Limno-CP: A natural-product-inspired 5-aryl-3(2 H)-furanone as scaffold for a library of α-modified enones

Article abstract of DOI:10.1055/s-0030-1260115

A library of 5-aryl-3(2H)-furanones that are modified in the α-position of the α,β-unsaturated carbonyl system was prepared via simple one- to three-step transformations from one common scaffold. The ¹³C NMR characterization of the enone system showed a strong influence of the α-substituents, especially on the shifts of the α- and β-carbon atoms. Probing the addition chemistry of nucleophiles versus our α-modified enones, a 1,2-addition-elimination- was found, but no 1,4-addition. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260115

PAPER
2671
Limno-CP: A Natural-Product-Inspired 5-Aryl-3(2H)-furanone as Scaffold
for a Library of a-Modified Enones
Sabine Amslinger,* Simon K. Lindner
Universität Regensburg, Institut für Organische Chemie, Universitätstr. 31, 93053 Regensburg, Germany
Fax +49(941)9434121; E-mail: sabine.amslinger@chemie.uni-regensburg.de
Received 29 April 2011; revised 18 May 2011
Me
O
O
Abstract: A library of 5-aryl-3(2H)-furanones that are modified in
the a-position of the a,b-unsaturated carbonyl system was prepared
via simple one- to three-step transformations from one common
scaffold. The 13C NMR characterization of the enone system
showed a strong influence of the a-substituents, especially on the
shifts of the a- and b-carbon atoms. Probing the addition chemistry
of nucleophiles versus our a-modified enones, a 1,2-addition–
elimination was found, but no 1,4-addition.
X
Me
OH
O
O
Me
O
COOMe
X = F, CN, COOEt
O
Me
X
H
Key words: furanones, substituent effects, enones, spiro com-
O
H
OH
OH
pounds, 1,2-addition–elimination
R
X = Cl, Br, CN, COOH,
COOMe, CONH2
CN
R = NH2, NHPh, NHBn, 3,4-(HO)2C6H3
3(2H)-Furanones represent an important subgroup of a,b-
unsaturated carbonyl compounds, which contain a num-
ber of very attractive, biologically active natural products.
Geiparvarin,1 eremantholides,2 and jatrophone3 possess
antitumor activity, and pseurotin4 is known to inhibit im-
munoglobulin E production. Therefore, the synthesis of
3(2H)-furanones is not only important as part of the total
synthesis of more complex natural products, but also ef-
fective to get an easy access to these compounds for a po-
tential application in drug development.5 Importantly,
when not substituted, the a-position of the a,b-unsatu-
rated carbonyl unit can be used to introduce different sub-
stituents while maintaining the reactive enone system
(Figure 1).6
Figure 2 a-Modified enone compounds with biological activity
ther Michael acceptor based, or in the case of phenolic
compounds, also particularly antioxidative activity.
Compounds featuring both potential reactivities are re-
ferred to as bifunctional antioxidants since they can either
induce anti-inflammatory and cytoprotective enzymes via
thiol-dependent Michael additions or scavenge radicals/
act as reductants.11
So far, no systematic studies on the influence of substitu-
ent X on the biological activity exist for scaffolds with the
3(2H)-furanone unit. To introduce a system where X pos-
sesses certain variability, for example, halogen, nitrile, or
aryl, a natural product where a-substituted variants could
be produced would be a good target. As a point of inspira-
tion, the highly oxidized plant ingredient limnophila-
spiroketone (1) (Scheme 1) was chosen. This compound
was isolated from Limnophila geoffrayi, whose extracts
are used in the traditional medicine of Thailand for detox-
ification.12
Figure 1 Substituent X can have a significant influence both on
Michael acceptor activity, but also on antioxidative properties
O
O
O
X
OMe
OMe
Despite the fact that the formation of a-modified enones
seems to be an attractive regime, this concept has not been
used very extensively. Nevertheless, there are examples
for chalcones (1,3-diphenylpropenoids),7 benzenemalono-
nitriles, and related compounds (tyrphostins),8 as well as
triterpenoids (Figure 2).9 And, in that way the biological
activities could be strongly influenced by the a-substitu-
ent X.7,9,10 The underlying reactivities addressed were ei-
O
HO
O
O
HO
HO
MeO
α-X-Limno-CP
1
O
O
HO
Limno-CP (2)
SYNTHESIS 2011, No. 16, pp 2671–2683
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260115; Art ID: T46111SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Natural product limnophilaspiroketone (1), model com-
pound Limno-CP (2), and a-modified derivatives thereof

2672
S. Amslinger, S. K. Lindner
PAPER
Limnophilaspiroketone (1) has two major features, which
caught our interest: (1) the two orthogonal, spirocyclic
a,b-unsaturated carbonyl systems, and (2) the phenolic
unit conjugated with one of the enone units. To be able to
test the influence of a-substituent X on the 3(2H)-furan-
ones, it was decided to use a simple model system derived
from 1 (Scheme 1). Model compound Limno-CP (2) con-
tains the a-unsubstituted (a-H)-3(2H)-furanone unit of
natural product 1 whereas the second a,b-unsaturated car-
bonyl unit, the spirocyclic 2,3-dimethoxycyclopent-2-
enone-5,5-diyl system, was replaced by a simple spirocy-
clopentane-1,1-diyl (CP) unit.
O
KOH
or
HNEt2
or
Ar3PAuCl/
AgOTf
R1
O
O
R3
R2
R3
R2
R1
HCl (aq)
OH
OSiMe3
O
R3
R2
PtCl2
or
AuCl3
O
R1
t-BuOK
or
NaHMDS
R1
O
The underlying 1-oxaspiro[4.4]non-2-en-4-one motif of 1
and 2 is found in only one natural product apart from 1,
namely jatrophone, in which this moiety is part of a larger
ring system.3 Similarly, pseurotins contain a spiro-3(2H)-
furanone-g-lactam (1-oxa-7-azaspiro[4.4]non-2-ene-4,6-
dione) unit.13 It is known that 3(2H)-furanones display a
rather weak Michael acceptor activity,14 which makes
them an ideal skeleton to start modifications from. The
phenolic unit in 2 allows apart from its potential antioxi-
dant activity additional modifications such as the attach-
ment of chromophores or affinity tags, which could be
useful for biological studies.
O
O
R3
R3
R2
Ar
+
(R1)Ph
CN
HO R2
Br
Scheme 2 Syntheses of 3(2H)-furanones
aryl-2,2-dialkyl-4-phenyl-3(2H)-furanone derivatives18
(see Scheme 2, upper left). We picked this particular se-
quence, since 7 can be prepared in four simple transforma-
tions with inexpensive standard reagents requiring only
two chromatographic separations (Scheme 3).
The synthesis was carried out by first protecting 4-hy-
droxybenzaldehyde (3) quantitatively as its isopropyl
ether 4.19 The orthogonal behavior of phenolic isopropoxy
versus methoxy groups is essential for further studies to-
wards methoxy-substituted compounds such as 1. Addi-
tionally, the isopropyl ethers, which should be quite stable
under physiological conditions, give rise to a second set of
potentially biologically active compounds, where the phe-
nolic hydroxy group is blocked. From 4-propoxybenzal-
dehyde (4), diol 5 was obtained by a coupling with
lithiated 1-ethynylcyclopentanol. Diol 5 was subjected to
a standard MnO2 oxidation without prior purification to
give ketone 6 in an overall yield of 72% over two steps.
Initial attempts to form the 5-aryl-3(2H)-furanone unit in
pure ethanol under literature conditions18 (Table 1, entry
1) gave low yields. But the reaction was optimized ac-
cordingly (Table 1, entry 3).
In this work, we present a straightforward synthetic
scheme for an easy access to a rational library of a-substi-
tuted derivatives of 3(2H)-furanones, namely, the simple
model compound Limno-CP (2), as a starting point for a
later biological characterization of these a,b-unsaturated
carbonyl compounds.
Instead of finding the best route to any of the potential a-
modified variants of 2, where the a-substituent could be
for example any halogen, an aryl, or a nitrile group we de-
cided to synthesize the parent compound i-Pr-a-H-Limno-
CP (7) (see Scheme 3) as a common precursor to produce
all other derivatives based on this molecule. A synthetic
access to this spirocyclic structure has been known since
1966,15 and until now several different approaches have
been used (Scheme 2).16,17
For the synthesis of 7, a strategy was used that was applied
in the formation of novel COX-2 inhibitors, namely 5-
OH
CHO
2-bromopropane
K2CO3, DMF
CHO
1-ethynyl-
cyclopentanol
MnO2, CH2Cl2
r.t., 1.5 h
55 °C, 2 h
99%
HO
n-BuLi, THF
–78 °C, 1.5 h
72%
(over 2 steps)
i-PrO
i-PrO
HO
O
3
4
5
O
Et2NH
EtOH–H2O (9:1)
O
r.t., 30 min
76%
i-PrO
HO
i-PrO
6
7
Scheme 3 Synthesis of i-Pr-a-H-Limno-CP (7)
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

PAPER
Limno-CP as Scaffold for a Library of a-Modified Enones
2673
Table 1 Formation of i-Pr-a-H-Limno-CP (7) by Cyclization of 6
(Table 2). i-Pr-a-Cl-Limno-CP (12), i-Pr-a-Br-Limno-CP
(13), and i-Pr-a-I-Limno-CP (14) could be prepared di-
rectly from 7 using the corresponding N-halosuccinimides
as electrophile sources in 88 to 91%. These reagents were
applied likewise in the more reactive 3(2H)-pyrrolone
system.28 Alternative conditions with a common addition–
elimination pathway using bromine and triethylamine29
gave a-Br compound 13 in 92% yield. The iodine substit-
uent could also be installed with I2 and catalytic amounts
of PDC30 to afford the a-I derivative 14 in 72% yield. In-
troducing a fluorine substituent in the a-position was ex-
ceedingly more challenging and the two examples that
have been reported in the literature (where one is a patent
from 1981 about steroidal spirodihydrofuranones)24 have
the F-atoms already installed prior to the cyclization trans-
formations. Paleta and co-workers started from a trifluori-
nated acyclic starting material31 and prepared a compound
with Different Nucleophiles/Bases
Entry Nuc/Base Solvent
Temp
r.t.
