Synthesis of β-allylbutenolides via one-pot copper-catalyzed hydroallylation/cyclization of γ-hydroxybutynoate derivatives

Article abstract of DOI:10.1021/jo500536b

One-pot copper-catalyzed hydroallylation/lactone cyclization of γ-hydroxybutynoate derivatives was developed to afford β-allylbutenolides.

Full text of DOI:10.1021/jo500536b

Article
pubs.acs.org/joc
Synthesis of β‑Allylbutenolides via One-Pot Copper-Catalyzed
Hydroallylation/Cyclization of γ‑Hydroxybutynoate Derivatives
Yoshihiko Yamamoto,* Shinya Shibano, Takashi Kurohara, and Masatoshi Shibuya
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya 464-8601,
Japan
S
* Supporting Information
ABSTRACT: One-pot copper-catalyzed hydroallylation/lactone cyclization of
γ-hydroxybutynoate derivatives was developed to afford β-allylbutenolides.
(1,4-diene) products. The introduced allylic substituent
enabled further derivatization; the allyl group was successfully
utilized in hydroboration/oxidation, hydroboration/Suzuki−
Miyaura cross-coupling, ring-closing metathesis (RCM), and
cross metathesis (CM). To further demonstrate the synthetic
potential of the copper-catalyzed hydroallylation, we inves-
tigated the one-pot hydroallylation/lactone cyclization of γ-
hydroxybutynoate derivatives to afford β-allylbutenolides.
Although various synthetic methods for β-allylbutenolides
have been developed because of their synthetic utility, they
essentially rely on the transformation of substrates bearing a
pre-introduced allylic moiety or the allylation of preformed
butenolides.9 To the best of our knowledge, only a few
examples are reported on the synthesis of β-allylated
butenolides via combined catalytic allylation and lactone-ring
formation. For example, Trost and co-workers reported the
one-pot ruthenium-catalyzed allylation of γ-hydroxybuty-
noates/lactone cyclization.10 However, this method afforded
regioisomeric products depending on the substrate structure.
Ma and Yu developed the palladium-catalyzed allylative
cyclization of 2,3-allenoic acids with allylic halides.11a Later,
Chen and Ma also reported a similar synthesis of β-
allylbutenolides from 2,3-allenoates and allylic bromides using
the Pd/Fe combined catalytic system.11b Furthermore, Blum
and co-workers designed an interesting Au/Pd bimetallic
catalyst system, which used allyl 2,3-allenoates as the substrates
bearing a latent allylating agent; β-allylbutenolides were
produced via the gold-catalyzed lactone cyclization of the
allenoates and subsequent allylation with the resultant π-
allylpalladium species.12 Although these methods are regiose-
lective with wide substrate scope, precious metal catalysts and
an excess amount of toxic allylic halides are required to obtain
the desired products. Therefore, a new protocol for synthesiz-
ing β-allylbutenolides should be developed using an inexpensive
catalyst and a less toxic allylating agent. Herein, we report the
INTRODUCTION
■
Furan-2(5H)-one or Δα,β-butenolide has attracted considerable
attention because this privileged heterocyclic motif has been
found in numerous natural products with interesting biological
activities.1 Therefore, various synthetic procedures have been
devised to construct the furan-2(5H)-one framework.2 Among
these, the one-pot catalytic hydroarylation/lactone cyclization
of readily available γ-hydroxybutynoates is one of the most
powerful strategies for assembling arylated butenolides.3,4 Aryl
iodides have been employed as the arylating reagents in a
pioneering study by Cacchi and co-workers.3 Later, arylboron
reagents were utilized as less toxic and stable alternatives.4
Although these methods enabled the synthesis of butenolides
with an aryl group at the α or β positions, a related method to
introduce a functionalizable substituent has been under-
developed. In a seminal study, the Cacchi group has also
investigated the palladium-catalyzed hydrovinylation/lactone
cyclization using alkenyl halides and triflates to afford α- or β-
alkenylbutenolides.5 However, no further development has
been made in this field.
Our group has independently developed the copper-
catalyzed hydroarylation of electron-deficient alkynes.6 Our
method has several advantages over previous hydroarylations:
(1) Inexpensive copper(I) or copper(II) acetate is employed as
the catalyst, and no extra ligand is required. (2) Readily
available and easy-to-handle arylboronic acids are used as the
arylating reagents. (3) The reaction proceeds under mild
conditions. (4) Diverse functional groups are tolerated. (5)
Trisubstituted alkene products are obtained regio- and
stereoselectively. Taking advantage of these features of the
copper-catalyzed hydroarylation, we have successfully synthe-
sized biologically interesting compounds such as 4-arylcoumar-
ins,7a 3,3-diarylacrylonitriles including the potential anticancer
agent CC-5079,7b and 3-arylindole-2-carboxylates.7c As an
extension of these studies, we recently investigated the
copper-catalyzed hydroallylation of electron-deficient alkynes
using a commercially available allylboronic acid pinacol ester.8
The hydroallylation regio- and stereoselectively proceeds under
mild reaction conditions to afford the desired skipped diene
Received: March 6, 2014
Published: April 18, 2014
© 2014 American Chemical Society
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development of copper-catalyzed one-pot hydroallylation/
lactone cyclization.
consumed within 2 h. Next, we examined the effect of the
protecting group of the γ-hydroxyl group (Scheme 2b). When
tert-butyldimethylsilyl (TBS)-protected γ-hydroxybutynoate 3a
was subjected to the same reaction for 6 h followed by the
acidic desilylation, the same butenolide 6 was obtained along
with unexpected bisbutenolide 7.15 The isolated yields of 6 and
7 were 56% and 31%, respectively. This is in striking contrast to
the reactions of a higher homologue, i.e., the TBS-ether of δ-
hydroxypentynoate afforded the corresponding β-phenylpente-
nolide as the sole product in a high yield.14 We also repeated
the reaction of 3a using 1 equiv of phenylboronic acid pinacol
ester. In this case, a longer reaction time of 24 h was required
for the hydroarylation, and bisbutenolide 7 was obtained as the
major product along with 6 after the one-pot deprotection.
With these previous results in mind, we examined the
selectivity of the one-pot hydroallylation/lactone cyclization of
3a as the substrate (Scheme 3a). Under the previously
RESULTS AND DISCUSON
■
1. Preparation of Butynoate Substrates. The required
butynoate substrates were prepared from readily available
propargylic alcohol derivatives 1 as outlined in Scheme 1a.
Scheme 1. Preparation of Substrates
Scheme 3. One-Pot Hydroallylation/Cyclization of
Alkynoates 3a−c with Allylboronate 8a
Alkyne 1 can be obtained from commercial suppliers or
prepared by the ethynylation of the corresponding carbonyl
compounds. After protecting the γ-hydroxyl group with an
appropriate silyl group, the alkyne terminal of 1 was
methoxycarbonylated according to the reported procedure.13
Thus, obtained silylated substrates 3 were used for this study
without deprotection. However, desilylation was performed
using tetrabutylammonium fluoride (TBAF) if required (vide
infra). Other alkyne substrates with a methoxymethyl (MOM)
protecting group were also obtained from 1 and methox-
ymethyl chloride using the standard procedures. Alternatively,
γ-hydroxybutynoates were directly prepared by the addition of
silver acetylide 4, derived from methyl propiolate, to aldehydes
using the procedure reported by Shahi and Koide (Scheme
1b).14 The subsequent silylation of the obtained γ-hydrox-
ybutynoates with trimethylsilyl (TMS) chloride afforded
secondary propargylic alcohol derivatives 3.
optimized reaction conditions for hydroallylation, 3a and
allylboronate 8a (1.5 equiv) were treated with 3 mol %
Cu(OAc)2 for 3 h, and the resultant reaction mixture was then
treated with 50 mol % TsOH at room temperature for 12 h in
the same pot. The latter procedure effectively removed the silyl
group under mild conditions to afford the desired β-
allylbutenolide 9a in 80% yield. To our delight, the anticipated
bisbutenolide byproduct was not formed in this case. The
2. One-Pot Hydroallylation/Lactone Cyclization. Pre-
viously, we attempted the one-pot hydroarylation/lactone
cyclization of γ-hydroxybutynoate 5a with phenylboronic acid
under the optimal copper-catalyzed hydroarylation conditions
(Scheme 2a).6 However, the desired β-phenylbutenolide 6 was
isolated in 61% yield, even though substrate 5a was completely
1
formation of 9a was confirmed as follows: In the H NMR
Scheme 2. One-Pot Hydroarylation/Cyclization of
Alkynoates 5a and 3a with Phenylboronic Acid
spectra of 9a, the singlet peaks corresponding to the methoxy
and TBS groups of 3a were not observed. Instead, the signals of
the newly introduced allyl group appeared at δ ppm 3.17 (d, J =
6.8 Hz, 2 H), 5.22 (dd, J = 16.8, 2.4, 1.2 Hz, 1 H), 5.24 (dd, J =
10.0, 1.2 Hz, 1 H), and 5.85 (ddt, J = 16.8, 10.0, 6.8 Hz, 1 H)
along with the vinylic proton at the α position to the lactone
carbonyl group at δ ppm 5.88 (t, J = 1.2 Hz, 1 H). The 13C
NMR spectra of 9a also showed two peaks for the sp3 carbons
at δ ppm 32.5 and 72.6 and five peaks for the sp2 carbons at δ
ppm 115.6, 118.8, 131.4, 168.4, and 173.6. The high-resolution
mass spectroscopy (HRMS) measurement also supported the
formation of 9a.
