Pd(ii)-SDP-catalyzed enantioselective 5-exo-dig cyclization of γ-alkynoic acids: Application to the synthesis of functionalized dihydofuran-2(3H)-ones containing a chiral quaternary carbon center

Article abstract of DOI:10.1039/c3ob41103f

The Pd(ii)-SDP-catalyzed first enantioselective intramolecular cyclization of α,α-disubstituted γ-alkynoic acids is described. This 5-exo-dig cyclization afforded dihydrofuran-2(3H)-ones bearing a chiral quaternary carbon center in excellent yields with e

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ARTICLE TYPE
Pd(II)-SDP-Catalyzed enantioselective 5-exo-dig cyclization of γ-
alkynoic acids: application to the synthesis of functionalized
dihydofuran-2(3H)-ones containing a chiral quaternary carbon center
Vellaisamy Sridharan,*a,b Lulu Fan,a Shinobu Takizawa,a Takeyuki Suzukia and Hiroaki Sasai *a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The Pd(II)-SDP-catalyzed first enantioselective intramolecular cyclization of α,α-disubstituted γ-alkynoic
acids is described. This 5-exo-dig cyclization afforded dihydrofuran-2(3H)-ones bearing a chiral
quaternary carbon center in excellent yields with enantioselectivities up to 71%. A mechanism involving
10 palladium(II) species is proposed to rationalize the outcome of the reaction.
Introduction
Oxygen-containing heterocyclic compounds and their fused
analogs have significant application in biology and medicine.
R
OH
O
O
O
Me
HO
OH
Small-sized oxygen heterocycles, such as furan and its saturated
15 derivatives, are present in a number of natural products and
pharmaceutically relevant compounds. In particular, as
represented in Fig. 1, the dihydrofuran-2(3H)-one scaffold is an
essential fragment in numerous biologically important natural
products including the tornabeatins 1,1 matairesinol 22 and
20 muricatacin 3.3 A considerable number of coumarin-attached
dihydrofuran-2(3H)-ones, exemplified by clauslactones A and B
(4),4 and fused dihydrofuran-2(3H)-ones5 such as helenalin 5,
costunolide 6 and alantolactone 7 are widespread in nature. Apart
from these compounds, a large number of synthetic and natural
25 dihydrofuran-2(3H)-ones have revealed interesting biological
activities.6
O
11
O
O
MeO
Muricatacin, 3
R = alkyl or alkenyl
Tornabeatins, 1
MeO
O
H
HO
O
Matairesinol, 2
O
O
O
O
HO
O
Helenalin, 5
R
O
H
Me OH
O
O
R =
O
O
Clauslactone A, 4a
H
The intramolecular cyclization of alkynes bearing tethered
nucleophiles, in the presence of suitable catalytic systems, is an
attractive protocol for the synthesis of simple carbo- and
30 heterocyclic compounds, with the nature of the final product
being dependent on the nature of the attached nucleophiles.7
O
O
Me OH
Alantolactone, 7
Costunolide, 6
O
R =
OH
Me
Clauslactone B, 4b
Although
a considerable number of strategies have been
Fig. 1 Representative examples of dihydrofuran-2(3H)-one natural
50
products
established for the synthesis of dihydrofuran-2(3H)-one
derivatives, the most straightforward approach to the construction
35 of their skeleton involves metal-catalyzed8 intramolecular 5-exo-
dig cyclizations of γ-alkynoic acids.9 While palladium catalysts
were initially employed to achieve this synthetically important
transformation, gold catalysts were also found to be attractive in
this regard in recent years.10,11 Other metal catalysts, including the
40 salts or complexes of rhodium,12 ruthenium,13 iridium,14
molybdenum,15 tungsten16 and silver,17 have also been proved to
catalyze the aforementioned transformation effectively. The
intermediates obtained through the intramolecular cyclization of
alkynoic acids were also employed as starting compounds for
45 subsequent cascade transformations that afford structurally
complex compounds in a single operation.18
Results and Discussion
Although
a significant number of procedures have been
developed for the intramolecular cyclization of γ-alkynoic acids,
including the α,α-disubstituted derivatives 8, to afford the
55 corresponding dihydrofuran-2(3H)-one derivatives 9, the
enantioselective version of this useful desymmetrization reaction
has not yet been explored. Hence we envisioned developing an
enantioselective procedure for this important transformation. Our
initial aim was to identify a suitable bulky chiral catalytic system
60 that would induce high enantioselectivity in this
desymmetrization process. As discussed previously, palladium
catalysts would be the best choice to allow the intramolecular
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Organic & Biomolecular Chemistry
Page 2 of 8
Table 1 Screening of substrates and ligands
View Article Online
DOI: 10.1039/C3OB41103F
R2
R2
R2
Pd(II) source (10 mol%)
O
O
ligand (12 mol%)
R1
solvent, temp.,
reaction time
R1 CO2H
R2
9
8
Entry Substrate/
Product
R1
R2
Pd source
Solvent
Ligand
Temp
Time
Yield
ee of 9
(oC)
(Conversion) of (%)
9 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8a/9a
8b/9b
8c//9c
8d/9d
8e/9ec
8e/9e
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
H
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Dioxane (M,S,S)-i-Pr-SPRIX
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
65
4 h
4 h
3 h
3 h
4 h
1 d
3 d
3 d
3 d
3 d
1.5 d
1 d
12 h
8 h
5 h
5 h
3 h
5 d
1 d
88 (100)
93 (100)
92 (100)
94 (100)
89 (100)
86 (100)
71a
rac
5
rac
rac
rac
19
rac
-6
rac
-4
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
CHCl3
(M,S,S)-i-Pr-SPRIX
(-)-Spartein
(S,S)-t-BuBOX
-
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-BINAP
-
9a
[(η3-C3H5)PdCl]2
PdCl2-(S)-BINAPb
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
16a
8a
(R)-SEGPHOS
(R)-DIFLUORPHOS
(R)-SYNPHOS
(S)-MOP
83 (100)
8
13
18a
83 (100)
86 (100)
78 (100)
84 (100)
69 (100)
84 (90)
77 (84)
rac
rac
rac
rac
rac
33
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-BINAP
CO2Me
Ph
Ph
Ph
Ph
Ph
22
a The remaining unreacted starting material was recovered. bIsolated PdCl2-(S)-BINAP complex (10 mol%) was used. c Lowering the reaction temperature
5 to 10 or 0 oC reduced the reaction rate without improving the ee.
cyclization smoothly. It is relevant to mention here that Czekelius
ligand, Pd(OAc)2-i-Pr-SPRIX complex and Pd(OAc)2-i-Pr-
and co-workers have recently reported gold-catalyzed 35 SPRIX complex in the presence of excess of substrate 8a in
a
enantioselective cyclization of diynamides to pyrrolidines.19
Unlike our substrates (1,6-diynes), these authors have employed
10 1,4-diynamides and thus the prochiral carbon is adjacent to the
reaction site.