Time (h) 7 (%)a
1
2
3
4
5
6
7
Et2NH
Et2NH
Et2NH
-
EtOH (100%)
0.5
4
26
35
90
7
EtOH (100%)
reflux
r.t.
EtOH–H2O (9:1)
EtOH–H2O (9:1)
EtOH–H2O (9:1)
EtOH–H2O (9:1)
EtOH–H2O (9:1)
0.5
4
reflux
reflux
r.t.
Et3N
KOH
KOH
4
8
0.5
4
35
90
reflux
a Estimated by 1H NMR spectroscopy.
It was found that water is needed to gain an effective pro- very similar to our target substance 11 (Scheme 5).26 Ini-
tonation within the addition of diethylamine to the acety- tially, we used Selectfluor, a common reagent for electro-
lene unit of precursor 6. Ethanol is not sufficiently acidic. philic fluorinations,32 to introduce the F-substituent
In the earlier given mechanism of the bullatenone synthe- directly into the 3(2H)-furanone system. This reagent to-
sis from 1958, which is the basis for our considerations, gether with 7 yielded complex mixtures in N,N-dimethyl-
this issue was not addressed.20 Furthermore, potassium formamide, acetone, or acetonitrile at a reaction
hydroxide in water–ethanol was not as effective (Table 1, temperature of 0 °C, whereas refluxing tetrahydrofuran,
entries 6 and 7) indicating that the harder nucleophile hy- chloroform, ethyl acetate, and toluene gave the desired
droxide is inferior to diethylamine. Triethylamine, or no product, but with very low conversions.
additional base at all, gave only very poor product forma-
tion. A plausible mechanism is shown in Scheme 4.21 The
purification by chromatography and recrystallization gave
i-Pr-a-H-Limno-CP (7) in a total yield of 54% over four
steps.
OH
F
F
F
hν
Δ
F
F
+
MeOOC
F
or R
HO
MeOOC
F
F
O
F
NEt2
H
F
i. RLi
ii. TFA
F
F
O
H
Et3N
H
O
NEt2
Et2NH
H2O
– H
+ H
O
O
O
O
O
R
OH
O
R = Me, Ph
i-PrO
HO
i-PrO
6
8
Scheme 5 Preparation of a-F-substituted enones of a 3(2H)-furan-
one by Paleta26,31
NEt2
NEt2
N-Fluorobenzenesulfonimide (NFSI) was slightly better.
Overall, i-Pr-a-F-Limno-CP (11) could be successfully
prepared in 5% isolated yield in refluxing tetrahydrofuran.
When a reaction time of 16 hours was not exceeded, 87%
of unreacted starting material could be reisolated. Other-
wise the formation of other, unidentified fluorination
products that were hard to separate was observed. Exper-
iments to develop a gold-catalyzed fluorination using
Au(PPh3)Cl/AgSbF6 as catalyst together with Selectfluor
failed.
H2O
7
O
OH
O
– OH
i-PrO
i-PrO
9
10
Scheme 4 Reaction mechanism for the formation of 7
With compound 7 in our hands, the preparation of the cor-
responding a-substituted derivatives of 7 was continued.
First, the halogen series were probed. In the literature, sin-
gle examples for related a-halogen 3(2H)-furanones as
precursors for aryl compounds (a-Br22 and a-I23) are
known as well as a-Cl, a-F, a-Br,24 and a-OH25 deriva-
tives with the 1-oxaspiro[4.4]non-2-ene-4-on system par-
tially attached to the steroid skeleton. Moreover, an a-F26
and an a-CN analogue27 of a very similar spirocyclic
3(2H)-furanone were described. A series of a-modified
enones were prepared from isopropyl-protected Limno-
CP 7 by very simple one- to three-step modifications
An adapted Rosenmund von Braun reaction of bromo
compound 13 with sodium cyanide and nickel(II) bromide
led to the corresponding nitrile 15 in 89%.33 The best
yields in the microwave-assisted formation of 15 could be
achieved when the pressure did not rise above the ambient
pressure. i-Pr-a-CN-Limno-CP (15) could be hydrolyzed
in basic media34 to yield amide 16 in 73% yield. Acid hy-
drolysis of amide 16 to the corresponding carboxylic acid
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

2674
S. Amslinger, S. K. Lindner
PAPER
strong effect of a fluorine substituent in the a-position.
This finding is in complete agreement with the litera-
ture.26
Table 2 Synthesis of a-Modified Derivatives of i-Pr-a-H-Limno-
CP
O
O
X
Table 3 13C NMR Chemical Shifts of i-Pr-a-X-Limno-CPs and a-
X-Limno-CPs
O
O
Product
7
X
Ra
C=O, db
205.7
193.4c
199.2
200.0
202.5
199.6
193.0
204.3
203.8
191.6f
197.5
198.5
201.9
199.0
191.6
202.8
a-C, d
98.8
b-C, d
183.6
167.2e
175.6
176.9
179.1
185.3
179.7
178.3
183.0
166.8h
175.4
176.7
178.8
185.1
178.5
177.9
i-PrO
i-Pr-α-H-Limno-CP (7)
i-PrO
i-Pr-α-X-Limno-CP
H
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
OH
SMa Conditionsb
Product X
Yield
(%)c
11
12
13
14
15
16
17
2
F
140.5d
104.9
92.2
Cl
7
7
7
7
7
7
NFSI, THF, reflux, 16 h
NCS, MeOH, reflux, 16 h
NBS, MeCN, 0 °C, 30 min
Br2, Et3N, CH2Cl2, 0 °C, 3 h
NIS, MeCN, reflux, 16 h
I2, PDC, CH2Cl2, r.t., 3 h
11
12
13
13
14
14
15
F
5
91
88
92
88
72
89
Br
Cl
Br
Br
I
I
62.8
CN
86.5
CONH2
95.1
Ph
113.6
97.3
I
H
13 NaCN, NiBr2, NMP, mw, 200 °C,
CN
139.4g
103.1
90.8
10 min
18
19
20
21
22
23
24
F
OH
15 aq 12 M NaOH–1,4-dioxane (1:1),
16
CONH2 73
Cl
OH
r.t., 1.5 h
Br
OH
13 PhB(OH)2, Pd2(dba)3, PPh3, Et2NH, 17
Ph
79
I
OH
63.3
toluene–EtOH–H2O, reflux, 20 h
a SM: starting material.
CN
OH
84.8
b NFSI: N-fluorobenzenesulfonimide; NMP: N-methyl-2-pyrrolidone.
c Isolated yield.
CONH2
Ph
OH
93.6
OH
112.3
as well as attempts to directly hydrolyze nitrile 16 failed,
complex, inseparable mixtures were obtained under vari-
ous conditions. In a Suzuki reaction, the a-phenyl deriva-
tive 17 could be synthesized in 79% yield.35
a Substituent at position 4 of the aromatic ring.
b Carbonyl carbon of 3(2H)-furanone.
c d, 2JC,F = 10.1 Hz.
d d, 1JC,F = 259.3 Hz.
e d, 2JC,F = 13.7 Hz.
To complete the syntheses of Limno-CP (2) and its a-
modified variants, the isopropyl compounds could be suc-
cessfully deprotected using six equivalents of boron
trichloride in dichloromethane in very good to excellent
isolated yields after chromatography (Scheme 6).
f d, 2JC,F = 10.1 Hz.
g d, 1JC,F = 256.5 Hz.
h d, 2JC,F = 14.0 Hz.
But, the system could be only slightly pushed towards
even more low field-shifted values as seen for a-CN 22
with a shift of 185.1 ppm (185.3 ppm for i-Pr-a-CN 15).
O
#: X, isolated
yield
O
X
X
BCl3
2: H, 99%
18: F, 98%
19: Cl, 95%
20: Br, 93%
21: I, 82%
22: CN, 98%
23: CONH2, 84%
24: Ph, 94%
The introduction of further substituents in the a-position
was attempted by a-metalation–electrophile addition se-
quences. A direct deprotonation of 7 with tert-butyl-
lithium that Takeda et al. used for the analogous proton
abstraction of a 2(5H)-furanone36 led only to the decom-
position of 7. Also, no reaction was observed with lithium
diisopropylamide, which was reported to undergo a Baylis–
Hilman-type reaction with pyranones.37 Alternative ex-
O
O
i-PrO
i-Pr-α-X-Limno-CP
HO
α-X-Limno-CP
Scheme 6 Deprotection of isopropyl ethers of a-X-Limno-CPs
In comparing the 13C NMR chemical shifts, it was found periments using halogenated compounds 13 and 14 also
that we were indeed able to modify the properties of the failed with lithium, tin,38 or magnesiumorganic com-
a,b-unsaturated carbonyl system (Table 3). As especially pounds.39,40
pivotal for Michael-addition chemistry the chemical shifts
In order to determine whether the a-modified enones dis-
play differential reactivities, nucleophilic additions with
alkyllithium reagents and Gilman cuprate were per-
of the b-position could be significantly changed. ‘Trans-
forming’ a-H compound 2 with a value of 183.0 ppm to a
shift of 166.8 ppm in the case of a-F 18 proved the very
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

PAPER
Limno-CP as Scaffold for a Library of a-Modified Enones
2675
formed. Indeed, with n-alkyllithium reagents, such as n- Hydrogenation using hydrogen over palladium-on-car-
butyl-, n-hexyl-, and methyllithium, a 1,2-addition to the bon, however, gave ring-opened, stable product 27 in 89%
enone system of 7 was observed. This addition was unex- yield as the only product (Scheme 6). Employing n-hexyl-
pected and has not been described for a 3(2H)-furanone lithium gave the analoguous products 28a, 28b in the
entity. The reaction is only possible because a subsequent same isomeric ratio of 95:5 and an isolated yield of 91%.
elimination to the corresponding alkylidene compounds MeLi on the other hand yielded exomethylene compound
occurs instantaneously. More precisely, when n-butyl- 29, but only in 38% as determined from a mixture by the
lithium was used together with 7, 3-methylene-2,3-di- use of an internal standard. Since phenyllithium and tert-
hydrofuran 26a was obtained (Scheme 7).
butyllithium lack a-methylenic groups no formation of
the corresponding alkylidene products a, b was antici-
pated. Indeed, only complex mixtures were observed.
