CO2-activation for γ-butyrolactones and its application in the total synthesis of (±)-heteroplexisolide e

Article abstract of DOI:10.1002/asia.201200467

An efficient nickel(0)-catalyzed highly regio- and stereoselective hydrocarboxylation of homopropargylic alcohols with ZnEt₂ in the presence of CO₂ (1 atm, balloon) to synthesize α-alkylidene- γ-butyrolactones is described. The catal

Full text of DOI:10.1002/asia.201200467

DOI: 10.1002/asia.201200467
CO2-Activation for g-Butyrolactones and Its Application in the Total
Synthesis of (ꢀ)-Heteroplexisolide E
Suhua Li[a] and Shengming Ma*[a, b]
Abstract: An efficient nickel(0)-catalyzed highly regio- and stereoselective hydro-
carboxylation of homopropargylic alcohols with ZnEt2 in the presence of CO2
(1 atm, balloon) to synthesize a-alkylidene-g-butyrolactones is described. The cata-
lyst is highly active and can be applied for the synthesis of (optically active) mono-
or bicyclic a-alkylidene-g-butyrolactones with excellent regio- and stereoselectivity
and good functional group tolerance. The potential of the reaction has been dem-
onstrated in the first synthesis of (ꢀ)-heteroplexisolide E.
Keywords: alkynes
tones · carbon dioxide · hydrocar-
boxylation · nickel
·
butyrolac-
Introduction
The a-alkylidene-g-butyrolactone moiety is widely present
in a large number of natural compounds (Figure 1),[1] which
show anticancer, antimalarial, antiviral, antibacterial, anti-
fungal, and antiinflammatory activities.[2,3] The exo-cyclic
double bond is considered not only to be responsible for
their interesting biological properties but also to serve as
a functional group for further manipulations in organic syn-
thesis.[4] Thus, the synthesis of a-methylene or alkylidene-g-
butyrolactones is still of current interest.[2] Recently, we
have developed the nickel-catalyzed hydrocarboxylation of
alkynes.[5] From retrosynthetic analysis, we envisioned that
hydrocarboxylation of
a
homopropargylic alcohol with
[6,7]
CO2
followed by lactonization would be the most effi-
cient way for the synthesis of a-alkylidene-g-lactones with
a hydrogen atom at the exo-cyclic double bond, in which the
hydroxy group could control the regioselectivity (Scheme 1).
Here, we would like to report the successful realization of
this reaction, which provides a straightforward route to a-al-
kylidene-g-butyrolactones with excellent functional group
tolerance and regio- and stereoselectivity.
Figure 1. Natural products bearing the a-alkylidene-g-butyrolactone sub-
structure.
Results and Discussion
To develop such a practical method, which could be used in
natural product synthesis, 4-phenyl-3-butyn-1-ol (1a) was
chosen as the model substrate for our initial study. The ex-
pected hydrolactonization product a-alkylidene-g-butyrolac-
tone (E)-2a was formed in 49% yield together with the eth-
yllactonization product (E)-3a in 17% yield in the presence
[a] S. Li, Prof. Dr. S. Ma
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032(P. R. China)
Fax : (+86)21-6260-9305
of 1 mol% of [NiACTHNUTRGNEUNG(cod)2] (cod=cycloocta-l,5-diene),
1.0 equivalent of CsF, 4 equivalents of ZnEt2, and a balloon
of CO2 in CH3CN (Table 1, entry 1).[5] Fortunately, when di-
methyl sulfoxide (DMSO) was used as the solvent, the selec-
tivity of (E)-2a/(E)-3a was improved dramatically (Table 1,
entry 2). After optimization, we observed that when the
loading of CsF was reduced to 20 mol%, the selectivity was
further improved to 93:1 ((E)-2a/(E)-3a). Reducing the cat-
E-mail: masm@sioc.ac.cn
[b] Prof. Dr. S. Ma
Shanghai Key Laboratory of Green Chemistry and Chemical Process
Department of Chemistry
East China Normal University
3663 North Zhongshan Lu, Shanghai 200062 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200467.
alyst loading of [NiACHTNUGTRNEUNG(cod)2] to 1 mol% had no effect on the
Chem. Asian J. 2012, 00, 0 – 0
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FULL PAPER
Scheme 1. Retrosynthetic analysis based on CO2 activation.
Table 1. Optimization of reaction conditions.[a]
Table 2. Stereoselective synthesis of a-alkylidene-g-butyrolactones by hy-
drocarboxylation of homopropargylic alcohols.[a]
Entry
CsF [equiv]
ZnEt2 [equiv]
T [8C]
Yield[b] [%]
(E)-2a
(E)-3a
Entry
R1/R2/R3/R4
t [h]
Yield of (E)-2[b] [%]
1[c]
2[d]
3
1.0
1.0
1.0
1.0
1.0
1.0
0.8
0.5
0.2
0
4
4
4
4
3
2
3
3
3
3
3
3
3
60
rt
40
50
rt
rt
rt
rt
rt
rt
rt
rt
rt
49
89
89
84
94
68[e]
93
92
93
85
94
91
90
17
5
5
6
3
2
2.5
2
1
1
Ph/H/H/H (1a)
0.67
3.0
3.0
3.0
2.0
0.75
1.0
0.5
–
84 (E)-2a
90 (E)-2b
84 (E)-2c
87 (E)-2d
84 (E)-2e
89 (E)-2 f
89 (E)-2g
90 (E)-2h
86 (E)-2i
2[c]
3
p-MeOC6H4/H/H/H (1b)
a-naphthyl/H/H/H (1c)
2-thienyl/H/H/H (1d)
nC5H11/H/H/H (1e)
Ph/H/Et/H (1 f)
Ph/H/Ph/H (1g)
p-MeOC6H4/H/Ph/Me (1h)
Ph/H/Me/Me (1i)
4[e]
5
4
5[d]
6
6
7
8
9
10
11[f]
12[g]
13[h]
7
8
9[e]
2
[a] The reaction was carried out with 0.5 mmol of 1, 1 mol% of [Ni-
AHCTUNGRTEG(NUNN cod)2] (1.4 mg, 0.005 mmol), 20 mol% of CsF (15.2 mg, 0.1 mmol),
3 equiv of ZnEt2 (1.5m in toluene, 1.0 mL), and a balloon of CO2 (about
0.2
0.2
0.2
trace
trace
trace
1 L) in DMSO (3 mL) at rt. [b] Yield of isolated product. [c] 3 mol% of
[NiACHTNUTRGNENG(U cod)2] was used and t=4 h (t=time for the hydrocarboxylation).
[d] 50 mol% of TsOH·H2O (47.8 mg, 0.251 mmol) was used. [e] No
TsOH·H2O was used.
[a] The reaction was carried out with 0.5 mmol of 1a, [NiACTHNUTRGNEUNG(cod)2]
(3 mol%), the indicated amount of CsF, ZnEt2 (1.5m in toluene, 1.0 mL),
and a balloon of CO2 (ca. 1 L) in DMSO (3 mL) at the indicated temper-
ature. [b] Yield as determined by 1H NMR spectroscopy. [c] CH3CN was
used as the solvent, t=12 h. [d] t=3 h. [e] 4% of (Z)-4-phenyl-3-buten-1-
ol was observed. [f] 1 mol% of [NiACHTNUGTRENNUNG
With the optimized reaction conditions in hand, we began
to explore the scope of this reaction (Table 2). To accelerate
the lactonization step, 20 mol% of TsOH·H2O (TSOH=p-
toluenesulfonic acid) was added. Different substituents at
the terminal position of the alkyne such as 4-methoxyphen-
yl, 1-naphthyl, 2-thienyl, and alkyl, were examined and af-
forded (E)-2b, (E)-2c, (E)-2d, (E)-2e, respectively, in good
yields (Table 2, entries 2–5). Secondary alcohols and tertiary
alcohols produced good to excellent yields of the corre-
sponding a-alkylidene-g-butyrolactones (Table 2, entries 6–
9).
of [Ni
16 h.