CDCl3. After the addition of substrate 8a to Pd(OAc)2-i-Pr-
SPRIX complex, only the dissociated free i-Pr-SPRIX ligand
signals were observed in the 1H-NMR spectra, together with
signals of the product 9a, but no traces of the Pd(OAc)2-i-Pr-
Our first choice of ligands for this enantioselective 5-exo-dig 40 SPRIX complex were detected in the solution. These experiments
cyclization was chiral bidentate nitrogen ligands, especially the
spiro bis(isoxazoline) ligands (SPRIXs), which have been
15 excellent to achieve a number of enantioselective intramolecular
cyclization reactions when combined with suitable palladium
confirmed that the chiral Pd(II)-ligand complex is dissociated or
decomposed in the presence of the substrate to allow the
background reaction. In a separate experiment, it was also
confirmed that the reaction proceeded splendidly in the presence
salts.20,21 We started our preliminary studies for the 45 of Pd(OAc)2 without any ligand (entry 5).
intramolecular cyclization of γ-alkynoic acid 8a in the presence
of in situ generated Pd(II)-i-Pr-SPRIX complex under mild
20 conditions (Table 1, Fig. 2). The reaction proceeded smoothly in
various solvents including dioxane, DCM, CHCl3, MeCN,
Next, we moved to the relatively strong coordinating chiral
bidentate phosphine ligands anticipating that they would form
strong complexes with Pd(II) species that would be stable in the
presence of the dialkyne substrates. As shown in entry 6, the
MeOH, AcOH and toluene to furnish dihydrofuran-2(3H)-one 9a 50 Pd(II)-(S)-BINAP complex afforded product 9a in high yields
in excellent yields in short reaction times, although as a racemic
compound (entries 1 and 2). Palladium complexes of other
25 commercially available chiral bidentate nitrogen ligands (-)-
spartein and (S,S)-t-BuBOX also failed to induce
with 19% ee. Prompted by this encouraging result, we carried out
an extensive optimization study to improve the enantioselectivity
by altering various factors including reaction solvents, additives
and reaction temperatures (see the Supporting Information for
enantioselectivity (entries 3 and 4). We assumed that the Pd(II)- 55 details), but unfortunately we were unable to improve the
ligand complexes might not be stable in the presence of excess of
the coordinating diakyne substrate 8a. The relatively weakly
30 coordinated ligands might be replaced by the substrate to allow
enantioselectivity significantly. Change of reaction solvents to
CHCl3, MeCN, MeOH, dioxane and Et2O, and addition of one
equivalent of additives including K2CO3, KOH, Et3N and AcOH
were not effective. The reaction was also carried out at different
the background reaction to afford the racemic product. To support
1
this assumption we carried out a set of H-NMR experiments in 60 temperatures (45 oC, 10 oC, 0 oC, -20 oC and -40 oC), however the
which we measured the 1H-NMR spectra of pure i-Pr-SPRIX
enantioselectivity was not improved. Utilization of chiral
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Page 3 of 8
Organic & Biomolecular Chemistry
Table 2 Optimization of the enantioselective intramolecular cyclization
of substrate 8e
catalysts derived from the (S)-BINAP ligand and a number of
palladium(II) species (entries 7 to 9) or the use of isolated PdCl2-
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(S)-BINAP complex as catalyst (entry 10) were not effective in
terms of both reactivity and enantioselectivity. Similarly other
chiral catalysts obtained by the combination Pd(OAc)2 with chiral
bidentate phosphine ligands including (R)-SEGPHOS, (R)-
DIFLUORPHOS and (R)-SYNPHOS (entries 11 to 13) or
monodentate ligand (S)-MOP (entry 14) were unable to provide
good enantioselectivity. The substrate 8b (R1 = H, R2 = Me) also
DOI: 10.1039/C3OB41103F
Ph
Ph
Ph
Pd(OAc)2 (10 mol%)
ligand (12 mol%)
O
O
5
Ph
solvent, temp.,
reaction time
Ph
CO2H
Ph
9e
8e
10 furnished the racemic product under similar conditions (entry 15).
Eventually we presumed that the nature of the substrate itself
imposed a constraint that prevented high enantioselectivity due to
the distance between the reaction site and the prochiral center.
For this reason, we introduced another substituent at the α-
15 position of the carboxylic acid group of substrate 8 aiming to
improve enantioselectivity because of the added steric hindrance,
and also with a view to synthesize dihydrofuran-2(3H)-one
derivatives 9 bearing a quaternary chiral carbon. Screening of
other substrates (8c to 8e, entries 16 to 18) bearing different
20 substituents at R1 and R2 positions suggested that the nature of
substituents is crucial to allow higher enantioselectivity. As
shown in entry 18, the substrate 8e bearing three phenyl
substituents afforded the maximum ee of 33% in chloroform at
room temperature. Change of solvents (DCM or MeCN) and the
25 reaction temperatures (10 oC, 0 oC and 65 oC) did not improve the
ee value (entries 18 and 19). The geometry of the products across
the exocyclic double bond was confirmed as Z through NOESY
experiments and by comparison with literature data.