Adding n-butyllithium to our i-Pr-a-modified enones
gave different ratios of E/Z-isomers a, b in the case of i-
Pr-a-F 11, i-Pr-a-Cl 12, and i-Pr-a-Ph derivatives 17,
where X is inert to the reaction conditions (Table 4).
H
O
Li
n-BuLi
i-PrO
H2O
7
O
O
Interestingly, a-Cl derivatives 31a, 31b were found in an
opposite isomeric ratio than observed in the other cases,
which might be explained by the greater steric demand of
the chloro substituent. Both i-Pr-a-Br 13 and i-Pr-a-
I compounds 14 gave mixtures with dehalogenation prod-
ucts either of elimination products or the corresponding
starting materials, leading to 26a and 7. This shows that a
protonation of the a-lithiated compounds must be very
fast and explains why we could not get other a-modified
enones by the use of electrophiles such as diethyl car-
bonate, tributyltin chloride or trimethylborate. These are
inferior to H+ in our system. Primarily an addition to the
nitrile group was observed with i-Pr-a-CN compound 15.
Using more than 1.0 equivalent of n-butyllithium gave ad-
ditionally 1,2-addition–elimination products in a range of
20%. Amide 16 gave very little conversion and no 1,2-ad-
dition–elimination product could be proven. This is prob-
ably because the deprotonation of the amide-H2 group is
faster than a nulcleophilic attack at the 2-position.
25
i-PrO
26a
H2, Pd/C
OH
i-PrO
27
Scheme 7 Addition of n-butyllithium to enone 7 and ring opening
to form alcohol 27
Compound 26a is formed within three minutes and could
be isolated through an aqueous workup together with the
Z-isomer as the only two products in an E/Z ratio of 95:5
in 87% yield (Table 4 and Figure 3). A full characteriza-
tion was easy to achieve when done quickly after its for-
mation. Nevertheless, 26a, 26b are not stable even at
–20 °C and decompose within hours at this temperature.
Different attempts to trap 26a, 26b with electrophiles or
nucleophiles did not succeed.
Attempts to perform classical 1,4-additions with lithium
dimethylcuprate (Gilman cuprate) failed under conditions
where we were able to fully convert 2,2-dimethyl-3(2H)-
furanone into its conjugate addition product within min-
utes at –30 °C.42 Instead, when using Gilman cuprate with
i-Pr-a-H 7 or i-Pr-a-F 11 we could not get any reaction at
–30 °C within six to eight hours. Warming to 0 °C result-
ed in a slow decomposition. Two reasons for the dimin-
ished reactivity towards a conjugate addition could come
into play: (1) the relatively large aryl-substituent at the b-
position, and, (2) the low to moderate electrophilicity as
judged from the 13C NMR chemical shifts. Comparing 7
and 11 with 2,2-dimethyl-3(2H)-furanone, at least 11
should be reactive enough to be a Michael acceptor since
its shift of 167.2 ppm is even more up-field than the one
of 2,2-dimethyl-3(2H)-furanone with a value of 176.2
ppm. Typically, enone systems with chemical shifts of
120–170 ppm show intermediate to high reactivities in
conjugate additions. Especially, exomethylenic enone en-
tities like in helenalin with a 13C NMR value of 122.1 ppm
are very reactive.43 In this case the 1,4-addition is respon-
sible for its antitumor activity/cytotoxicity. We are aiming
for a moderate to low reactivity, which could be expected
in the range of chemical shifts of our compounds. Since
Figure 3 Crude 1H NMR spectrum of 26a and 26b as obtained di-
rectly after aqueous workup from reaction of 7 with n-BuLi
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

2676
S. Amslinger, S. K. Lindner
PAPER
Table 4 Reaction of i-Pr-a-X-Limno-CPs with Different Alkyl(aryl)lithium Reagentsa
R2
R2
X
X
1. R1Li
2. H2O
+
i-Pr-α-X-Limno-CP
O
O
i-PrO
i-PrO
a
b
Entry
1
Product
X
H
H
H
H
H
F
R1Li
n-BuLi
Conversion
quant
quant
94%
Product
26a, 26b
28a, 28b
29
Yield (%), a/bb
7
87,c 95:5
2
7
n-HexLi
MeLi
91,c 95:5
3
7
38
d
4
7
PhLi
quant
quant
quant
quant
quant
89%
-
-
d
5
7
t-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
-
-
6
11
12
13
14
15
16
17
30a, 30b
31a, 31b
7, 26ae
52, 65:35
7
Cl
Br
I
86, 10:90
8
-
9
7, 26af
-
g
10
11
12
CN
quant
<5%
-
-
CONH2
Ph
n.d.h
-
quant
32a, 32b
33, 60:40
a Reaction procedure: addition of R1Li (1.0 equiv) in n-hexane or Et2O dropwise at –78 °C to a solution of 3(2H)-furanone (1.0 equiv) in THF,
then addition of H2O. R2 contains (n – 1) carbon atoms of R1.
b Determined by 1H NMR with hexamethyldisilane as internal standard.41
c Isolated yield.
d Complex mixture.
e Yield of 7: 67%; 26a: 15%.
f Yield of 7: 44%; 26a: 22%; 14: 11%.
g Addition products to nitrile group.
h Not determined.
no reaction was found, it is clear that the 13C NMR chem- known, biologically active 3(2H)-furanones such as gei-
ical shifts alone are not sufficient to predict reactivity in parvarin derivatives and eremantholides since these com-
1,4-additions. This is particularly true when steric hin- pounds possess unsubstituted a-positions in their
drance in the b-position interferes with the addition of the corresponding 3(2H)-furanone unit.
nucleophile.
In preparing a-substituted variants of Limno-CP via a fac-
ile synthesis we could demonstrate that the a-substituent
has a very strong influence on the 13C NMR chemical
shifts of the 3(2H)-furanone system. This distinction to-
gether with the variation in sterical demand give a strong
indication for differential activities as seen in the forma-
tion of the 1,2-addition–elimination products. Important-
All reactions were carried out under N2 atmosphere in oven-heated
glassware (110 °C), when dry conditions were required, and moni-
tored by TLC on silica gel plates 60 F254 by Merck. Spots were de-
tected under UV light (l = 254 and 366 nm) or visualized by
staining with vanillin/H2SO4 (6 g vanillin in 100 mL 95% EtOH–
concd H2SO4 100:1). Column chromatography was performed on
silica gel Geduran Si 60 (0.063–0.200 mm) by Merck. Melting
points are determined with a Büchi SMP 20 apparatus, they are un-
ly, we were able to access a 13C NMR chemical shift for corrected. IR spectroscopy was carried out on a Specac Golden Gate
Diamond Single Reflection ATR System Excalibur Series
FTS3000MX by BIO-RAD. NMR spectra were recorded on Bruker
the b-position of up to 167 ppm – a range where the very
potent, biologically active synthetic triterpenoids are
Avance 300, Bruker Avance 400, and Bruker Avance III 600 spec-
found.9 Nevertheless, a Michael addition reaction was not
trometers. 1H NMR spectra are referenced to CDCl3 (7.26 ppm) or
observed with Gilman cuprate. Further studies concerning
antioxidant activity and inhibition of the proinflammatory
enzyme inducible NO synthase (iNOS) are ongoing and
show first promising results. Moreover, the modification
regime could be applied to modulate the activity of
DMSO-d6 (2.50 ppm); 13C NMR spectra to CDCl3 (77.0 ppm) or
DMSO-d6 (39.43 ppm). Mass spectra were obtained on Varian
MAT 311A, Finnigan MAT 95 or Thermoquest Finnigan TSQ 7000
instruments.
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

PAPER
Limno-CP as Scaffold for a Library of a-Modified Enones
2677
4-Isopropoxybenzaldehyde (4) was prepared according to a litera-
IR (neat): 2972, 1674, 1603, 1562, 1499, 1429, 1366, 1298, 1253,
1182, 1109, 1074, 1051, 948, 893, 820, 666 cm–1.
ture procedure19 in 99% yield.
1H NMR (300 MHz, CDCl3): d = 1.37 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.90–2.14 (m, 8 H, CH2), 4.65 [sept, J = 6.1 Hz, 1 H,
(CH3)2CH], 5.88 (s, 1 H, CH), 6.94 (d, J = 8.9 Hz, 2 H, CHAr), 7.75
(d, J = 8.9 Hz, 2 H, CHAr).
13C NMR (100 MHz, CDCl3): d = 21.9, 25.7, 37.1, 70.2, 98.2, 98.8,
115.6, 121.3, 129.1, 161.6, 183.6, 205.7.
MS (EI, 70 eV): m/z (%) = 272.1 (40, [M+]), 231.1 (62), 189.0
(100), 118.0 (86).
HRMS (EI-MS): m/z (M+) calcd for C17H20O3: 272.1412; found:
272.1410.
1-[3-Hydroxy-3-(4-isopropoxyphenyl)prop-1-ynyl]cyclo-
pentanol (5)
To a suspension of 1-ethynylcyclopentanol (5.00 g, 45.4 mmol, 1.3
equiv) in THF (100 mL) was added dropwise a 1.6 M solution of n-
BuLi in n-hexane (45.8 mL, 73.3 mmol, 2.1 equiv) at –78 °C. After
stirring for 30 min, aldehyde 4 (5.64 g, 34.4 mmol, 1.0 equiv) was
added dropwise and the solution allowed to warm to r.t. After 1.5 h,
the solvent was removed and the residue dissolved in H2O (100
mL). The solution was neutralized with aq 1 M HCl and extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with H2O (100 mL), dried (MgSO4), and the solvent evap-
orated. Crude diol 5 (yellow solid, 8.82 g) obtained was used with-
out further purification. A sample of 5 was purified (SiO2, hexanes–
EtOAc, 4:1) for obtaining analytical and spectral data; mp 108 °C;
Rf = 0.1 (SiO2, hexanes–EtOAc, 4:1).