A
ACHTUNGTRENNUNG
yield of (E)-2a, however, a slightly higher (E)-2a/(E)-3a se-
lectivity (Table 1, entry 11) was observed; this reaction
could even be carried out with 0.25 mol% of [NiACTHNUGTRENUNG(cod)2] with
no obvious erosion in the yields (Table 1, entries 12 and 13),
thus showing the high efficiency of this modified catalytic
system.
It should be noted that tolerance of functional groups is
also challenging in modern organic synthesis. To our delight,
functional groups such as an ester (Table 3, entry 1), ketone
(Table 3, entry 2), cyano (Table 3, entry 3), amide (Table 3,
entry 4), phenol (Table 3, entry 5), and p-Br-substituted
phenyl groups (Table 3, entry 6) could all survive this trans-
formation.
Abstract in Chinese:
Optically active a-alkylidene-g-butyrolactone (S,E)-2p
was synthesized with >99% ee from optically active alcohol
(S)-1p [Scheme 2, Eq. (1)]. Substrates with a conjugated C=
C bond [Scheme 2, Eq. (2)] or an unconjugated C=C bond
[Scheme 2, Eq. (3)] could also be used. Fused bicyclic a-al-
kylidene-g-butyrolactones (trans,E)-2s could also be synthe-
sized by this method efficiently [Scheme 2, Eq. (4)].
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Stereoselective Synthesis of a-Alkylidene-g-Butyrolactones
Table 3. The compatibility of functional groups in hydro-lactonization of
homopropargylic alcohols.[a]
total synthesis of (ꢀ)-heteroplexisolide E was then accom-
plished efficiently by hydrocarboxylation of 7 under the
standard reaction conditions in 77% yield.
Conclusions
In conclusion, we have successfully developed a nickel(0)-
catalyzed CO2 activation under mild conditions for the syn-
thesis of relatively complex molecules. Due to readily avail-
ability of various homopropargylic alcohols, excellent cata-
lytic activity, high regio- and stereoselectivity, and good
functional group tolerance, this transformation will be
a practical method for the highly selective synthesis of natu-
ral lactones. Further studies in this area including natural
product synthesis, alkyl- or arylative carboxylation of vari-
ous alkynes and its analogues are being pursued in our labo-
ratory.
Entry
R’
t [h]
Yield of (E)-2[b] [%]
1
2
3
4
EtO2C (1j)
Ac (1k)
NC (1l)
Et2NCO (1m)
HO (1n)
Br (1o)
1.5
4.5
4.0
3.0
1.5
3.0
83 (E)-2j
81 (E)-2k
71 (E)-2l
80 (E)-2m
85 (E)-2n
69 (E)-2o
5[c]
6[d]
[a] The reaction was carried out with 0.5 mmol of 1, 1 mol% of [Ni-
ACHTUNGTRENNUNG(cod)2] (1.4 mg, 0.005 mmol), 20 mol% of CsF (15.2 mg, 0.1 mmol),
3 equiv of ZnEt2 (1.5m in toluene, 1.0 mL), and a balloon of CO2 (about
1 L) in DMSO (3 mL ) at rt. [b] Yield of isolated product. [c] 4 equiv of
ZnEt2 (1.5m in toluene, 1.33 mL, 2.0 mmol) were used. [d] The reaction
time is 5 h.
Experimental Section
With this method in hand, heteroplexisolide E that bears
an a-alkylidene-g-butyrolactone moiety together with a sen-
sitive ketone and an isocrotyl group, which was isolated
from Heteroplexis micocephala in 2009,[1a] was selected as
our target (Scheme 3).[8] Homopropargylic alcohol 4 was
prepared from 3-bromopropyne and 3-methyl-2-butenal in
the presence of Mg and HgCl2 (0.5 mol%). After protecting
the hydroxy group in 4 by treating it with vinyl ethyl ether,
product 7 was obtained by alkylation of terminal alkyne 5
and the subsequent removal of the protecting group. The
General Information
All reactions were carried out in oven-dried Schlenk tubes. [NiACHTUNGTRENNUNG(cod)2]
was purchased from Sigma–Aldrich. Et2Zn (1.5m in toluene) was pur-
chased from Acros (New Jersey, USA). CsF (purity: 99.9%) was pur-
chased from Alfa (Ward Hill, USA). CH3CN and DMSO were dried
over calcium hydride before distillation. The purity of CO2 is over
99.995% and used without purification. All the temperatures are referred
to the bath temperature. Petroleum ether (b.p. 60–908C) was used, unless
otherwise stated.
Typical procedure for the synthesis of
(E)-3-benzylidenedihydro-2ACTHNUTRGENUG(N 3H)-
furanone ((E)-2a)
[NiACTHNURTGNENG(U cod)2] (1.4 mg, 0.005 mmol), CsF
(15.4 mg, 0.101 mmol), alkynol 1a
(73.4 mg, 0.502 mmol), and DMSO
(3 mL) were added to an oven dried
Schlenk tube under an argon atmos-
phere. The mixture was then frozen
with a liquid nitrogen bath and the
argon inside was completely replaced
with a CO2 balloon (ca. 1 L). Then the
reaction flask was allowed to stand
until the mixture thawed. ZnEt2
(1.0 mL, 1.5m in toluene, 1.50 mmol)
was added to the resulting suspension
with a syringe. Then the resulting mix-
ture was stirred at room temperature
(20–308C) for 6.0 h (until completion
of the reaction as monitored by TLC),
the resulting mixture was quenched
with 3m HCl (5 mL). The aqueous
layer was extracted with EtOAc
(5 mLꢁ5) and concentrated. The
crude product was dissolved in CH2Cl2
(5 mL), which was followed by the ad-
dition
of
TsOH·H2O
(19.2 mg,
0.101 mmol). The mixture was stirred
at room temperature for 40 minutes.
Then CH2Cl2 (15 mL) was added and
the resulting mixture was washed with
water (5 mLꢁ2) and brine, dried over
Scheme 2. Synthesis of other functionalized a-alkylidene-g-butyrolactones.
Chem. Asian J. 2012, 00, 0 – 0
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Shengming Ma et al.
FULL PAPER
(E)-2c[10] (84%, 94.4 mg) as a white
solid. M.p. 103–1048C (petroleum
ether/ethyl acetate) (Lit.[10] m.p. 104–
1058C); 1H NMR (300 MHz, CDCl3):
d=8.29 (t, J=2.7 Hz, 1H, C=CH),
8.14–8.06 (m, 1H, ArH), 7.91–7.83 (m,
2H, ArH), 7.60–7.45 (m, 4H, ArH),
4.41 (t, J=7.2 Hz, 2H, CH2O),
3.15 ppm (td, J1 =7.2 Hz, J2 =2.7 Hz,
2H, C=CCH2); 13C NMR (75 MHz,
CDCl3): d=171.9, 133.5, 133.3, 131.6,
131.3, 130.1, 128.7, 126.9, 126.3, 126.1,
125.0, 123.5, 65.5, 27.4 ppm; MS (m/z):
224 (M+, 28.30), 165 (100); IR (neat):
n˜ =3056, 2981, 2923, 1735, 1644, 1619,
1573, 1508, 1477, 1428, 1398, 1375,
1363, 1335, 1267, 1243, 1215, 1191,
1168, 1095, 1056, 1021 cmꢁ1
.
(E)-3-(2-thienylmethylene)dihydro-
(3H)-furanone ((E)-2d)
2ACHTUNGTRENNUNG
Same procedure as that described for
(E)-2a: The reaction of alkyne 1d
Scheme 3. Synthesis of (ꢀ)-heteroplexisolide E.