After identifying the appropriate substrate for the
30 enantioselective intramolecular cyclization reaction, we made an
extensive effort to identify a suitable catalytic system and
reaction conditions to afford good enantioselectivity (Table 2,
Fig. 2). Based on our previous optimization studies, we
understood that the only option left to improve the
35 enantioselectivity was to find out a suitable chiral ligand that
would control the enantioselectivity of the cyclization reaction,
overcoming the difficulties imposed by the distance between the
reaction site and the prochiral carbon. Although it was a
challenging task, we screened a wide number of chiral bidentate
40 phosphine ligands combined with palladium(II) acetate, as shown
in Table 2 and Fig. 2, for the intramolecular cyclization of
substrate 8e in halogenated solvents. The catalysts derived from
Pd(OAc)2 and (R)-SEGPHOS, (R)-DIFLUORPHOS, (R)-
SYNPHOS, (S)-MOP, (S)-Tol-BINAP or (R,R)-Chiraphos were
45 not effective to improve the enantioselectivity (entries 3-13).
Interestingly the Pd(OAc)2/(R)-SDP system was found to be
efficient to allow good enantioselectivity (entries 14-18). The
maximum ee of 60% was achieved in the presence of the
Pd(OAc)2/(R)-SDP complex in chloroform solvent at room
50 temperature (entry 15). While lowering the reaction temperature
slightly improved the ee (up to 64%) the reaction rate was
reduced significantly (entries 17 and 18). Other chiral ligands
including Josiphos-1, (S,S)-BenzP*, (R,R)-QuinoxP*, (R,R,S,S)-
DuanPhos, (R)-BINAPHANE and (R)-Tol-SDP were not
55 competent to improve the enantioselectivity (entries 19-24).
Entry Solvent
Ligand
Temp Time
(oC)
Yield
(Conversion) 9e (%)
of 9e (%)
84 (90)
96 (100)
91 (100)
43 (49)
ee of
1
CHCl3
(S)-BINAP
(S)-BINAP
(R)-SEGPHOS
(R)-SEGPHOS
25
25
25
25
5 d
5 d
5 d
5 d
5 d
5 d
5 d
5 d
3 h
33
19
15
5
23
24
10
2
7
2
22
6
6
43
(42)b
60
(58)b
36
63
64
14
35
rac
-20
4
2a CHCl3
3
4
DCM
CHCl3
5
6
DCM (R)-DIFLUORPHOS 25
CHCl3 (R)-DIFLUORPHOS 25
39 (47)
15 (21)
7
8
9
10
DCM
CHCl3
DCM
DCM
(R)-SYNPHOS
(R)-SYNPHOS
(S)-MOP
(S)-Tol-BINAP
(S)-Tol-BINAP
(R,R)-Chiraphos
(R,R)-Chiraphos
(R)-SDP
25
25
25
94 (100)
97 (100)
93 (100)
91 (100)
94 (100)
95 (100)
96 (100)
98 (100)
25 12 h
25 2 d
25 12 h
25 12 h
25 12 h
11 CHCl3
12 DCM
13 CHCl3
14 DCM
15 CHCl3
(R)-SDP
25
2 d
96 (100)
16 DCE
(R)-SDP
(R)-SDP
(R)-SDP
25
10
0
25
25
1 d
5 d
7 d
3 d
5 d
91 (100)
71 (75)
84 (90)
93 (100)
77 (90)
68 (100)
82 (100)
89 (100)
82 (100)
17 CHCl3
18 CHCl3
19 CHCl3
20 CHCl3
21 CHCl3
22 CHCl3 (R,R,S,S)-DuanPhos 25 43 h
23 CHCl3 (R)-BINAPHANE 25 43 h
24 CHCl3 (R)-Tol-SDP 25 1 d
Josiphos-1
(S,S)-BenzP*
(R,R)-QuinoxP*
25 43 h
16
a
b
Molecular sieves (3Å) was used as additive. ee values given in
60 parenthesis were obtained from a second run.
The scope and limitations of this protocol were then studied
by employing the optimized reaction conditions (Pd(OAc)2/(R)-
SDP, 25 oC, CHCl3) to the enantioselective intramolecular
cyclization of a number of α,α-disubstituted γ-alkynoic acids 8
65 (Table 3). As shown in entries 1-6, the γ-alkynoic acids bearing
substituted aryl groups afforded the corresponding dihydrofuran-
2(3H)-one derivatives 9 in good to excellent yields with
enantioselectivities up to 71%. Surprisingly the alkynoic acid 8j
bearing an electron-withdrawing substituent (p-bromo) afforded
70 almost racemic product 9j (entry 7). The sterically hindered o-
tolyl substrate 8k was found to be very slow and gave only 23%
of the cyclized product, as a racemic compound, ever after seven
days reaction at room temperature (entry 8). The poor reactivity
and enantioselectivity are presumably due to the bulky o-methyl
75 substituents, which prevent the Pd(II)-SDP complex from
approaching the alkyne moiety to trigger the annulation process.
At the same time a slow background reaction, catalyzed by traces
of free Pd(OAc)2 present in the reaction mixture, produced small
amount of the racemic product. In order to extend the scope of
80 the reaction, we synthesized two more γ-alkynoic acids (8l and
8m) bearing different substituents both at α- and terminal
positions. While compound 8l bearing terminal methyl
substituents afforded the corresponding cyclized product in 93%
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Journal Name, [year], [vol], 00–00 | 3

Organic & Biomolecular Chemistry
Page 4 of 8
O
View Article Online
O
F
DOI: 10.1039/C3OB41103F
Me
N
Me
N
M
F
O
O
O
O
O
PPh2
PPh2
PPh2
PPh2
S
PPh2
PPh2
S
H
H
i-Pr
i-Pr
i-Pr
i-Pr
O
N
N
F
N
N
O
O
t-Bu
t-Bu
F
O
O
(-)-Spartein
(M,S,S)-i-Pr-SPRIX
(S,S)-t-BuBOX
(R)-SEGPHOS
(R)-DIFLUORPHOS
(S)-BINAP
O
Me
Me
P(p-tol)2
P(p-tol)2
PPh2
PPh2
OMe
PPh2
O
O
PPh2
PPh2
Ph2P
PPh2
P
Ph
P
Fe
Ph
Me
(R,R)-Chiraphos
O
(S)-Tol-BINAP
(R)-SDP
Josiphos-1
(R)-SYNPHOS
(S)-MOP
t-Bu
Me
Me
t-Bu
N
P
P
P
H
P(p-tol)2
P(p-tol)2
P
P
P
P
N
P
H
t-Bu
Me
Me
(R,R)-QuinoxP*
Fig. 2 Chiral ligands used for the reactions shown in tables 1 to 3
t-Bu
t-Bu
t-Bu
(R)-Tol-SDP
(S,S)-BenzP*
(R,R,S,S)-Duanphos
(R)-BINAPHANE
yield (32% ee), the α-ester substituted substrate 8m furnished the
product in 92% yield with 15% ee (entries 9 and 10). The
enantioselectivity of the product obtained from the terminal
unsubstituted alkynoic acid 8d was also poor, giving 13% ee
(93% yield, entry 11). These results demonstrated that both α-
and terminal substituents should be aryl, not only in terms of
Fine-tuning of the SDP ligands, utilization of other nucleophiles
as well as detailed mechanistic studies are under investigation in
our laboratory.