3-Fluoro-2-(4-isopropoxyphenyl)-1-oxaspiro[4.4]non-2-en-4-
one (11)
A solution of furanone 7 (300 mg, 1.10 mmol, 1.0 equiv) and N-flu-
orobenzenesulfonimide (382 mg, 1.21 mmol, 1.1 equiv) in anhyd
THF (30 mL) was heated under reflux for 16 h. The solution was
evaporated in the presence of SiO2 and purified by FC [SiO2 (dry-
load), hexanes–EtOAc, 20:1 to 5:1] to afford a-F-furanone 11 as a
white solid (17.0 mg, 0.0586 mmol, 5%); mp 94 °C; Rf = 0.36
(SiO2, hexanes–EtOAc, 5:1). Additionally, 261 mg (0.958 mmol,
87%) of starting material 7 was reisolated.
IR (neat): 3273, 2973, 2870, 1609, 1506, 1381, 1240, 1180, 1122,
994, 958, 844, 812, 728, 631, 597, 567, 530 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.67–1.88 (m, 4 H, CH2), 1.90–2.00 (m, 4 H, CH2), 2.46
(s, 1 H, OH), 2.78 (s, 1 H, OH), 4.54 [sept, J = 6.1 Hz, 1 H,
(CH3)2CH], 5.41 (s, 1 H, CH), 6.86 (d, J = 8.7 Hz, 2 H, CHAr), 7.41
(d, J = 8.6 Hz, 2 H, CHAr).
13C NMR (75 MHz, CDCl3): d = 22.0, 23.4, 42.2, 64.1, 69.9, 74.4,
83.0, 90.2, 115.8, 128.1, 132.6, 157.9.
IR (neat): 2970, 1701, 1616, 1566, 1511, 1432, 1404, 1385, 1306,
1259, 1178, 1153, 1118, 948, 885, 837, 745, 647, 632, 517, 490, 445
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.96–2.11 (m, 8 H, CH2), 4.66 [sept, J = 6.1 Hz, 1 H,
(CH3)2CH], 6.97 [d, J = 9.0 Hz, 2 H, CHAr), 7.90 (d, J = 9.0 Hz, 2
H, CHAr).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.5, 37.3, 70.2, 96.2 (d,
J = 7.1 Hz), 115.7, 119.4 (d, J = 5.1 Hz), 129.3 (d, J = 6.6 Hz),
140.5 (d, J = 259.3 Hz), 161.6 (d, J = 1.8 Hz), 167.2 (d, J = 13.7
Hz), 193.4 (d, J = 10.1 Hz).
19F NMR (282 MHz, CDCl3): d = –181.0.
MS (EI, 70 eV): m/z (%) = 290.1 (34, [M+]), 249.1 (12), 220.0 (16),
207.0 (100), 136.0 (11), 121.0 (12).
HRMS (EI-MS): m/z (M+) calcd for C17H19FO3: 290.1318; found:
MS (EI, 70 eV): m/z (%) = 274.2 (100, [M+]), 214.1 (33), 185.1
(66), 157.0 (48), 147.0 (36), 121.0 (82), 120.1 (68), 107.0 (64), 95.1
(32), 55.1 (24).
HRMS (EI): m/z (M+) calcd for C17H22O3: 274.1569; found:
274.1567.
3-(1-Hydroxycyclopentyl)-1-(4-isopropoxyphenyl)propynone
(6)
A suspension of crude diol 5 (8.82 g) and an excess of MnO2 (27.8
g, 0.320 mol) in CH2Cl2 (200 mL) was stirred for 1.5 h at r.t. The
suspension was filtered through a pad of Celite, evaporated to dry-
ness, and the product purified by flash chromatography (FC) (SiO2,
hexanes–EtOAc, 6:1) to give ketone 6 as a yellow solid (6.76 g, 24.8
mmol, 72% over two steps); mp 82 °C; Rf = 0.4 (SiO2, hexanes–
EtOAc, 5:1).
290.1321.
3-Chloro-2-(4-isopropoxyphenyl)-1-oxaspiro[4.4]non-2-en-4-
one (12)
IR (neat): 3339, 2973, 2208, 1618, 1583, 1505, 1385, 1318, 1260,
1170, 1106, 1003, 946, 844, 757, 692, 632, 575 cm–1.
A stirred solution of furanone 7 (200 mg, 0.734 mmol, 1.0 equiv)
and N-chlorosuccinimide (118 mg, 0.881 mmol, 1.2 equiv) in
MeOH (10 mL) was refluxed for 16 h. After removal of solvent and
addition of sat. aq NaHCO3 (10 mL), the mixture was extracted with
EtOAc (5 × 10 mL), the combined organic layers were washed with
brine (50 mL), dried (MgSO4), and the solvent was evaporated. Pu-
rification by FC (SiO2, hexanes–EtOAc, 10:1) gave a-Cl-furanone
12 (204 mg, 0.665 mmol, 91%) as light yellow crystals; mp 94 °C;
Rf = 0.62 (SiO2, hexanes–EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): d = 1.37 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.77–1.95 (m, 4 H, CH2), 2.03–2.19 (m, 5 H, CH2, OH),
4.66 [sept, J = 6.1 Hz, 1 H, (CH3)2CH], 6.91 (d, J = 8.9 Hz, 2 H,
CHAr), 8.07 (d, J = 8.9 Hz, 2 H, CHAr).
13C NMR (75 MHz, CDCl3): d = 21.9, 23.6, 42.4, 70.3, 74.4, 81.1,
96.4, 115.1, 129.5, 132.1, 163.1, 176.5.
MS (EI, 70 eV): m/z (%) = 272.2 (68, [M+]), 201.2 (40), 173.1
(100), 121.1 (66).
HRMS (EI): m/z (M+) calcd for C17H20O3: 272.1412; found:
272.1411.
IR (neat): 2977, 1698, 1603, 1561, 1501, 1428, 1351, 1298, 1261,
1188, 1086, 949, 926, 834, 747, 631, 445 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.95–2.18 (m, 8 H, CH2), 4.66 [sept, J = 6.1 Hz, 1 H,
(CH3)2CH], 6.97 (d, J = 9.0 Hz, 2 H, CHAr), 8.15 (d, J = 9.0 Hz, 2
H, CHAr).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.5, 37.4, 70.2, 96.8,
104.9, 115.4, 120.4, 130.3, 161.7, 175.6, 199.1.
MS (EI, 70 eV): m/z (%) = 306.1 (24, [M+]), 265.1 (12), 225.0 (31),
223.0 (100), 152.0 (18), 121.0 (14).
2-(4-Isopropoxyphenyl)-1-oxaspiro[4.4]non-2-en-4-one (7)
To a solution of ketone 6 (1.86 g, 6.83 mmol, 1.0 equiv) in EtOH–
H2O (35 mL, 9:1) was added dropwise Et2NH (0.750 g, 10.3 mmol,
1.5 equiv) at r.t. After 30 min, the solvent was removed and the
crude product purified by FC (SiO2, hexanes–EtOAc, 20:1). Re-
crystallization from hexanes yielded the furanone 7 as light yellow
crystals (1.42 g, 5.21 mmol, 76%); mp 93 °C; Rf = 0.45 (SiO2, hex-
anes–EtOAc, 3:1).
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

2678
S. Amslinger, S. K. Lindner
PAPER
HRMS (EI-MS): m/z (M+) calcd for C17H19ClO3: 306.1023; found:
306.1025.
13C NMR (100 MHz, CDCl3): d = 21.8, 25.4, 37.6, 62.8, 70.2, 96.4,
115.2, 121.2, 130.9, 161.6, 179.1, 202.5.
MS (EI, 70 eV): m/z (%) = 398.0 (37, [M+]), 357.0 (14), 315.0 (62),
145.0 (100), 121.0 (17).
HRMS (EI-MS): m/z (M+) calcd for C17H19IO3: 398.0379; found:
398.0379.
3-Bromo-2-(4-isopropoxyphenyl)-1-oxaspiro[4.4]non-2-en-4-
one (13)
Method A: To a stirred solution of furanone 7 (500 mg, 1.84 mmol,
1.0 equiv) in MeCN (20 mL) was added N-bromosuccinimide (359
mg, 2.02 mmol, 1.1 equiv) in portions at 0 °C. After 30 min, sat. aq
NaHCO3 (20 mL) was added and the mixture extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were washed with brine
(50 mL), dried (MgSO4), and the solvent was removed. Recrystalli-
zation from EtOAc gave a-Br-furanone 13 (570 mg, 1.62 mmol,
88%) as white crystals.
2-(4-Isopropoxyphenyl)-4-oxo-1-oxaspiro[4.4]non-2-ene-3-car-
bonitrile (15)
In a microwave glass tube with a magnetic stirring bar were placed
a-bromofuranone 13 (0.20 g, 0.57 mmol, 1.0 equiv), NaCN (56 mg,
1.1 mmol, 2.0 equiv), and NiBr2 (0.12 g, 0.57 mmol, 1.0 equiv) in
N-methylpyrrolidinone (4 mL). The sealed reaction vessel was put
into the cavity of a CEM Discover S microwave synthesis system
reactor using a noncontact, infrared sensor for temperature control
and heated up to 200 °C. Once the temperature was reached, the
brown mixture was held at 200 °C for 10 min. Then the green mix-
ture was allowed to cool down to r.t., diluted with H2O (2 mL), and
extracted with EtOAc (3 × 5 mL). The combined organic layers
were washed with H2O (5 × 5 mL), dried (MgSO4), and the solvent
was evaporated. Purification by FC (SiO2, hexanes–EtOAc, 8:1)
gave nitrile 15 as white crystals (0.15 g, 0.50 mmol, 89%); mp
126 °C; Rf = 0.6 (SiO2, hexanes–EtOAc, 5:1).
Method B: A solution of furanone 7 (500 mg, 1.84 mmol, 1.0 equiv)
in CH2Cl2 (15 mL) was treated with a solution of Br2 (293 mg, 1.84
mmol, 1.0 equiv) in CH2Cl2 (5 mL) at 0 °C. After 20 min, a solution
of Et3N (557 mg, 5.51 mmol, 3.0 equiv) in CH2Cl2 (3 mL) was add-
ed dropwise to the mixture. The solution was stirred for 1 h at 0 °C
and 2 h at r.t., then diluted with H2O (20 mL), and extracted with
CH2Cl2 (2 × 25 mL). The combined organic layers were washed
with brine (50 mL), dried (MgSO4), and the solvent was evaporated.
