.0 equiv.) was dissolved
the activity of compounds 47–52 decreased with the in-
in anhydrous diethyl ether (30 mL) and anhydrous THF (6 mL).
creasing size of the substituents. As a consequence, the best
The resulting solution was cooled to –25 °C, and nBuLi (1.6 m solu-
results were obtained with unsubstituted valerenic amide 47
which was more than twice as active as valerenic acid (1).
To get a better understanding of this class of substances, a
second series of derivatives with a modified valerenane core
has also been synthesized. A more detailed discussion of
tion, 3.9 mL, 6.240 mmol, 2.0 equiv.) was added dropwise. After
1
6
5 min, the solution was warmed to 0 °C and stirred for another
0 min. Then, the resulting mixture was cooled again to –25 °C and
treated with racemic vinyloxirane (0.25 mL, 3.103 mmol,
.0 equiv.). As the reaction mixture was stirred overnight, the solu-
1
these highly active and easily available substrates will be tion was slowly warmed to room temperature. After quenching
published in due course.
with a saturated aqueous solution of NH
was extracted with diethyl ether (4ϫ), dried with Na
4
Cl, the aqueous phase
SO , and con-
2
4
centrated in vacuo. Purification by column chromatography (pent-
ane/diethyl ether, from 20:1 to 10:1) provided the slightly impure
rac-11 as a clear, slightly yellow oil (370 mg, 65%). Analytical data
Conclusions
In conclusion, we developed a concise, protecting-group- is in agreement with the data reported in the literature.[27] 1H NMR
free, and highly stereoselective total synthesis of valerenic (400 MHz, CDCl
3
): δ = 5.87 (ddd, J = 17.2, 10.5, 6.0 Hz, 1 H),
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Total Synthesis of Valerenic Acid and Some Bioactive Derivatives
5.27 (dt, J = 17.2, 1.4 Hz, 1 H), 5.14 (dt, J = 10.4, 1.3 Hz, 1 H),
(S)-1-Tosylhex-5-yne-1,2-diol (18): Diol 17 (1.560 g, 13.667 mmol,
4
.27 (m, 1 H), 2.35 (m, 2 H), 1.84–1.70 (m, 3 H), 0.15 (s, 9 H) ppm.
1.0 equiv.) was dissolved in anhydrous DCM (140 mL). The re-
1
3
C NMR (100 MHz, CDCl
3
): δ = 140.5, 115.2, 106.9, 85.6, 72.3, sulting solution was cooled to 0 °C, and dibutyltin oxide (67.9 mg,
3
1
5.6, 16.3, 0.2 ppm. IR (film): ν˜ = 3345, 2958, 2927, 2175, 1426, 0.2728 mmol, 0.02 equiv.), triethylamine (2.08 mL, 1.518 g,
–1
249, 1122, 1043, 989, 923, 841, 760 cm . HRMS (ESI): calcd. for
15.005 mmol, 1.1 equiv.), and toluenesulfonyl chloride (2.864 g,
15.022 mmol, 1.1 equiv.) were added. After 10 min, the ice bath was
removed, and the reaction mixture was stirred for 22 h. Then, the
solids were removed by filtration, and the filtrate was concentrated
in vacuo. Purification by chromatography (hexane/ethyl acetate,
+
10
C H18NaOSi [M + Na] 205.1019; found 205.1026.
tert-Butyl(hept-1-en-6-yn-3-yloxy)dimethylsilane (rac-13, Racemic
Approach): A solution of alcohol rac-11 (931 mg, 5.106 mmol,
1
to 0 °C, and imidazole (869 mg, 12.76 mmol, 2.5 equiv.) and tert-
butyldimethylsilyl chloride (927 mg, 6.150 mmol, 1.20 equiv.) were
added. The solution was warmed to room temperature and stirred
overnight. The solution was quenched by the addition of water,
and the aqueous phase was extracted with diethyl ether (3ϫ). The
combined organic phases were washed with brine, dried with
.0 equiv.) in anhydrous dimethylformamide (20 mL) was cooled
4
:1) provided compound 18 as a clear, colorless oil (2.95 g, 80%).
1
H NMR (400 MHz CDCl
3
): δ = 7.81 (d, J = 8.3 Hz, 2 H), 7.36
(
d, J = 8.0 Hz, 2 H), 4.10–3.99 (m, 2 H), 3.94 (dd, J = 9.6, 6.4 Hz,
1
1
H), 2.46 (s, 3 H), 2.38–2.28 (m, 2 H), 2.18 (d, J = 4.6 Hz, 1 H),
1
3
.95 (t, J = 2.7 Hz, 1 H), 1.64 (dd, J = 13.6, 6.8 Hz, 2 H) ppm.
): δ = 145.3, 132.8, 130.1, 128.1, 83.3, 73.7,
9.4, 68.4, 31.3, 21.8, 14.7 ppm. IR (film): ν˜ = 3360, 2922, 2852,
C
NMR (100 MHz, CDCl
3
6
1
Na
solved in methanol (35 mL) and THF (35 mL), and K
1065 mg, 7.706 mmol, 1.5 equiv.) was added. The resulting mixture
was stirred overnight, cooled to 0 °C, and finally quenched by the
addition of a diluted aqueous solution of NH Cl. The aqueous
2
SO
4
, and concentrated in vacuo. The crude yellow oil was dis-
–
1
654, 1458, 1355, 1174, 965, 668, 554, 421, 416 cm . HRMS (ESI):
2
CO
3
16 4 D
H O = –0.4
S [M]+ 268.0769; found 268.0764. [α]
20
calcd. for C13
c = 1.24, DCM).
(
(
4
(S)-tert-Butyl(hept-1-en-6-yn-3-yloxy)dimethylsilane (13, Glycidol
Approach): A suspension of trimethylsulfonium iodide (4.032 g,
19.758 mmol, 5.3 equiv.) in anhydrous THF (60 mL) was treated
with nBuLi (1.6 m solution, 11.75 mL, 18.8 mmol, 5.0 equiv.) at
–15 °C. After stirring for 30 min, tosylate 18 (1.002 g, 3.733 mmol,
1.0 equiv.) was dissolved in anhydrous THF (30 mL), and the re-
phase was extracted (diethyl ether/pentane, 1:1, 3ϫ), and the com-
bined organic extracts were washed with brine and dried with
Na SO . The solvent was then evaporated. Column chromatog-
2 4
raphy (hexane/ethyl acetate, 100:1) furnished the TBS-protected
1
alcohol rac-13 (918 mg, 80% yield over two steps). H NMR
(400 MHz CDCl
3
): δ = 5.78 (ddd, J = 17.1, 10.4, 6.1 Hz, 1 H), sulting solution was added dropwise within 45 min to the reaction
5
2
0
.21–5.03 (m, 2 H), 4.23 (dd, J = 12.2, 6.2 Hz, 1 H), 2.32–2.16 (m,
mixture. The resulting reaction mixture was stirred at the same tem-
perature for 1 h and then slowly warmed to room temperature dur-
ing the night, before it was quenched by the addition of water. The
solution was extracted with diethyl ether (4ϫ), and the combined
H), 1.94 (t, J = 2.7 Hz, 1 H), 1.76–1.62 (m, 2 H), 0.90 (s, 9 H),
.07 (s, 3 H), 0.04 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl
): δ
141.1, 114.5, 84.6, 72.4, 68.5, 36.8, 26.0, 18.4, 14.5, –4.2,
4.7 ppm. IR (film): ν˜ = 3314, 2929, 2857, 1939, 1645, 1472, 1362,
3
=
–
1
2 4
organic phases were washed with brine and dried with Na SO .
–1
251, 1091, 1027, 987, 923, 837, 776, 633 cm . HRMS (ESI): calcd.
Because of the volatility of (S)-hept-1-en-6-yn-3-ol, the organic
phase was carefully concentrated under slightly reduced pressure.
The crude (S)-hept-1-en-6-yn-3-ol was dissolved in anhydrous
DCM (37 mL), and the resulting solution was cooled to 0 °C. Tri-
ethylamine (1.55 mL, 1.132 g, 11.182 mmol, 3.0 equiv.) and tert-
butyldimethylsilyl triflate (2.15 mL, 2.475 g, 9.362 mmol,
+
for C
9
H
15OSi [M – C
S)-Hex-5-yne-1,2-diol (17): A mixture of magnesium turnings
4.745 g, 195.2 mmol), mercury(II) chloride (269.1 mg,
.991 mmol), and a single crystal of iodide in freshly distilled ether
100 mL) was carefully treated with a solution of propargyl brom-
4 9
H ] 167.0892; found 167.0894.
(
(
0
(
2.5 equiv.) were added, and the solution was stirred for 1 h at 0 °C
ide (80% in toluene, 10.5 mL, 11.59 g, 97.4 mmol) dissolved in
freshly distilled ether (40 mL). After the reaction had started, the
mixture was cooled to 0 °C, and the rest of the propargyl bromide
solution was slowly added within 1 h. The resulting mixture was
stirred for another 1 h at 0 °C and an additional 1 h at room tem-
perature. (R)-Glycidol (97%, 1.0 mL, 1.077 g, 14.53 mmol,
and then was warmed to room temperature. After stirring for an
additional 1 h, water was added, and the solution was extracted
with diethyl ether (4ϫ). The combined organic phases were washed
with brine, dried with Na SO , and concentrated in vacuo.