After achieving the selective one-pot hydroallylation/lactone
cyclization for simple γ-silyloxybutynoate 3a, the effect of the
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propargylic substituents of alkynoate substrates was examined.
The use of alkynoate 3b bearing n-pentyl and tert-
butyldimethylsilyloxy substituents at the propargylic position
was subjected to the same reaction conditions with 3a to afford
the corresponding β-allylbutenolide 9b in 90% yield (Scheme
3a). Although a γ-hydroxybutynoate substrate having a phenyl
group at the γ position (10c, Scheme 9) was directly obtained
from the addition of a silver acetylide of methyl propiolate to
benzaldehyde, the copper-catalyzed hydroallylation of this
unprotected substrate resulted in a lower conversion. More-
over, an increased catalyst loading (10 mol %) afforded the
desired butenolide 9c in a moderate yield. Therefore, TMS-
protected substrate 3c was subjected to the hydroallylation to
afford 9c in 76% yield (Scheme 3b). The use of a TBS
protecting group instead of the TMS group in this case resulted
in a lower conversion. In addition, similar substrates 3c-OMe
and 3c-F with an electron-donating methoxy group or an
electron-withdrawing fluorine substituent at the para positions
of the propargylic phenyl ring were subjected to the one-pot
reaction, affording the corresponding butenolide products 9c-
OMe and 9c-F in comparable yields. Therefore, these para
substituents on the propargylic phenyl rings have virtually no
effect on the efficiency of the present one-pot hydroallylation/
lactone cyclization.
Scheme 5. One-Pot Hydroallylation/Cyclization of
Alkynoates 3g and 10h with Allylboronate 8a
steric crowding, the effect of the protecting group was
examined. As expected, an alkynoate with a smaller protecting
group, i.e., MOM group, showed an improved reactivity.
Although the hydroallylation did not complete, the desired
product was detected, albeit in a low yield after acidic
deprotection. Thus, we attempted to use an unprotected
substrate. The hydroallylation of γ-hydroxybutynoate 10h with
allylboronate 8a was performed under the standard conditions.
Consequently, β-allylbutenolide 9h was obtained in 80% yield
without the deprotection procedure. The decreased catalyst
loading of 5 mol % afforded 9h in a still good yield (75%).
The protection-free procedure was further applied to the
synthesis of several spirocyclic β-allylbutenolides as shown in
Figure 1. Spirocyclic butenolide 9i containing a bulky
Next, alkynoate substrates bearing two propargylic sub-
stituents were investigated because the steric hindrance at the
propargylic position would cause negative effects on both the
hydroallylation and subsequent lactone cyclization. The
reaction of dimethyl-substituted alkynoate 3d with allylboro-
nate 8a in the presence of 5 mol % of Cu(OAc)2 for 3 h,
followed by the same deprotection procedure, afforded the
desired β-allylbutenolide 9d in 88% yield (Scheme 4). In the
Scheme 4. One-Pot Hydroallylation/Cyclization of
Alkynoayes 3d−f with Allylboronate 8a
same manner, vinyl-substituted pentynoate 3e was converted
into the corresponding β-allylbutenolide 9e in 87% yield. In
contrast, the hydroallylation of pentynoate 3f with a homoallyl
substituent was sluggish under the similar reaction conditions
using 10 mol % Cu(OAc)2, resulting in an incomplete reaction.
Consequently, 9f was obtained in 66% yield along with the
deprotected alkynoate (10f, 31%).
Interesting spirocyclic β-allylbutenolide 9g was also obtained
without difficulty in 89% yield when this one-pot procedure was
applied to fluorenone-derived alkynoate 3g (Scheme 5a).
However, the transformation of a similar alkynoate 3h bearing
two phenyl substituents in place of a fluorenyl group failed
(Scheme 5b). This is probably because of the higher
conformational flexibility of the two phenyl rings compared
with that of the rigid fluorenyl moiety. Therefore, to reduce the
Figure 1. Results of one-pot hydroallylation/cyclization of alkynoates
10f and 10i−k with allylboronate 8a.
dibenzocycloheptyl moiety was obtained in 76% yield from γ-
hydroxybutynoate 10i, which was derived from dibenzosuber-
one. Although the hydroallylation of less sterically demanding
cyclohexanone-derived γ-siloxybutynoate 3j failed, the corre-
sponding unprotected butynoate 10j successfully afforded
spirocyclic butenolide 9j in 79% yield. Similarly, tetrahydropyr-
an derivative 9k was obtained in a comparable yield when the
hydroallylation/cyclization was performed for 1 h. In contrast,
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N-Boc piperidine analogue 9l was obtained in 58%, albeit with
increased loadings of the catalyst (15 mol %) and allylboronate
8a (2.5 equiv). Moreover, butenolide 9f bearing both allyl and
homoallyl substituents was obtained in 90% yield (Figure 1)
when the corresponding protection-free pentynoate 10f was
used in place of 3f with the TMS protecting group (Scheme 4).
To examine the scope of the allylboronate, the reaction of
10j with methallylboronate 8b was performed as shown in
Scheme 6. In our previous study on the copper-catalyzed
fact, the reaction of 12m with 8a in the presence of 10 mol %
Cu(OAc)2 followed by the removal of the MOM group by
treatment with 6 M HCl at 25 °C for 1 h successfully afforded
the desired 9m in 66% yield. In this case, a small amount of
regioisomer 13m was also isolated. The formation of 13m can
probably be attributed to the directing effect of the MOM
group.
3. Synthesis of Nonracemic β-Allylbutenolides. As
shown in Scheme 3, the racemic γ-monosubstituted 4-silyloxy-
2-butynoate, 3b, underwent smooth hydroallylation to afford
the desired butenolide, 9b, in a good yield after the acidic
deprotection. We then revisited this reaction using optically
pure substrate (S)-3b, which was prepared from commercially
available (S)-oct-1-yn-3-ol. The γ chiral center of butenolides is
prone to undergo epimerization under basic conditions.17 In
our hand, the desired 9b was obtained in 85% yield with no
significant decrease in the optical purity when the reaction was
performed in the same manner as the racemic substrate
(Scheme 8). Thus, the acidic deprotection procedure was
compatible to the synthesis of nonracemic γ-alkyl-substituted
butenolides.
Scheme 6. One-Pot Hydroallylation/Cyclization of
Alkynoates 10j with Methallylboronate 8b
hydroallylation of electron-deficient alkynes, methallylboronate
8b was found to be less reactive than parent allylboronate 8a.8
Therefore, the reaction was conducted using an increased
loading of Cu(OAc)2 (10 mol %) and 8b (2.4 equiv). However,
the reaction was very sluggish, and ca. 30% conversion of 10j
Scheme 8. Synthesis of Nonracemic β-Allylbutenolide (S)-9b
1
was observed after 1 h, even though the H NMR analysis of
the crude reaction mixture showed that 8b was completely
consumed. The desired product, 11j, was obtained in 25%
yield, and 10j was recovered (71%).