Purification by FC (SiO2, hexanes–EtOAc, 10:1) afforded 13 (592
mg, 1.69 mmol, 92%), mp 94 °C; Rf = 0.58 (SiO2, hexanes–EtOAc,
5:1).
IR (neat): 2984, 2221, 1706, 1603, 1578, 1504, 1429, 1387, 1314,
1261, 1190, 1156, 1127, 1102, 951, 842, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.95–2.20 (m, 8 H, CH2), 4.69 [sept, J = 6.1 Hz, 1 H,
(CH3)2CH], 7.00 (d, J = 9.1 Hz, 2 H, CHAr), 8.19 (d, J = 9.0 Hz, 2
H, CHAr).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.6, 37.3, 70.7, 86.5,
100.2, 113.4, 115.9, 119.0, 131.0, 163.6, 185.3, 199.6.
MS (EI, 70 eV): m/z (%) = 297.2 (21, [M+]), 255.2 (7), 214.1 (100),
143.1 (20), 121.0 (9).
IR (neat): 2954, 1696, 1601, 1556, 1497, 1425, 1347, 1293, 1256,
1187, 1106, 1070, 951, 919, 831, 746 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.95–2.18 (m, 8 H, CH2), 4.66 [sept, J = 6.1 Hz, 1 H,
(CH3)2CH], 6.97 (d, J = 9.1 Hz, 2 H, CHAr), 8.19 (d, J = 9.1 Hz, 2
H, CHAr).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.5, 37.5, 70.2, 92.2, 96.8,
115.3, 120.7, 130.5, 161.6, 176.9, 200.0.
MS (EI, 70 eV): m/z (%) = 350.0 (26, [M+]), 309.0 (15), 269.0 (84),
267.0 (84), 145.0 (100), 121.0 (29).
HRMS (EI-MS): m/z (M+) calcd for C18H19NO3: 297.1365; found:
297.1362.
HRMS (EI-MS): m/z (M+) calcd for C17H19BrO3: 350.0518; found:
350.0512.
2-(4-Isopropoxyphenyl)-4-oxo-1-oxaspiro[4.4]non-2-ene-3-car-
boxylic Acid Amide (16)
3-Iodo-2-(4-isopropoxyphenyl)-1-oxaspiro[4.4]non-2-en-4-one
(14)
Nitrile 15 (0.10 g, 0.34 mmol, 1.0 equiv) was dissolved in a 1:1 so-
lution of aq 12 M NaOH–1,4-dioxane (9 mL) and the mixture stirred
at r.t. for 2 h. After dilution with aq 1 M HCl (5 mL) and extraction
with EtOAc (3 × 10 mL), the combined organic layers were washed
with brine (30 mL), dried (MgSO4), and the solvent was evaporated.
Recrystallization from EtOAc gave amide 16 as white crystals (81
mg, 0.25 mmol, 73%); mp 175 °C; Rf = 0.47 (SiO2, hexanes–
EtOAc, 5:1).
Method A: A stirred solution of furanone 7 (100 mg, 0.367 mmol,
1.0 equiv) and N-iodosuccinimide (90.9 mg, 0.404 mmol, 1.1 equiv)
in MeCN (10 mL) was refluxed for 16 h. Sat. aq NaHCO3 (10 mL)
was added and the mixture extracted with EtOAc (3 × 20 mL). The
combined organic layers were washed with brine (50 mL), dried
(MgSO4), and the solvent removed. Recrystallization from EtOAc
gave a-I-furanone 14 (592 mg, 1.49 mmol, 88%) as light yellow
crystals.
IR (neat): 3321, 3183, 2966, 1597, 1483, 1245, 1184, 1121, 1045,
947, 931, 855, 830, 792, 652, 608, 545, 480 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.84–1.94 (m, 6 H, CH2), 2.07–2.18 (m, 2 H, CH2), 4.63
[sept, J = 6.1 Hz, 1 H, (CH3)2CH], 6.03 (s, 1 H, NH), 6.89 (d, J = 8.9
Hz, 2 H, CHAr), 7.92 (d, J = 8.9 Hz, 2 H, CHAr), 9.28 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 22.0, 25.4, 36.7, 69.8, 95.1, 99.7,
114.3, 130.4, 131.3, 161.2, 179.7, 189.0, 193.0.
MS (EI, 70 eV): m/z (%) = 315.2 (47, [M+]), 272.2 (23), 232.1
(100), 138.0 (86), 121.0 (73), 95.0 (33).
Method B: To a solution of furanone 7 (50 mg, 0.18 mmol, 1.0
equiv) in CH2Cl2 (1.2 mL) were added I2 (70 mg, 0.28 mmol, 1.5
equiv) and pyridinium dichromate (21 mg, 55 mmol, 0.3 equiv). The
reaction flask was covered with aluminum foil and the mixture
stirred for 3 h at r.t. The contained solids were filtered off and the
filtrate washed with H2O (3 mL), sat. aq Na2S2O3 (3 mL), and brine
(3 mL). The organic layer was dried (MgSO4) and the solvent evap-
orated. Purification by FC (SiO2, hexanes–EtOAc 10:1) afforded 14
(52 mg, 0.13 mmol, 72%); mp 135 °C; Rf = 0.57 (SiO2, hexanes–
EtOAc, 5:1).
IR (neat): 2955, 1677, 1599, 1545, 1491, 1422, 1342, 1291, 1253,
1175, 1107, 1060, 950, 915, 832, 747 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.37 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.95–2.16 (m, 8 H, CH2), 4.66 [sept, J = 6.1 Hz, 1 H,
(CH3)2CH], 6.96 (d, J = 9.0 Hz, 2 H, CHAr), 8.21 (d, J = 9.0 Hz, 2
H, CHAr).
HRMS (EI-MS): m/z (M+) calcd for C18H21NO4: 315.1471; found:
315.1467.
2-(4-Isopropoxyphenyl)-3-phenyl-1-oxaspiro[4.4]non-2-en-4-
one (17)
To solution of a-bromofuranone 13 (20 mg, 57 mmol, 1.0 equiv) in
toluene (0.32 mL) and EtOH (0.10 mL) were added Pd2(dba)3 (2.6
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

PAPER
Limno-CP as Scaffold for a Library of a-Modified Enones
2679
mg, 2.8 mmol, 0.05 equiv), PPh3 (1.5 mg, 5.7 mmol, 0.1 equiv), and
PhB(OH)2 (8.3 mg, 68 mmol, 1.2 equiv). After stirring for 10 min,
Et2NH (7.5 mL) and H2O (0.10 mL) were added and the mixture was
refluxed for 16 h. The solution was diluted with EtOAc (3 mL) and
washed successively with aq 0.2 M NaOH (3 mL), aq 0.05 M HCl
(3 mL), and brine (3 mL). The organic layer was dried (MgSO4) and
the solvent removed. Purification by FC (SiO2, hexanes–EtOAc,
6:1) afforded a-Ph-furanone 17 as colorless crystals (16 mg, 45
mmol, 79%); mp 119 °C; Rf = 0.33 (SiO2, toluene–MeOH, 99:1).
13C NMR (150 MHz, DMSO-d6): d = 24.8, 36.5, 95.5 (d, J = 7.6
Hz), 116.2, 117.1 (d, J = 5.0 Hz), 129.2 (d, J = 6.2 Hz), 139.4 (d,
J = 256.5 Hz), 162.0 (d, J = 1.2 Hz), 166.8 (d, J = 14.0 Hz), 191.6
(d, J = 10.1 Hz).
19F NMR (282 MHz, DMSO-d6): d = –181.5.
MS (EI, 70 eV): m/z (%) = 248.2 (47, [M+]), 220.2 (18), 207.1
(100), 136.1 (23), 121.1 (29).
HRMS (EI-MS): m/z (M+) calcd for C14H13FO3: 248.0849; found:
248.0853.
IR (neat): 2969, 1686, 1603, 1486, 1384, 1252, 1168, 1106, 1045,
948, 835, 695, 623, 514, 447 cm–1.
3-Chloro-2-(4-hydroxyphenyl)-1-oxaspiro[4.4]non-2-en-4-one
(19)
Compound 12 (10 mg, 33 mmol) gave after 16 h of reaction time, 8.2
mg (31 mmol, 95%) of 19; mp 209 °C; Rf = 0.43 (SiO2, hexanes–
EtOAc, 2:1).
1H NMR (300 MHz, CDCl3): d = 1.34 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.92–2.21 (m, 8 H, CH2), 4.57 [sept, J = 6.1 Hz, 1 H,
(CH3)2CH], 6.80 (d, J = 9.0 Hz, 2 H, CHAr), 7.27–7.39 (m, 5 H,
CHAr), 7.59 (d, J = 9.0 Hz, 2 H, CHAr).
13C NMR (100 MHz, CDCl3): d = 21.9, 25.7, 37.5, 70.0, 96.8,
113.6, 115.1, 121.9, 127.3, 128.6, 129.7, 130.3, 130.6, 160.8, 178.3,
204.3.
MS (EI, 70 eV): m/z (%) = 348.2 (98, [M+]), 307.2 (75), 265.1
(100), 194.1 (58), 165.0 (24), 121.0 (18).
HRMS (EI-MS): m/z (M+) calcd for C23H24O3: 348.1725; found:
348.1727.
IR (neat): 3139, 2924, 1670, 1606, 1552, 1489, 1370, 1284, 1170,
1095, 933, 837, 744, 659, 505, 450 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.81–2.00 (m, 8 H, CH2), 6.98
(d, J = 8.9 Hz, 2 H, CHAr), 8.03 (d, J = 8.9 Hz, 2 H, CHAr), 10.65 (s,
1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 24.9, 36.7, 96.1, 103.0, 115.9,
118.3, 130.2, 162.1, 175.3, 197.5.