5
Ar
Ar
10 reactivity but also to achieve good enantioselectivity.
plausible reaction mechanism for the palladium(II)-
Ph
A
Ph
H
Ar
P
catalyzed enantioselective cyclization of alkynoic acids 8 is
shown in Fig. 3. Initial coordination of the chiral Pd(II)-SDP
complex 10 with substrate 8 afforded the cationic palladium
15 intermediate A after elimination of a molecule of acetic acid.
Subsequent nucleopalladation of the activated species A in a 5-
OAc
O
Pd
O
*
O
OAc
P
Ar
OH
9
10
8
AcOH
Ar
AcOH
exo-dig fashion furnished the cyclic intermediate
B thus
Ar
Ph
O-
controlling the enantioselectivity. Final protonation of the
palladium(II) intermediate B afforded the dihydrofuran-2(3H)-
20 one derivative 9 after releasing the catalyst 10. Although we are
convinced that the proposed mechanism involving Pd(II) species
constitutes the best explanation for our findings, an alternative
pathway involving Pd(0) and Pd(II) intermediates, where the key
steps would be oxidative addition of carboxylic acid to Pd(0),
25 migratory insertion to the alkyne moiety and reductive
elimination, cannot be completely ruled out.
AcO
Ph
+
P
AcO
*
P
Pd
*
Pd
P
O
P
O
Ar
O
Ar
A
B
40
Fig. 3 Plausible reaction mechanism
Conclusions
Experimental
In conclusion, we have developed the first enantioselective 5-exo-
dig cyclization of α,α-disubstituted-γ-alkynoic acids catalyzed by
30 a chiral Pd(II)-(R)-SDP complex under mild conditions. The
reaction allowed access to chiral dihydrofuran-2(3H)-one
derivatives bearing a quaternary carbon center in excellent yields
and enantioselectivities up to 71%. A plausible catalytic cycle
involving coordination, nucleopalladation and protonation steps
35 is proposed to explain the product formation and enantiocontrol.
General Information
Commercially available reagents were used as received without
further purification and solvents were purified and dried using
45 standard procedures prior to use. Reactions were monitored by
thin layer chromatography, on glass plates coated with silica gel
with fluorescent indicator (Merck). Compounds were purified
through flash column chromatography on silica gel (Kanto Silica
4 | Journal Name, [year], [vol], 00–00
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Organic & Biomolecular Chemistry
Table 3 Substrate scopea
chromatography using hexane/ethyl acetate as eluent to afford the
desired dihydrofuran-2(3H)-one 9. The reaction was also carried
Entry
Starting compound, 8
Product, 9
(temp., time, yield, ee)
Ar
out in the absence of chiral ligand to obtain the VcioewrrAesrtpicolenOdninlinge
DOI: 10.1039/C3OB41103F
racemic products.
Ar
Ph
O
O
30
HO2C
Ar
(Z)-5-Benzylidene-3-(3-phenylprop-2-ynyl)dihydrofuran-
2(3H)-one (9a).22 Yield: 86%; yellow solid; mp: 59-62 oC; IR
(KBr): ν = 3060, 2919, 2360, 1804, 1732, 1598, 1491, 1442,
Ph
Ar
9e, 25 oC, 2 d, 96%, 60% ee
9e, 0 oC, 7 d, 84%, 64% ee
9f, 25 oC, 20 h, 75%, 60% ee
9g, 25 oC, 2 d, 88%, 60% ee
9h, 25 oC, 4 d, 92%, 71% ee
9i, 25 oC, 1 d, 73%, 60% ee
9j, 25 oC, 1 d, 66%, 8% ee
9k, 25 oC, 7 d, 23%, 0% ee
Me
1
1233, 1110, 1025 cm-1; H-NMR (400 MHz, CDCl3): δ = 2.86-
1
2
3
4
5
6
7
8
9
8e, Ar = Ph
8e, Ar = Ph
35 2.98 (m, 2H), 3.07-3.17 (m, 2H), 3.21-3.26 (m, 1H), 5.61 (s, 1H),
7.19-7.29 (m, 4H), 7.30-7.38 (m, 4H), 7.55-7.57 (m, 2H); 13C-
NMR (100 MHz, CDCl3): δ = 21.1, 32.2, 38.5, 83.5, 84.6, 105.3,
122.9, 126.9, 128.3, 128.4, 128.5, 128.6, 131.8, 133.9, 146.7,
175.6; HRMS (ESI): calcd for C20H16NaO2, m/z 311.1048
40 ([M+Na]+); found, m/z 311.1036.