We then turned to the synthesis of a trifluoromethyl-
substituted β-allylbutenolide because CF3-substituted com-
pounds have been extensively used as pharmaceuticals and
agrochemicals.16 To this aim, CF3-substituted γ-silyloxyalky-
noate 3m, which was prepared from commercially available
trifluoroacetophenone, was subjected to the one-pot hydro-
allylation/lactone cyclization (Scheme 7). However, a complex
Then, (R)-10c bearing a phenyl substituent at the
propargylic position was prepared with 68% enantiomeric
excess (ee) by the asymmetric addition of methyl propiolate to
benzaldehyde using a chiral ligand, i.e., ProPheno1 (S,S)-14,
according to the procedure reported by Trost and co-workers
(Scheme 9a).18 After the silylation of the hydroxyl group, the
obtained (R)-3c (68% ee) was subjected to one-pot hydro-
allylation/deprotection to afford (S)-9c in 74% yield (Scheme
9b). However, in contrast to the case of (S)-9b, the ee
decreased to 51%. This is clearly attributed to the phenyl
substituent that makes the γ proton more labile. Thus,
Scheme 7. One-Pot Hydroallylation/cyclization of Alkynoate
12m with Allylboronate 8a
Scheme 9. Synthesis of Nonracemic β-Allylbutenolide (S)-9c
mixture containing a small amount of desired 9m was obtained
along with deprotected substrate 10m. We suspected that the
bulkiness of the CF3 group caused a detrimental effect on the
allylation. Therefore, deprotected alkynoate 10m was then
subjected to the hydroallylation conditions; however, the yield
of 9m only moderately improved. Although the reason for the
unsuccessful reaction of 10m was not clear, probably the
protonation of allylcopper species with the hydroxyl group was
enhanced by the inductive effect of the CF3 substituent. Finally,
MOM-protected substrate 12m was prepared, with the
expectation that the small MOM group would make this
substrate amenable to the copper-catalyzed hydroallylation. In
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butenolide (S)-9c probably underwent epimerization under
acidic deprotection conditions. In contrast, deprotection using
1.1 equiv of TBAF or CsF was sluggish, and the increased
loading of CsF (3 equiv) resulted in the formation of complex
mixture. Therefore, we attempted the hydroallylation of
protection-free (R)-10c, which directly produces (S)-9c
without the acidic deprotection (Scheme 9c). Consequently,
the reaction of (R)-10c with allylboronate 8a in the presence of
5 mol % Cu(OAc)2 afforded (S)-9c in 43% yield with the
improved ee of 64%, even though the reaction did not complete
(76% conversion). Furthermore, the catalyst loading was
increased to 10 mol % to reach complete conversion of (R)-
10c. However, the ee of obtained (S)-9c was lowered to 57%.
This is presumably attributed to copper salts acting as Lewis
acids.
Scheme 10. Derivatization of β-Allylbutenolides 9d−f Using
Alkene Metathesis
4. Derivatization of β-Allylbutenolides. As discussed
above, we successfully developed a synthetic method for
butenolides with a skipped diene moiety via the regio- and
stereoselective hydroallylation and subsequent lactone cycliza-
tion. The introduced allyl group is very useful because it can be
used as a synthetic handle for further derivatization of the
products. In our previous study, similar skipped dienes, which
were obtained by the hydroallylation of activated alkynes, were
subjected to several functionalization reactions such as
hydroboration/oxidation, hydroboration/Suzuki−Miyaura
cross-coupling, and ring-closing diene metathesis.8 Although
these reactions were effective for the selective functionalization
of the terminal alkene moiety of the introduced allyl group, the
CM of the skipped diene product with methyl acrylate was
problematic, resulting in the isomerizations of the skipped
diene moiety. In the β-allylbutenolides prepared in this study,
the skipped diene moiety was combined with the 2(5H)-
furanone framework; thus, this situation demands further
investigation of the selective functionalization of the β-
allylbutenolide products.
We also attempted the CM of butenolide 9d with ethyl
acrylate 20 (Scheme 10c).23 In our previous study, extensive
isomerization of activated alkene moiety was observed in the
CM of a skipped diene product bearing a sulfonyl group with
methyl acrylate. Therefore, BQ was used in this study to
suppress the alkene isomerization. In the presence of 5 mol %
15 and 10 mol % BQ, 9d and 5 equiv of 20 were refluxed in
dichloromethane for 2 h. The analysis of the crude material by
1H NMR showed that the expected CM product 21 was
obtained selectively. However, the purification by silica gel
column chromatography afforded alkene isomerization product
22 along with a trace of 21 in 69% yield.
With the above considerations in mind, we first investigated
the RCM of butenolide 9e as shown in Scheme 10a.19
However, the treatment of 9e with the Hoveyda−Grubbs
catalyst, 15,20 in refluxing dichloromethane resulted in an
undesirable isomerization of the allyl substituent to an internal
alkene.21 Therefore, we repeated the same reaction by adding
10 mol % 1,4-benzoquinone (BQ) to suppress the alkene
isomerization according to the report by Grubbs and co-
workers.22 Consequently, the alkene isomerization was
effectively suppressed, affording new product 16 along with
1
intact 9e (17%). The H NMR analysis of 16 showed that the
vinyl moiety, α to the lactone oxygen, is intact. A new peak for
an internal alkene appeared at δ ppm 5.65 instead of the
absorption of the terminal alkene moiety of the allyl
substituent. The 13C NMR spectrum of 16 showed nine
peaks (one peak less than those presents in parent 9e). These
facts indicate that 16 is a homometathesis product rather than
the expected RCM product 17. This was also corroborated by
the HRMS measurement.
The failure of the RCM of 9e can be attributed to the
inaccessibility of the ruthenium alkylidene moiety to the
hindered alkene moiety adjacent to the fully substituted carbon,
thus preventing the RCM of 18. This was also confirmed by the
fact that the RCM of butenolide 9f with the homoallyl
substituent was much more amenable (Scheme 10b). When 9f
was subjected to the same reaction conditions, the reaction
completed within 15 min to afford the expected cycloheptene-
fused product, 19, in 80% yield.
CONCLUSION
■
In conclusion, we developed the one-pot copper-catalyzed
hydroallylation/lactone cyclization of γ-hydroxyalkynoate de-
rivatives to afford β-allylbutenolides in good yields. The
efficiency of the hydroallylation step was found to be
dependent on the environment around the (protected) alcohol
moiety at the γ position. For instance, sterically demanding
tertiary alcohol substrates were used without protection, even
though silyl protecting groups were effective for most
substrates. As an exception, a trifluoromethyl-substituted
derivative required a MOM protecting group to complete the
reaction. As a synthetic application of the β-allylbutenolide
products, we also demonstrated the feasibility of the RCM and
CM reactions involving the introduced allyl moiety by using the
Hoveyda−Grubbs catalyst. In these reactions, a BQ additive
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114.6, 137.9, 153.8; IR (neat) 2234 (CC), 1721 (CO) cm−1;
HRMS (DART) m/z calcd for C13H22O3Si·NH4 272.1682, found
272.1668 [M + NH4]+.
was necessary to inhibit the undesired isomerization of the allyl
moiety.
Methyl 3-(9-(Trimethylsilyloxy)-9H-fluoren-9-yl)propiolate
(3g). Colorless solids, mp 115.0−116.0 °C (685 mg, 47%); 1H
NMR (400 MHz, CDCl3, 25 °C) δ −0.13 (s, 9 H), 3.72 (s, 3 H), 7.34
(t, J = 7.2 Hz, 2 H), 7.41 (t, J = 7.6 Hz, 2 H), 7.62 (d, J = 7.2 Hz, 2 H),
7.66 (d, J = 7.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 1.5,
52.6, 73.1, 76.0, 88.8, 120.2, 125.2, 128.4, 129.9, 139.2, 145.9, 153.7; IR
(neat) 2224 (CC), 1711 (CO) cm−1; HRMS (ESI) m/z calcd for
C20H20O3Si·Na 359.1079, found 359.1092 [M + Na]+.
Methyl 4-Hydroxy-4-methyloct-7-en-2-ynoate (10f). Color-
less oil (292 mg, 59%, 2 steps); 1H NMR (400 MHz, CDCl3, 25 °C) δ
1.55 (s, 3 H), 1.79−1.85 (m, 2 H), 2.21−2.39 (m, 2 H), 3.79 (s, 3 H),
5.01 (ddd, J = 10.0, 2.8, 1.6 Hz, 1 H), 5.10 (ddd, J = 16.8, 3.2, 1.2 Hz,
1 H), 5.86 (ddt, J = 16.8, 10.0, 6.4 Hz, 1 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 28.8, 29.0, 41.7, 52.7, 67.8, 75.0, 90.5, 115.2, 137.6,
153.9; IR (neat) 3415 (OH), 2235 (CC), 1719 (CO) cm−1;
HRMS (DART) m/z calcd for C10H14O3·NH4 200.1287, found
200.1276 [M + NH4]+.