MS (EI, 70 eV): m/z (%) = 264.1 (35, [M+]), 225.0 (30), 223.0 (100,
Deprotection of Isopropyl Ethers; General Procedure
[M+ – C3H5], 152.0 (33), 145.1 (16), 121.0 (24).
Protected furanone (8.0–20 mg, 28 mmol–57 mol, 1.0 equiv) was
dissolved in anhyd CH2Cl2 (0.5 mL) and a solution of 1 M BCl3 in
n-hexane (6.0 equiv) was added slowly at –78 °C to the solution.
The solution was warmed to r.t. and stirred until the reaction was
complete (1 to 40 h). THF (0.5 mL) and aq 1 M HCl (0.5 mL) were
added and the solvent was removed. The residue was taken up in
EtOAc (10 mL) and H2O (10 mL), extracted with EtOAc (3 × 10
mL), and the combined organic layers were dried (MgSO4). Ab-
sorption on SiO2 was done from a solution of EtOH and purification
achieved by FC [SiO2 (dryload), hexanes–EtOAc–EtOH (40:10:1)
and CHCl3–EtOH (25:1)] to yield the deprotected furanones. For
the purification of amide 23, only CHCl3–EtOH (25:1) was applied.
HRMS (EI-MS): m/z (M+) calcd for C14H13ClO3: 264.0553; found:
264.0548.
3-Bromo-2-(4-hydroxyphenyl)-1-oxaspiro[4.4]non-2-en-4-one
(20)
Compound 13 (20 mg, 57 mmol) gave after 16 h of reaction time, 16
mg (53 mmol, 93%) of 20; mp 216 °C; Rf = 0.48 (SiO2, hexanes–
EtOAc, 2:1).
IR (neat): 3158, 2958, 1666, 1603, 1552, 1484, 1361, 1281, 1235,
1171, 1079, 921, 846, 747, 665, 597, 438 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.75–2.03 (m, 8 H, CH2), 6.97
(d, J = 8.9 Hz, 2 H, CHAr), 8.07 (d, J = 8.9 Hz, 2 H, CHAr), 10.63 (s,
1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 24.9, 36.8, 90.8, 96.0, 115.7,
118.7, 130.5, 162.0, 176.7, 198.5.
2-(4-Hydroxyphenyl)-1-oxaspiro[4.4]non-2-en-4-one (2)
Compound 7 (10 mg, 37 mmol) gave after 16 h of reaction time, 8.4
mg (36 mmol, 99%) of 2; mp 231 °C; Rf = 0.15 (SiO2, hexanes–
EtOAc, 5:1).
IR (neat): 2918, 2728, 2609, 1638, 1548, 1501, 1431, 1366, 1234,
1161, 1051, 895, 789, 592 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.73–1.94 (m, 8 H, CH2), 6.13
(s, 1 H, CH), 6.90 (d, J = 8.7 Hz, 2 H, CHAr), 7.77 (d, J = 8.7 Hz, 2
H, CHAr), 10.44 (s, 1 H, OH).
MS (EI, 70 eV): m/z (%) = 308.0 (32, [M+]), 268.9 (79), 267.0 (82),
145.0 (100), 121.0 (28).
HRMS (EI-MS): m/z (M+) calcd for C14H13BrO3: 308.0048; found:
308.0047.
13C NMR (75 MHz, DMSO-d6): d = 25.1, 36.4, 97.3, 97.4, 115.7,
119.3, 129.2, 161.7, 183.0, 203.8.
2-(4-Hydroxyphenyl)-3-iodo-1-oxaspiro[4.4]non-2-en-4-one
(21)
Compound 14 (20 mg, 50 mmol) gave after 1 h of reaction time, 15
mg (41 mmol, 82%) of 21; mp 201 °C; Rf = 0.43 (SiO2, hexanes–
EtOAc, 2:1).
MS (EI, 70 eV): m/z (%) = 230.1 (26, [M+]), 189.0 (86), 118.0
(100), 89.1 (13), 44.0 (16), 40.1 (32).
HRMS (EI-MS): m/z (M+) calcd for C14H14O3: 230.0943; found:
230.0944.
IR (neat): 3139, 2923, 1656, 1600, 1545, 1476, 1352, 1279, 1231,
1168, 1070, 915, 841, 746, 665, 594, 523, 450 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.76–1.98 (m, 8 H, CH2), 6.96
(d, J = 8.8 Hz, 2 H, CHAr), 8.08 (d, J = 8.8 Hz, 2 H, CHAr), 10.55 (s,
1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 25.0, 36.9, 63.3, 95.5, 115.5,
119.6, 130.8, 161.7, 178.8, 201.9.
3-Fluoro-2-(4-hydroxyphenyl)-1-oxaspiro[4.4]non-2-en-4-one
(18)
Compound 11 (8.0 mg, 28 mmol) gave after 3 h of reaction time, 6.7
mg (27 mmol, 98%) of 18; mp 208 °C; Rf = 0.33 (SiO2, hexanes–
EtOAc, 2:1).
IR (neat): 3121, 2946, 1675, 1563, 1508, 1414, 1285, 1154, 1107,
961, 843, 743, 581, 512, 413 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.80–1.99 (m, 8 H, CH2), 6.98
(d, J = 8.8 Hz, 2 H, CHAr), 7.78 (d, J = 8.8 Hz, 2 H, CHAr), 10.61 (s,
1 H, OH).
MS (EI, 70 eV): m/z (%) = 355.9 (65, [M+]), 314.9 (80), 145.0
(100), 121.0 (17).
HRMS (EI-MS): m/z (M+) calcd for C14H13IO3: 355.9909; found:
355.9902.
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

2680
S. Amslinger, S. K. Lindner
PAPER
2-(4-Hydroxyphenyl)-4-oxo-1-oxaspiro[4.4]non-2-ene-3-carbo-
nitrile (22)
Compound 15 (10 mg, 34 mmol) gave after 40 h of reaction time, 8.4
mg (33 mmol, 98%) of 22; mp 255 °C; Rf = 0.35 (SiO2, hexanes–
EtOAc, 2:1).
hexamethyldisilane (internal standard) solution in CDCl3 or a 1.89
mM hexamethyldisilane solution in CDCl3–C6D6 (1:1) in the case
of phenyl compound 32a, 32b. Yields of compounds 26a, 26b and
28a, 28b were isolated yields of homogenous materials without in-
ternal standard, but were verified by using the internal standard.
IR (neat): 3200, 2972, 2231, 1701, 1605, 1559, 1505, 1382, 1286,
1170, 1117, 956, 845, 707, 665, 575, 510 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.82–2.07 (m, 8 H, CH2), 7.04
(d, J = 8.9 Hz, 2 H, CHAr), 8.05 (d, J = 8.9 Hz, 2 H, CHAr), 11.09 (s,
1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 24.9, 36.5, 84.8, 99.8, 113.7,
116.4, 117.3, 131.0, 164.2, 185.1, 199.0.
MS (EI, 70 eV): m/z (%) = 255.1 (20, [M+]), 214.1 (100, [M+ –
C3H5]), 143.0 (45), 121.0 (13).
HRMS (EI-MS): m/z (M+) calcd for C15H13NO3: 255.0895; found:
255.0889.
4-Butylidene-2-(4-isopropoxyphenyl)-1-oxaspiro[4.4]non-2-
enes (26a, 26b)
Compound 7 (20 mg, 73 mmol, 1.0 equiv) gave 20 mg (64 mmol,
87%) of 26a, 26b as a colorless oil; Rf = 0.97 (SiO2, hexanes–
EtOAc, 5:1).
IR (neat): 2927, 1609, 1504, 1245, 1119, 1058, 953, 833, 770, 638,
601 cm–1.
MS (EI, 70 eV): m/z (%) = 312.3 (56, [M+]), 283.2 (100), 241.2
(21), 121.0 (40).
HRMS (EI-MS): m/z (M+) calcd for C21H28O2: 312.2089; found:
312.2087.
2-(4-Hydroxyphenyl)-4-oxo-1-oxaspiro[4.4]non-2-ene-3-car-
boxylic Acid Amide (23)
Compound 16 (10 mg, 32 mmol) gave after 16 h of reaction time, 7.3
mg (27 mmol, 84%) of 23; mp 190 °C; Rf = 0.09 (SiO2, hexanes–
EtOAc, 5:1).
26a
1H NMR (600 MHz, CDCl3): d = 0.93 (t, J = 7.3 Hz, 3 H, CH3, Bu),
1.34 [d, J = 6.1 Hz, 6 H, (CH3)2CH], 1.43 (sext, J = 7.3 Hz, 2 H,
CH2, Bu), 1.61–1.66 (m, 2 H, CH2), 1.78–1.85 (m, 2 H, CH2), 1.90–
1.96 (m, 2 H, CH2), 2.06–2.10 (m, 2 H, CH2), 2.13 (q, J = 7.3 Hz, 2
H, CH2, Bu), 4.57 [sept, J = 6.1 Hz, 1 H, (CH3)2CH], 4.76 (dt,
J = 7.4, 0.7 Hz, 1 H, =CH, Bu), 5.97 (d, J = 0.8 Hz, 1 H, =CH), 6.85
(d, J = 8.9 Hz, 2 H, CHAr), 7.56 (d, J = 8.9 Hz, 2 H, CHAr).
IR (neat): 3283, 3057, 2962, 1610, 1581, 1452, 1274, 1244, 1024,
1000, 934, 789, 710, 636, 605, 525, 480, 440 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.80–1.99 (m, 8 H, CH2), 6.75
(d, J = 8.7 Hz, 2 H, CHAr), 7.68 (d, J = 8.7 Hz, 2 H, CHAr), 9.00 (s,
1 H, NH), 9.28 (s, 1 H, NH), 10.01 (s, 1 H, OH).
13C NMR (150 MHz, CDCl3): d = 13.8, 22.0, 23.4, 24.9, 31.5, 42.4,
69.9, 96.3, 97.5, 110.7, 115.6, 123.9, 126.8, 147.7, 158.4, 159.0.
13C NMR (300 MHz, DMSO-d6): d = 24.9, 36.1, 93.5, 97.4, 113.9,
129.7, 131.1, 160.6, 178.5, 187.1, 191.6.