2 4
Chromatography (pentane/diethyl ether, 200:1) furnished com-
pound 13 as a clear, colorless oil (489 mg, 58%). Analytical data is
1.0 equiv.) was dissolved in freshly distilled diethyl ether (290 mL),
2
0
consistent with the reported data for rac-13. [α]
D
= –4.9 (c = 0.82,
and the resulting solution was cooled to –78 °C. Under vigorous
stirring, freshly prepared propargylmagnesium bromide (112.5 mL,
DCM).
7
2.788 mmol, 5.0 equiv.) was very slowly added within 1 h. During
(S)-tert-Butyl(oct-1-en-6-yn-3-yloxy)dimethylsilane (14): Com-
pound 13 (1028 mg, 4.581 mmol, 1.0 equiv.) was dissolved in anhy-
drous THF (46 mL), and the resulting solution was cooled to
–78 °C and then treated with nBuLi (1.6 m solution, 4.3 mL,
6.88 mmol, 1.5 equiv.) dropwise. The resulting solution was stirred
for 15 min at the same temperature, and then methyl iodide
(1.15 mL, 18.48 mmol, 4.0 equiv.) was added. During the night, the
mixture was slowly warmed to room temperature, and then the
reaction was quenched with water. The solution was extracted with
the night, the mixture was slowly warmed to room temperature.
After 14 h, the reaction mixture was quenched with a saturated
aqueous solution of NH Cl. For a better phase separation, potas-
4
sium sodium tartrate was added, and the solution was extracted
with diethyl ether (4ϫ) and ethyl acetate (4ϫ). The combined ex-
tracts were dried with Na SO and concentrated in vacuo. Purifica-
2 4
tion by chromatography (hexane/ethyl acetate, from 10:1 to pure
ethyl acetate) provided compound 17 as a clear, yellow oil (1.560 g,
1
9
3
7
4%). H NMR (400 MHz, CDCl
3
): δ = 3.89 (ddd, J = 13.1, 7.0, diethyl ether (3ϫ), and the combined extracts were washed with
.2 Hz, 1 H), 3.68 (dd, J = 11.1, 3.2 Hz, 1 H), 3.49 (dd, J = 11.1,
.3 Hz, 1 H), 2.47 (br. s, 1 H), 2.36 (dt, J = 7.0, 2.7 Hz, 2 H), 2.16
2 4
brine, dried with Na SO , and concentrated in vacuo. Purification
by chromatography (hexane/ethyl acetate, 100:1) provided com-
1
(br. s, 1 H), 1.99 (t, J = 2.7 Hz, 1 H), 1.66 (dd, J = 13.6, 6.8 Hz, 2
pound 14 as a clear, colorless oil (977 mg, 89%). H NMR
13
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 83.9, 71.2, 69.2, 66.7,
3
(400 MHz CDCl ): δ = 5.78 (ddd, J = 17.1, 10.4, 6.0 Hz, 1 H),
3
1
1
1.7, 15.0 ppm. IR (film): ν˜ = 3296, 2924, 2853, 1654, 1437, 1099,
5.20–5.01 (m, 2 H), 4.21 (dt, J = 6.8, 5.8 Hz, 1 H), 2.25–2.09 (m,
–1
+
044, 944, 890, 636 cm . HRMS (ESI): calcd. for C
6
H
10
O
2
[M]
2 H), 1.78 (t, J = 2.6 Hz, 3 H), 1.69–1.58 (m, 2 H), 0.90 (s, 9 H),
14.0681; found 114.0680. [α]2
0
= –19.9 (c = 0.72, DCM).
0.07 (s, 3 H), 0.04 (s, 3 H) ppm. C NMR (100 MHz, CDCl
13
): δ
D
3
Eur. J. Org. Chem. 2012, 2041–2053
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2047

J. Ramharter, J. Mulzer
141.4, 114.1, 79.1, 75.8, 72.6, 37.4, 26.0, 18.4, 14.8, 3.6, –4.2, raphy (pentane/diethyl ether, from 4:1 to 2:1) furnished compound
FULL PAPER
=
–
9
1
4.8 ppm. IR (film): ν˜ = 2929, 2857, 1472, 1361, 1251, 1089, 989,
23 as a yellow solid (71.5 mg, 49% over two steps). H NMR
(400 MHz, CDCl ): δ = 6.10 (t, J = 1.5 Hz, 1 H), 5.55 (s, 1 H),
5.32 (t, J = 1.3 Hz, 1 H), 2.79 (m, 2 H), 2.48 (m, 2 H), 2.02 (s, 3
–1
22, 837, 776 cm . HRMS (ESI): calcd. for C10
4 9 D
H ] 181.1049; found 181.1052. [α] = –4.8 (c = 1.67, DCM).
H
17OSi [M –
3
+
20
C
1
3
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 210.1, 174.2, 139.8,
28.8, 119.8, 35.4, 27.8, 20.5 ppm. IR (film): ν˜ = 2925, 2362, 2341,
707, 1693, 1673, 1622, 1576, 1441, 1253, 1232, 1183, 919,
(
(
1
S)-tert-Butyldimethyl[3-(prop-1-en-2-yl)cyclopent-2-enyloxy]silane
15): solution of compound 14 (263.8 mg, 1.106 mmol,
.0 equiv.) and freshly distilled and degassed DCM (37 mL) was
1
1
8
1
A
–1
10O [M]+ 122.0732; found
8
H
66 cm . HRMS (EI): calcd. for C
22.0732.
cooled to –78 °C. The flask was flushed with ethylene gas over a
period of 10 min, before ethylene gas was bubbled through the solu-
tion itself for an additional 3 min. Grubbs I catalyst (136.4 mg,
3-(Prop-1-en-2-yl)cyclopent-2-enol (rac-9, Oxidative Rearrangement
Approach): A solution of dienone 23 (22.8 mg, 0.1866 mmol,
.0 equiv.) and anhydrous DCM (0.93 mL) was cooled to –78 °C
and treated with diisobutylaluminium hydride (1.0 m solution,
.23 mL, 0.230 mmol, 1.25 equiv.). After stirring for 1 h, the re-
maining DIBALH was quenched by the addition of methanol. Af-
ter warming to room temperature, a diluted potassium sodium tar-
trate solution was added, and the resulting mixture was stirred
overnight. The aqueous phase was extracted with DCM (5ϫ). The
0
.1657 mmol, 0.15 equiv.) was added, and once again, ethylene gas
1
was bubbled through the resulting mixture for 1 min. The dry ice
bath was removed, and the mixture was stirred for 24 h. The flask
was flushed with argon, and the solvent was evaporated.
Chromatography of the residue (pentane/diethyl ether, 200:1) fur-
nished compound 15 as a clear, colorless oil (226.6 mg, 86%). H
NMR (400 MHz CDCl
0
1
3
): δ = 5.68 (d, J = 1.4 Hz, 1 H), 5.00–4.94
(m, 3 H), 2.69–2.59 (m, 1 H), 2.39–2.25 (m, 2 H), 1.93 (s, 3 H),
1
.80–1.69 (m, 1 H), 0.91 (s, 9 H), 0.09 (s, 6 H) ppm. 13C NMR
): δ = 146.0, 140.0, 129.9, 114.2, 78.5, 34.3, 30.7,
2 4
combined organic phases were dried with Na SO , and the solvent
was evaporated. Purification of the residue by column chromatog-
raphy (pentane/diethyl ether, from 3:1 to 1:1) provided alcohol rac-
(100 MHz, CDCl
3
2
1
7
2
6.2, 20.7, 18.5, –4.3, –4.4 ppm. IR (film): ν˜ = 3360, 2927, 2855,
9
as a slightly yellow oil (22.9 mg, 99%). Analytical data is consis-
661, 1634, 1600, 1464, 1361, 1251, 1108, 1051, 1005, 910, 835,
–1
+
tent with the reported data for compound 9 listed above.
75 cm . HRMS (ESI): calcd. for C14
H
26OSi [M] 238.1753; found
38.1750. [α]2
0
= –98.6 (c = 1.96, DCM).
D
(
S)-3-(Prop-1-en-2-yl)cyclopent-2-enol (9) and (R)-3-(Prop-1-en-2-
yl)cyclopent-2-enyl Acetate (24, Racemic Resolution): To a solution
of dienol rac-9 (520.5 mg, 4.191 mmol, 1.0 equiv.) and anhydrous
MTBE (14.5 mL) were added Amano lipase PS (111.0 mg) and vi-
nyl acetate (0.4 mL, 4.340 mmol, 1.0 equiv.). The resulting mixture
was stirred at ambient temperature for 24 h. After a small NMR
sample indicated Ͼ50% conversion, the solids were removed by
filtration, and the resulting filtrate was concentrated in vacuo. Puri-
fication of the residue by chromatography (hexane (H)/diethyl ether
(
S)-3-(Prop-1-en-2-yl)cyclopent-2-enol (9, Glycidol Approach): A
solution of compound 15 (402.8 mg; 1.689 mmol, 1.0 equiv.) in an-
hydrous THF (34 mL) was cooled to 0 °C and then treated with
tetrabutylammonium fluoride (1.0 m solution, 2.55 mL, 2.55 mmol,
1
.5 equiv.). For the next 3.5 h, the reaction mixture was stirred at
room temperature and then was quenched with a saturated aqueous
solution of NH Cl. The resulting solution was extracted with DCM
3ϫ) and ethyl acetate (1ϫ), dried with Na SO , and concentrated
4
(
2
4
(
0
EE), from 10:1 to 1:1) using Merck aluminium oxide 90 (0.063–
.200 mm, 70–230 mesh) provided ester 24 (321.0 mg, 46%) and
in vacuo. Purification by chromatography (pentane/diethyl ether,
from 3:1 to 2:1) provided compound 9 as a clear, slightly yellow oil
(
1
2
7
1
2
C
1
optically enriched alcohol 9 (234.8 mg, 45%, ee Ն 95%). (Atten-
tion: Ester 24 is acid-labile and should be stored below 0 °C.) Analyt-
ical data for compound 9 is consistent with alcohol rac-9, see above.