EXPERIMENTAL SECTION
■
General Considerations. Column chromatography was per-
formed on silica gel (Cica silica gel 60N) with solvents specified
1
below. H, 13C, and 19F NMR spectra were obtained for samples in
1
CDCl3 solutions at 25 °C. H NMR chemical shifts are reported in
terms of chemical shift (δ, ppm) relative to the singlet at 7.26 ppm for
chloroform. Splitting patterns are designated as follows: s, singlet; d,
doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; sept, septet;
m, multiplet. Coupling constants are reported in hertz. 13C NMR
spectra were fully decoupled and are reported in terms of chemical
shift (δ, ppm) relative to the triplet at 77.0 ppm for CDCl3. 19F NMR
spectra were fully decoupled and are reported in terms of chemical
shift (δ, ppm) relative to the singlet at −63.7 ppm for CF3Ph as an
external standard. High-resolution mass spectra were acquired on a
TOF mass spectrometer using ESI or DART methods. Cu(OAc)2,
allylboronate 8a, and dry solvents were purchased and used directly as
received.
Methyl 4-Hydroxy-4,4-diphenylbut-2-ynoate (10h). Colorless
solids, mp 103.2−105.0 °C, lit.3 mp 90−92 °C (86 mg, 67%, 2 steps);
1H NMR (400 MHz, CDCl3, 25 °C) δ 2.93 (s, 1 H), 3.81 (s, 3 H),
Synthesis of γ-Hydroxybutynoate Derivatives. General
Procedure A. Synthesis of Methyl 4-(tert-Butyldimethylsilyl-
oxy)non-2-ynoate (3b). To a solution of 3-(tert-butyldimethylsilyl-
oxy)oct-1-yne (481 mg, 2.0 mmol) in dry THF (10 mL) was added
dropwise n-BuLi (1.6 M hexane solution, 1.9 mL, 3.0 mmol) at −78
°C, and the solution was stirred at 0 °C for 30 min. To the resultant
solution was then added methyl chloroformate (386 μL, 5.0 mmol) at
−78 °C, and the solution was stirred at 0 °C for 1 h. The reaction was
quenched with sat. NH4Cl (10 mL). The aqueous layer was extracted
with AcOEt (10 mL × 2). The combined organic layer was washed
with brine (10 mL × 2) and dried over MgSO4. The organic layer was
concentrated in vacuo. The obtained crude product was purified with
column chromatography on silica gel (elution with hexane/AcOEt =
300:1) to give 3b (535 mg, 90% yield) as colorless oil: 1H NMR (400
MHz, CDCl3, 25 °C) δ 0.11 (s, 3 H), 0.14 (s, 3 H), 0.89 (t, J = 6.8 Hz,
3 H), 0.90 (s, 9 H), 1.27−1.34 (m, 4 H), 1.35−1.46 (m, 2 H), 1.67−
1.72 (m, 2 H), 3.00 (s, 3 H), 4.44 (t, J = 6.8 Hz, 1 H); 13C NMR (100
MHz, CDCl3, 25 °C) δ −5.2, −4.6, 13.9, 18.1, 22.5, 24.6, 25.7, 31.3,
37.7, 52.6, 62.6, 89.2, 154.0; IR (neat) 2236 (CC), 1721 (CO)
cm−1; HRMS (ESI) m/z calcd for C16H30O3Si·Na 321.1862, found
321.1876 [M + Na]+.
7.28−7.37 (m, 6 H), 7.55−7.58 (m, 4 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 52.9, 74.3, 78.2, 88.8, 126.0, 128.3, 128.5, 143.0,
153.8.
Methyl 10,11-Dihydro-5-hydroxy-5H-dibenzo[a,d]cyclo-
heptene-5-propiolate (10i). Brown solids, mp 79.7−81.0 °C (31
1
mg, 59%, 2 steps); H NMR (400 MHz, CDCl3, 25 °C) δ 3.13 (s, 1
H), 3.24−3.34 (m, 2 H), 3.52−3.62 (m, 2 H), 3.79 (s, 3 H), 7.14−7.24
(m, 6 H), 7.90−7.93 (m, 2 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ
32.3, 52.9, 72.6, 78.5, 88.8, 124.9, 126.2, 128.7, 131.0, 138.3, 139.5,
153.8; IR (neat) 3463 (OH), 2231 (CC), 1714 (CO) cm−1;
HRMS (ESI) m/z calcd for C19H16O3·Na 315.0997, found 315.0991
[M + Na]+.
Methyl 3-(1-Hydroxycyclohexyl)propiolate (10j). Colorless
solids, mp 56.5−58.2 °C, lit.3 mp 55−57 °C (254 mg, 56%, 2
1
steps); H NMR (400 MHz, CDCl3, 25 °C) δ 1.25−1.34 (m, 1 H),
1.50−1.74 (m, 8 H), 1.94−2.00 (m, 2 H), 3.78 (s, 3 H); 13C NMR
(100 MHz, CDCl3, 25 °C) δ 22.8, 24.8, 39.0, 52.8, 68.5, 75.7, 90.7,
154.0.
Methyl 3-(4-Hydroxytetrahydro-2H-pyran-4-yl)propiolate
Other alkynoates were also prepared in a similar manner, and
desilylation was performed by the treatment with TBAF or CsF (1.1
equiv) in THF at 0 °C. Alkynoates 3a,24a 10c,14 10h,24b and 10j5b
were known compounds.
Methyl 4-(tert-Butyldimethylsilyloxy)but-2-ynoate (3a). Col-
orless oil (388 mg, 57% yield); 1H NMR (400 MHz, CDCl3, 25 °C) δ
0.13 (s, 6 H), 0.91 (s, 9 H), 3.78 (s, 3 H), 4.43 (s, 2 H); 13C NMR
(100 MHz, CDCl3, 25 °C) δ −5.3, 18.2, 25.6, 51.3, 52.6, 76.3, 86.1,
153.7.
1
(10k). Colorless oil (515 mg, 75%, 2 steps); H NMR (400 MHz,
CDCl3, 25 °C) δ 1.85 (ddd, J = 12.0, 8.8, 3.6 Hz, 2 H), 1.97−2.05 (m,
2 H), 3.80 (s, 3 H), 3.66 (ddd, J = 12.8, 8.8, 3.6 Hz, 2 H), 3.90 (ddd, J
= 11.6, 5.6, 4.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 38.7,
52.8, 64.0, 65.1, 75.8, 89.4, 153.7; IR (neat) 3368 (OH), 2233 (C
C), 1716 (CO) cm−1; HRMS (DART) m/z calcd for C9H12O4·NH4
202.1079, found 202.1076 [M + NH4]+.
tert-Butyl 4-Hydroxy-4-(3-methoxy-3-oxoprop-1-ynyl)-
1
piperidine-1-carboxylate (10l). Colorless oil (540 mg, 93%); H
Methyl 4-Methyl-4-(trimethylsilyloxy)pent-2-ynoate (3d).
1
NMR (400 MHz, CDCl3, 25 °C) δ 1.46 (s, 9 H), 1.76 (ddd, J = 12.8,
8.8, 4.0 Hz, 2 H), 1.91−1.99 (m, 2 H), 3.34 (ddd, J = 13.2, 8.8, 4.0 Hz,
2 H), 3.67−3.76 (m, 2 H), 3.79 (s, 3 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 28.3, 37.9, 40.0 (broad), 52.8, 66.2, 75.9, 80.0, 89.3,
153.7, 154.6; IR (neat) 3384 (OH), 2234 (CC), 1719 (CO),
1697 (CO) cm−1; HRMS (ESI) m/z calcd for C14H21NO5·Na
306.1317, found 306.1327 [M + Na]+.
Colorless oil (133 mg, 59%); H NMR (400 MHz, CDCl3, 25 °C)
δ 0.21 (s, 9 H), 1.53 (s, 6 H), 3.78 (s, 3 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 1.7, 32.1, 52.6, 66.2, 74.7, 92.0, 154.0; IR (neat) 2234
(CC), 1720 (CO) cm−1; HRMS (DART) m/z calcd for
C10H18O3Si·NH4 232.1369, found 232.1386 [M + NH4]+.
Methyl 4-Methyl-4-(trimethylsilyloxy)hex-5-en-2-ynoate
1
(3e). Colorless oil (591 mg, 85%); H NMR (400 MHz, CDCl3, 25
°C) δ 0.20 (s, 9 H), 1.57 (s, 3 H), 3.79 (s, 3 H), 5.13 (d, J = 10.0 Hz, 1
H), 5.45 (d, J = 16.8 Hz, 1 H), 5.89 (dd, J = 16.8, 10.0 Hz, 1 H); 13C
NMR (100 MHz, CDCl3, 25 °C) δ 1.7, 31.5, 52.7, 69.4, 89.2, 113.9,
141.3, 153.8; IR (neat) 2237 (CC), 1722 (CO) cm−1; HRMS
(DART) m/z calcd for C11H18O3Si·NH4 244.1369, found 244.1355
[M + NH4]+.
