Lewis acid-promoted cyclization/halogenation of allenyl ethenetricarboxylates and the corresponding amides: Stereoselective synthesis of haloalkenyl five-membered heterocycles

Article abstract of DOI:10.1039/c4ob00233d

Lewis acid-promoted intramolecular reactions of allenyl ethenetricarboxylates and the corresponding amides have been examined. Reactions of allenyl ethenetricarboxylates and the amides with Lewis acids such as AlCl₃, AlBr₃ and ZnX

Full text of DOI:10.1039/c4ob00233d

Organic &
Biomolecular Chemistry
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Lewis acid-promoted cyclization/halogenation
of allenyl ethenetricarboxylates and the
corresponding amides: stereoselective
synthesis of haloalkenyl five-membered
heterocycles†
Cite this: Org. Biomol. Chem., 2014,
12, 3964
Yugo Fukushima,a Shoko Yamazaki*b and Akiya Ogawaa
Lewis acid-promoted intramolecular reactions of allenyl ethenetricarboxylates and the corresponding
amides have been examined. Reactions of allenyl ethenetricarboxylates and the amides with Lewis acids
such as AlCl3, AlBr3 and ZnX2 (X = Cl, Br, I) gave 3,4-trans haloalkenyl five-membered heterocycles
stereoselectively. The stereochemistry was determined by NOE experiments and reduction of the cyclized
products. Various transformations of the haloalkenyl functionalized cyclic compounds have also been
performed.
Received 30th January 2014,
Accepted 10th April 2014
DOI: 10.1039/c4ob00233d
www.rsc.org/obc
3,4-trans stereoselective cyclization of alkenyl ethenetricarboxy-
Introduction
lates has also been investigated (eqn (1)).11
Development of new synthetic reactions utilizing allenes has
attracted attention due to their structural features.1 Transition
metal catalyzed cyclization of allenes containing additional
multiple bonds such as alkynes, alkenes, arynes, aldehydes
and ketones has been recognized as an efficient method to
prepare highly substituted carbocycles and heterocycles.2
Thermal,3 photochemical,4 reductive5 and base-promoted6
cyclization reactions of these allenes have been reported. Lewis
acid-promoted carbon–carbon bond-forming cyclizations of
allenyl-aldehyde acetals7 and aryl-allenes8 have also been
studied. Few examples are known for the intramolecular Lewis
acid-mediated cyclization of allenes containing electron-
deficient alkenes (as Michael acceptors).
ð1Þ
We have studied various Lewis acid-promoted intermolecu-
lar reactions of ethenetricarboxylate derivatives and reported
that they function as highly electrophilic Michael acceptors.12
The reaction of arylallenes and ethenetricarboxylate with SnCl4
gave indene derivatives efficiently.13 In addition, the reactions
of 1,1-dialkylallenes and ethenetricarboxylate with SnCl4 gave
γ-lactones.
In this work, Lewis acid-promoted intramolecular reactions
containing allenes as an extension of the reaction of alkenyl
substrates (eqn (1)) have been examined.14
Snider and Roush reported that Lewis acid-promoted intra-
molecular reactions of alkenyl and alkynyl ethenetricarboxy-
lates gave chlorinated γ-lactones.9 We have developed Lewis
acid-promoted stereoselective cyclization of alkynyl ethenetri-
carboxylates with high generality10 and Lewis acid-promoted
Results and discussion
aDepartment of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture
University, Gakuen-cho 1-1, Nakaku, Sakai, Osaka 599-8531, Japan
Allenyl esters 3a–c were prepared by the reaction of 1,1-
diethyl 2-hydrogen ethenetricaboxylate 1 (prepared from 1,1-
diethyl 2-tert-butyl ethenetricarboxylate upon treatment with
CF3CO2H) with the corresponding allenyl alcohols 2a–c in
bDepartment of Chemistry, Nara University of Education, Takabatake-cho,
Nara 630-8528, Japan. E-mail: yamazaks@nara-edu.ac.jp
†Electronic supplementary information (ESI) available: The optimized geo-
metries, and 1H and 13C NMR spectral data. See DOI: 10.1039/c4ob00233d
3964 | Org. Biomol. Chem., 2014, 12, 3964–3975
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the presence of PPh3 and DEAD (diethyl azodicarboxylate)
(eqn (2)).