(76.2 mg,
0.501 mmol),
[NiACHTUNGTRENNUNG(cod)2]
(1.4 mg, 0.005 mmol), CsF (15.5 mg,
0.102 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.50 mmol), in DMSO
(3 mL) afforded the crude product, which was then treated with
TsOH·H2O (19.6 mg, 0.103 mmol) in CH2Cl2 (5 mL) for 3 h to afford
(E)-2d[11] (87%, 78.5 mg, petroleum ether/ethyl acetate=6:1) as a white
solid. M.p. 130–1318C (petroleum ether/ethyl acetate) (Lit.[11] m.p. 130.3–
131.28C); 1H NMR (300 MHz, CDCl3): d=7.75 (s, 1H, C=CH), 7.57 (d,
J=5.1 Hz, 1H, H-thiophene), 7.33 (d, J=3.3 Hz, 1H, H-thiophene), 7.16
(t, J=4.4 Hz, 1H, H-thiophene), 4.48 (t, J=7.4 Hz, 2H, CH2O),
3.14 ppm (td, J1 =7.2 Hz, J2 =2.7 Hz, 2H, C=CCH2); 13C NMR (75 MHz,
CDCl3): d=172.1, 138.9, 132.2, 130.1, 129.0, 128.0, 121.0, 65.2, 27.2 ppm;
MS (m/z): 180 (M+, 71.72), 122 (100); IR (neat): n˜ =3116, 3086, 3001,
2977, 2919, 1731, 1642, 1511, 1471, 1416, 1385, 1358, 1318, 1274, 1233,
anhydrous MgSO4, filtrated, and concentrated. The crude product was
purified by column chromatography on silica gel (petroleum ether
(b.p. 30–608C)/ethyl acetate=5:1) to afford (E)-2a[9] (84%, 73.7 mg)) as
a
white solid. M.p. 1208C (petroleum ether/ethyl acetate) (Lit.[9]
m.p. 1208C); 1H NMR (300 MHz, CDCl3): d=7.55 (t, J=3.0 Hz, 1H, C=
CH), 7.52–7.35 (m, 5H, ArH), 4.45 (t, J=7.2 Hz, 2H, CH2O), 3.22 ppm
(td, J1 =7.2 Hz, J2 =3.0 Hz, 2H, C=CCH2); 13C NMR (75 MHz, CDCl3):
d=172.4, 136.4, 134.5, 129.8, 129.7, 128.8, 123.5, 65.3, 27.3 ppm; MS (m/
z): 174 (M+, 4.07), 51 (100); IR (KBr): n˜ =3086, 3049, 2994, 2920, 2845,
1737, 1649, 1596, 1572, 1491, 1447, 1390, 1365, 1314, 1293, 1275, 1226,
1189, 1059, 1028 cmꢁ1
(E)-3-(4-methoxybenzylidene)dihydro-2
Same procedure as that described for (E)-2a: The reaction of alkyne 1b
.
1206, 1174, 1076, 1043, 1026 cmꢁ1
(E)-3-hexylidenedihydro-2(3H)-furanone ((E-2e)
Same procedure as that described for (E)-2a: The reaction of alkyne 1e
.
AHCTUNGERTG(NNUN 3H)-furanone ((E)-2b)
AHCTUNGTRENNUNG
(88.7 mg, 0.503 mmol), [Ni(cod)2] (4.1 mg, 0.015 mmol), CsF (15.6 mg,
ACHTUNGTRENNUNG
0.103 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.50 mmol), in DMSO
(3 mL) for 4 h afforded the crude product, which was treated with
TsOH·H2O (19.2 mg, 0.101 mmol) in CH2Cl2 (5 mL) for 3 h to afford
(E)-2b[9] (90%, 92.3 mg, petroleum ether/ethyl acetate=3:1) as a white
solid. M.p. 125–1268C (petroleum ether/ethyl acetate) (Lit.[9] m.p. 124–
1268C); 1H NMR (400 MHz, CDCl3): d=7.51 (s, 1H, C=CH), 7.46 (d,
J=8.0 Hz, 2H, ArH), 6.96 (d, J=8.0 Hz, 2H, ArH), 4.45 (t, J=7.2 Hz,
2H, CH2O), 3.85 (s, 3H, OMe), 3.21 ppm (t, J=7.2 Hz, 2H, C=CCH2);
13C NMR (100 MHz, CDCl3): d=172.8, 160.8, 136.3, 131.7, 127.4, 120.6,
114.4, 65.2, 55.3, 27.3 ppm; MS (m/z): 204 (M+, 100); IR (KBr): n˜ =3066,
2996, 2967, 2916, 2842, 1735, 1651, 1599, 1514, 1464, 1443, 1387, 1363,
(70.0 mg, 0.499 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.1 mg,
ACHTUNGTRENNUNG
0.099 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.50 mmol), in DMSO
(3 mL) afforded the crude product, which was then treated with
TsOH·H2O (47.8 mg, 0.251 mmol) in CH2Cl2 (5 mL) for 2 h to afford
(E)-2e[12] (84%, 70.7 mg, petroleum ether/ethyl acetate=7:1) as a liquid.
1H NMR (300 MHz, CDCl3): d=6.80–6.68 (m, 1H, C=CH), 4.37 (t, J=
7.5 Hz, 2H, CH2O), 2.88 (t, J=7.4 Hz, 2H, C=C(CO)CH2), 2.20 (q, J=
7.4 Hz, 2H, CH2C=C(CO)), 1.56–1.42 (m, 2H, CH2 in C5H11), 1.39–1.24
(m, 4H, CH2CH2 in C5H11), 0.90 ppm (t, J=6.3 Hz, 3H, Me); 13C NMR
(100 MHz, CDCl3): d=171.2, 140.8, 125.1, 65.2, 31.3, 30.0, 27.6, 24.9, 22.3,
13.8 ppm; MS (m/z): 168 (M+, 1.43), 99 (100); IR (neat): n˜ =2957, 2930,
2860, 1756, 1680, 1485, 1466, 1380, 1351, 1284, 1217, 1191, 1146,
1307, 1258, 1235, 1170, 1121, 1054, 1027 cmꢁ1
(E)-3-(1-naphthylidene)dihydro-2(3H)-furanone ((E)-2c)
Same procedure as that described for (E)-2a: The reaction of alkyne 1c
.
1027 cmꢁ1
(E)-3-benzylidene-5-ethyldihydro-2
Same procedure as that described for (E)-2a: The reaction of alkyne 1 f
.
AHCTUNGTRENNUNG
AHCTUNGERTG(NNUN 3H)-furanone ((E)-2 f)
(98.2 mg, 0.500 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.7 mg,
ACHTUNGTRENNUNG
0.103 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.50 mmol), in DMSO
(3 mL) at rt afforded the crude product, which was treated with
TsOH·H2O (19.3 mg, 0.101 mmol) in CH2Cl2 (5 mL) for 3 h, then CH2Cl2
(15 mL) was added and the resulting mixture was washed with water
(5 mLꢁ2) and brine (5 mL), dried over anhydrous MgSO4, filtrated, and
concentrated until 5 mL of CH2Cl2 remained. Then pyridinium toluene-4-
sulphonate (PPTS; 12.6 mg, 0.050 mmol) and ethyl vinyl ether (100 mL)
were added to remove a trace amount of protonlysis product by trans-
forming it to the corresponding acetal (about 1.6%), which could not be
isolated from the reaction by column chromatography. After stirring at rt
for 30 min, the mixture was concentrated and purified by column chro-
matography on silica gel (petroleum ether/ethyl acetate=5:1) to afford
(87.3 mg, 0.501 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.8 mg,
ACHTUNGTRENNUNG
0.104 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.0 mg, 0.100 mmol) in CH2Cl2 (5 mL) for 45 min to afford (E)-2 f
(89%, 90.6 mg, petroleum ether/ethyl acetate=10:1) as a white solid.
M.p. 44–458C (petroleum ether); 1H NMR (400 MHz, CDCl3): d=7.56–
7.35 (m, 6H, ArH and C=CH), 4.54 (quint, J=6.4 Hz, 1H, CHO), 3.31
(dd, J1 =17.4 Hz, J2 =7.8 Hz, 1H, H in C=CCH2), 2.81 (d, J=17.6 Hz,
1H, H in C=CCH2), 1.85–1.65 (m, 2H, CH2 in Et), 1.03 ppm (t, J=
7.4 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3): d=171.8, 136.0, 134.5,
129.7, 129.5, 128.7, 124.7, 78.6, 32.9, 29.2, 8.9 ppm; MS (m/z): 202 (M+,
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Stereoselective Synthesis of a-Alkylidene-g-Butyrolactones
26.06), 116 (100); IR (KBr): n˜ =1742, 1653, 1596, 1575, 1491, 1450, 1389,
1355, 1307, 1274, 1228, 1189, 1159, 1110, 1069, 1055, 1011 cmꢁ1; Anal.
calcd for C13H14O2: C 77.20, H 6.98; found: C 77.38, H 7.35.