Methyl 4-Methyl-4-(trimethylsilyloxy)oct-7-en-2-ynoate (3f).
Colorless oil (1.2 g, 74%); 1H NMR (400 MHz, CDCl3, 25 °C) δ 0.21
(s, 9 H), 1.51 (s, 3 H), 1.69−1.83 (m, 2 H), 2.14−2.32 (m, 2 H), 3.78
(s, 3 H), 4.96 (ddd, J = 10.0, 2.8, 1.6 Hz, 1 H), 5.04 (ddd, J = 16.8, 3.2,
1.2 Hz, 1 H), 5.83 (ddt, J = 16.8, 10.0, 6.4 Hz, 1 H); 13C NMR (100
MHz, CDCl3, 25 °C) δ 1.6, 28.7, 30.3, 43.5, 52.6, 68.9, 76.1, 91.0,
Methyl 5,5,5-Trifluoro-4-(methoxymethoxy)-4-phenylpent-
2-ynoate (12m). Pale-yellow oil (195 mg, 65%); 1H NMR (400
MHz, CDCl3, 25 °C) δ 3.45 (s, 3 H), 3.86 (s, 3 H), 4.92 (d, J = 6.4
Hz, 1 H), 4.98 (d, J = 6.4 Hz, 1 H), 7.43−7.45 (m, 3 H), 7.69−7.72
(m, 2 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 53.1, 56.7, 77.8 (q, J
= 32.0 Hz), 78.7, 81.2, 94.2, 122.4 (q, J = 284.1 Hz), 127.8, 128.5,
130.1, 132.5, 152.6; 19F NMR (370 MHz, CDCl3, 25 °C) δ −72.9; IR
(neat) 2248 (CC), 1724 (CO) cm−1; HRMS (DART) m/z calcd
for C14H13F3O4·H 303.0844, found 303.0842 [M + H]+.
Synthesis of Methyl 4-Phenyl-4-(trimethylsilyloxy)but-2-
ynoate (3c). To a solution of methyl 4-hydroxy-4-phenylbut-2-ynoate
(10c, 288 mg, 1.51 mmol) and imidazole (370 mg, 5.44 mmol) in dry
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THF (5 mL) was added Me3SiCl (3.84 μL, 3.62 mmol) at room
temperature, and the solution was stirred for 2 h. After filtration
through a pad of Celite, the filtrate was concentrated in vacuo. The
obtained crude product was purified with column chromatography on
silica gel (elution with hexane/AcOEt = 100:1−50:1) to give 3c (328
mg, 83% yield) as pale-yellow oil: 1H NMR (400 MHz, CDCl3, 25 °C)
δ 0.20 (s, 9 H), 3.77 (s, 3 H), 5.56 (s, 1 H), 7.32−7.40 (m, 3 H),
7.45−7.48 (m, 2 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 0.05,
52.7, 64.3, 87.4, 126.4, 128.4, 128.6, 139.4, 153.7; IR (neat) 2237 (C
C), 1719 (CO) cm−1; HRMS (ESI) m/z calcd for C14H18O3Si·NH4
280.1369, found 280.1384 [M + NH4]+.
MHz, CDCl3, 25 °C) δ 32.4, 55.2, 85.3, 114.3, 115.8, 119.0, 125.8,
128.3, 131.5, 160.4, 170.8, 173.0; IR (neat) 1757 (CO) cm−1;
HRMS (DART) m/z calcd for C14H14O3·NH4 248.1287, found
248.1288 [M + NH4]+.
4-Allyl-5-(4-fluorophenyl)furan-2(5H)-one (9c-F). Pale-red oil
1
(40 mg, 73%); H NMR (400 MHz, CDCl3, 25 °C) δ 2.85 (dd J =
17.2, 7.2 Hz, 1 H), 2.91 (ddd, J = 17.2, 6.4, 1.2 Hz, 1 H), 5.10 (dd, J =
17.2, 1.2 Hz, 1 H), 5.19 (dd, J = 10.0, 1.2 Hz, 1 H), 5.76 (ddt, J = 17.2,
10.0, 7.0 Hz, 1 H), 5,76 (s, 1 H), 5.96 (q, J = 1.6 Hz, 1 H), 7.10 (t, J =
8.4 Hz, 2 H), 7.21 (dd, J = 8.4, 5.0 Hz, 2 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 32.5, 84.7, 116.1, 116.2 (d, J = 21.9 Hz), 119.3, 128.8
(d, J = 8.6 Hz), 130.0 (d, J = 2.9 Hz), 131.3, 163.3 (d, J = 247.9 Hz),
170.5, 172.7; 19F NMR (370 MHz, CDCl3, 25 °C) δ −111.3; IR
(neat) 1758 (CO) cm−1; HRMS (DART) m/z calcd for
C13H11FO2·NH4 236.1087, found 236.1068 [M + NH4]+.
4-Allyl-5,5-dimethylfuran-2(5H)-one (9d). Colorless oil (67 mg,
88%); 1H NMR (400 MHz, CDCl3, 25 °C) δ 1.46 (s, 6 H), 3.01 (ddd,
J = 6.8, 2.6, 1.4 Hz, 2 H), 5.23 (ddd, J = 17.0, 2.6, 1.6 Hz, 1 H), 5.25
(ddd, J = 10.2, 2.6, 1.0 Hz, 1 H), 5.71 (t, J = 1.4 Hz, 1 H), 5.86 (ddt, J
= 17.0, 10.2, 6.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ
24.8, 31.4, 87.1, 115.0, 119.0, 131.7, 171.8, 175.4; IR (neat) 1751 (C
O) cm−1; HRMS (DART) m/z calcd for C9H12O2·H 153.0916, found
153.0926 [M + H]+.
Methyl 4-(4-Methoxyphenyl)-4-(trimethylsilyloxy)but-2-
1
ynoate (3c-OMe). Pale-yellow oil (105.7 mg, 66%); H NMR (400
MHz, CDCl3, 25 °C) δ 0.18 (s, 9 H), 3.77 (s, 3 H), 3.81 (s, 3 H), 5.50
(s, 1 H), 6.89 (d, J = 8.4 Hz, 2 H), 7.38 (d, J = 8.4 Hz, 2 H); 13C NMR
(100 MHz, CDCl3, 25 °C) δ 0.07, 52.7, 55.3, 64.0, 76.8, 87.6, 113.9,
127.8, 131.6, 153.8, 159.7; IR (neat) 2236 (CC), 1718 (CO)
cm−1; HRMS (ESI) m/z calcd for C15H20O4Si·Na 315.1029, found
315.1036 [M + Na]+.
Methyl 4-(4-Fluorophenyl)-4-(trimethylsilyloxy)but-2-
ynoate (3c-F). Pale-yellow oil (90.4 mg, 79%); 1H NMR (400
MHz, CDCl3, 25 °C) δ 0.20 (s, 9 H), 3.78 (s, 3 H), 5.53 (s, 1 H), 7.05
(t, J = 8.4 Hz, 2 H), 7.43 (dd, J = 8.4, 5.4 Hz, 2 H); 13C NMR (100
MHz, CDCl3, 25 °C) δ 0.00, 52.7, 63.7, 77.1, 87.0, 115.5 (d, J = 21.9
Hz), 128.1 (d, J = 8.6 Hz), 135.3 (d, J = 3.8 Hz), 153.6, 162.6 (d, J =
245.0 Hz); 19F NMR (370 MHz, CDCl3, 25 °C) δ −113.5; IR (neat)
2238 (CC), 1719 (CO) cm−1; HRMS (DART) m/z calcd for
C14H17FO3Si·NH4 298.1275, found 298.1281 [M + NH4]+.
Synthesis of β-Allylbutenolides. General Procedure A.