190.4 mg, 95%). H NMR (400 MHz CDCl
3
): δ = 5.80 (d, J =
.7 Hz, 1 H), 5.02 (s, 2 H), 4.96–4.89 (m, 1 H), 2.73–2.63 (m, 1 H),
.45–2.31 (m, 2 H), 1.94 (s, 3 H), 1.80–1.73 (m, 1 H), 1.44 (d, J =
2
0
13
D
[α] = –124.9 (c = 1.175 g/100 mL, DCM). Analytical data for ester
3
.4 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 147.7, 139.8,
1
2
4: H NMR (400 MHz, CDCl
3
): δ = 5.81–5.71 (m, 2 H), 5.05 (s,
29.0, 114.9, 78.1, 34.1, 30.6, 20.7 ppm. IR (film): ν˜ = 3324, 2924,
–1
2 H), 2.74–2.65 (m, 1 H), 2.52–2.33 (m, 2 H), 2.04 (s, 3 H), 1.95 (s,
854, 1599, 1458, 1032, 970, 888 cm . HRMS (ESI): calcd. for
1
3
12O [M]+ 124.0888; found 124.0884. [α]
20
3 H), 1.93–1.85 (m, 1 H) ppm. C NMR (100 MHz, CDCl
71.2, 150.0, 139.5, 124.9, 115.6, 81.0, 30.7, 30.3, 21.5, 20.6 ppm.
IR (film): ν˜ = 2947, 2857, 1732, 1600, 1454, 1372, 1238, 1165, 1100,
3
): δ =
8
H = –119.3 (c = 0.83,
D
1
DCM).
–
1
+
3
1
-(Prop-1-en-2-yl)cyclopent-2-enone (23): 2-Bromopropene (160 μL,
.801 mmol, 1.5 equiv.) was dissolved in anhydrous diethyl ether
10 14 2
1027, 962, 888 cm . HRMS (ESI): calcd. for C H O [M]
2
0
166.0994; found 166.0995. [α]D = +213.7 (c = 1.11, DCM).
-(Prop-1-en-2-yl)cyclopent-2-enol (rac-9, Racemization): To a solu-
tion of acetate 24 (251.4 mg, 1.512 mmol, 1.0 equiv.) and THF
8 mL) cooled to 0 °C were added water (8 mL) and Merck silica
(5.1 mL), and the resulting solution was cooled to –78 °C. Then,
3
tBuLi (1.7 m solution, 2.12 mL, 3.604 mmol, 3.0 equiv.) was added.
After stirring for 2 h, the slightly turbid solution was warmed to
ambient temperature. After 15 min, the resulting 2-propenyllithium
was slowly added to a solution of cyclopent-2-enone (100 μL,
1
–
of a diluted aqueous solution of NH Cl, and the resulting mixture
4
was warmed to room temperature. The aqueous phase was ex-
tracted with diethyl ether (3ϫ), and the combined organic phases
were washed with brine and dried with Na SO , followed by careful
2 4
(
gel (0.04–0.063 mm, 240–400 mesh, 256.5 mg). The resulting mix-
ture was vigorously stirred for 36 h at ambient temperature, and
then the solids were removed by filtration. The filtrate was treated
.194 mmol, 1.0 equiv.) and anhydrous diethyl ether (4.8 mL) at
78 °C. After 60 min, the reaction was quenched by the addition
with a saturated aqueous solution of NaHCO
mixture was extracted with dichloromethane (4ϫ). The combined
organic extracts were washed with brine, dried with Na SO , and
3
, and the resulting
2
4
concentrated in vacuo. Purification of the residue by chromatog-
raphy (H/EE, 4:1) provided 3-isopropenylcyclopent-2-enol (rac-9,
concentration under slightly reduced pressure. (Attention: Tertiary
alcohol 22 is volatile.) The crude alcohol was then dissolved in an-
hydrous DCM (12 mL). To this solution was added Celite (930 mg),
and the resulting mixture was treated with pyridinium dichromate
2
0
1
1
D
78.1 mg, 95%). For analytical data, see above. [α] = 0.000 (c =
.05, DCM).
3-(Prop-1-en-2-yl)cyclopent-2-enol (rac-9, One-Pot Reaction Ap-
proach): 2-Bromopropene (3.1 mL, 34.85 mmol, 2.0 equiv.) was dis-
solved in anhydrous diethyl ether (35.0 mL), and the resulting solu-
tion was cooled to –78 °C. After treatment with tBuLi (1.9 m solu-
(905 mg, 2.406 mmol, 2.0 equiv.). After stirring for 24 h at room
temperature, the solids were removed by filtration, and the remain-
ing solution was concentrated in vacuo. Purification by chromatog-
2048
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2041–2053

Total Synthesis of Valerenic Acid and Some Bioactive Derivatives
–
1
tion, 36.0 mL, 68.4 mmol, 3.9 equiv.), the slightly turbid solution
was stirred for 2 h at the same temperature, and then it was warmed
to ambient temperature. After 15 min, the clear, yellow solution
was transferred through a cannula to a solution of cyclopent-2-
enone (98%, 1.5 mL, 17.55 mmol, 1.0 equiv.) and anhydrous di-
ethyl ether (140 mL) cooled to –78 °C. The resulting turbid mixture
was stirred for 60 min. Then, it was warmed to 0 °C, and water
1258, 1189, 1056, 995, 966, 912, 749 cm . HRMS (EI): calcd. for
12O [M]+ 124.0888; found 124.0884.
-Vinylcyclohept-2-enol (31): According to the general procedure
described above, the reaction of 2-cycloheptenone (50 μL,
.4484 mmol, 1.0 equiv.) with vinylmagnesium bromide (1.0 m solu-
tion, 0.90 mL, 0.90 mmol, 2.0 equiv.) in anhydrous diethyl ether
4.5 mL) and subsequent treatment with water (4.5 mL) and tri-
8
C H
3
0
(
(175 mL) was added. The biphasic solution was slowly treated with
fluoroacetic acid (87 μL, 1.1293 mmol, 2.5 equiv.) for 1.5 h at ambi-
trifluoroacetic acid (3.4 mL, 44.13 mmol, 2.5 equiv.), and the re-
sulting mixture was then vigorously stirred for another 1 h at the
same temperature. The reaction mixture was quenched with a satu-
ent temperature provided 3-vinylcyclohept-2-enol which was puri-
fied by column chromatography (H/EE, 5:1) to give a colorless oil
1
(
49.7 mg, 80%). H NMR (400 MHz, CDCl
3
): δ = 6.30 (dd, J =
rated aqueous solution of NaHCO
aqueous phase was extracted with DCM (3ϫ), and the combined
organic phases were washed with brine, dried with Na SO , and
3
, and DCM was added. The
1
4
7.4, 10.7 Hz, 1 H), 5.81–5.75 (m, 1 H), 5.15 (d, J = 5.15 Hz, 1 H),
.98 (dd, J = 10.7, 0.58 Hz, 1 H), 4.56–4.47 (m, 1 H), 2.54–2.43
2
4
(
m, 1 H), 2.10–2.00 (m, 1 H), 2.00–1.89 (m, 1 H), 1.89–1.79 (m, 1
reduced in vacuo. Column chromatography (hexane/ethyl acetate,
from 5:1 to 3:1) furnished alcohol rac-9 as a colorless oil (1.57 g,
13
H), 1.77–1.59 (m, 4 H), 1.32–1.22 (m, 1 H) ppm. C NMR
100 MHz, CDCl ): δ = 140.2, 140.0, 139.3, 111.3, 71.8, 36.6, 27.8,
6.5, 25.7 ppm. IR (film): ν˜ = 3343, 2928, 2853, 1605, 1450, 1351,
(
2
1
3
72%). Analytical data is consistent with the reported data for com-
pound 9 listed above.
–1
9 14
276, 1028, 989, 891, 839 cm . HRMS (EI): calcd. for C H O
+
[M] 138.1045; found 138.1047.
General Procedure for the Preparation of 2,4-Dienols: A solution of
cycloalkenone (1.0 equiv.) and anhydrous diethyl ether (0.1 m solu-
tion) was cooled to 0 °C and treated with vinylmagnesium bromide
1-Methyl-3-vinylcyclopent-2-enol (33): A solution of 3-methylcy-
clopent-2-enone (97%, 60 μL, 0.5879 mmol, 1.0 equiv.) and anhy-
drous diethyl ether (6.0 mL) was cooled to 0 °C. Vinylmagnesium
bromide (1.0 m solution, 1.10 mL, 1.10 mmol, 2.0 equiv.) was
slowly added, and the resulting solution was stirred for 60 min.