8f, Ar = 3-Me-C6H4-
8g, Ar = 4-Me-C6H4-
8h, Ar = 4-i-Pr-C6H4-
8i, Ar = 4-OMe-C6H4-
8j, Ar = 4-Br-C6H4-
8k, Ar = 2-Me-C6H4-
Me
Me
Ph
O
O
(Z)-3-(But-2-ynyl)-5-ethylidenedihydrofuran-2(3H)-one
(9b).11a Yield: 99%; colorless oil; IR (KBr): ν = 2922, 2861,
1800, 1711, 1440, 1223, 1126 cm-1; 1H-NMR (400 MHz, CDCl3):
45 δ = 1.66-1.69 (m, 3H), 1.76 (t, J = 2.7 Hz, 3H), 2.50-2.62 (m,
2H), 2.77-2.97 (m, 3H), 4.62-4.68 (m, 1H); 13C-NMR (100 MHz,
CDCl3): δ = 3.6, 10.5, 20.3, 30.7, 39.6, 74.4, 78.6, 99.6, 147.0,
176.1; HRMS (ESI): calcd for C10H12NaO2, m/z 187.0735
([M+Na]+); found, m/z 187.0726.
HO2C
Ph
8l
Me
9l, 25 oC, 24 h, 93%, 32% ee
Ph
10
11
Ph
Ph
MeO2C
O
O
HO2C
MeO2C
50
8m
(Z)-Methyl 3-(but-2-ynyl)-5-ethylidene-2-oxotetrahydrofuran-
3-carboxylate (9c).11a Yield: 84%; colorless oil; IR (KBr): ν =
Ph
9m, 25 oC, 24 h, 92%, 15% ee
1
2926, 2361, 1802, 1744, 1438, 1219, 1135, 1036 cm-1; H-NMR
(400 MHz, CDCl3): δ = 1.69-1.71 (m, 3H), 1.75 (d, J = 1.8 Hz,
55 3H), 2.77-2.87 (m, 2H), 3.11-3.24 (m, 2H), 3.78 (d, J = 1.8 Hz,
3H), 4.67-4.73 (m, 1H); 13C-NMR (100 MHz, CDCl3): δ = 3.6,
10.6, 24.4, 34.8, 53.6, 54.8, 72.6, 79.9, 100.1, 145.5, 169.2,
172.1; HRMS (ESI): calcd for C12H14NaO4, m/z 245.0790
([M+Na]+); found, m/z 245.0782.
O
O
Ph
HO2C
Ph
8d
9d, 25 oC, 24 h, 93%, 13% ee
a Reaction conditions: Pd(OAc)2 (10 mol%), (R)-SDP (12 mol%), CHCl3,
60
25 oC.
5-Methylene-3-phenyl-3-(prop-2-ynyl)dihydrofuran-2(3H)-
one (9d).11a Yield: 93%; colorless oil; IR (KBr): ν = 3292, 2357,
1799, 1677, 1261, 1146, 1038 cm-1; 1H-NMR (400 MHz,
CDCl3): δ = 2.09-2.10 (m, 1H), 2.83 (dd, J = 16.9, 1.8 Hz, 1H),
65 2.98 (dd, J = 16.9, 1.8 Hz, 1H), 3.28 (d, J = 16.0 Hz, 1H), 3.46
(dd, J = 16.0, 1.8 Hz, 1H), 4.40 (s, 1H), 4.79 (s, 1H), 7.32-7.44
(m, 5H); 13C-NMR (100 MHz, CDCl3): δ = 28.6, 37.9, 52.1, 72.3,
79.1, 89.8, 126.0, 128.3, 129.2, 138.5, 153.1, 175.8; HRMS
(ESI): calcd for C14H12NaO2, m/z 235.0735 ([M+Na]+); found,
70 m/z 235.0728.
Gel 60 (40-100 µm). 1H- and 13C-NMR spectra were recorded on
JEOL JMN ECS400 FT-NMR spectrometer (400 MHz for 1H and
100 MHz for 13C). ESI-MS spectra were obtained with JMS-
T100LC (JEOL) instrument. Optical rotations were measured
with JASCO P-1030 polarimeter. HPLC analyses were performed
on JASCO HPLC system (JASCO PU 980 pump and UV-975
10 UV/Vis detector) using a mixture of hexane and i-PrOH or EtOH
as eluents. FT-IR spectra were recorded on a JASCO FT-IR
system (FT/IR4100). Melting points were measured on
SHIMADZU DSC-60 apparatus.
5
(Z)-5-Benzylidene-3-phenyl-3-(3-phenylprop-2-
General
procedure
for
the
palladium-catalyzed
ynyl)dihydrofuran-2(3H)-one (9e). Yield: 96%; colorless solid;
15 enantioselective cyclization of alkynoic acids (Tables 1, 2 and
3)
o
23
mp: 113-115 C; [α]D = +11.9 (c = 1.1, CHCl3); IR (KBr): ν =
75 3069, 3022, 2360, 1802, 1691, 1597, 1493, 1442, 1317, 1227,
1
1178, 1108, 1033 cm-1; H-NMR (400 MHz, CDCl3): δ = 3.09
A screw cap tube was charged with palladium salt (0.005 mmol,
10 mol%), suitable chiral ligand (0.006 mmol, 12 mol%) and
solvent (0.5 mL). The mixture was stirred at 25 oC under N2 for 2
20 h. The corresponding alkynoic acid 8 (0.05 mmol, 1 eq) was
added and stirring was continued until complete consumption of
the starting material, as indicated by TLC, or the reaction times
shown in tables 1, 2 and 3. The reaction mixture was then filtered
through a short pad of silica gel and the solvent was evaporated.
25 The residue was purified through short silica column
(dd, J = 16.9, 1.8 Hz, 1H), 3.23 (dd, J = 16.9, 1.8 Hz, 1H), 3.47
(d, J = 16.5 Hz, 1H), 3.72 (d, J = 16.5 Hz, 1H), 5.63 (s, 1H),
7.18-7.26 (m, 4H), 7.28-7.34 (m, 5H), 7.37-7.42 (m, 2H), 7.52-
80 7.57 (m, 4H); 13C-NMR (100 MHz, CDCl3): δ = 30.0, 39.6, 51.4,
84.3, 84.4, 105.5, 122.8, 126.1, 127.0, 128.31, 128.34, 128.36,
128.5, 128.6, 129.2, 131.8, 133.9, 138.8, 145.8, 176.0; HRMS
(ESI): calcd for C26H20NaO2, m/z 387.1361 ([M+Na]+); found,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Organic & Biomolecular Chemistry
Page 6 of 8
m/z 387.1353. Enantiomeric excess: 60%, determined by HPLC
flow rate: 0.5 mL/min, 254 nm): major enantiomer: tR = 17.8 min,
(Chiralpak OD-H, n-hexane/i-PrOH = 9/1, flow rate: 1.5 mL/min,
254 nm): major enantiomer: tR =17.7 min, minor enantiomer: tR =
11.4 min.
minor enantiomer: tR = 13.5 min.