(E)-3-(4-acetylbenzylidene)dihydro-2
ACHTUNGERTN(NUNG 3H)-furanone ((E)-2k)
Same procedure as that described for (E)-2a: The reaction of alkyne 1k
(94.4 mg, 0.502 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.6 mg,
ACHTUNGTRENNUNG
0.103 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.50 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.3 mg, 0.101 mmol) in CH2Cl2 (5 mL) for 4.5 h to afford (E)-2k (81%,
(E)-3-benzylidene-5-phenyldihydro-2
ACHTUNGERTN(NUNG 3H)-furanone ((E)-2g)
Same procedure as that described for (E)-2a: The reaction of alkyne 1g
(111.3 mg, 0.501 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.6 mg,
ACHTUNGTRENNUNG
87.8 mg, petroleum ether/ethyl acetate=3:1–2:1) as
a white solid.
M.p. 164–1658C (petroleum ether/ethyl acetate); 1H NMR (400 MHz,
CDCl3): d=8.02 (d, J=7.6 Hz, 2H, ArH), 7.63–7.55 (m, 3H, ArH and
C=CH), 4.51 (t, J=7.0 Hz, 2H, CH2O), 3.30 (t, J=6.8 Hz, 2H, C=
CCH2), 2.64 ppm (s, 3H, Me); 13C NMR (100 MHz, CDCl3): d=197.2,
171.9, 138.8, 137.3, 135.0, 129.9, 128.7, 126.2, 65.4, 27.4, 26.6 ppm; MS (m/
z): 216 (M+, 29.23), 201 (100); IR (KBr): n˜ =3070, 2990, 2925, 1737,
1678, 1651, 1600, 1513, 1481, 1413, 1358, 1306, 1269, 1225, 1179, 1121,
1056, 1022 cmꢁ1; Anal. calcd for C13H12O3: C 72.21, H 5.59; found: C
72.13, H 5.76.
0.103 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.4 mg, 0.102 mmol) in CH2Cl2 (5 mL) for 1 h to afford (E)-2g[13] (89%,
111.0 mg, petroleum ether/ethyl acetate=8:1) as
a
white solid.
M.p. 1278C (petroleum ether/ethyl acetate) (Lit.[14] m.p. 1198C);
1H NMR (400 MHz, CDCl3): d=7.63 (s, 1H, C=CH), 7.53–7.30 (m, 10H,
ArH), 5.60 (t, J=6.6 Hz, 1H, CHO), 3.69 (dd, J1 =17.4 Hz, J2 =8.2 Hz,
1H, H in C=CCH2), 3.15 ppm (dt, J1 =17.2 Hz, J2 =2.4 Hz, 1H, H in C=
CCH2); 13C NMR (100 MHz, CDCl3): d=172.0, 140.2, 136.9, 134.5, 130.0,
129.9, 128.90, 128.85, 128.5, 125.3, 124.0, 78.1, 36.5 ppm; MS (m/z): 250
(M+, 6.20), 116 (100); IR (KBr): n˜ =1735, 1650, 1575, 1494, 1452, 1320,
(E)-3-(4-cyanobenzylidene)dihydro-2
ACHTUNGERTN(NUNG 3H)-furanone ((E-2l)
1229, 1190, 1069, 1027 cmꢁ1
.
Same procedure as that described for (E)-2a: The reaction of alkyne 1l
(85.8 mg, 0.501 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.3 mg,
ACHTUNGTRENNUNG
(E)-3-(4-methoxybenzylidene)-5-methyl-5-phenyldihydro-2ACTHNUTRGNEUGN(3H)-furanone
0.101 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.4 mg, 0.102 mmol) in CH2Cl2 (5 mL) for 4 h to afford (E)-2l[16] (71%,
71.1 mg, petroleum ether/ethyl acetate=3:1) as a white solid. M.p. 159–
1608C (petroleum ether/ethyl acetate) (Lit.[16] m.p. 158–1608C); 1H NMR
(300 MHz, CDCl3): d=7.75 (d, J=8.4 Hz, 2H, ArH), 7.61 (d, J=8.4 Hz,
2H, ArH), 7.56 (t, J=2.7 Hz, 1H, C=CH), 4.52 (t, J=7.2 Hz, 2H,
OCH2), 3.29 ppm (td, J1 =7.1 Hz, J2 =2.9 Hz, 2H, C=CCH2); 13C NMR
(75 MHz, CDCl3): d=171.5, 138.7, 134.1, 132.5, 130.1, 127.4, 118.2, 112.7,
65.4, 27.3 ppm; MS (m/z): 199 (M+, 55.14), 141 (100); IR (neat): n˜ =
2924, 2852, 2221, 1738, 1653, 1604, 1505, 1486, 1462, 1416, 1389, 1363,
((E)-2h)
Same procedure as that described for (E)-2a: The reaction of alkyne 1h
(133.7 mg, 0.502 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.5 mg,
0.102 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.4 mg, 0.102 mmol) in CH2Cl2 (5 mL) for 0.5 h to afford (E)-2h (90%,
AHCTUNGTRENNUNG
132.7 mg, petroleum ether/ethyl acetate=7:1) as
a
white solid.
1
M.p. 1028C (petroleum ether/ethyl acetate); H NMR (400 MHz, CDCl3):
d=7.54 (s, 1H, C=CH), 7.48–7.32 (m, 6H, ArH), 7.31–7.24 (m, 1H,
ArH), 6.93 (d, J=8.4 Hz, 2H, ArH), 3.81 (s, 3H, OMe), 3.38 (s, 2H, C=
CCH2), 1.76 ppm (s, 3H, OCMe); 13C NMR (100 MHz, CDCl3): d=
171.6, 160.8, 145.0, 136.7, 131.7, 128.5, 127.4, 127.1, 124.0, 121.9, 114.2,
83.7, 55.2, 42.8, 30.2 ppm; MS (m/z): 294 (M+, 10.14), 146 (100); IR
(neat): n˜ =1734, 1648, 1600, 1511, 1493, 1443, 1421, 1385, 1373, 1315,
1313, 1289, 1224, 1185, 1121, 1058, 1028 cmꢁ1
(E)-3-(4-cyanobenzylidene)dihydro-2(3H)-furanone ((E)-2m)
Same procedure as that described for (E)-2a: The reaction of alkyne 1m
.
AHCTUNGTRENNUNG
1294, 1282, 1246, 1205, 1172, 1147, 1123, 1077, 1040, 1028, 1016 cmꢁ1
Anal. calcd for C19H18O3: C 77.53, H 6.16; found: C 77.46, H 5.97.
;
(122.9 mg, 0.501 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.6 mg,
ACHTUNGTRENNUNG
0.103 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.4 mg, 0.102 mmol) in CH2Cl2 (5 mL) for 3 h to afford (E)-2m (80%,
(E)-3-benzylidene-5,5-dimethyldihydro-2
ACHTUNGERTN(NUNG 3H)-furanone ((E)-2i)
109.0 mg, petroleum ether/ethyl acetate=1:1–1:2) as
a white solid.
Same procedure as that described for (E)-2a: The reaction of alkyne 1i
M.p. 108–1098C (petroleum ether/ethyl acetate); 1H NMR (300 MHz,
CDCl3): d=7.58 (t, J=2.9 Hz, 1H, C=CH), 7.54 (d, J=8.1 Hz, 2H,
ArH), 7.45 (d, J=8.1 Hz, 2H, ArH), 4.50 (t, J=7.4 Hz, 2H, OCH2),
3.68–3.44 (m, 2H, CH2 in Et), 3.40–3.14 (m, 4H, C=CCH2 and CH2 in
Et), 1.38–1.10 ppm (m, 6H, Me in Et); 13C NMR (75 MHz, CDCl3): d=
172.1, 170.1, 138.2, 135.4, 135.1, 129.8, 126.7, 124.6, 65.3, 43.1, 39.1, 27.2,
14.1, 12.7 ppm; MS (m/z): 273 (M+, 16.89), 42 (100); IR (neat): n˜ =1741,
1653, 1620, 1604, 1510, 1478, 1461, 1433, 1405, 1386, 1357, 1309, 1294,
1231, 1192, 1176, 1097, 1075, 1056, 1030. Anal. calcd for C16H19NO3: C
70.31, H 7.01, 5.12 cmꢁ1; found: C 70.24, H 6.87, N 5.01.