Then, the solution was warmed to 0 °C, and water (6.0 mL) was
added. The biphasic solution was slowly treated with acetic acid
(
(
1.0 m solution, 2.0 equiv.). After TLC indicated full conversion
usually in 1 h), water (same volume as that of diethyl ether) and
trifluoroacetic or acetic acid (2.5 equiv.) were added. The biphasic
solution was vigorously stirred at 0 °C or ambient temperature un-
til full conversion was observed by TLC. Then, a saturated aqueous
solution of NaHCO was added, and the organic layer was sepa-
3
rated. The aqueous layer was extracted with dichloromethane (3ϫ),
(
85 μL, 1.4863 mmol, 2.5 equiv.), and the resulting mixture was
then vigorously stirred for 45 min at the same temperature. The
reaction was quenched with a saturated aqueous solution of
and the combined organic extracts were washed with brine, dried
NaHCO
with DCM (3ϫ), and the combined organic phases were washed
with brine, dried with Na SO , and reduced in vacuo to provide
3
, and DCM was added. The aqueous phase was extracted
with Na
2 4
SO , and concentrated in vacuo. Purification of the resi-
due by chromatography provided the corresponding 2,4-dienol.
2
4
3
-Vinylcyclopent-2-enol (27): According to the general procedure
described above, the reaction of 2-cyclopentenone (98%, 50 μL,
.5853 mmol, 1.0 equiv.) with vinylmagnesium bromide (1.0 m solu-
tion, 1.16 mL, 1.16 mmol, 2.0 equiv.) in anhydrous diethyl ether
5.9 mL) and subsequent treatment with water (5.9 mL) and tri-
racemic alcohol 33 as a slightly yellow oil (72.3 mg, 99%). Purifica-
tion by column chromatography was not necessary. (Attention: Di-
0
1
enol 33 should be stored below 0 °C.) H NMR (400 MHz, CDCl
3
):
δ = 6.53 (dd, J = 17.5, 10.6 Hz, 1 H), 5.67–5.64 (m, 1 H), 5.21 (dd,
J = 17.5, 0.9 Hz, 1 H), 5.16 (dd, J = 10.6, 1.3 Hz, 1 H), 2.66–2.57
(
fluoroacetic acid (113 μL, 1.4668 mmol, 2.5 equiv.) for 1.0 h at 0 °C
provided 3-vinylcyclopent-2-enol which was purified by column
(
m, 1 H), 2.47–2.37 (m, 1 H), 2.13–1.95 (m, 2 H), 1.55–1.48 (br. s,
H), 1.40 (s, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 143.8,
3
36.5, 133.4, 116.5, 83.3, 40.0, 29.3, 27.6 ppm. IR (film): ν˜ = 3354,
13
1
1
2
8
1
chromatography (H/EE, 5:1) to give a slightly yellow oil (50.6 mg,
1
7
8%). (Attention: Dienol 27 should be stored below 0 °C.) H NMR
967, 2928, 2855, 2346, 1600, 1452, 1368, 1304, 1180, 1133, 1084,
(400 MHz, CDCl
3
): δ = 6.58 (dd, J = 17.5, 10.6 Hz, 1 H), 5.79–
–1
+
7 9 3
89, 851 cm . HRMS (EI): calcd. for C H O [M – CH ]
5.75 (m, 1 H), 5.27–5.15 (m, 2 H), 4.94–4.85 (br. s, 1 H), 2.70–2.57
09.0653; found 109.0651.
(
m, 1 H), 2.42–2.30 (m, 2 H), 1.83–1.72 (m, 1 H), 1.43 (d, J =
.6 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 146.1, 133.3,
3
32.1, 117.0, 77.6, 33.7, 29.2 ppm. IR (film): ν˜ = 3297, 2922, 2853,
2-Methyl-3-vinylcyclopent-2-enol (35): According to the general
13
5
1
2
7
1
procedure described above, the reaction of 2-methyl-2-cyclopen-
tenone (98%, 50 μL, 0.5097 mmol, 1.0 equiv.) with vinylmagnesium
bromide (1.0 m solution, 1.02 mL, 1.02 mmol, 2.0 equiv.) in anhy-
drous diethyl ether (5.0 mL) and subsequent treatment with water
359, 1591, 1455, 1416, 1319, 1275, 1264, 1158, 1042, 986, 968, 905,
–1
+
50 cm . HRMS (EI): calcd. for C
10.0728.
7
H10O [M] 110.0732; found
(
5.0 mL) and trifluoroacetic acid (98 μL, 1.2721 mmol, 2.5 equiv.)
for 0.75 h at 0 °C provided 2-methyl-3-vinyl-cyclopent-2-enol which
was purified by column chromatography (H/EE, 5:1) to give a col-
3
-Vinylcyclohex-2-enol (29): According to the general procedure de-
scribed above, the reaction of 2-cyclohexenone (95%, 20 μL,
.1957 mmol, 1.0 equiv.) with vinylmagnesium bromide (1.0 m solu-
tion, 0.40 mL, 0.40 mmol, 2.0 equiv.) in anhydrous diethyl ether
2.0 mL) and subsequent treatment with water (2.0 mL) and tri-
orless oil (49.8 mg, 79%). (Attention: Dienol 35 should be stored
0
1
below 0 °C.) H NMR (400 MHz, CDCl
3
): δ = 6.65 (dd, J = 17.2,
10.8 Hz, 1 H), 5.21–5.13 (m, 2 H), 4.71–4.60 (m, 1 H), 2.65–2.53
(
(
1
m, 1 H), 2.38–2.26 (m, 2 H), 1.83 (s, 3 H), 1.71–1.62 (m, 1 H),
fluoroacetic acid (38 μL, 0.4932 mmol, 2.5 equiv.) for 1.5 h at 0 °C
provided 3-vinylcyclohex-2-enol which was purified by column
1
3
.45 (d, J = 4.7 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ =
138.9, 136.7, 131.3, 115.4, 81.6, 32.5, 29.4, 11.3 ppm. IR (film): ν˜
chromatography (H/EE, 5:1) to give a colorless oil (19.2 mg, 79%).
1
= 3345, 2960, 2936, 2912, 2854, 1443, 1421, 1276, 1261, 1198, 1049,
3
H NMR (400 MHz, CDCl ): δ = 6.35 (dd, J = 17.5, 10.8 Hz, 1
–
1
1
005, 986, 900, 750 cm . HRMS [APCI (atmospheric pressure
H), 5.80–5.74 (m, 1 H), 5.21 (d, J = 17.5 Hz, 1 H), 5.05 (d, J =
0.8 Hz, 1 H), 4.35–4.26 (m, 1 H), 2.24–2.04 (m, 2 H), 1.97–1.76
8 2
H11 [M – H
O + H]+ 107.0855;
chemical ionization)]: calcd. for C
found 107.0850.
1
13
(
(
1
m, 2 H), 1.69–1.54 (m, 2 H), 1.53–1.42 (br. s, 1 H) ppm. C NMR
100 MHz, CDCl ): δ = 139.4, 138.9, 130.9, 113.1, 66.4, 32.3, 23.9,
9.0 ppm. IR (film): ν˜ = 3389, 2934, 2869, 1714, 1666, 1453, 1427,
3
3-Phenylcyclohex-2-enol (37): According to the general procedure
described above, the reaction of 2-cyclohexenone (95%, 50 μL,
Eur. J. Org. Chem. 2012, 2041–2053
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2049

J. Ramharter, J. Mulzer
FULL PAPER
0.4892 mmol, 1.0 equiv.) with phenylmagnesium bromide (1.0 m
LiAlH
4
(95%, 0.3304 mmol, 3.0 equiv.) in three portions. The re-
solution, 0.98 mL, 0.98 mmol, 2.0 equiv.) in anhydrous diethyl
ether (4.9 mL) and subsequent treatment with water (4.9 mL) and
trifluoroacetic acid (95 μL, 1.2331 mmol, 2.5 equiv.) for 48 h at am-
bient temperature provided of 3-phenylcyclohex-2-enol which was
purified by column chromatography (H/EE, 3:1) to give a colorless
sulting mixture was warmed to room temperature and stirred for
4 h. After cooling again to 0 °C, the mixture was diluted with di-
ethyl ether (1.5 mL), and the reaction was quenched with the subse-
quent addition of water (24 μL), NaOH (10% aqueous solution,
24 μL), and water (72 μL). Then, the mixture was warmed to room
oil (80.5 mg, 94%). 1H NMR (400 MHz, CDCl
m, 2 H), 7.36–7.30 (m, 2 H), 7.29–7.23 (m, 1 H), 6.17–6.09 (m, 1
H), 4.45–4.34 (br. s, 1 H), 2.53–2.43 (m, 1 H), 2.43–2.32 (m, 1 H),
.01–1.86 (m, 2 H), 1.82–1.63 (m, 2 H), 1.55 (d, J = 5.2 Hz, 1
): δ = 7.44–7.39 temperature and vigorously stirred for 30 min. The clear, colorless
3
(
solution was filtered through Celite, and the white residue was once
again treated with diethyl ether (2 mL), water (56 μL), and NaOH
(10% aqueous solution, 14 μL). After stirring for another 30 min,
the white precipitate was removed by filtration, and the combined
organic filtrates were dried with Na SO and concentrated in
2 4
vacuo. Purification by chromatography (hexane/ethyl acetate, 1:1)
2
13
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 141.5, 140.4, 128.5,
27.6, 126.7, 125.5, 66.5, 31.9, 27.7, 19.6 ppm. IR (film): ν˜ = 3336,
934, 2862, 2358, 1494, 1446, 1344, 1276, 1053, 973, 907, 757,
1
2
6
1
–1
14NaO [M + Na]+
95 cm . HRMS (ESI): calcd. for C12
97.0937; found 197.0938.