View Article Online
DOI: 10.1039/C3OB41103F
60
(E)-5-(4-Methoxybenzylidene)-3-(3-(4-methoxyphenyl)prop-2-
5
ynyl)-3-phenyldihydrofuran-2(3H)-one (9i). Yield: 73%; pale
o
22
(E)-5-(3-Methylbenzylidene)-3-phenyl-3-(3-m-tolylprop-2-
ynyl)dihydrofuran-2(3H)-one (9f). Yield: 75%; pale yellow
yellow solid; mp: 97-99 C; [α]D = -0.7 (c = 0.9, CHCl3); IR
(KBr): ν = 2959, 2839, 2359, 1793, 1688, 1604, 1505, 1451,
solid; mp: 111-112 C; [α]D = +3.4 (c = 0.7, CHCl3); IR (KBr): 65 1293, 1254, 1181, 1118, 1036 cm-1; 1H-NMR (400 MHz, CDCl3):
o
22
ν = 3033, 2927, 2360, 1798, 1697, 1504, 1445, 1357, 1189, 1106,
δ = 3.05 (d, J = 16.9 Hz, 1H), 3.20 (d, J = 16.9 Hz, 1H), 3.42 (d, J
= 16.0 Hz, 1H), 3.69 (d, J = 16.0 Hz, 1H), 3.77 (s, 3H), 3.80 (s,
3H), 5.57 (s, 1H), 6.75 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 7.8 Hz,
2H), 7.24-7.26 (m, 2H), 7.29-7.33 (m, 1H), 7.36-7.41 (m, 2H),
10 1013 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 2.31 (s, 3H), 2.33 (s,
3H), 3.07 (d, J = 16.5 Hz, 1H), 3.22 (d, J = 16.9 Hz, 1H), 3.44
(dd, J = 16.0, 0.9 Hz, 1H), 3.72 (dd, J = 16.0, 1.8 Hz, 1H), 5.60
(s, 1H), 7.04 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 7.22 70 7.48-7.52 (m, 4H); 13C-NMR (100 MHz, CDCl3): δ = 30.0, 39.5,
(d, J = 8.2 Hz, 2H), 7.30-7.34 (m, 1H), 7.36-7.41 (m, 2H), 7.46
15 (d, J = 8.2 Hz, 2H), 7.50-7.53 (m, 2H); 13C-NMR (100 MHz,
CDCl3): δ = 21.4, 21.6, 30.0, 39.5, 51.5, 83.7, 84.5, 105.4, 119.7,
126.1, 128.2, 128.5, 129.08, 129.10, 129.3, 131.0, 131.7, 136.7,
51.6, 55.4, 82.9, 84.2, 104.9, 113.9, 113.95, 114.0, 115.0, 126.2,
126.7, 128.2, 129.1, 129.9, 133.3, 139.0, 144.2, 158.5, 159.6,
176.2; HRMS (ESI): calcd for C28H24NaO4, m/z 447.1572
([M+Na]+); found, m/z 447.1562. Enantiomeric excess: 60%,
138.4, 138.9, 145.1, 176.1; HRMS (ESI): calcd for C28H24NaO2, 75 determined by HPLC (Chiralpak AS, n-hexane/EtOH = 9/1, flow
m/z 415.1674 ([M+Na]+); found, m/z 415.1664. Enantiomeric
20 excess: 60%, determined by HPLC (Chiralpak OD-H, n-hexane/i-
PrOH = 9/1, flow rate: 1 mL/min, 254 nm): major enantiomer: tR
= 59.3 min, minor enantiomer: tR = 19.2 min.
rate: 1.0 mL/min, 254 nm): major enantiomer: tR = 25.0 min,
minor enantiomer: tR = 12.7 min.
(E)-5-(4-Bromobenzylidene)-3-(3-(4-bromophenyl)prop-2-
80 ynyl)-3-phenyldihydrofuran-2(3H)-one (9j). Yield: 66%;
o
23
(E)-5-(4-Methylbenzylidene)-3-phenyl-3-(3-p-tolylprop-2-
colorless solid; mp: 199-200 C; [α]D = -1.3 (c = 1.0, CHCl3);
IR (KBr): ν = 3072, 2360, 1813, 1685, 1486, 1259, 1177, 1104,
1001 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 3.06 (d, J = 16.9 Hz,
1H), 3.21 (d, J = 16.9 Hz, 1H), 3.46 (d, J = 16.5 Hz, 1H), 3.66
25 ynyl)dihydrofuran-2(3H)-one (9g). Yield: 88%; pale yellow oil;
22
[α]D = +8.9 (c = 0.9, CHCl3); IR (KBr): ν = 3033, 2921, 2360,
1799, 1689, 1598, 1490, 1442, 1319, 1259, 1189, 1113, 1033 cm-
1; H-NMR (400 MHz, CDCl3): δ = 2.31 (s, 3H), 2.33 (s, 3H), 85 (dd, J = 16.5, 1.8 Hz, 1H), 5.57 (s, 1H), 7.16 (d, J = 8.7 Hz, 2H),
1
3.07 (d, J = 16.5 Hz, 1H), 3.22 (d, J = 16.9 Hz, 1H), 3.44 (dd, J =
30 16.0, 0.9 Hz, 1H), 3.72 (dd, J = 16.0, 1.8 Hz, 1H), 5.60 (s, 1H),
7.04 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.2
Hz, 2H), 7.30-7.34 (m, 1H), 7.36-7.41 (m, 2H), 7.46 (d, J = 8.2
7.32-7.37 (m, 3H), 7.38-7.44 (m, 6H), 7.49-7.52 (m, 2H); 13C-
NMR (100 MHz, CDCl3): δ = 30.2, 39.7, 51.3, 83.5, 85.5, 104.4,
120.8, 121.7, 122.7, 126.1, 128.5, 129.3, 130.1, 131.6, 131.7,
132.8, 133.3, 138.6, 146.4, 175.7; HRMS (ESI): calcd for
Hz, 2H), 7.50-7.53 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ = 90 C26H18Br2NaO2, m/z 542.9571 ([M+Na]+); found, m/z 542.9557.