(87.1 mg, 0.500 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.3 mg,
ACHTUNGTRENNUNG
0.101 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in DMSO
(3 mL) (no TsOH·H2O was used) afforded (E)-2i[15] (86%, 87.3 mg, pe-
troleum ether (b.p. 30–608C)/ethyl acetate=10:1) as
a white solid.
M.p. 76–778C (petroleum ether/ethyl acetate) (Lit.[15] m.p. 778C);
1H NMR (400 MHz, CDCl3): d=7.56 (s, 1H, C=CH), 7.52–7.35 (m, 5H,
ArH), 3.04 (s, 2H, C=CCH2), 1.48 ppm (s, 6H, CMe2); 13C NMR
(100 MHz, CDCl3): d=171.4, 136.6, 134.6, 129.8, 129.6, 128.8, 126.0, 81.7,
41.2, 28.7 ppm; MS (m/z): 202 (M+, 13.01), 116 (100); IR (neat): n˜ =
1727, 1656, 1574, 1493, 1464, 1449, 1385, 1373, 1331, 1317, 1281, 1193,
1147, 1058 cmꢁ1
(E)-3-(4-ethoxycarbonylbenzylidene)dihydro-2
Same procedure as that described for (E)-2a: The reaction of alkyne 1j
.
(E)-3-(4-hydroxybenzylidene)dihydro-2
ACHTUNGERTN(NUNG 3H)-furanone ((E)-2n)
AHCTUNGERTG(NNUN 3H)-furanone ((E)-2j)
Same procedure as that described for (E)-2a: The reaction of alkyne 1n
(81.3 mg, 0.501 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.5 mg,
ACHTUNGTRENNUNG
0.102 mmol), ZnEt2 (1.33 mL, 1.5m in toluene, 2.0 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.3 mg, 0.101 mmol) in CH2Cl2 (5 mL) for 1.5 h to afford (E)-2n[10]
(85%, 81.1 mg, petroleum ether/ethyl acetate=2:1) as a white solid.
M.p. 181–1828C (petroleum ether/ethyl acetate) (Lit.[10] m.p. 181–1828C);
1H NMR (300 MHz, [D6]DMSO): d=10.04 (s, 1H, OH), 7.48 (d, J=
8.4 Hz, 2H, ArH), 7.33 (s, 1H, C=CH), 6.87 (d, J=8.4 Hz, 2H, ArH),
4.39 (t, J=7.2 Hz, 2H, CH2O), 3.18 ppm (td, J1 =7.2 Hz, J2 =2.1 Hz, 2H,
C=CCH2); 13C NMR (75 MHz, [D6]DMSO): d=172.3, 159.1, 135.0, 132.1,
125.6, 120.7, 115.9, 65.2, 26.8 ppm; MS (m/z): 190 (M+, 5.74), 43 (100);
IR (neat): n˜ =3316, 1717, 1650, 1599, 1517, 1483, 1440, 1360, 1310, 1273,
(109.6 mg, 0.502 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.4 mg,
ACHTUNGTRENNUNG
0.101 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.50 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.4 mg, 0.102 mmol) in CH2Cl2 (5 mL) for 1.5 h to afford (E)-2j (83%,
103.1 mg, petroleum ether/ethyl acetate=3:1) as a white solid. M.p. 150–
1518C (petroleum ether/ethyl acetate); 1H NMR (300 MHz, CDCl3): d=
8.10 (d, J=8.1 Hz, 2H, ArH), 7.62–7.52 (m, 3H, ArH and C=CH), 4.50
(t, J=7.1 Hz, 2H, CH2O), 4.40 (q, J=7.1 Hz, 2H, CH2 in Et), 3.29 (td,
J1 =7.1 Hz, J2 =3.0 Hz, 2H, C=CCH2), 1.41 ppm (t, J=7.1 Hz, 3H, Me);
13C NMR (75 MHz, CDCl3): d=171.9, 165.8, 138.6, 135.2, 131.2, 129.9,
129.6, 126.0, 65.4, 61.2, 27.4, 14.2 ppm; MS (m/z): 246 (M+, 10.72), 115
(100); IR (neat): n˜ =1746, 1699, 1645, 1605, 1566, 1471, 1443, 1417, 1386,
1369, 1318, 1282, 1224, 1187, 1128, 1110, 1059, 1026 cmꢁ1; Anal. calcd for
C14H14O4: C 68.28, H 5.73; found: C 68.01, H 5.79.
1237, 1187, 1168, 1062, 1023 cmꢁ1
.
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
5
&
&
&
These are not the final page numbers! ÞÞ

Shengming Ma et al.
FULL PAPER
(E)-3-(4-bromobenzylidene)dihydro-2
(3H)-furanone ((E)-2o)
136.1, 134.7, 129.9, 129.7, 128.8, 125.0, 123.6, 74.3, 34.8, 25.7, 18.4 ppm;
MS (m/z): 228 (M+, 5.10), 116 (100); IR (neat): n˜ =1745, 1653, 1576,
Same procedure as that described for (E)-2a: The reaction of alkyne 1o
(112.0 mg, 0.498 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.4 mg,
1493, 1448, 1378, 1319, 1293, 1270, 1224, 1177, 1107, 1066, 1018 cmꢁ1
;
AHCTUNGTRENNUNG
HRMS calcd for C15H16O2 [M+]: 228.1150; found: 228.1152.
0.101 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.50 mmol), in DMSO
(3 mL) at rt for 5 h afforded the crude product, which was treated with
TsOH·H2O (19.3 mg, 0.101 mmol) in CH2Cl2 (5 mL) for 3 h to afford
(E)-2o[17] (69%, 86.8 mg, petroleum ether/ethyl acetate=12:1–5:1) as
a white solid. M.p. 153–1548C (petroleum ether/ethyl acetate) (Lit.[17]
m.p. 151–1528C); 1H NMR (400 MHz, CDCl3): d=7.57 (d, J=7.2 Hz,
2H, ArH), 7.48 (s, 1H, C=CH), 7.36 (d, J=7.2 Hz, 2H, ArH), 4.47 (t, J=
6.6 Hz, 2H, CH2O), 3.21 ppm (t, J=6.8 Hz, 2H, C=CCH2); 13C NMR
(100 MHz, CDCl3): d=172.0, 135.1, 133.5, 132.1, 131.2, 124.4, 124.1, 65.3,
G
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
(15.6 mg, 0.103 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in
DMSO (3 mL) afforded the crude product, which was treated with
TsOH·H2O (19.4 mg, 0.102 mmol) in CH2Cl2 (5 mL) for 37 h to afford
(trans,E)-2s[19] (90%, 102.8 mg, petroleum ether/ethyl acetate=10:1) as
a white solid. M.p. 108–1098C (petroleum ether/ethyl acetate); 1H NMR
(400 MHz, CDCl3): d=7.60 (s, 1H, C=CH), 7.42–7.29 (m, 5H, ArH),
3.75 (t, J=11.0 Hz, 1H, OCH), 2.72 (t, J=10.8 Hz, 1H, C=CCH), 2.35–
2.15 (m, 2H, CH2 in cyclohexane), 1.95–1.85 (m, 1H, H in cyclohexane),
1.80–1.57 (m, 2H, H in cyclohexane), 1.45–1.24 (m, 2H, H in cyclohex-
27.3 ppm; MS (m/z): 254 (M
(100); IR (KBr): n˜ =1735, 1648, 1580, 1486, 1436, 1402, 1379, 1354, 1305,
1277, 1231, 1183, 1116, 1068, 1031, 1004 cmꢁ1
+A(81Br), 27.36), 252 (M+A(79Br), 29.70), 115
CHUTGTNRENNUG HCTUNGTRENNUGN
.