H
provided racemic diol 40 as a clear, colorless oil (18.0 mg, 90%).
1
3
H NMR (400 MHz, CDCl ): δ = 4.38 (t, J = 3.6 Hz, 1 H), 3.78
(
(
(
t, J = 10.2 Hz, 1 H), 3.54 (dd, J = 10.8, 2.3 Hz, 1 H), 3.48–3.01
3
-(Prop-1-en-2-yl)cyclopent-2-enyl Acrylate (38): A solution of race-
br. s, 2 H), 2.47 (m, 2 H), 2.29 (m, 2 H), 1.84 (m, 2 H), 1.81–1.63
mic hydroxy diene 9 (25.0 mg, 0.2013 mmol, 1.0 equiv.) and pyr-
idine (0.28 mL, 3.469 mmol, 15 equiv.) in anhydrous DCM
13
3
m, 4 H), 1.61 (s, 3 H) ppm. C NMR (100 MHz, CDCl ): δ =
1
32.0, 124.8, 74.5, 63.5, 49.7, 37.5, 33.4, 28.4, 27.9, 26.0, 19.4 ppm.
(
(
2.0 mL) was cooled to 0 °C and treated with acryloyl chloride
0.19 mL, 2.339 mmol, 10 equiv.). After stirring for 2 h, a saturated
IR (film): ν˜ = 3234, 2925, 2333, 2158, 1439, 1164, 1110, 1056, 1012,
9
found 182.1304.
–1
+
59, 786 cm . HRMS (EI): calcd. for C11
18 2
H O [M] 182.1307;
3
aqueous solution of NaHCO was added. The resulting solution
was diluted with diethyl ether, and the aqueous phase was extracted
with DCM (3ϫ). The combined organic phases were dried with
2 4
Na SO and reduced in vacuo. Chromatography using Merck alu-
minium oxide 90 (0.063–0.200 mm, 70–230 mesh, hexane/ethyl
acetate, 30:1) afforded ester 38 as a clear and colorless oil (12.9 mg,
3
1
(
1S,3aR,4R,7R,7aS)-7-(Hydroxymethyl)-4-methyloctahydro-1H-
inden-1-ol (41): A solution of racemic diol 40 (18.0 mg,
.0988 mmol, 1.0 equiv.) and freshly distilled and degassed DCM
4 mL) was cooled to 0 °C. The flask was flushed with hydrogen
0
(
1
over a period of 2 min, and then hydrogen was bubbled through the
solution for an additional 1 min. After adding Crabtree’s catalyst
(
flushed with hydrogen for 3 min, and then hydrogen was bubbled
through the solution for 2 min until it became colorless. The ice
bath was removed, and the mixture was stirred for 24 h. Argon was
bubbled through the reaction mixture, and the solvent was evapo-
rated. Chromatography (hexane/ethyl acetate, 3:2) of the residue
2%). H NMR (400 MHz, CDCl
3
): δ = 6.39 (dd, J = 17.3, 1.5 Hz,
H), 6.11 (dd, J = 17.3, 10.4 Hz, 1 H), 5.86–5.76 (m, 3 H), 5.06
5.2 mg, 0.00646 mmol, 0.065 equiv.), the flask was once again
(s, 2 H), 2.80–2.65 (m, 1 H), 2.53–2.36 (m, 2 H), 1.99–1.90 (m, 4
13
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 166.4, 150.1, 139.6,
130.5, 129.0, 124.8, 115.6, 81.2, 30.8, 30.3, 20.6 ppm. IR (film): ν˜
=
2948, 1721, 1600, 1406, 1295, 1269, 1192, 1165, 1041, 1024, 984,
–1
+
9
1
65, 890, 811 cm . HRMS (EI): calcd. for C11
78.0994; found 178.0997.
14 2
H O [M]
1
afforded racemic compound 41 as a white solid (16.5 mg, 91%). H
(
[
3
2aR,7aS,7bR)-5-Methyl-3,4,6,7,7a,7b-Hexahydro-2aH-indeno-
1,7-bc]furan-2-one (8a): Anhydrous MgBr ·Et O (977 mg,
.783 mmol, 2.0 equiv.) was suspended in anhydrous dichlorometh-
NMR (400 MHz, CDCl
H), 3.77–3.49 (br. s, 2 H), 3.46 (d, J = 11.0 Hz, 1 H), 2.33 (m, 1
H), 2.15 (m, 2 H), 1.88–1.52 (m, 5 H), 1.49–1.29 (m, 4 H), 0.87 (d,
3
): δ = 4.26 (s, 1 H), 4.07 (t, J = 10.7 Hz,
2
2
1
ane (4.5 mL), and the resulting mixture was treated with diisopro-
pylethylamine (1.3 mL, 7.644 mmol, 4.0 equiv.) and stirred for
13
J = 7.1 Hz, 3 H) ppm. C NMR (100 MHz, CDCl
3.3, 45.4, 39.7, 36.4, 33.6, 30.0, 29.5, 25.9, 23.6, 12.0 ppm. IR
film): ν˜ = 3190, 2957, 2926, 2903, 2882, 2861, 1460, 1439, 1371,
3
): δ = 74.8,
6
(
1
C
15 min until the suspension turned magenta. Then, a solution of
compound 9 (234.8 mg, 1.891 mmol, 1.0 equiv.) dissolved in dichlo-
romethane (14.5 mL) was added slowly through a cannula. After
stirring for 1 h, methyl acrylate (0.34 mL, 3.776 mmol, 2.0 equiv.)
was added dropwise. The resulting mixture was stirred for 6 h and
–1
340, 1276, 1049, 1009, 949, 764, 750 cm . HRMS (EI): calcd. for
+
11
H
18O [M – H
2
O] 166.1358; found 166.1357.
(
3aS,4R,7R,7aR)-7-Methyl-3-oxooctahydro-1H-indene-4-carb-
aldehyde (42): Racemic diol 41 (16.5 mg, 0.0895 mmol, 1.0 equiv.)
was dissolved in anhydrous DMSO (1.8 mL), and the resulting
solution was treated with
0
ring for 5 h, water was added, and the white precipitate was re-
moved by filtration. The precipitate was washed with DMSO/water
(1:2) and pentane/diethyl ether (1:1). The filtrate was extracted with
DCM (4ϫ), and the combined organic phases were dried with
4
then was quenched with a saturated aqueous solution of NH Cl.
For a better phase separation, potassium sodium tartrate was
added, and the solution was extracted with diethyl ether (2ϫ) and
dichloromethane (3ϫ). The combined extracts were dried with
a solution of IBX (102.0 mg,
.3643 mmol, 4.0 equiv.) in anhydrous DMSO (1.2 mL). After stir-
Na
2 4
SO and concentrated in vacuo. Purification by chromatog-
raphy (H/EE, 6:1) furnished compound 8a as a white solid
1
(
5
(
273.7 mg, 81%). H NMR (400 MHz CDCl
.5, 1.0 Hz, 1 H), 3.02 (ddd, J = 6.5, 6.0, 3.2 Hz, 1 H), 2.88–2.80
m, 1 H), 2.63–2.51 (m, 1 H), 2.32–2.18 (m, 1 H), 2.15–1.87 (m, 6
3
): δ = 4.84 (dt, J =
Na
2
SO
4
and then concentrated in vacuo. Purification by
13
chromatography (hexane/ethyl acetate, 5:1) provided racemic com-
pound 42 as a clear, colorless oil (12.8 mg, 80%). (Attention: Com-
pound 42 tends to epimerize and should be stored below 0 °C.) H
NMR (400 MHz, CDCl
H), 1.65 (s, 3 H) ppm. C NMR (100 MHz, CDCl
1
3
): δ = 178.7,
30.4, 129.3, 83.4, 43.8, 39.7, 29.1, 27.5, 27.2, 20.2, 20.0 ppm. IR
1
–
1
(film): ν˜ = 2925, 1763, 1449, 1335, 1142, 1020, 985, 932, 877 cm .
+
3
): δ = 9.57 (s, 1 H), 3.10 (m, 1 H), 2.57–
14 2
HRMS (EI): calcd. for C11H O [M] 178.0994; found 178.0997.
2
0
2.03 (m, 5 H), 2.01–1.85 (m, 2 H), 1.72 (m, 1 H), 1.62–1.48 (m, 2
[α]
D
= –94.4 (c = 0.71, DCM).
1
3
H), 1.39 (m, 1 H), 0.92 (d, J = 7.0 Hz, 3 H) ppm. C NMR
): δ = 217.2, 201.9, 47.4, 47.3, 41.5, 37.9, 29.95,
29.85, 24.8, 19.6, 11.1 ppm. IR (film): ν˜ = 2934, 2877, 1738, 1458,
(
1S,7R,7aR)-7-(Hydroxymethyl)-4-methyl-2,3,5,6,7,7a-hexahydro- (100 MHz, CDCl
3
1H-inden-1-ol (40): Racemic compound 8a (19.6 mg, 0.1100 mmol,
–
1
1.0 equiv.) was dissolved in anhydrous diethyl ether (1.5 mL). The
1389, 1306, 1262, 1161, 1142, 1082, 959, 878, 750 cm . HRMS
(EI): calcd. for C H O [M – C H ] 152.0832; found 152.0835.