21.4, 21.6, 30.0, 39.5, 51.5, 83.7, 84.5, 105.4, 119.7, 126.1,
35 128.2, 128.5, 129.08, 129.10, 129.3, 131.0, 131.7, 136.7, 138.4,
138.9, 145.1, 176.1; HRMS (ESI): calcd for C28H24NaO2, m/z
415.1674 ([M+Na]+); found, m/z 415.1664. Enantiomeric excess:
Enantiomeric excess: 8%, determined by HPLC (Chiralpak IE, n-
hexane/i-PrOH = 9/1, flow rate: 1.0 mL/min, 254 nm): major
enantiomer: tR = 10.8 min, minor enantiomer: tR = 13.3 min.
60%, determined by HPLC (Chiralpak OD-H, n-hexane/i-PrOH = 95 (E)-5-(2-Methylbenzylidene)-3-phenyl-3-(3-o-tolylprop-2-
9/1, flow rate: 1 mL/min, 254 nm): major enantiomer: tR = 59.3
40 min, minor enantiomer: tR = 19.2 min.
ynyl)dihydrofuran-2(3H)-one (9k). Yield: 23%; yellow oil; IR
(KBr): ν = 3466, 3061, 2922, 2360, 1797, 1689, 1601, 1490,
1453, 1203, 1115 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 2.27 (s,
3H), 2.31 (s, 3H), 3.16 (d, J = 16.9 Hz, 1H), 3.29 (d, J = 16.5 Hz,
(E)-5-(4-Isopropylbenzylidene)-3-(3-(4-isopropylphenyl)prop-
2-ynyl)-3-phenyldihydrofuran-2(3H)-one (9h). Yield: 92%; 100 1H), 3.50 (dd, J = 16.5, 1.4 Hz, 1H), 3.78 (dd, J = 16.0, 1.8 Hz,
colorless solid; mp: 98-100 oC; [α]D23 = -1.2 (c = 1.0, CHCl3); IR
45 (KBr): ν = 3050, 2958, 2358, 1795, 1690, 1501, 1450, 1319,
1H), 5.77 (s, 1H), 7.07-7.20 (m, 6H), 7.31-7.35 (m, 2H), 7.38-
7.42 (m, 2H), 7.52-7.55 (m, 2H), 7.75 (d, J = 7.3 Hz, 1H); 13C-
NMR (100 MHz, CDCl3): δ = 20.3, 20.8, 30.0, 39.6, 51.6, 83.2,
88.3, 102.8, 122.7, 125.6, 126.12, 126.14, 127.1, 128.3, 128.4,
1
1248, 1181, 1116, 1041 cm-1; H-NMR (400 MHz, CDCl3): δ =
1.20 (d, J = 6.9 Hz, 6H), 1.24 (d, J = 6.9 Hz, 6H), 2.80-2.93 (m,
2H), 3.07 (d, J = 16.9 Hz, 1H), 3.21 (d, J = 16.9 Hz, 1H), 3.43 (d, 105 129.2, 129.3, 129.5, 130.1, 132.2, 132.3, 135.3, 138.8, 140.4,
J = 16.5 Hz, 1H), 3.71 (dd, J = 16.0, 1.8 Hz, 1H), 5.61 (s, 1H),
50 7.09 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.24-7.26 (m,
2H), 7.29-7.33 (m, 1H), 7.38 (t, J = 8.2 Hz, 2H), 7.48-7.52 (m,
4H); 13C-NMR (100 MHz, CDCl3): δ = 23.9, 24.1, 29.9, 34.0,
145.9, 176.1; HRMS (ESI): calcd for C28H24NaO2, m/z 415.1674
([M+Na]+); found, m/z 415.1660.
(Z)-3-(But-2-ynyl)-5-ethylidene-3-phenyldihydrofuran-2(3H)-
23
34.2, 39.5, 51.5, 83.6, 84.5, 105.4, 120.2, 126.2, 126.5, 126.6, 110 one (9l). Yield: 93%; colorless oil; [α]D = +12.4 (c = 0.5,
128.2, 128.6, 129.1, 131.5, 131.9, 138.9, 145.2, 147.8, 149.4,
55 176.1; HRMS (ESI): calcd for C32H32NaO2, m/z 471.2300
([M+Na]+); found, m/z 471.2289. Enantiomeric excess: 71%,
determined by HPLC (Chiralpak AS, n-hexane/i-PrOH = 99/1,
CHCl3); IR (KBr): ν = 3468, 2923, 2360, 1792, 1495, 1443, 1222,
1137, 1038 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 1.67-1.69 (m,
3H), 1.77 (t, J = 2.7 Hz, 3H), 2.69-2.75 (m, 1H), 2.88-2.94 (m,
1H), 3.13-3.18 (m, 1H), 3.39-3.45 (m, 1H), 4.65-4.71 (m, 1H),
115 7.28-7.32 (m, 1H), 7.34-7.38 (m, 2H), 7.41-7.44 (m, 2H); 13C-
6 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 8
Organic & Biomolecular Chemistry
NMR (100 MHz, CDCl3): δ = 3.7, 10.5, 29.1, 37.8, 52.3, 74.0,
79.6, 99.8, 126.1, 128.0, 129.0, 139.3, 146.0, 176.4; HRMS
(ESI): calcd for C16H16NaO2, m/z 263.1048 ([M+Na]+); found,
m/z 263.1039. Enantiomeric excess: 32%, determined by HPLC
(Chiralpak OD-H, n-hexane/i-PrOH = 9/1, flow rate: 0.5 mL/min,
254 nm): major enantiomer: tR = 9.9 min, minor enantiomer: tR =
13.9 min.