26b
1H NMR (600 MHz, CDCl3): d = 0.93 (t, J = 7.3 Hz, 3 H, CH3, Bu)
1.34 [d, J = 6.1 Hz, 6 H, (CH3)2CH], 1.43 (sext, J = 7.3 Hz, 2H,
CH2, Bu), 1.61–1.66 (m, 2H, CH2), 1.78–1.85 (m, 2 H, CH2), 1.90–
1.96 (m, 2 H, CH2), 2.06–2.10 (m, 2 H, CH2), 2.13 (q, J = 7.3 Hz, 2
H, CH2, Bu), 4.57 [sept, J = 6.1 Hz, 1 H, (CH3)2CH], 5.13 (t, J = 8.0
Hz, 1 H, =CH, Bu), 5.72 (s, 1 H, =CH), 6.85 (d, J = 8.9 Hz, 2 H,
CHAr), 7.49 (d, J = 8.9 Hz, 2 H, CHAr).
MS (EI, 70 eV): m/z (%) = 273.1 (38, [M+]), 232.0 (49, [M+
C3H5], 138.0 (43), 121.0 (100), 93.0 (37), 65.1 (44).
HRMS (EI-MS): m/z (M+) calcd for C15H15NO4: 273.1001; found:
273.0994.
–
2-(4-Hydroxyphenyl)-3-phenyl-1-oxaspiro[4.4]non-2-en-4-one
(24)
4-Butylidene-3-fluoro-2-(4-isopropoxyphenyl)-1-oxa-
spiro[4.4]non-2-enes (30a, 30b)
Compound 11 (7.7 mg, 27 mmol, 1.0 equiv) gave 4.6 mg (14 mmol,
52%) of 30a, 30b; Rf = 0.81 (SiO2, hexanes–EtOAc, 5:1).
Compound 17 (10 mg, 29 mmol) gave after 16 h of reaction time, 8.3
mg (27 mmol, 94%) of 24; mp 221 °C; Rf = 0.45 (SiO2, hexanes–
EtOAc, 2:1).
IR (neat): 3260, 2919, 1670, 1604, 1562, 1483, 1397, 1287, 1219,
1168, 1052, 841, 701, 594, 524, 450 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.79–2.04 (m, 8 H, CH2), 6.77
(d, J = 8.8 Hz, 2 H, CHAr), 7.22–7.25 (m, 2 H, CHAr), 7.29–7.46 (m,
5 H, CHAr), 10.35 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 25.2, 36.8, 95.8, 112.3, 115.4,
119.8, 127.2, 128.4, 129.4, 130.0, 130.6, 161.0, 177.9, 202.8.
30a
1H NMR (600 MHz, CDCl3): d = 0.93 (t, J = 7.4 Hz, 3 H, CH3, Bu),
1.34 [d, J = 6.1 Hz, 6 H, (CH3)2CH], 1.41–1.49 (m, 2 H, CH2, Bu),
1.58–1.68 (m, 3 H, CH2), 1.77–2.02 (m, 5 H, CH2), 2.34 (q, J = 7.5
Hz, 1 H, CH2, Bu), 4.58 [sept, J = 6.0 Hz, 1 H, (CH3)2CH], 4.80 (t,
J = 8.0 Hz, 1 H, =CH, Bu), 6.89 (d, J = 9.0 Hz, 2 H, CHAr), 7.62 (d,
J = 8.9 Hz, 2 H, CHAr).
MS (EI, 70 eV): m/z (%) = 306.1 (48, [M+]), 265.1 (100, [M+ –
C3H5]), 194.1 (51), 121.0 (16).
HRMS (EI-MS): m/z (M+) calcd for C20H18O3: 306.1256; found:
306.1252.
30b
1H NMR (600 MHz, CDCl3): d = 0.96 (t, J = 7.4 Hz, 3 H, CH3, Bu),
1.34 [d, J = 6.1 Hz, 6 H, (CH3)2CH], 1.41–1.49 (m, 2 H, CH2, Bu),
1.58–1.68 (m, 3 H, CH2), 1.77–2.02 (m, 5 H, CH2), 2.14 (q, J = 7.5
Hz, 1 H, CH2, Bu), 4.57 [sept, J = 6.0 Hz, 1 H, (CH3)2CH], 5.16 (t,
J = 8.1 Hz, 1 H, =CH, Bu), 6.89 (d, J = 9.0 Hz, 2 H, CHAr), 7.59 (d,
J = 8.9 Hz, 2 H, CHAr).
Reaction of i-Pr-a-X-Limno-CPs with Alkyllithium Reagents
With n-BuLi
To a stirred solution of respective 3(2H)-furanone (5.0–20 mg, 14–
73 mmol, 1.0 equiv) in anhyd THF (1.0 mL) was added a 1.6 M so-
lution of n-BuLi in n-hexane (1.0 equiv) dropwise at –78 °C. Then
H2O (0.5 mL) was added, the mixture warmed to r.t., diluted with
sat. aq NaHCO3 (0.5 mL), and extracted with EtOAc (3 × 1.0 mL).
The combined organic layers were washed with brine (3 mL), dried
(MgSO4), and the solvent was evaporated to give the dihydrofuran,
which decomposed within hours even at –20 °C. The yield was de-
termined by dissolving the crude material in 600 mL of a 3.77 mM
30a, 30b
13C NMR (150 MHz, CDCl3): d = 13.6, 13.8, 22.0, 23.7, 23.8, 24.5,
25.0, 29.3, 29.4, 39.9, 42.5, 69.9, 93.9 (d, J = 6.2 Hz), 94.6 (d,
J = 8.4 Hz), 111.9 (d, J = 4.0 Hz), 112.6 (d, J = 7.6 Hz), 115.6,
122.0 (d, J = 5.8 Hz), 126.8 (d, J = 6.3 Hz), 127.0 (d, J = 6.9 Hz),
137.8 (d, J = 12.8 Hz), 137.9 (d, J = 14.8 Hz), 138.2 (d, J = 19.5
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

PAPER
Limno-CP as Scaffold for a Library of a-Modified Enones
With n-Hexyllithium
2681
Hz), 141.1 (d, J = 21.2 Hz), 142.5 (d, J = 255.8 Hz), 143.8 (d,
J = 257.5 Hz), 157.8, 158.0.
4-Hexylidene-2-(4-isopropoxyphenyl)-1-oxaspiro[4.4]non-2-
enes (28a, 28b)
19F NMR (282 MHz, CDCl3): d = –174.4, –170.7.
To a stirred solution of furanone 7 (5.0 mg, 18 mmol, 1.0 equiv) in
anhyd THF (0.5 mL) was added dropwise a solution of 2.45 M n-
HexLi in n-hexane (9.0 mL, 22 mmol, 1.2 equiv) at –78 °C. Workup
and isolation of the product were done as in the case of n-BuLi. Di-
hydrofurans 28a, 28b were obtained as a colorless oil (6.2 mg, 18
mmol, 91%); Rf = 0.88 (SiO2, hexanes–EtOAc, 5:1).
MS (EI, 70 eV): m/z (%) = 330.2 (81, [M+]), 301.2 (100), 259.1
(23), 121.0 (29).
HRMS (EI-MS): m/z (M+) calcd for C21H27FO2: 330.1995; found:
330.1993.
4-Butylidene-3-chloro-2-(4-isopropoxyphenyl)-1-oxa-
spiro[4.4]non-2-enes (31a, 31b)
Compound 12 (5.0 mg, 16 mmol, 1.0 equiv) gave 4.9 mg (14 mmol,
86%) of 31a, 31b; Rf = 0.61 (SiO2, hexanes–EtOAc, 5:1).
MS (EI, 70 eV): m/z (%) = 346.2 (76, [M+]), 317.1 (100), 121.0
(46).
HRMS (EI-MS): m/z (M+) calcd for C21H27ClO2: 346.1700; found:
IR (neat): 2924, 1608, 1503, 1245, 1179, 1119, 1057, 952, 834, 770,
637, 601 cm–1.
MS (EI, 70 eV): m/z (%) = 340.3 (38, [M+]), 284.2 (20), 283.2 (100,
[M+ – C4H9]), 241.1 (19), 163.1 (17), 121.0 (35).
HRMS (EI-MS): m/z (M+) calcd for C23H32O2: 340.2402; found:
340.2397.
346.1696.
28a
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.0 Hz, 3 H, CH3,
Hex), 1.30–1.34 [m, 10 H, (CH3)2CH, CH2, Hex), 1.38–1.43 (m, 2
H, CH2, Hex), 1.60–1.66 (m, 2 H, CH2), 1.77–1.84 (m, 2 H, CH2),
1.89–1.97 (m, 2 H, CH2), 2.06–2.10 (m, 2 H, CH2), 2.14 (q, J = 7.4
Hz, 2 H, CH2, Hex), 4.57 [sept, J = 6.1 Hz, 1 H, (CH3)2CH], 4.76
(dt, J = 7.3, 0.3 Hz, 1 H, =CH, Hex), 5.96 (d, J = 0.6 Hz, 1 H, =CH),
6.85 (d, J = 8.8 Hz, 2 H, CHAr), 7.56 (d, J = 8.8 Hz, 2 H, CHAr).
31a
1H NMR (600 MHz, CDCl3): d = 0.95 (t, J = 7.4 Hz, 3 H, CH3, Bu),
1.34 [d, J = 6.1 Hz, 6 H, (CH3)2CH], 1.47 (sext, J = 7.4 Hz, 2 H,
CH2, Bu), 1.79–2.10 (m, 8 H, CH2), 2.58 (q, J = 7.5 Hz, 2 H, CH2,
Bu), 4.59 [sept, J = 6.1 Hz, 1 H, (CH3)2CH], 4.88 (t, J = 7.9 Hz, 1
H, =CH, Bu), 6.89 (d, J = 9.0 Hz, 2 H, CHAr), 7.86 (d, J = 9.0 Hz, 2
H, CHAr).
13C NMR (75 MHz, CDCl3): d = 14.1, 22.0, 22.6, 24.9, 29.5, 30.0,
31.5, 42.4, 69.9, 96.2, 97.5, 111.0, 115.6, 123.9, 126.8, 147.5,
158.4, 158.9.