9 12 2 2 4
+
resulting solution was cooled to 0 °C, and then it was treated with
2050
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2041–2053

Total Synthesis of Valerenic Acid and Some Bioactive Derivatives
(
E)-Ethyl-2-methyl-3-[(3aR,4S,7R,7aR)-7-methyl-3-oxooctahydro-- 10.7, 1.4 Hz, 1 H), 4.26–4.12 (m, 3 H), 3.13–3.04 (m, 1 H), 2.45–
H-inden-4-yl]acrylate (6b): A solution of racemic diketo com- 2.34 (m, 1 H), 2.26–2.16 (m, 1 H), 1.94–1.46 (m, 9 H), 1.41–1.24
pound 42 (12.8 mg, 0.0710 mmol, 1.0 equiv.) and anhydrous DCM
1.0 mL) was treated with (1-ethoxycarbonylethyliden)-triphenyl-
1
1
3
(m, 7 H), 0.90 (d, J = 7.2 Hz, 3 H) ppm. C NMR (100 MHz,
CDCl ): δ = 168.2, 144.0, 127.0, 75.5, 60.7, 46.7, 37.2, 35.3, 33.2,
29.8, 28.7, 27.0, 24.8, 14.5, 12.6, 12.1 ppm. IR (film): ν˜ = 3483,
(
3
phosphorane (94%, 54.6 mg, 0.1416 mmol, 2.0 equiv.), and the re-
action mixture was heated to reflux for 24 h. Then, silica gel was
added, and the solvent was evaporated. Purification of the residue
by chromatography (hexane/ethyl acetate, 7:1) furnished compound
–
1
2926, 1701, 1636, 1459, 1367, 1247, 1171, 1106, 1042, 750 cm .
HRMS (ESI): calcd. for C16H O [M] 266.1882; found 266.1890.
26 3
+
2
0
[α]
D
= –118.7 (c = 0.72, DCM).
6
6
b as a white solid (12.2 mg, 65%) and a slightly impure compound
Ethyl (E)-2-Methyl-3-[(3aS,4S,7R,7aR)-7-methyl-3-oxo-octahydro-
inden-4-yl]acrylate (6a): Compound 45 (157.9 mg, 0.5928 mmol,
a (2.7 mg, 14%). Analytical data for 6b: 1H NMR (400 MHz,
CDCl
4
1
3
): δ = 6.58 (dd, J = 9.7, 1.4 Hz, 1 H), 4.18 (dq, J = 7.1,
.2 Hz, 2 H), 2.46–2.24 (m, 3 H), 2.15 (m, 1 H), 2.03 (m, 1 H),
.96–1.77 (m, 3 H), 1.73 (d, J = 1.4 Hz, 3 H), 1.70–1.57 (m, 2
1
.0 equiv.) was dissolved in anhydrous DMSO (2.4 mL), and the
resulting solution was treated with a solution of IBX (335.6 mg,
.199 mmol, 2.0 equiv.) in anhydrous DMSO (4.8 mL). After stir-
1
13
H), 1.33–1.22 (m, 5 H), 0.98 (d, J = 6.9 Hz, 3 H) ppm. C NMR
100 MHz, CDCl ): δ = 218.1, 168.1, 143.6, 128.2, 60.7, 54.0, 41.8,
6.7, 33.5, 31.1, 31.0, 28.3, 19.7, 19.2, 14.4, 12.9 ppm. IR (film): ν˜
ring for 2.5 h, water was added, and the white precipitate was re-
moved by filtration. The precipitate was washed with DMSO/water
(
3
=
1
3
(
1:2) and a small amount of ethyl acetate. The filtrate was extracted
with DCM (4ϫ), and the combined organic phases were dried with
Na SO and concentrated in vacuo. Purification by chromatog-
raphy (hexane/ethyl acetate, 7:1) provided compound 6a as a clear,
2954, 2926, 2871, 1741, 1705, 1650, 1458, 1368, 1274, 1232, 1204,
–1
24 3
160, 1106, 1071, 748 cm . HRMS (EI): calcd. for C16H O
2
4
+
[
M] 264.1725; found 264.1723.
Ethyl (E)-3-[(3S,3aR,4S)-3-Hydroxy-7-methyl-2,3,3a,4,5,6-hexahy- pale yellow oil (146.5 mg, 93%). H NMR (400 MHz CDCl
dro-1H-inden-4-yl]-2-methyl-acrylate (7): A solution of compound 6.83 (ddd, J = 10.2 Hz, J = 2.8 Hz, J = 1.4 Hz, 1 H), 4.16 (dq, J
a (183.5 mg, 1.030 mmol, 1.0 equiv.) in DCM (10 mL) was cooled = 7.1 Hz, J = 1.4 Hz, 2 H), 3.24–3.16 (m, 1 H), 2.32–2.21 (m, 3
to –78 °C, and diisobutylaluminium hydride (1.0 m solution, H), 2.14–1.86 (m, 6 H), 1.79–1.68 (m, 2 H), 1.63–1.39 (m, 3 H),
.5 mL, 1.5 mmol, 1.5 equiv.) was added dropwise. After stirring
1
3
): δ =
8
1
3
1
1.27 (t, J = 7.1 Hz, 3 H), 0.97 (d, J = 6.9 Hz, 3 H) ppm. C NMR
(100 MHz, CDCl ): δ = 217.4, 168.4, 139.9, 129.5, 60.6, 51.4, 40.1,
the mixture for 2.25 h, the reaction was quenched by the addition
of ethyl acetate (1 mL), and the mixture was stirred for another
3
37.8, 32.6, 30.4, 28.4, 25.6, 24.5, 14.4, 13.0, 11.6 ppm. IR (film): ν˜
1
5 min. A saturated aqueous solution of potassium sodium tartrate
= 2925, 2855, 1743, 1713, 1465, 1366, 1312, 1246, 1210, 1157, 1111,
1043, 752 cm . HRMS (ESI): calcd. for C16H O [M] 264.1725;
24 3
–
1
+
was added, and the mixture was warmed to room temperature. The
aqueous layer was separated and extracted with DCM (5ϫ). The
combined organic phases were dried with Na SO and concen-
2 4
trated in vacuo. Filtration through a short pad of silica gel afforded
a crude mixture of the two isomers of lactol 44 as a clear, slightly
yellow oil. Lactol 44 was dissolved in benzene (10 mL). To this
solution was added (1-ethoxycarbonylethyliden)-triphenylphos-
phorane (94%, 794.2 mg, 2.060 mmol, 2.0 equiv.), and the reaction
mixture was heated to reflux for 24 h. A saturated aqueous solution
2
0
found 264.1727. [α]
Valerenic Ethyl Ester (46): A solution of compound 6a (16.1 mg,
.0609 mmol, 1.0 equiv.) and anhydrous DCM (2.4 mL) was cooled
to 0 °C and treated with freshly distilled triflic anhydride (101 μL,
D
= –160.9 (c = 0.86, DCM).
0
1
0
71.7 mg, 0.609 mmol, 10.0 equiv.) and pyridine (49 μL, 48.1 mg,
.608 mmol, 10 equiv.) under vigorous stirring. The ice bath was
removed after 15 min, and the mixture was stirred for 24 h. The
reaction mixture was cooled to 0 °C and washed consecutively with
of NH
4
Cl was added, and the solution was extracted with DCM
SO and concen-
a saturated aqueous solution of CuSO
solution of NaHCO . Both aqueous layers were extracted with
DCM (1ϫ). The combined organic phases were washed with brine,
dried with Na SO , and concentrated in vacuo. Filtration through
4
and a saturated aqueous
(4ϫ). The combined extracts were dried with Na
2
4
3
trated in vacuo. Purification by chromatography (hexane/ethyl acet-
ate, from 10:1 to 5:1) furnished compound 7 as a clear colorless oil
2
4
1
(226.9 mg, 83%). H NMR (400 MHz CDCl
3
): δ = 7.06 (dd, J =
a short pad of silica gel afforded a crude mixture of the two isomers
as a clear, colorless oil. The mixture of isomers was dissolved in
THF (1.2 mL), and the solution was cooled to 0 °C, before tetrakis-
1
0.5, 1.4 Hz, 1 H), 4.29 (dd, J = 6.0, 3.4 Hz, 1 H), 4.24–4.11 (m, 2
H), 3.12 (ddd, J = 10.2, 8.8, 5.0 Hz, 1 H), 2.58–2.22 (m, 3 H), 2.09–
.59 (m, 12 H), 1.31 (d, J = 3.4 Hz, 1 H), 1.27 (t, J = 7.1 Hz, 3
1
(
triphenylphosphane)palladium (6.9 mg, 0.00597 mmol, 0.1 equiv.)