Sharma, Int. J. Integrative Biol., 2007, 1, 72–87; (e) K. Kawazoe, Y.
Tsubouchi, N. Abdullah, Y. Takaishi, H. Shibata, T.VHieiwguAtrit,icHle.OHnolinrie
DOI: 10.1039/C3OB41103F
and M. Ogawa, J. Nat. Prod., 2003, 66, 538-539; (f) A. N. Pearce, E.
W. Chia, M. V. Berridge, E. W. Maas, M. J. Page, V. L. Webb, J. L.
Harper and B. R. Copp, J. Nat. Prod., 2007, 70, 111-113; (g) Y.-Y.
Ma, D.-G. Zhao and K. Gao, J. Nat. Prod., 2013, 76, 564-570; (h) H.
Takayama, T. Ichikawa, M. Kitajima, M. G. Nonato and N. Aimi.
Chem. Pharm. Bull., 2002, 50, 1303-1304.
5
7
For recent examples of intramolecular cyclization of alkynes, see: (a)
J. K. Vandavasi, W.-P. Hu, H.-Y. Chen, G. C. Senadi, C.-Y. Chen
and J.-J. Wang, Org. Lett., 2012, 14, 3134-3137; (b) D. Fujino, H.
Yorimitsu, and A. Osuka, Org. Lett., 2012, 14, 2914-2917; (c) S.
Sarkar, S. Dutta, R. Dey and S. Naskar, Tetrahedron Lett., 2012, 53,
6789-6792; (d) R. Rüttinger, J. Leutzow, M. Wilsdorf, K. Wilckens
and C. Czekelius, Org. Lett., 2011, 13, 224-227; (e) M. Yoshida, Y.
Fujino and T. Doi, Org. Lett., 2011, 13, 4526-4529; (f) C. S. Cho and
H. B. Kim, J. Organomet. Chem., 2011, 696, 3264-3267; (g) N.
Gouault, M. Le Roch, A. Cheignon, P. Uriac and M. David, Org.
Lett., 2011, 13, 4371-4373.
(Z)-Methyl
5-benzylidene-2-oxo-3-(3-phenylprop-2-
10 ynyl)tetrahydrofuran-3-carboxylate (9m).11a Yield: 92%; pale
23
yellow oil; [α]D = +15.7 (c = 0.7, CHCl3); IR (KBr): ν = 3059,
2955, 2360, 1805, 1745, 1697, 1599, 1490, 1440, 1246, 1115,
1031cm-1; 1H-NMR (400 MHz, CDCl3): δ = 3.15 (d, J = 16.9 Hz,
1H), 3.21 (d, J = 16.9 Hz, 1H), 3.45 (dd, J = 16.9, 1.8 Hz, 1H),
15 3.54 (dd, J = 16.9, 1.8 Hz, 1H), 3.83 (s, 3H), 5.64 (s, 1H), 7.18-
7.25 (m, 4H), 7.29-7.35 (m, 4H), 7.55 (d, J = 7.3 Hz, 2H); 13C-
NMR (100 MHz, CDCl3): δ = 25.2, 36.4, 53.8, 53.9, 82.7, 84.6,
105.8, 122.5, 127.1, 128.3, 128.5, 128.6, 128.6, 131.9, 133.6,
145.1, 168.8, 171.9; HRMS (ESI): calcd for C22H18NaO4, m/z
20 369.1103 ([M+Na]+); found, m/z 369.1093. Enantiomeric excess:
15%, determined by HPLC (Chiralpak OD-H, n-hexane/i-PrOH =
9/1, flow rate: 1.5 mL/min, 254 nm): major enantiomer: tR = 19.2
min, minor enantiomer: tR = 11.9 min.
8
For
a
review on transition-metal-catalyzed addition of
heteroatom−hydrogen bonds to alkynes, see: F. Alonso, I. P.
Beletskaya and M. Yus, Chem. Rev., 2004, 104, 3079-3160.
For a review on cyclization of alkynes highlighting Baldwin’s rules
for ring closure, see, K. Gilmore and I. V. Alabugin, Chem. Rev.,
2011, 111, 6513-6556.
For selected examples of palladium-catalyzed intramolecular
cyclization of γ-alkynoic acids, see: (a) J. García-Álvarez, J. Díez and
C. Vidal, Green Chem., 2012, 14, 3190-3196; (b) F. Neaţu, L.
Proteşescu, M. Florea, V. I. Pârvulescu, C. M. Teodorescu, N.
Apostol, P. Y. Toullec and V. Michelet, Green Chem., 2010, 12,
2145-2149; (c) Z. Huo, N. T. Patil, T. Jin, N. K. Pahadi and Y.
Yamamoto, Adv. Synth. Catal., 2007, 680-684; (d) A. Arcadi, A.
Burini, S. Cacchi, M. Delmastro, F. Marinelli, B. R. Pietroni, J. Org.
Chem., 1992, 57, 976-982; (e) R. W. Spencer, T. F. Tam, E. Thomas,
V. J. Robinson and A. Krantz, J. Am. Chem. Soc., 1986, 108, 5589-
5597; (f) C. Lambert, K. Utimoto and H. Nozaki, Tetrahedron Lett.,
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Acknowledgements
25 V.S. thanks Japan Society for the Promotion of Science (JSPS)
for a postdoctoral fellowship and SASTRA University for the
TRR research fund.
Notes and references
a The Institute of Scientific and Industrial Research (ISIR), Osaka
30 University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan. E-mail:
sasai@sanken.osaka-u.ac.jp; Fax: +81 6 6879 8465; Tel: +81 6 6879
8469
11
b Department of Chemistry, School of Chemical and Biotechnology,
SASTRA University, Thanjavur – 613 401, Tamil Nadu, India. E-mail:
35 vsridharan@scbt.sastra.edu, vesridharan@gmail.com
† Electronic Supplementary Information (ESI) available: Experimental
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