A
ACHTUNGTRENNUNG
ane), 1.01 ppm (q, J=11.7 Hz, 1H,
H
in cyclohexane); 13C NMR
(100 MHz, CDCl3): d=171.9, 135.8, 133.8, 130.6, 129.2, 128.8, 128.0, 83.4,
48.0, 30.3, 26.2, 25.3, 23.9 ppm; MS (m/z): 228 (M+, 28.54), 115 (100); IR
(neat): n˜ =1743, 1660, 1576, 1495, 1446, 1390, 1344, 1318, 1278, 1229,
1p (80.4 mg, 0.502 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.4 mg,
ACHTUNGTRENNUNG
0.101 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.3 mg, 0.101 mmol) in CH2Cl2 (5 mL) for 0.5 h to afford (S,E)-2p[18]
(89%, 83.6 mg, petroleum ether/ethyl acetate=8:1) as a white solid.
1207, 1187, 1132, 1093, 1067, 1035, 1012 cmꢁ1
.
Synthesis of (ꢀ)-Heteroplexisolide E
M.p. 598C
Lit.[18] m.p. 54–54.58C; 99.6% ee; HPLC conditions: Chiralpak AS-H, n-
hexane/2-propanol=70:30, 0.6 mLminꢁ1
l=230 nm, tr 18.587 min
(petroleum
ether/ethyl
acetate)
(For
(rac,E)-2p,
Synthesis of 4[20]: Magnesium turnings (1.3392 g, 55.1 mmol) were added
to a 250 mL three-necked flask. The vessel was dried with a heating gun
under vacuum. Then HgCl2 (75.3 mg, 0.277 mmol) was added at room
temperature followed by dry Et2O (50 mL). After being stirred for 0.5 h
at room temperature, the mixture was cooled to 08C followed by addi-
tion of propargyl bromide (0.3 mL). After being stirred at 08C for
20 min, the reaction was initiated and the remaining propargyl bromide
(total 6.1913 g, 52.2 mmol) was added slowly dropwise to keep the inter-
nal temperature at 5–108C. After an additional 1 h at 08C (bath tempera-
ture), a solution of 3-methyl-2-butenal (3.5356 g, 42.0 mmol) in Et2O
(20 mL) was added dropwise at ꢁ408C over a period of 25 min. Then the
mixture was warmed to room temperature and stirred overnight, poured
into a solution of sat. aqueous NH4Cl and extracted with Et2O (30 mLꢁ
4), washed with brine, dried over anhydrous MgSO4, filtrated, and con-
centrated. The product 4[21] (4.8652 g, 93%, liquid) can be directly used
without further purification: 1H NMR (300 MHz, CDCl3): d=5.26 (dt,
J1 =8.4 Hz, J2 =1.4 Hz, 1H, C=CH), 4.60–4.47 (m, 1H, OCH), 2.44–2.38
,
(minor), 20.527 min (major). ½aꢂ2D0 =ꢁ92.8 (c=0.99, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.58–7.35 (m, 6H, ArH and C=CH), 4.74 (sext,
J=6.2 Hz, 1H, CH2O), 3.37 (dd, J1 =17.6 Hz, J2 =8.0 Hz, 1H, H in C=
CCH2), 2.79 (dt, J1 =17.3 Hz, J2 =2.6 Hz, 1H, H in C=CCH2), 1.46 ppm
(d, J=6.0 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3): d=171.9, 136.3,
134.5, 129.8, 129.6, 128.7, 124.8, 73.9, 35.1, 22.2 ppm; MS (m/z): 188 (M+,
43.98), 116 (100); IR (KBr): n˜ =1741, 1651, 1598, 1573, 1494, 1450, 1430,
1387, 1345, 1279, 1232, 1190, 1130, 1097, 1065, 1036 cmꢁ1; Anal. calcd for
C12H12O2: C 76.57, H 6.43; found: C 76.67, H 6.53.
(E)-3-((E)-2,3-dibenzyl-5-hydroxypent-2-enylidene)hexylidenedihydro-
2ACHTUNGTRENNUNG
Same procedure as that described for (E)-2a: The reaction of alkyne 1q
(160.4 mg, 0.501 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.3 mg,
ACHTUNGTRENNUNG
0.101 mmol), ZnEt2 (1.33 mL, 1.5m in toluene, 2.0 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.1 mg, 0.100 mmol) in CH2Cl2 (5 mL) for 3 h to afford (E,E)-2q (85%,
ꢁ
(m, 2H, CH2), 2.05 (t, J=2.7 Hz, 1H, H in C triple bond), 1.98 (brs,
1H, OH), 1.74 (d, J=1.2 Hz, 3H, C=CMe), 1.72 ppm (d, J=1.2 Hz, 3H,
C=CMe); 13C NMR (75 MHz, CDCl3): d=136.8, 125.8, 80.8, 70.4, 66.7,
27.6, 25.7, 18.3 ppm; MS (m/z): 123 [MꢁH]+, 1.24), 85, (100); IR (neat):
n˜ =3297, 2973, 2932, 2915, 2120, 1676, 1446, 1377, 1260, 1218, 1169, 1115,
147.5 mg, petroleum ether/ethyl acetate=1:1) as
a
white solid.
1
M.p. 1048C (petroleum ether/ethyl acetate); H NMR (300 MHz, CDCl3):
d=7.77 (s, 1H, C=CH), 7.34–7.15 (m, 8H, ArH), 7.11 (d, J=7.5 Hz, 2H,
ArH), 4.18 (t, J=7.2 Hz, 2H, CH2O), 3.85 (s, 2H, CH2 in Bn), 3.77 (s,
2H, CH2 in Bn), 3.62 (dd, J1 =11.4 Hz, J2 =6.3 Hz, 2H, CH2 in HOCH2),
2.76 (td, J1 =7.2 Hz, J2 =2.2 Hz, 2H, C=CCH2), 2.45 (t, J=6.9 Hz, 2H,
BnC=C(Bn)CH2), 1.47 ppm (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d=172.8, 145.3, 139.1, 138.9, 136.3, 131.5, 128.7, 128.62, 128.57, 127.7,
126.5, 126.3, 122.9, 65.2, 61.1, 38.7, 36.1, 35.0, 26.6 ppm; MS (ESI) (m/z):
371 [M+Na]+, 349 [M+H]+; IR (neat): n˜ =3444, 1723, 1618, 1594, 1493,
1033, 1007 cmꢁ1
.
Synthesis of 5
Vinyl ethyl ether (440.1 mg, 6.1 mmol) was added to a solution of alkynol
(620.9 mg, 5.0 mmol) and PPTS (12.8 mg, 0.051 mmol) in CH2Cl2
4
(20 mL). After being stirred at rt for 4.2 h, the crude product was concen-
trated and purified by chromatography on silica gel (petroleum ether/
ethyl acetate=10:1) to afford 5[22] as a colorless liquid (914.5 mg, 93%,
d.r.=51:49): 1H NMR (300 MHz, CDCl3): d=5.22 (d, J=9.0 Hz, 0.5H,
C=CCHO), 5.07 (d, J=9.3 Hz, 0.5H, C=CCHO), 4.77 (q, J=5.3 Hz,
0.5H, OCHO), 4.70 (q, J=5.4 Hz, 0.5H, OCHO), 4.57–4.35 (m, 1H, C=
CH), 3.73–3.35 (m, 2H, OCH2), 2.55–2.28 (m, 2H, CH2CꢃC), 1.95 (s,
1H, HCꢃC), 1.76 (d, J=3.6 Hz, 3H, C=CMe), 1.72 (d, J=5.1 Hz, 3H,
C=CMe), 1.31 (d, J=5.4 Hz, 1.5H, OC(Me)O), 1.28 (d, J=5.1 Hz, 1.5H,
OC(Me)O), 1.19 ppm (q, J=7.4 Hz, 3H, Me in Et); 13C NMR (75 MHz,
CDCl3): d=137.0, 135.0, 125.3, 124.5, 98.5, 96.6, 81.0, 80.9, 70.4, 70.0,
69.4, 69.2, 60.5, 58.8, 25.8, 25.7, 25.6, 20.3, 20.0, 18.3, 15.3, 15.0 ppm; MS
(ESI) (m/z): 219 [M+Na]+, 235 [M+K]+; IR (neat): n˜ =3311, 2977, 2934,
2915, 2880, 2122, 1677, 1446, 1379, 1334, 1275, 1229, 1128, 1096, 1057,
1461, 1450, 1392, 1364, 1326, 1284, 1207, 1189, 1155, 1053, 1026 cmꢁ1
Anal. calcd for C23H24O3: C 79.28, H 6.94; found: C 79.07, H 7.29.