Table 1 Reactions of allenyl esters 3a,b
Time
Yield By-product
Entry
3
R
MXn
(h)
4
X
(%)
(%)
1
2
3
4
5
6
7
8
7
8
9
3a
3a
3a
3a
3a
3a
3a
3a
H
H
H
H
H
H
H
H
AlCl3
AlBr3 18
SnCl4
TiCl4
TiBr4 18
FeCl3
18
4a Cl 75
4b Br 64
4a Cl 42
4a Cl 58
4b Br 46
4a Cl 36b
4a Cl 12
4b Br 40
4c Cl 66
4d Br 44
4c Cl 30
3
3
5 (ca. 19)a
5 (ca. 18)a
5 (30)
3
6 (54)b
InCl3 18
InBr3 18
6 (20), 3a (44%)
6 (36)
3b Me AlCl3
3b Me AlBr3 18
3b Me SnCl4 18
18
ð2Þ
c
The reaction of allenyl ethenetricarboxylates 3a,b with 1
equivalent of various Lewis acids such as AlCl3, AlBr3, SnCl4,
TiCl4, FeCl3, InCl3, or InBr3 in CH2Cl2 at room temperature
gave 3,4-trans haloalkenyl tetrahydrofuran derivatives 4a–d
stereoselectively (eqn (3), Table 1). Among these Lewis acids,
AlCl3 and AlBr3 gave chlorinated and brominated cyclic pro-
ducts 4a–d most efficiently. The reaction of 3a with SnCl4,
TiCl4 and TiBr4 also gave 4a,b along with the 4-ethynyltetra-
hydrofuran derivative 5 as a by-product via Lewis acid-catalyzed
ene-type reaction. The use of FeCl3, InCl3 and InBr3 gave 4a,b
and the noncyclized H2O adduct 6 as a by-product (entries
6–8). Furthermore, the reaction of 3a using ZnBr2, BF3·OEt2,
ZrCl4, and Zn(OTf)2 at room temperature gave the starting
material 3a. The reaction of 3a with ZnBr2, ZnI2, Sc(OTf)3, and
Zn(OTf)2 at 80 °C gave a complex mixture or the starting
material 3a.
a Small amounts of impurities could not be removed. b The yields were
estimated from the NMR spectra of the mixture of 4a and 6.
c Inseparable by-products were also produced.
of the by-product 4-ethynyltetrahydrofuran 5 did not give
enough information on the 3,4-stereochemistry.
In order to support the assignment of the stereochemistry
of 4a and determine the stereochemistry of the by-product
4-ethynyltetrahydrofuran 5, the following transformations have
been carried out. Hydrogenolysis of the 4-chlorovinyl-2-oxo-
tetrahydrofuran 4a gave 3,4-trans-4-ethyl-2-oxotetrahydrofuran 7t
in 51% yield (Scheme 1). Hydrogenolysis of both the carbon–
chlorine bond and carbon–carbon double bond occurred.16
3,4-trans-4-(1-Chloroethyl)-2-oxotetrahydrofuran 8 is obtained
by the Lewis acid-promoted reaction of alkenyl ester 9 stereo-
selectively.11 Dechlorination of compound 8 did not proceed
under the conditions used for 4a. The reaction of 8 with
Bu3SnH and AIBN gave a dechlorinated tetrahydrofuran in
ð3Þ
The γ-lactone structure of 4a–d was suggested by the pres-
ence of a characteristic CvO absorption (1780–1782 cm−1) and
disappearance of the 1958–1972 cm−1 absorption for the
1
CvCvC allene moiety in 3a,b. H, 13C and 2D NMR spectra
were in agreement with the five-membered ring structure. The
3,4-stereochemistry of 4a–d was examined by NOESY experi-
ments. NOEs between H-3 and H-4 could be observed for both
3,4-cis and trans diastereomers. The following peaks were used
for the assignment of haloalkenyl 2-oxotetrahydrofurans 4a–d.
NOEs between H-3 and CXvCHH (X = Cl, Br)15 for 4a,b and
between H-4 and CH(CO2Et)2 for 4a–d were observed. Thus,
the 3,4-trans stereochemistry of 4a–d was likely, similar to
cyclic products in eqn (1). On the other hand, NOESY spectra Scheme 1 Reduction of 4a, 8, and 5.