1
3
H) ppm. C NMR (100 MHz, CDCl
1
1
1
3
): δ = 168.2, 143.5, 132.0,
27.6, 125.5, 75.3, 60.7, 50.2, 34.0, 33.1 29.3, 27.7, 26.0, 19.5, 14.4,
2.7 ppm. IR (film): ν˜ = 3480, 2926, 1704, 1645, 1447, 1367, 1246,
was added. After stirring for 15 min, the resulting brown solution
was treated with dimethylzinc (1.0 m solution, 0.24 mL, 0.24 mmol,
4
.0 equiv.). The mixture was warmed to room temperature after
another 15 min and was then stirred for 15.5 h. After cooling to
°C, water and a saturated aqueous solution of NH Cl were
added, and the solution was extracted with diethyl ether (3ϫ). The
combined extracts were washed with brine, dried with Na SO , and
concentrated in vacuo. Purification by chromatography (hexane/
–1
110, 1033, 753 cm . HRMS (ESI): calcd. for C16
2 D
O] 246.1620; found 246.1614. [α] = –5.4 (c = 0.90, DCM).
H
22
O
2
[M –
+
20
H
0
4
Ethyl (E)-3-[(3S,3aS,4S,7R,7aR)-3-Hydroxy-7-methyl-octahydro-in-
den-4-yl]-2-methyl-acrylate (45): solution of compound
223.8 mg, 0.8466 mmol, 1.0 equiv.) and freshly distilled and de-
A
7
2
4
(
gassed DCM (34 mL) was cooled to 0 °C. The flask was flushed
with hydrogen over a period of 2 min, and then hydrogen was
bubbled through the solution for an additional 1 min. After adding
ethyl acetate, 50:1) with silica gel treated with 10% AgNO
nished compound 46 as a clear colorless oil (12.4 mg, 78%).
NMR (600 MHz CDCl
3
fur-
H
1
3
): δ = 7.01 (ddd, J = 9.8, 2.8, 1.3 Hz, 1 H),
Crabtree’s catalyst (68.0 mg, 0.0845 mmol, 0.1 equiv.), the flask was 4.18 (dq, J = 7.1, 1.1 Hz, 2 H), 3.53 (dd, J = 9.6, 5.2 Hz, 1 H), 2.96
once again flushed with hydrogen for 3 min, and then hydrogen
was bubbled through the solution for 2 min until it became color-
less. The ice bath was removed, and the mixture stirred for 2.25 h.
Argon was bubbled through the reaction mixture, and the solvent
was evaporated. Chromatography (hexane/ethyl acetate, from 7:1
(ddd, J = 9.0, 4.4, 2.3 Hz, 1 H), 2.19 (t, J = 7.6 Hz, 2 H), 2.02–
1.96 (m, 1 H), 1.90–1.71 (m, 6 H), 1.63 (td, J = 2.1, 1.1 Hz, 3 H),
1.57–1.51 (m, 1 H), 1.45–1.36 (m, 2 H), 1.29 (t, J = 7.1 Hz, 3 H),
0.78 (d, J = 7.0 Hz, 3 H) ppm. C NMR (150 MHz, CDCl ): δ =
3
168.8, 143.4, 133.6, 131.0, 126.1, 60.6, 47.5, 37.6, 34.5, 33.2, 28.9,
1
3
to 3:1) of the residue furnished compound 45 as a white solid
25.6, 24.7, 14.5, 13.7, 12.5, 12.2 ppm. IR (film): ν˜ = 2926, 1712,
1
–1
(162.7 mg, 72%). H NMR (400 MHz CDCl
3
): δ = 7.38 (dd, J = 1645, 1455, 1379, 1238, 1131, 1104, 1061, 753 cm . HRMS (ESI):
Eur. J. Org. Chem. 2012, 2041–2053
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2051

J. Ramharter, J. Mulzer
FULL PAPER
[M]+ 262.1933; found 262.1935. [α]
20
= –106.1
Valerenic N-Ethylamide (49): Using the same procedure as for the
calcd. for C17
H
26
O
2
D
(c = 0.70, DCM).
preparation of valerenic amide, valerenic acid (20.9 mg,
0
.0892 mmol, 1.0 equiv.) was treated with 1-chloro-N,N,2-trimeth-
Valerenic Acid (1): A solution of valerenic ethyl ester 46 (12.4 mg,
.0473 mmol, 1.0 equiv.), methanol (0.5 mL), and THF (0.5 mL)
was treated with LiOH (1.0 m aqueous solution, 0.36 mL,
.36 mmol, 7.5 equiv.). After stirring 24 h, the resulting mixture
was cooled to 0 °C and acidified with 10% citric acid, and the
resulting mixture was extracted with ethyl acetate (4ϫ). The com-
bined organic phases were washed with a small amount of brine,
ylpropenylamine (35 μL, 35.4 mg, 0.2646 mmol, 3.0 equiv.) and
ethylamine (2.0 m solution in THF, 0.45 mL, 0.9000 mmol,
0
10.0 equiv.) to afford valerenic N-ethylamide as a slightly yellow
0
1
solid (21.9 mg, 94%). H NMR (400 MHz, CDCl
J = 9.5 Hz, J = 1.3 Hz, 1 H), 5.66 (s, 1 H), 3.49 (dd, J = 9.3 Hz, J
4.9 Hz, 1 H), 3.34 (dq, J = 7.2 Hz, J = 5.6 Hz, 2 H), 2.95 (m, 1
3
): δ = 6.55 (dq,
=
H), 2.19 (t, J = 7.5 Hz, 2 H), 1.98 (m, 1 H), 1.89 (d, J = 1.4 Hz, 3
H), 1.78 (m, 3 H), 1.62 (m, 3 H), 1.54 (m, 1 H), 1.40 (m, 2 H), 1.17
2 4
dried with Na SO , and concentrated in vacuo. Purification by
chromatography (hexane/ethyl acetate, from 5:1 to pure ethyl acet-
13
(
(
t, J = 7.3 Hz, 3 H), 0.78 (d, J = 7.0 Hz, 3 H) ppm. C NMR
100 MHz, CDCl
1
ate) afforded valerenic acid (11.0 mg, 99%). H NMR (600 MHz
3
): δ = 169.9, 136.9, 134.0, 130.6, 129.6, 47.6, 37.6,
4.8, 34.1, 33.3, 28.9, 25.8, 24.7, 15.1, 13.6, 12.9, 12.2 ppm. IR
CDCl
3
): δ = 7.15 (ddd, J = 10.0, 2.7, 1.3 Hz, 1 H), 3.54 (dd, J =
3
9
7
1
2
.7, 5.0 Hz, 1 H), 2.95 (ddd, J = 8.3, 4.0, 1.9 Hz, 1 H), 2.20 (t, J =
.6 Hz, 2 H), 1.99 (dt, J = 7.2, 3.7 Hz, 1 H), 1.93–1.71 (m, 6 H),
(
film): ν˜ = 3308, 2925, 2884, 2855, 1653, 1639, 1616, 1533, 1456,
–1
+
1
2
17
379, 1309 cm . HRMS (ESI): calcd. for C H28NO [M]
.63 (td, J = 2.0, 1.0 Hz, 3 H), 1.59–1.51 (m, 1 H), 1.48–1.36 (m,
20
62.2165; found 262.2161. [α]
D
= –118.7 (c = 1.58, DCM).
H), 0.78 (d, J = 7.0 Hz, 3 H) ppm. 1 C NMR (150 MHz, CDCl
3
):
3
δ = 173.0, 146.3, 133.3, 131.4, 125.2, 47.6, 37.6, 34.7, 33.2, 28.9,
Valerenic N,N-Diethylamide (50): Using the same procedure as for
the preparation of valerenic amide, valerenic acid (30.2 mg,
0.1289 mmol, 1.0 equiv.) was treated with 1-chloro-N,N,2-trimeth-
ylpropenylamine (51 μL, 51.5 mg, 0.3855 mmol, 3.0 equiv.) and di-
ethylamine (135 μL, 95.9 mg, 1.311 mmol, 10.0 equiv.) to afford
2
5.5, 24.7, 13.6, 12.2, 12.2 ppm. IR (film): ν˜ = 2931, 1683, 1652,
–1
1558, 1423, 1299, 1256, 904, 671, 575 cm . HRMS (ESI): calcd.
+
20
22 2 D
for C15H O [M] 234.1620; found 234.1623. [α] = –159.9 (c =
2
0
D
0.76, DCM); m.p. 139–141 °C. Data of authentic sample: [α] =
1]
–
161.2 (c = 0.85 g/100 mL, DCM); m.p. 140–142 °C.[
valerenic N,N-diethylamide as a slightly yellow oil (35.2 mg, 94%).
1
H NMR (400 MHz, CDCl
H), 3.46 (dd, J = 8.5 Hz, J = 3.9 Hz, 1 H), 3.34 (m, 4 H), 2.85
m, 1 H), 2.17 (t, J = 7.4 Hz, 2 H), 1.96 (m, 1 H), 1.87 (d, J =
3
): δ = 5.75 (dq, J = 7.6 Hz, J = 0.5 Hz,
Valerenic Amide (47): Valerenic acid (104.3 mg, 0.4451 mmol,
.0 equiv.) was dissolved in anhydrous dichloromethane (4.4 mL).
The resulting solution was cooled to 0 °C, and then 1-chloro-N,N,2-
trimethylpropenylamine (0.21 mL, 212.1 mg, 1.587 mmol,
.5 equiv.) was added dropwise. After 5 min, the ice bath was re-
1
(
1
1
2
.5 Hz, 3 H), 1.77 (m, 3 H), 1.63 (m, 3 H), 1.52 (m, 1 H), 1.41 (m,
13
H), 1.13 (t, J = 7.1 Hz, 6 H), 0.77 (d, J = 7.0 Hz, 3 H) ppm.