31b
1H NMR (600 MHz, CDCl3): d = 0.96 (t, J = 7.4 Hz, 3 H, CH3, Bu),
1.34 [d, J = 6.1 Hz, 6 H, (CH3)2CH], 1.47 (sext, J = 7.4 Hz, 2 H,
CH2, Bu), 1.79–2.10 (m, 8 H, CH2), 2.16 (q, J = 7.3 Hz, 2 H, CH2,
Bu), 4.59 [sept, J = 6.1 Hz, 1 H, (CH3)2CH], 5.26 (t, J = 8.1 Hz, 1
H, =CH, Bu), 6.89 (d, J = 9.0 Hz, 2 H, CHAr), 7.86 (d, J = 9.0 Hz, 2
H, CHAr).
28b
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.0 Hz, 3 H, CH3,
Hex), 1.30–1.34 [m, 10 H, (CH3)2CH, CH2, Hex], 1.38–1.43 (m, 2
H, CH2, Hex), 1.60–1.66 (m, 2 H, CH2), 1.77–1.84 (m, 2 H, CH2),
1.89–1.97 (m, 2 H, CH2), 2.06–2.10 (m, 2 H, CH2), 2.14 (q, J = 7.4
Hz, 2 H, CH2, Hex), 4.57 [sept, J = 6.1 Hz, 1 H, (CH3)2CH], 5.12 (t,
J = 8.0 Hz, 1 H, =CH, Hex), 5.71 (s, 1 H, =CH), 6.85 (d, J = 8.8 Hz,
2 H, CHAr), 7.49 (d, J = 8.8 Hz, 2 H, CHAr).
13C NMR (150 MHz, CDCl3): d = 13.9, 22.0, 23.9, 25.2, 29.2, 40.0,
69.8, 95.3, 104.9, 114.4, 115.3, 122.5, 128.5, 143.3, 150.5, 158.4.
4-Butylidene-2-(4-isopropoxyphenyl)-3-phenyl-1-oxa-
spiro[4.4]non-2-enes (32a, 32b)
Compound 17 (5.0 mg, 14 mmol, 1.0 equiv) gave 1.8 mg (4.7 mmol,
33%) of 32a, 32b.
MS (EI, 70 eV): m/z (%) = 388.3 (89, [M+]), 359.2 (100), 121.0
(91).
HRMS (EI-MS): m/z (M+) calcd for C27H32O2: 388.2402; found:
388.2404.
With MeLi
2-(4-Isopropoxyphenyl)-4-methylene-1-oxaspiro[4.4]non-2-ene
(29)
To a stirred solution of furanone 7 (5.0 mg, 18 mmol, 1.0 equiv) in
anhyd THF (0.5 mL) was added dropwise a 1. 6 M solution of MeLi
in Et2O (12 mL, 18 mmol, 1.0 equiv) at –78 °C. The reaction was
worked up as described for the reaction of 7 with n-BuLi. Dihydro-
furan 29 was obtained in 38% yield (1.9 mg, 7.0 mmol); Rf = 0.92
(SiO2, hexanes–EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): d = 1.34 [d, J = 6.1 Hz, 6 H,
(CH3)2CH], 1.65–2.15 (m, 8 H, CH2), 4.38 (s, 1 H, =CH2), 4.58
[sept, J = 6.1 Hz, 1 H, (CH3)2CH], 4.69 (s, 1 H, =CH2), 5.88 (s, 1 H,
=CH), 6.86 (d, J = 8.9 Hz, 2 H, CHAr), 7.55 (d, J = 8.9 Hz, 2 H,
CHAr).
32a
1H NMR (600 MHz, CDCl3–C6D6, 1:1): d = 0.61 (t, J = 7.4 Hz, 3 H,
CH3, Bu), 1.01 or 1.03 or 1.05 [d, J = 6.0 Hz, 6 H, (CH3)2CH], 1.07–
1.16 (m, 2 H, CH2, Bu), 1.50–1.54 (m, 2 H, CH2, Bu), 1.57–1.65 (m,
2 H, CH2), 1.67–1.76 (m, 2 H, CH2), 1.86–1.98, (m, 2 H, CH2),
2.13–2.18 (m, 2 H, CH2), 4.16 [sept, J = 6.1 Hz, 1 H, (CH3)2CH],
4.74 (t, J = 7.9 Hz, 1 H, =CH, Bu), 6.49 or 6.52 or 6.54 (d, J = 8.9
Hz, 2 H, CHAr), 7.06–7.29 (m, 7 H, CHAr).
With PhLi and t-BuLi
The reactions of furanone 7 (1.0 equiv) with 1.8 M PhLi in Bu2O (1
equiv) or 1.6 M t-BuLi in pentane (1 equiv) were carried out as de-
scribed for the n-BuLi. No product was observed.
32b
1H NMR (600 MHz, CDCl3–C6D6, 1:1): d = 0.78 (t, J = 7.4 Hz, 3 H,
CH3, Bu), 1.01 or 1.03 or 1.05 [d, J = 6.0 Hz, 6 H, (CH3)2CH], 1.19–
1.26 (m, 2 H, CH2, Bu), 1.57–1.65 (m, 2 H, CH2), 1.67–1.76 (m, 2
H, CH2), 1.86–1.98 (m, 2 H, CH2), 1.99–2.04 (m, 2 H, CH2, Bu),
2.13–2.18 (m, 2 H, CH2), 4.11 [sept, J = 6.1 Hz, 1 H, (CH3)2CH],
4.83 (t, J = 8.0 Hz, 1 H, =CH, Bu), 6.49 or 6.52 or 6.54 (d, J = 8.9
Hz, 2 H, CHAr), 7.06–7.29 (m, 7 H, CHAr).
1-{1-[2-(4-Isopropoxyphenyl)ethyl]pentyl}cyclopentanol (27)
To a stirred solution of dihydrofurans 26a,26b (20 mg, 64 mmol, 1.0
equiv) in anhyd EtOAc (0.5 mL) was added 10% Pd/C (6.8 mg, 6.4
mmol, 0.1 equiv) at r.t. The mixture was stirred under H2 atmosphere
for 2 h. Filtration and evaporation of the solvent gave pure tertiary
alcohol 27 as a colorless oil (18 mg, 57 mmol, 89%); Rf = 0.61 (SiO2,
hexanes–EtOAc, 5:1).
IR (neat): 3421, 2928, 1509, 1239, 632, 536, 497 cm–1.
Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York

2682
S. Amslinger, S. K. Lindner
PAPER
1H NMR (300 MHz, CDCl3): d = 0.91 (t, J = 7.1 Hz, 3 H, CH3),
1.31–1.35 [m, 11 H, (CH3)2CH], 1.40–1.44 (m, 1 H), 1.53–1.66 (m,
9 H), 1.76–1.83 (m, 3 H), 2.54 (ddd, J = 13.8, 10.8, 6.1 Hz, 1 H,
ArCH2), 2.69 (ddd, J = 13.8, 11.0, 5.3 Hz, 1 H, ArCH2), 4.57 [sept,
J = 6.1 Hz, 1 H, (CH3)2CH], 6.81 (d, J = 8.6 Hz, 2 H, CHAr), 7.09
(d, J = 8.6 Hz, 2 H, CHAr).
(13) Shao, X.; Dolder, M.; Tamm, C. Helv. Chim. Acta 1990, 73,
483.
(14) Smith, A. B.; Levenberg, P. A.; Jerris, P. J.; Scarborough, R.
M.; Wovkulich, P. M. J. Am. Chem. Soc. 1981, 103, 1501.
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Lett. 1966, 7, 233.
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Tetrahedron Lett. 1973, 14, 577. (b) Kato, K.; Nouchi, H.;
Ishikura, K.; Takaishi, S.; Motodate, S.; Tanaka, H.;
Okudaira, K.; Mochida, T.; Nishigaki, R.; Shigenobu, K.;
Akita, H. Tetrahedron 2006, 62, 2545. (c) Kirsch, S. F.;
Binder, J. T.; Liébert, C.; Menz, H. Angew. Chem. Int. Ed.
2006, 45, 5878. (d) Bunnelle, E. M.; Smith, C. R.; Lee, S.
K.; Singaram, S. W.; Rhodes, A. J.; Sarpong, R. Tetrahedron
2008, 64, 7008. (e) Egi, M.; Azechi, K.; Saneto, M.;
Shimizu, K.; Akai, S. J. Org. Chem. 2010, 75, 2123.
(17) For the acid-induced cyclization of 4-hydroxy-1,3-diketones
no spirocyclic compound is reported. Examples for
monocyclic compounds are given in Ref. 1.
13C NMR (75 MHz, CDCl3): d = 14.1, 22.1, 23.3, 23.8, 30.8, 31.2,
33.5, 34.3, 38.6, 38.7, 47.2, 69.9, 86.2, 115.9, 129.2, 135.0, 155.9.
MS (EI, 70 eV): m/z (%) = 318.2 (6, [M+]), 162.1 (100), 120.0 (74),
107.0 (43).
HRMS (EI-MS): m/z (M+) calcd for C21H34O2: 318.2559; found:
318.2559.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
(18) Shin, S. S.; Byun, Y.; Lim, K. M.; Choi, J. K.; Lee, K.-W.;
Moh, J. H.; Kim, J. K.; Jeong, Y. S.; Kim, J. Y.; Choi, Y. H.;
Koh, H.-J.; Park, Y.-H.; Oh, Y. I.; Noh, M .-S.; Chung, S.
J. Med. Chem. 2004, 47, 792.
We thank the Fonds der Chemischen Industrie for a Liebig scholar-
ship to S.A. and a doctorate stipend to S.L.
(19) Solladié, G.; Pasturel-Jacopé, Y.; Maignan, J. Tetrahedron
2003, 59, 3315.
(20) Parker, W.; Raphael, R. A.; Wilkinson, D. I. J. Chem. Soc.
1958, 3871.
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Limno-CP as Scaffold for a Library of a-Modified Enones
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Synthesis 2011, No. 16, 2671–2683 © Thieme Stuttgart · New York