Cyclization of γ-Siloxybutynoate 3a. A solution of butynoate 3a
(114 mg, 0.50 mmol), allylboronate 8a (141 μL, 0.75 mmol), and
Cu(OAc)2 (2.72 mg, 0.015 mmol) in dry degassed MeOH (1.0 mL)
was stirred under an argon atmosphere at 25 °C for 3 h. The reaction
progress was traced by TLC analysis. After addition of TsOH·H2O
(47.6 mg, 0.25 mmol), the reaction mixture was further stirred for 12 h
at 25 °C. The resultant mixture was diluted with diethyl ether (10 mL)
and filtered through a pad of neutral alumina. The filtrate was
concentrated in vacuo, and the crude material was purified with silica
gel column chromatography (hexane/toluene = 5:1) to give β-
allylbutenolide 9a (49.5 mg, 80% yield) as colorless oil: 1H NMR (400
MHz, CDCl3, 25 °C) δ 3.17 (d, J = 6.8 Hz, 2 H), 4.75 (s, 2 H), 5.22
(ddd, J = 16.8, 2.4, 1.2 Hz, 1 H), 5.24 (dd, J = 10.0, 1.2 Hz, 1 H), 5.85
(ddt, J = 16.8, 10.0, 6.8 Hz, 1 H), 5.88 (t, J = 1.2 Hz, 1 H); 13C NMR
(100 MHz, CDCl3, 25 °C) δ 32.5, 72.6, 115.6, 118.8, 131.4, 168.4,
173.6; IR (neat) 1748 (CO) cm−1; HRMS (DART) m/z calcd for
C7H8O2·NH4 142.0868, found 142.0874 [M + NH4]+.
4-Allyl-5-pentylfuran-2(5H)-one (9b). Colorless oil (87 mg,
90%); 1H NMR (400 MHz, CDCl3, 25 °C) δ 0.89 (t, J = 6.8 Hz, 3 H),
1.24−1.59 (m, 8 H), 1.85−1.94 (m, 1 H), 3.00 (dd, J = 17.2, 6.4 Hz, 1
H), 3.13 (ddd, J = 17.2, 6.4, 1.6 Hz, 1 H), 4.87−4.91 (m, 1 H), 5.18−
5.25 (m, 2 H), 5.81 (d, J = 1.2 Hz, 1 H), 5.83 (ddt, J = 17.2, 10.4, 6.4
Hz, 1 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 13.9, 22.4, 24.0,
31.4, 32.0, 32.5, 83.7, 116.5, 119.1, 131.6, 170.9, 173.0; IR (neat) 1756
(CO) cm−1; HRMS (ESI) m/z calcd for C12H18O2·NH4 212.1651,
found 212.1651 [M + NH4]+.
4-Allyl-5-methyl-5-vinylfuran-2(5H)-one (9e). Colorless oil (72
1
mg, 87%); H NMR (400 MHz, CDCl3, 25 °C) δ 1.56 (s, 3 H), 2.98
(d, J = 6.8 Hz, 2 H), 5.21 (ddd, J = 17.0, 3.0, 1.4 Hz, 1 H), 5.23 (ddd, J
= 10.0, 2.4, 1.0 Hz, 1 H), 5.29 (d, J = 10.8 Hz, 1 H), 5.41 (d, J = 17.2
Hz, 1 H), 5.75 (t, J = 1.6 Hz, 1 H), 5.77 (dd, J = 17.2, 10.8 Hz, 1 H),
5.83 (ddt, J = 17.0, 10.0, 6.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3,
25 °C) δ 22.0, 31.3, 88.5, 115.2, 117.1, 119.1, 131.6, 136.3, 171.9,
173.9; IR (neat) 1747 (CO) cm−1; HRMS (DART) m/z calcd for
C10H12O2·NH4 182.1181, found 182.1197 [M + NH4]+.
3′-Allyl-5′H-spiro[fluorene-9,2′-furan]-5′-one (9g). Orange
solids, mp 77.0−77.5 °C (122 mg, 89%); 1H NMR (400 MHz,
CDCl3, 25 °C) δ 2.46 (ddd, J = 6.8, 2.8, 1.6 Hz, 2 H), 4.91 (ddd, J =
17.0, 2.8, 1.2 Hz, 1 H), 5.03 (dq, J = 10.0, 1.2 Hz, 1 H), 5.60 (ddt, J =
17.0, 10.0, 6.8 Hz, 1 H), 6.14 (dd, J = 2.0, 1.2 Hz, 1 H), 7.22 (dd, J =
7.6, 1.2 Hz, 2 H), 7.31 (dt, J = 7.6, 1.2 Hz, 2 H), 7.45 (dt, J = 7.6, 1.2
Hz, 2 H), 7.69 (dd, J = 7.6, 1.2 Hz, 2 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 30.9, 94.3, 116.3, 118.7, 120.6, 123.7, 128.4, 130.5,
131.3, 140.1, 141.0, 171.7, 172.9; IR (neat) 1765 (CO) cm−1;
HRMS (ESI) m/z calcd for C19H14O2·Na 297.0891, found 297.0905
[M + Na]+.
General Procedure B. Cyclization of γ-Hydroxybutynoate
10h. A solution of butynoate 10h (66.5 mg, 0.25 mmol), allylboronate
8a (70 μL, 0.38 mmol), and Cu(OAc)2 (2.28 mg, 0.0125 mmol) in dry
degassed MeOH (0.5 mL) was stirred under an argon atmosphere at
25 °C for 3 h. The reaction progress was traced by TLC analysis. The
resultant mixture was diluted with diethyl ether (10 mL) and filtered
through a pad of neutral alumina. The filtrate was concentrated in
vacuo, and the crude material was purified with silica gel column
chromatography (hexane/toluene = 5:1) to give β-allylbutenolide 9h
(51.8 mg, 75% yield) as colorless solids (mp 65.0−66.7 °C): 1H NMR
(400 MHz, CDCl3, 25 °C) δ 3.04 (ddd, J = 7.0, 2.8, 1.2 Hz, 2 H), 5.13
(ddd, J = 16.8, 2.8, 1.2 Hz, 1 H), 5.19 (dd, J = 10.4, 7.0 Hz, 1 H), 5.79
(ddt, J = 16.8, 10.4, 1.2 Hz, 1 H), 5.98 (t, J = 1.6 Hz, 1 H), 7.24−7.29
(m, 4 H), 7.35−7.40 (m, 6 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ
33.0, 93.8, 116.7, 119.1, 127.5, 128.5, 128.8, 131.5, 138.3, 171.8, 173.6;
IR (neat) 1763 (CO) cm−1; HRMS (DART) m/z calcd for
C19H16O2·H 277.1229, found 277.1225 [M + H]+.
4-Allyl-5-phenylfuran-2(5H)-one (9c). Pale-yellow oil (26 mg,
1
76%); H NMR (400 MHz, CDCl3, 25 °C) δ 2.86 (dd J = 17.6, 6.4
Hz, 1 H), 2.92 (ddd, J = 17.6, 6.4, 1.6 Hz, 1 H), 5.10 (dd, J = 17.2, 1.2
Hz, 1 H), 5.18 (dd, J = 10.0, 1.2 Hz, 1 H), 5.77 (ddt, J = 17.2, 10.0, 6.8
Hz, 1 H), 5.77 (s, 1 H), 5.95 (q, J = 1.6 Hz, 1 H), 7.21−7.24 (m, 2 H),
7.37−7.42 (m, 3 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 32.4,
85.5, 115.8, 119.1, 126.8, 129.0, 129.5, 131.5, 134.1, 170.8, 173.0; IR
(neat) 1758 (CO) cm−1; HRMS (DART) m/z calcd for C13H12O2·
NH4 218.1181, found 218.1197 [M + NH4]+.
4-Allyl-5-(but-3-enyl)-5-methylfuran-2(5H)-one (9f). Colorless
1
oil (257 mg, 90%); H NMR (400 MHz, CDCl3, 25 °C) δ 1.46 (s, 3
H), 1.71 (ddd, J = 13.2, 11.2, 4.4 Hz, 1 H), 1.80−1.91 (m, 1 H), 1.97
(ddd, J = 13.2, 11.2, 4.4 Hz, 1 H), 2.00−2.11 (m, 1 H), 2.94 (ddq, J =
18.0, 6.8, 1.2 Hz, 1 H), 3.00 (ddq, J = 18.0, 6.8, 1.2 Hz, 1 H), 4.97 (dq,
J = 10.0, 1.6 Hz, 1 H), 5.01 (dq, J = 17.2, 1.6 Hz, 1 H), 5.23 (dq, J =
17.2, 1.6 Hz, 1 H), 5.25 (dq, J = 10.0, 1.6 Hz, 1 H), 5.75 (ddt, J = 17.2,
10.0, 6.8 Hz, 1 H), 5.76 (t, J = 2.0 Hz, 1 H), 5.86 (ddt, J = 17.2, 10.0,
6.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 23.7, 27.0, 31.3,
35.8, 88.6, 115.0, 115.8, 118.9, 131.3, 136.7, 171.5, 174.0; IR (neat)
4-Allyl-5-(4-methoxyphenyl)furan-2(5H)-one (9c-OMe). Col-
1
orless oil (62 mg, 75%); H NMR (400 MHz, CDCl3, 25 °C) δ 2.85
(dd J = 17.2, 7.2 Hz, 1 H), 2.92 (dd, J = 17.2, 6.4 Hz, 1 H), 3.82 (s, 3
H), 5.10 (d, J = 16.4 Hz, 1 H), 5.18 (d, J = 10.0 Hz, 1 H), 5.73 (s, 1
H), 5.77 (ddt, J = 17.2, 10.0, 6.8 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H),
6.92 (d, J = 8.6 Hz, 2 H), 7.14 (d, J = 8.6 Hz, 2 H); 13C NMR (100
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1756 (CO) cm−1; HRMS (DART) m/z calcd for C12H16O2·NH4
130.0, 131.5, 131.7, 136.3, 143.3, 170.3; 19F NMR (370 MHz, CDCl3,
25 °C) δ −77.0; IR (neat) 1789 (CO) cm−1; HRMS (DART) m/z
calcd for C14H11F3O2·NH4 286.1055, found 286.1064 [M + NH4]+.