;
(E)-3-benzylidene-5-(2-methyl-1-propenyl)dihydro-2ACTHUNRTGNEUNG(3H)-furanone ((E)-
2r)
Same procedure as that described for (E)-2a: The reaction of alkyne 1r
(100.4 mg, 0.501 mmol), [Ni(cod)2] (1.4 mg, 0.005 mmol), CsF (15.8 mg,
AHCTUNGTRENNUNG
0.104 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in DMSO
(3 mL) afforded the crude product, which was treated with TsOH·H2O
(19.0 mg, 0.100 mmol) in CH2Cl2 (5 mL) for 4 h to afford (E)-2r (82%,
94.1 mg, petroleum ether/ethyl acetate=10:1) as an oil. 1H NMR
(300 MHz, CDCl3): d=7.56 (t, J=2.7 Hz, 1H, C=CH), 7.53–7.34 (m, 5H,
ArH), 5.36–5.24 (m, 2H, OCH-CH=C), 3.50–3.34 (m, 1H, one H in C=
1037, 1014 cmꢁ1
219.13555; found: 219.13579.
.
HRMS (ESI) calcd for C12H20O2Na [M+Na]+:
CCH2), 2.98–2.84 (m, 1H, one
H in C=CCH2), 1.79 (s, 3H, Me),
1.78 ppm (s, 3H, Me); 13C NMR (75 MHz, CDCl3): d=172.1, 139.6,
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Stereoselective Synthesis of a-Alkylidene-g-Butyrolactones
Synthesis of 6
appreciated. We thank Ms. Zhao Fang in this group for reproducing the
results presented in entry 1 of Table 3 and the last step in Scheme 3.
nBuLi (1.6 mL, 2.5m in hexane, 4.0 mmol) was added dropwise at ꢁ788C
over 5 min to a solution of 5 (391.7 mg, 2.0 mmol) in dry THF (6 mL).
Then hexamethylphosphoramide (HMPA; 0.70 mL, d=1.03 gmLꢁ1
,
[1] a) X. Fan, J. Zi, C. Zhu, W. Xu, W. Cheng, S. Yang, Y. Guo, J. Shi, J.
Nat. Prod. 2009, 72, 1184; b) J.-H. Sheu, A. F. Ahmed, R.-T. Shiue,
C.-F. Dai, Y.-H. Kuo, J. Nat. Prod. 2002, 65, 1904; c) A. B. Smith,
III, B. H. Toder, P. J. Carroll, J. Donohue, J. Crystallogr. Spectrosc.
Res. 1982, 12, 309; d) Y. Aoyagi, A. Yamazaki, C. Nakatsugawa, H.
Fukaya, K. Takeya, S. Kawauchi, H. Izum, Org. Lett. 2008, 10, 4429.
[2] For comprehensive reviews, see: a) P. A. Grieco, Synthesis 1975, 67;
b) H. M. R. Hoffmann, J. Rabe, Angew. Chem. 1985, 97, 96–112;
Angew. Chem. Int. Ed. Engl. 1985, 24, 94–110; c) J. C. Sarma, R. P.
Sharma, Heterocycles 1986, 24, 441; d) N. Petragnani, H. M. C.
Ferraz, G. V. J. Silva, Synthesis 1986, 157; e) R. R. A. Kitson, A. Mil-
lemaggi, R. J. K. Taylor, Angew. Chem. 2009, 121, 9590; Angew.
Chem. Int. Ed. 2009, 48, 9426.
721 mg, 4 mmol) was added and the reaction mixture was stirred at that
temperature for 50 min. A solution of 2-methyl-2-(2-iodoethyl)-1,3-dioxo-
lane (1.2108 g, 5.0 mmol) in THF (4 mL) was added dropwise over 5 min.
Then the mixture was warmed up to room temperature and stirred over-
night, quenched with a sat. aqueous NH4Cl solution, extracted with Et2O
(10 mLꢁ3), washed with brine, dried over anhydrous MgSO4, filtrated,
concentrated, and purified by chromatography on silica gel (petroleum
ether/ethyl acetate=10:1) to afford 6[22] as a liquid (317.5 mg, 51%, d.r.=
58:42): 1H NMR (300 MHz, CDCl3): d=5.19 (dt, J1 =6.0 Hz, J2 =1.2 Hz,
0.42H, C=CCHO), 5.04 (dt, J1 =6.0 Hz, J2 =1.2 Hz, 0.58H, C=CCHO),
4.76 (q, J=5.3 Hz, 0.42H, OCHO), 4.69 (q, J=5.4 Hz, 0.58H, OCHO),
4.50–4.28 (m, 1H, C=CH), 4.00–3.86 (m, 4H, OCH2CH2O), 3.70–3.36 (m,
2H, OCH2), 2.50–2.16 (m, 4H, CH2CꢃCCH2), 1.90–1.80 (m, 2H,
O2CCH2), 1.77–1.68 (m, 6H, CMe2), 1.33–1.25 (m, 6H, two of O2CMe),
1.24–1.14 ppm (m, 3H, Me in Et); 13C NMR (75 MHz, CDCl3): d=136.6,
134.7, 125.6, 124.8, 109.0, 98.5, 96.6, 80.9, 80.7, 76.5, 76.3, 71.2, 70.7, 64.6,
60.6, 58.7, 38.3, 26.1, 25.74, 25.68, 23.6, 20.4, 20.2, 18.35, 18.33, 15.3, 15.1,
13.6, 13.5 ppm; MS (ESI) (m/z): 333 [M+Na]+, 221 [MꢁOCH-
[3] a) M. De Bernardi, L. Garlaschelli, L. Toma, G. Vidari, P. Vita-
Finzi, Tetrahedron 1991, 47, 7109; b) G. Vidari, G. Lanfranchi, N.
Pazzi, S. Serra, Tetrahedron Lett. 1999, 40, 3063; c) S. Tesaki, H. Ki-
kuzaki, S. Yonemori, N. Nakatani, J. Nat. Prod. 2001, 64, 515;
d) P. G. Baraldi, M. C. Nunez, M. A. Tabrizi, E. D. Clercq, J. Balzari-
ni, J. Bermejo, F. Estꢂvez, R. Romagnoli, J. Med. Chem. 2004, 47,
2877; e) T. Janecki, E. Błaszczyk, K. Studzian, A. Janecka, U. Kra-
jewska, M. Rꢃz˙alski, J. Med. Chem. 2005, 48, 3516; f) R. Romagnoli,
P. G. Baraldi, M. A. Tabrizi, J. Bermejo, F. Estꢂvez, M. Borgatti, R.
Gambari, J. Med. Chem. 2005, 48, 7906; g) S. Oh, I. H. Jeong, W.-S.
Shin, Q. Wang, S. Lee, Bioorg. Med. Chem. Lett. 2006, 16, 1656.
[4] a) D. De, M. Seth, A. P. Bhaduri, Synthesis 1990, 956; b) T. Ohta, T.
Miyake, N. Seido, H. Kumobayashi, H. Takaya, J. Org. Chem. 1995,
60, 357; c) A. Arcadi, M. Chiarini, F. Marinelli, Z. Berente, L.
Kollꢄr, Org. Lett. 2000, 2, 69; d) A. Otto, J. Liebscher, Synthesis
2003, 1209; e) T. Gasperi, M. A. Loreto, P. A. Tardella, E. Veri, Tet-
ACHTUNGTRENNUNG
(CH3)OEt]+; IR (neat): n˜ =2981, 2932, 2880, 1676, 1446, 1377, 1255,
1222, 1126, 1097, 1055 cmꢁ1
; HRMS (ESI) calcd for C18H30O4Na
[M+Na]+: 333.20363; found: 333.20442.