): δ = 173.8, 134.3, 131.0, 130.3, 130.1,
7.7, 37.6, 33.5, 33.3, 29.0, 25.8, 24.8, 14.6, 13.6, 12.2 ppm. IR
C
3
NMR (100 MHz, CDCl
4
3
moved, and the reaction mixture was stirred for 4 h at room tem-
perature, before it was cooled again to 0 °C. Ammonia (0.5 m solu-
tion) in 1,4-dioxane (5.8 mL, 2.900 mmol, 6.5 equiv.) was rapidly
added. The ice bath was removed, and the resulting mixture was
stirred overnight. Diethyl ether was added, and the white precipi-
tate was removed by filtration. The filtrate was concentrated in
vacuo, and chromatography (hexane/EtOAc, from 2:1 to 1:2) of the
(
1
2
film): ν˜ = 2926, 2866, 2855, 1628, 1458, 1396, 1380, 1333, 1291,
–1
+
+
221, 1097 cm . HRMS (ESI): calcd. for C19H32NO [M]
20
90.2478; found 290.2488. [α]
D
= –109.8 (c = 1.63, DCM).
Valerenic Piperidine Amide (51): A solution of valerenic acid
(43.5 mg, 0.1856 mmol, 1.0 equiv.) and anhydrous dichloromethane
(1.8 mL) was cooled to 0 °C, and 1-chloro-N,N,2-trimethylpropen-
ylamine (86 μL, 86.9 mg, 0.6500 mmol, 3.5 equiv.) was added drop-
wise. After 5 min, the ice bath was removed, and the reaction mix-
residue provided valerenic amide as a white solid (99.8 mg, 96%).
1
H NMR (400 MHz, CDCl
3
): δ = 6.67 (dq, J = 9.3 Hz, J = 0.8 Hz,
1
1
3
0
1
2
2
H), 5.58 (s, 2 H), 3.50 (dd, J = 9.4 Hz, J = 4.7 Hz, 1 H), 2.93 (m,
H), 2.19 (t, J = 7.5 Hz, 2 H), 1.98 (m, 1 H), 1.90 (d, J = 3.3 Hz, ture was stirred for 4 h at room temperature. Then, the solvent and
H), 1.78 (m, 3 H), 1.63 (m, 3 H), 1.55 (m, 1 H), 1.40 (m, 2 H), volatile byproducts were removed in vacuo (3 Torr for 1 h), and the
.77 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl
): δ = crude acid chloride was dissolved again in dichloromethane
3
71.8, 139.1, 133.7, 130.9, 128.3, 47.6, 37.6, 34.3, 33.2, 28.9, 25.7,
(1.8 mL). After cooling to 0 °C, piperidine (74 μL, 63.6 mg,
0.7474 mmol, 4.0 equiv.) was added at once. The ice bath was re-
moved, and the resulting mixture was stirred for 1 h. Diethyl ether
was added, and the white precipitate was removed by filtration. The
filtrate was concentrated in vacuo, and chromatography (hexane/
EtOAc, from 5:1 to 2:1) of the residue provided valerenic piperidine
4.7, 13.6, 12.9, 12.2 ppm. IR (film): ν˜ = 3179, 3028, 2923, 2885,
–1
853, 1733, 1654, 1652, 1636, 1505, 1458, 1418, 1378 cm . HRMS
+
20
(ESI): calcd. for C15
H
21N [M] 215.1674; found 215.1661. [α]
D
=
–119.2 (c = 0.78, DCM).
Valerenic N-Methylamide (48): Using the same procedure as for the
preparation of valerenic amide, valerenic acid (49.7 mg,
1
amide as a slightly yellow oil (50.7 mg, 91%). H NMR (400 MHz,
CDCl
3
): δ = 5.78 (dq, J = 9.1 Hz, J = 1.5 Hz, 1 H), 3.45 (m, 5 H),
0.2121 mmol, 1.0 equiv.) was treated with 1-chloro-N,N,2-trimeth-
2.84 (m, 1 H), 2.18 (t, J = 4.9 Hz, 2 H), 1.96 (m, 1 H), 1.85 (d, J
ylpropenylamine (98 μL, 99.0 mg, 0.7408 mmol, 3.5 equiv.) and
methylamine (41% aqueous solution, 0.18 mL, 2.131 mmol,
=
1.5 Hz, 3 H), 1.77 (m, 3 H), 1.63 (m, 5 H), 1.54 (m, 5 H), 1.40
13
(
m, 2 H), 0.77 (d, J = 7.0 Hz, 3 H) ppm. C NMR (100 MHz,
CDCl ): δ = 172.8, 134.3, 131.9, 130.0, 129.8, 47.7, 37.6, 33.5, 33.4,
9.0, 25.9, 24.9, 24.8, 14.5, 13.6, 12.2 ppm. IR (film): ν˜ = 2925,
1
0.0 equiv.) to afford valerenic N-methylamide as a white solid
3
1
3
(49.9 mg, 95%). H NMR (400 MHz, CDCl ): δ = 6.54 (dq, J =
2
2
9.5 Hz, J = 1.3 Hz, 1 H), 5.71 (s, 1 H), 3.48 (dd, J = 9.2 Hz, J =
4.7 Hz, 1 H), 2.93 (m, 1 H), 2.86 (d, J = 4.9 Hz, 3 H), 2.19 (t, J =
7.3 Hz, 2 H), 1.97 (m, 1 H), 1.89 (d, J = 1.4 Hz, 3 H), 1.78 (m, 3
–1
854, 1629, 1443, 1379, 1256, 425, 423, 420, 412 cm . HRMS
+
20
(
ESI): calcd. for C20
H
31NO [M] 301.2406; found 301.2398. [α]
D
=
–90.0 (c = 0.35, DCM).
H), 1.62 (m, 3 H), 1.55 (m, 1 H), 1.39 (m, 2 H), 0.77 (d, J = 7.0 Hz,
3
1
1
1
H) ppm. 13C NMR (100 MHz, CDCl
30.7, 129.5, 47.6, 37.6, 34.1, 33.3, 28.9, 26.7, 25.8, 24.7, 13.6, 12.9, the preparation of valerenic amide, valerenic acid (43.4 mg,
3
): δ = 170.7, 137.0, 134.0,
Valerenic Morpholine Amide (52): Using the same procedure as for
2.2 ppm. IR (film): ν˜ = 3326, 2925, 1655, 1616, 1539, 1456, 1379,
0.1852 mmol, 1.0 equiv.) was treated with 1-chloro-N,N,2-trimeth-
ylpropenylamine (74 μL, 74.7 mg, 0.5593 mmol, 3.0 equiv.) and
morpholine (160 μL, 160.0 mg, 1.837 mmol, 10.0 equiv.) to afford
–1
311, 670, 667, 409 cm . HRMS (ESI): calcd. for C16H25NO
+
20
[M] 247.1936; found 247.1932. [α]
D
= –129.3 (c = 0.83, DCM).
2052
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2041–2053

Total Synthesis of Valerenic Acid and Some Bioactive Derivatives
1
valerenic morpholine amide as a colorless oil (50.4 mg, 90%). H
[11] N. Chatani, N. Furukawa, H. Sakurai, S. Murai, Organometal-
lics 1996, 15, 901–903.
3
NMR (400 MHz, CDCl ): δ = 5.82 (dq, J = 9.1 Hz, J = 1.5 Hz, 1
H), 3.66 (t, J = 4.5 Hz, 4 H), 3.56 (m, 4 H), 3.47 (dd, J = 9.0 Hz,
J = 2.8 Hz, 1 H), 2.82 (m, 1 H), 2.18 (t, J = 7.4 Hz, 2 H), 1.97 (m,
[
[
[
12] A. Kinoshita, N. Sakakibara, M. Mori, J. Am. Chem. Soc.
1997, 119, 12388–12389.
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(
(
H), 1.87 (d, J = 1.5 Hz, 3 H), 1.78 (m, 3 H), 1.64 (m, 3 H), 1.55
m, 1 H), 1.41 (m, 2 H), 0.77 (d, J = 7.0 Hz, 3 H) ppm. 1 C NMR
100 MHz, CDCl ): δ = 172.9, 134.0, 133.6, 130.4, 128.9, 67.1, 47.8,
7.6, 33.6, 33.4, 29.0, 25.9, 24.8, 14.5, 13.6, 12.2 ppm. IR (film): ν˜
3
3
3
5
449–5452.
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85.
=
2923, 1654, 1652, 1628, 1420, 1393, 1379, 1245, 1116, 1028,
[
–1
+
2
842 cm . HRMS (ESI): calcd. for C19H29NO [M] 303.2198;
6
20
found 303.2194. [α]
D
= –110.5 (c = 0.8, DCM).
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Supporting Information (see footnote on the first page of this arti-
1
13
[17] a) For a review of sulfuric acid-mediated isomerizations, see:
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cle): Copies of the H and C NMR spectra of all compounds.
Acknowledgments
224.
We thank S. Felsinger, L. Brecker, and H. P. Kählig, all at the Uni-
versity of Vienna, Institute of Organic Chemistry, for the NMR
analysis, S. Khom, B. Strommer, and S. Hering, all at the Univer-
sity of Vienna, Department of Pharmacology and Toxicology, for
the fruitful discussions, and the Austrian Science Fund (FWF) for
financial support (projects P21241-N19 and TRP 107-B11).
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Published Online: February 21, 2012
Eur. J. Org. Chem. 2012, 2041–2053
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2053