Derivatization of β-Allylbutenolides Using Alkene Meta-
thesis. Ring-Closing Metathesis of Butenolide 9f. A degassed
solution of butenolide 9g (96.1 mg, 0.50 mmol), Hoveyda−Grubbs
catalyst 15 (15.7 mg, 0.025 mmol), and 1,4-benzoquinone (5.4 mg,
0.050 mmol) in dry CH2Cl2 (25 mL) was stirred at 40 °C under an
argon atmosphere for 15 min. The reaction mixture was concentrated
in vacuo, and the residue was purified with chromatography on silica
gel (hexane/AcOEt = 10:1−5:1) to afford RCM product 19 (65.7 mg,
80% yield) as colorless oil: 1H NMR (400 MHz, CDCl3, 25 °C) δ 1.54
(s, 3 H), 1.74−1.81 (m, 1 H), 2.00−2.25 (m, 3 H), 3.03 (dsext, J =
16.4, 2.0 Hz, 1 H), 3.29 (dd, J = 16.4, 7.2 Hz, 1 H), 5.62−5.68 (m, 1
H), 5.68 (d, J = 1.6 Hz, 1 H), 5.82 (ddt, J = 11.4, 6.0, 2.8 Hz, 1 H); 13C
NMR (100 MHz, CDCl3, 25 °C) δ 22.4, 22.9, 28.0, 36.6, 89.9, 114.9,
124.4, 131.7, 172.3, 172.7; IR (neat) 1755 (CO) cm−1; HRMS
(ESI) m/z calcd for C10H12O2·NH4 182.1181, found 182.1167 [M +
NH4]+.
The reaction of butenolide 9e (49.3 mg, 0.30 mmol) was also
carried out using 15 (9.4 mg, 0.015 mmol) and 1,4-benzoquinone (3.2
mg, 0.030 mmol) in dry CH2Cl2 (15 mL) at 40 °C for 12 h.
Purification with chromatography on silica gel (hexane/AcOEt = 5:1−
3:1) afforded homo metathesis product 16 (19.6 mg, 44% yield) as
brown solids (mp 63.5 °C decomp) along with unreacted 9e (8.4 mg,
17%).
4,4′-(But-2-ene-1,4-diyl)bis(5-methyl-5-vinylfuran-2(5H)-
one) (16). 1H NMR (400 MHz, CDCl3, 25 °C) δ 1.55 (s, 6 H), 2.98−
3.01 (m, 24/7 H) [2.91−2.94 (m, 4/7 H) for the minor isomer], 5.29
(d, J = 10.0 Hz, 12/7 H) [5.30 (d, J = 10.0 Hz, 2/7 H) for the minor
isomer], 5.40 (d, J = 17.2 Hz, 2 H), 5.65 (ddd, J = 5.4, 3.6, 1.8 Hz, 12/
7 H) [the corresponding peak for the minor isomer obscurely
appeared at δ 5.77], 5.69 (t, J = 1.2 Hz, 1 H), 5.75 (dd, J = 17.2, 10.0
Hz, 1 H); 13C NMR (100 MHz, CDCl3, 25 °C): For major isomer: δ
21.9, 30.0, 88.3, 115.2, 117.2, 128.0, 136.1, 171.6, 173.6; IR (neat)
1749 (CO) cm−1; HRMS (ESI) m/z calcd for C18H20O4·Na
323.1259, found 323.1274 [M + Na]+.
210.1494, found 210.1504 [M + NH4]+.
3′-Allyl-5′H-spiro[10,11-dihydro-5H-dibenzo[a,d]cyclo-
heptene-5,2′-furan]-5′-one (9i). Colorless solids, mp 93.2−93.5 °C
1
(53 mg, 76%); H NMR (400 MHz, CDCl3, 25 °C) δ 2.87 (dd, J =
6.8, 1.6 Hz, 2 H), 3.08−3.24 (m, 4 H), 5.05 (dd, J = 16.8, 1.2 Hz, 1
H), 5.15 (d, J = 10.0 Hz, 1 H), 5.73 (ddt, J = 16.8, 10.0, 6.8 Hz, 1 H),
5.95 (t, J = 1.6 Hz, 1 H), 7.17−7.32 (m, 8 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 33.1, 36.2, 94.6, 114.6, 119.3, 126.8, 128.6, 128.8,
130.5, 131.4, 134.1, 142.8, 173.2, 178.3; IR (neat) 1759 (CO) cm−1;
HRMS (ESI) m/z calcd for C21H18O2·Na 325.1204, found 325.1194
[M + Na]+.
4-Allyl-1-oxaspiro[4.5]dec-3-en-2-one (9j). Colorless solids, mp
1
54.8−56.5 °C (76 mg, 79%); H NMR (400 MHz, CDCl3, 25 °C) δ
1.15−1.30 (m, 1 H), 1.55−1.80 (m, 9 H), 3.00 (ddd, J = 7.0, 2.8, 1.6
Hz, 2 H), 5.21 (ddd, J = 17.0, 2.8, 1.6 Hz, 1 H), 5.23 (ddd, J = 10.0,
2.4, 1.6 Hz, 1 H), 5.70 (t, J = 1.6 Hz, 1 H), 5.84 (ddt, J = 17.0, 10.0,
7.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 21.8, 24.5, 31.5,
33.6, 88.8, 115.1, 118.9, 131.8, 172.1, 175.6; IR (neat) 1750 (CO)
cm−1; HRMS (DART) m/z calcd for C12H16O2·H 193.1229, found
193.1221 [M + H]+.
4-Allyl-1,8-dioxaspiro[4.5]dec-3-en-2-one (9k). Pale-yellow oil
(69 mg, 71%); 1H NMR (400 MHz, CDCl3, 25 °C) δ 1.42 (d, J = 13.0
Hz, 2 H), 2.08 (dt, J = 13.0, 5.6 Hz, 2 H), 3.03 (dq, J = 6.8, 1.4 Hz, 2
H), 3.86 (dt, J = 12.0, 2.0 Hz, 2 H), 3.97 (dd, J = 12.0, 5.6 Hz, 2 H),
5.23 (ddd, J = 17.0, 2.8, 1.6 Hz, 1 H), 5.26 (ddd, J = 10.0, 2.4, 0.8 Hz,
1 H), 5.79 (t, J = 1.6 Hz, 1 H), 5.84 (ddt, J = 17.0, 10.0, 6.8 Hz, 1 H);
13C NMR (100 MHz, CDCl3, 25 °C) δ 31.4, 33.4, 63.7, 85.8, 116.1,
119.2, 131.4, 171.3, 173.8; IR (neat) 1751 (CO) cm−1; HRMS
(DART) m/z calcd for C11H14O3·NH4 212.1287, found 212.1295 [M
+ NH4]+.
tert-Butyl 4-Allyl-2-oxo-1-oxa-8-azaspiro[4.5]dec-3-ene-8-
carboxylate (9l). Colorless solids, mp 134.5−135.8 °C (96 mg,
58%); 1H NMR (400 MHz, CDCl3, 25 °C) δ 1.48 (s, 9 H), 1.45−1.49
(m, 2 H), 1.85−1.93 (m, 2 H), 2.99 (ddd, J = 6.8, 2.8, 1.2 Hz, 2 H),
3.16 (br s, 2 H), 4.16 (br s, 2 H), 5.22 (ddd, J = 17.0, 2.8, 1.6 Hz, 1 H),
5.25 (ddd, J = 10.0, 2.0, 1.2 Hz, 1 H), 5.79 (t, J = 1.2 Hz, 1 H), 5.83
(ddt, J = 17.0, 10.0, 6.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3, 25
°C) δ 28.3, 31.4, 33.1, 39.6 (broad), 79.9, 86.5, 116.1, 119.3, 131.3,
154.4, 171.3, 174.0; IR (neat) 1755 (CO), 1692 (CO) cm−1;
HRMS (ESI) m/z calcd for C16H23NO4·Na 316.1525, found 316.1544
[M + Na]+.