Synthesis of 7
PPTS (10.6 mg, 0.042 mmol) was added to a solution of 6 (247.3 mg,
0.80 mmol) in CH3OH (2 mL). After being stirred at rt for 2.5 h, the
crude product was concentrated and purified by chromatography on
silica gel (petroleum ether/ethyl acetate=5:1–4:1) to afford 7[22] as a col-
orless liquid (161.4 mg, 85%): 1H NMR (300 MHz, CDCl3): d=5.23 (d,
J=8.7 Hz, 1H, C=CH), 4.50–4.39 (m, 1H, CHO), 4.00–3.88 (m, 4H,
OCH2CH2O), 2.43–2.22 (m, 5H, CH2, CH2 and OH), 1.89 (t, J=7.5 Hz,
2H, CH2), 1.73 (s, 3H, C=CMe), 1.70 (d, J=0.9 Hz, 3H, C=CMe),
1.33 ppm (s, 3H, O2CMe); 13C NMR (75 MHz, CDCl3): d=135.9, 126.2,
109.2, 82.4, 76.2, 67.0, 64.6, 38.0, 28.1, 25.7, 23.5, 18.2, 13.6 ppm; MS
(ESI) (m/z): 261 [M+Na]+, 221 [MꢁOH]+; IR (neat): n˜ =3432, 2982,
ˇ
rahedron Lett. 2003, 44, 4953; f) J. Castulꢅk, J. Marek, C. Mazal, Tet-
rahedron 2001, 57, 8339; g) A. Otto, B. Ziemer, J. Liebscher, Synthe-
sis 1999, 965; h) A. Otto, B. Ziemer, J. Liebscher, Eur. J. Org. Chem.
1998, 2667; i) A. Otto, B. Abegaz, B. Ziemer, J. Liebscher, Tetrahe-
dron: Asymmetry 1999, 10, 3381; j) K. Nishimura, K. Tomioka, J.
Org. Chem. 2002, 67, 431; k) J. Read de Alaniz, T. Rovis, J. Am.
Chem. Soc. 2005, 127, 6284.
2931, 1741, 1677, 1581, 1522, 1449, 1377, 1212, 1132, 1101, 1053 cmꢁ1
;
HRMS (ESI) calcd for C14H22O3Na [M+Na]+: 261.14612; found:
[5] S. Li, W. Yuan, S. Ma, Angew. Chem. 2011, 123, 2626; Angew. Chem.
Int. Ed. 2011, 50, 2578.
261.14654.
Synthesis of (ꢀ)-heteroplexisolide E
[6] For recent reviews of CO2 fixation, see: a) J. Louie, Curr. Org.
Chem. 2005, 9, 605; b) T. Sakakura, J.-C. Choi, H. Yasuda, Chem.
Rev. 2007, 107, 2365; c) M. Aresta, A. Dibenedotto, Dalton Trans.
2007, 2975; d) A. Correa, R. Martꢅn, Angew. Chem. 2009, 121, 6317;
Angew. Chem. Int. Ed. 2009, 48, 6201; e) S. N. Riduan, Y. Zhang,
Dalton Trans. 2010, 39, 3347; f) Y. Zhang, S. N. Riduan, Angew.
Chem. 2011, 123, 6334; Angew. Chem. Int. Ed. 2011, 50, 6210; g) K.
Huang, C. Sun, Z. Shi, Chem. Soc. Rev. 2011, 40, 2435; h) M.
Cokoja, C. Bruckmeier, B. Rieger, W. A. Herrmann, F. E. Kꢆhn,
Angew. Chem. 2011, 123, 8662; Angew. Chem. Int. Ed. 2011, 50,
8510; i) W. Zhang, X. Lꢆ, Chin. J. Catal. 2012, 33, 745.
[7] For other examples of the carboxylation of alkynes with CO2, see:
a) K. Shimizu, M. Takimoto, Y. Sato, M. Mori, Org. Lett. 2005, 7,
195; b) K. Shimizu, M. Takimoto, Y. Sato, M. Mori, Synlett 2006,
3182; c) T. Fujihara, T. Xu, K. Semba, J. Terao, Y. Tsuji, Angew.
Chem. 2011, 123, 543; Angew. Chem. Int. Ed. 2011, 50, 523.
[8] During the submission of this manuscript, Kutsumura et al. reported
the total synthesis of (+)-heteroplexisolide E, see: N. Kutsumura, A.
Kiriseko, T. Saito, Tetrahedron Lett. 2012, 53, 3274.
Following the same procedure as that described for (E)-2a: The reaction
of alkyne 7 (119.4 mg, 0.501 mmol), [NiACHTUNRGTNEUNG(cod)2] (1.4 mg, 0.005 mmol), CsF
(15.7 mg, 0.103 mmol), ZnEt2 (1.0 mL, 1.5m in toluene, 1.5 mmol), in
DMSO (3 mL) afforded the crude product, which was treated with
TsOH·H2O (19.2 mg, 0.101 mmol) in acetone (5 mL) for 15 h to afford
(ꢀ)-heteroplexisolide E[1a] (77%, 85.2 mg, petroleum ether/ethyl ace-
tate=2.5:1) as a liquid: 1H NMR (300 MHz, [D6]acetone): d=6.59–6.49
(m, 1H, (C=O)C=CH), 5.35–5.24 (m, 2H, OCH, and OCCH=C), 3.30–
3.14 (m, 1H, one H of CH2 in lactone), 2.75 (t, J=7.1 Hz, 2H, O=
CCH2), 2.66–2.54 (m, 1H, one H of CH2 in lactone), 2.48–2.36 (m, 2H,
O2CC=CCH2), 2.16 (s, 3H, O=CMe), 1.80 ppm (s, 6H, CMe2); 13C NMR
(75 MHz, [D6]acetone): d=206.6, 170.5, 138.9, 138.2, 128.5, 124.9, 74.4,
41.4, 32.5, 29.8, 25.4, 24.4, 18.0 ppm; MS (m/z) 222 (M+, 0.72), 43 (100);
IR (neat): n˜ =2973, 2916, 2858, 1750, 1715, 1679, 1440, 1366, 1319, 1272,
1191, 1166, 1112, 1018 cmꢁ1
.
[9] Y. Meng, Y. Guan, Chin. Chem. Lett. 2002, 13, 1039.
[10] H. Zimmer, J. Rothe, J. Org. Chem. 1959, 24, 28.
ˇ
Acknowledgements
[11] J. Castulꢅk, C. Mazal, Tetrahedron Lett. 2000, 41, 2741.
[12] S. Matsui, Bull. Chem. Soc. Jpn. 1987, 60, 1853.
Financial support from National Basic Research Program of China
(2009CB825300), National Natural Science Foundation of China
(20732005) and Project for Basic Research in Natural Science Issued by
Shanghai Municipal Committee of Science (No. 08dj1400100) is greatly
[13] K. Liang, W. Li, S. Peng, S. Wang, R. Liu, J. Am. Chem. Soc. 1997,
119, 4404.
[14] G. S. Reddy, P. Neelakantan, D. S. Iyengar, Synth. Commun. 2002,
32, 2601.
Chem. Asian J. 2012, 00, 0 – 0
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Shengming Ma et al.
FULL PAPER
[15] R. M. Carlson, J. C. DeLane, T.-L. Liu, Synth. Commun. 1985, 15,
657.
[20] X. Cheng, X. Jiang, Y. Yu, S. Ma, J. Org. Chem. 2008, 73, 8960.
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shita, K. Watanabe, Chem. Pharm. Bull. 1986, 34, 121.
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Received: May 26, 2012
Published online: && &&, 0000
[19] K. Nozaki, K. Oshima, K. Utimoto, Bull. Chem. Soc. Jpn. 1990, 63,
2578.
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FULL PAPER
Synthetic Methods
Suhua Li, Shengming Ma* &&&& — &&&&
CO2-Activation for g-Butyrolactones
and Its Application in the Total
Synthesis of (ꢀ)-Heteroplexisolide E
Fine tuning: A nickel(0)-catalyzed
highly regio- and stereoselective
hydrocarboxylation of homopropar-
gylic alcohols with ZnEt2 in the pres-
ence of CO2 (1 atm, balloon) has been
described for the efficient synthesis of
a-alkylidene-g-butyrolactones.
Chem. Asian J. 2012, 00, 0 – 0
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