Cross Metathesis of Butenolide 9d with Ethyl Acrylate (20).
A degassed solution of butenolide 9d (45.7 mg, 0.30 mmol), acrylate
20 (163 μL, 1.5 mmol), Hoveyda−Grubbs catalyst 15 (9.4 mg, 0.015
mmol), and 1,4-benzoquinone (3.2 mg, 0.030 mmol) in dry CH2Cl2
(1.2 mL) was stirred at 40 °C under an argon atmosphere for 2 h. The
1
reaction mixture was concentrated in vacuo. The H NMR analysis of
4-(2-Methylallyl)-1-oxaspiro[4.5]dec-3-en-2-one (11j). Color-
1
the crude product showed that CM product 21 is the major product:
1H NMR (400 MHz, CDCl3, 25 °C) δ 1.31 (t, J = 7.2 Hz, 3 H), 1.48
(s, 6 H), 3.16 (dt, J = 7.6, 1.6 Hz, 2 H), 4.23 (q, J = 7.2 Hz, 2 H), 5.16
(s, 1 H), 5.99 (dt, J = 15.4, 1.6 Hz, 1 H), 6.95 (dt, J = 15.4, 7.6 Hz, 1
H).
Purification with chromatography on silica gel (hexane/AcOEt =
10:1−5:1) ultimately afforded a mixture of 21 and 22 (1/16, 46.8 mg,
69% yield) as a yellow oil.
less solids, mp 69.2−71.5 °C (25 mg, 25%); H NMR (400 MHz,
CDCl3, 25 °C) δ 1.15−1.29 (m, 1 H), 1.55 (br t, J = 14.0 Hz, 2 H),
1.64−1.80 (m, 7 H), 1.73 (s, 3 H), 2.96 (s, 2 H), 4.86 (s, 1 H), 4.97 (t,
J = 2.0 Hz, 1 H), 5.70 (t, J = 1.6 Hz, 1 H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 21.9, 22.0, 24.5, 33.5, 36.0, 89.0, 114.9, 115.8, 139.8,
172.2, 175.0; IR (neat) 1736 (CO) cm−1; HRMS (DART) m/z
calcd for C13H18O2·H 207.1385, found 207.1390 [M + H]+.
Cyclization of MOM-Protected γ-Hydroxybutynoate 12m.
The deprotection step was carried out using 6 M HCl/MeOH (1:1)
instead of TsOH·H2O in the general procedure B.
(E)-Ethyl 4-(2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)but-3-
1
enoate (22). H NMR (400 MHz, CDCl3, 25 °C) δ 1.29 (t, J = 7.2
Hz, 3 H), 1.54 (s, 6 H), 3.28 (dd, J = 7.0, 1.2 Hz, 2 H), 4.19 (q, J = 7.2
Hz, 2 H), 5.90 (s, 1 H), 6.20 (d, J = 16.0 Hz, 1 H), 6.42 (dt, J = 16.0,
7.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 14.1, 25.6, 38.5,
61.2, 86.2, 114.1, 122.8, 133.5, 168.9, 170.0, 171.7; IR (neat) 1745
(CO) cm−1; HRMS (ESI) m/z calcd for C12H16O4·NH4 242.1392,
found 242.1401 [M + NH4]+.
4-Allyl-5-phenyl-5-(trifluoromethyl)furan-2(5H)-one (9m).
1
Colorless oil (88 mg, 66%); H NMR (400 MHz, CDCl3, 25 °C) δ
3.00 (dd, J = 18.8, 6.8 Hz, 1 H), 3.23 (dd, J = 18.8, 6.8 Hz, 1 H), 5.16
(dd, J = 17.0, 1.2 Hz, 1 H), 5.23 (dd, J = 10.0, 1.2 Hz, 1 H), 5.74 (ddt,
J = 17.0, 10.0, 6.8 Hz, 1 H), 6.06 (s, 1 H), 7.43−7.48 (m, 3 H), 7.49−
7.55 (m, 2 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 32.1, 88.4 (q, J
= 30.5 Hz), 119.1, 120.0, 122.9 (q, J = 284.1 Hz), 125.8, 126.2, 130.0,
130.6, 130.8, 168.1, 169.9; 19F NMR (370 MHz, CDCl3, 25 °C) δ
−78.0; IR (neat) 1785 (CO) cm−1; HRMS (DART) m/z calcd for
C14H11F3O2·NH4 286.1055, found 286.1057 [M + NH4]+.
Analysis of Nonracemic γ-Allylbutenolides. (S)-9b ([α]25
=
D
−35.4° (c 1.02, CHCl3)) was obtained in 85% yield from (S)-3b
([α]25D = +16.4° (c 0.99, CHCl3)) according to the general procedure
A. The optical purities of (S)-3b and (S)-9b were determined as >99%
ee by HPLC analysis with DAICEL CHIRALCEL OD-H (hexane, 1.0
mL/min, λ = 215 nm, tR = 5.7/6.1 min) or CHIRALPAC AD-H
(hexane/iPrOH = 100:1−95:5 per 30 min, 1.0 mL/min, λ = 215 nm,
tR = 22.4/23.4 min), respectively (Supplemental Figures S1 and S2).
3-Allyl-5-phenyl-5-(trifluoromethyl)furan-2(5H)-one (13m).
1
Colorless oil (14 mg, 10%); H NMR (400 MHz, CDCl3, 25 °C) δ
3.07 (dd, J = 17.6, 6.8 Hz, 1 H), 3.14 (dd, J = 17.6, 6.8 Hz, 1 H), 5.20
(dd, J = 16.8, 1.2 Hz, 1 H), 5.21 (dd, J = 10.0, 1.2 Hz, 1 H), 5.88 (ddt,
J = 16.8, 10.0, 6.8 Hz, 1 H), 7.38 (t, J = 1.6 Hz, 1 H), 7.43−7.48 (m, 3
H), 7.53−7.58 (m, 2 H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 29.6,
85.6 (q, J = 32.4 Hz), 118.9, 122.6 (q, J = 282.2 Hz), 126.6, 128.9,
(S)-9c ([α]25 = −140.4° (c 0.80, CHCl3)) was obtained in 43%
D
yield with 64% ee from (R)-10c ([α]25 = +2.7° (c 0.97, CHCl3))
D
according to the general procedure A. The optical purities of (R)-3c,
4510
dx.doi.org/10.1021/jo500536b | J. Org. Chem. 2014, 79, 4503−4511

The Journal of Organic Chemistry
Article
(S)-9c, and (R)-10c were determined as 68% ee by HPLC analysis
with DAICEL CHIRALCEL OD-H (hexane, 1.0 mL/min, λ = 220 nm,
tR = 22.6/32.0 min), as 51% ee by CHIRALPAC AD-H (hexane/
iPrOH = 90:1, 1.0 mL/min, λ = 220 nm, tR = 11.0/12.0 min), and 68%
ee by HPLC analysis with CHIRALCEL OD-H (hexane/iPrOH =
90:10, 1.0 mL/min, λ = 220 nm, tR = 13.2/16.7 min), respectively
(Supplementary Figures S3−S5).
(14) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525−
2527.
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̈
ASSOCIATED CONTENT
(f) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 237−432. (g) Hagmann, W. K. J. Med. Chem. 2008, 51,
4359−4369.
■
S
* Supporting Information
HPLC and NMR charts. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) Yu, Q.; Wu, Y.; Wu, Y.-L.; Xia, L.-J.; Tang, M.-H. Chirality 2000,
12, 127−129.
(18) Trost, B. M.; Bartlett, M. J.; Weiss, A. H.; von Wangelin, A. J.;
Chan, V. S. Chem.Eur. J. 2012, 18, 16498−16509.
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J. Curr. Top. Med. Chem. 2005, 5, 1473−14945. (b) Michaut, A.;
Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740−5750.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yamamoto-yoshi@ps.nagoya-u.ac.jp.
Notes
■
́
(c) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45,
The authors declare no competing financial interest.
6086−6101. (d) Brown, R. C. D.; Satcharoen, V. Heterocycles 2006, 70,
705−736. (e) Majumdar, K. C.; Rahaman, H.; Roy, B. Curr. Org.
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Chem. Rev. 2009, 109, 3783−3816. (h) Majumdar, K. C.; Muhuri, S.;
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ACKNOWLEDGMENTS
■
This work was partially supported by Platform for Drug
Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
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