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89% yield. This was identical to 7t obtained from 4a. Thus, between H-3 and CXvCHH (X = Cl, Br, I)15 and between H-4
the stereochemistry of 7t was assigned as 3,4-trans. The and CH(CO2Et)2 were observed.
stereochemistry of 7t was also determined by the NOESY
experiment. Next, hydrogenolysis of the ethynyl group of 5
was conducted. The hydrogenated product 7c is different
from 7t and could be assigned as 3,4-cis-4-ethyl-2-oxotetra-
hydrofuran. Therefore, the stereochemistry of 5 is determined
as 3,4-cis.
ð5Þ
The Lewis acid-promoted reaction of 2-penta-3,4-dienyl
ester 3c (shown in eqn (2)) was also examined. However, the
reaction of 3c with 1 equivalent of AlCl3, AlBr3, and SnCl4 gave
complex mixtures. Six-membered ring formation was not an
In order to demonstrate the utility of the cyclization reac-
efficient process.
tion, synthetic transformations of the products were examined.
Oxidative cleavage of the double bond of tetrahydrofuran 4a
with NaIO4-RuCl3·xH2O and a neutral work-up gave acid 13 in
98% yield (Scheme 2). Subsequent treatment of 13 with
Me3SiCHN2 in methanol/benzene led to methyl ester 14 in
71% yield. The stereochemistry of 13 and 14 was determined
as 3,4-trans by the NOESY experiment. Derivatization of 13
with benzylamines gave functionalized 3-oxotetrahydrofurans
15a–b.
ð4Þ
Furthermore, the Suzuki-coupling reaction of halogenovinyl
heterocycles was performed. The reaction of iodovinyl pyrroli-
dines 12c,12f with phenylboronic acid proceeds smoothly to
give phenyl-substituted pyrrolidines (16a,b) (eqn (6)).
Next, allenyl amide substrates 11a–b were prepared by the
condensation reaction of 1,1-diethyl 2-hydrogen ethenetrica-
boxylate 1 with the corresponding allenyl amines 10a–b in the
presence of HOBT, EDCI and Et3N (eqn (4)). Reaction of
diethyl 2-((N-allenyl-N-benzylcarbamoyl)methylene)malonate
(11a) with AlCl3, ZnCl2, ZnBr2, and ZnI2 at room temperature
gave 3,4-trans-4-(1-chloro(or bromo/iodo)vinyl)-2-oxopyrroli-
dines 12a–c in 55–76% yields (eqn (5), Table 2). Reaction of
the N-allenyl-N-propylcarbamoyl derivative 11b also gave 3,4-
trans pyrrolidines 12d–f in 64–68% yields. Reaction of 11a,b
with AlBr3 also gave 12b,e but in lower yields than those of
ð6Þ
ZnBr2 (16% for 12b, ca. 50% (including a small amount of
inseparable impurity) for 12e). The γ-lactam structures of 12a–f
were suggested by the presence of a characteristic CvO
absorption (1688–1698 cm−1). 1H, 13C and 2D NMR spectra
were in agreement with the five-membered ring structure. The
3,4-trans stereochemistry was determined by NOEs. NOEs
The reaction mechanism to give the halogenated five-mem-
bered heterocycles with 3,4-trans stereochemistry is proposed
similar to that for the reaction of the allyl ester of ethenetricar-
boxylates (eqn (1))11 and is shown in Scheme 3. The trans pre-
cursor A1 and the cis precursor A2 in Scheme 4 may be formed
Table 2 Reactions of allenyl amides 11
Entry
R
MXn
(equiv.)
X
12
Yield (%)
1
2
3
4
5
6
7
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
AlCl3
1
Cl
Cl
Br
I
Cl
Br
I
12a
12a
12b
12c
12d
12e
12f
55
76
64
58
68
64
68
a
ZnCl2a
ZnBr2
ZnI2
1 × 2
1 × 2
2
AlCl3
1
a
ZnBr2
1 × 2
1 × 2
a
ZnI2
a The reaction with ZnX2 (1 equiv.) for 18 h gave crude products
including impurities (possibly non-cyclized water-adducts) after work-
up. The crude products were further treated with ZnX2 (1 equiv.) to
give the products 12.
Scheme 2 Transformation of 4a.
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Scheme 3 Proposed reaction mechanism for cyclization of the allyl
ester model compound 3m (R = Me) with Al2Cl6. Relative Gibbs free
energies (T = 298.15 K and P = 1 atm) for intermediates and TSs (tran-
sition states) of the model compounds (3m + Al2Cl6) are obtained by
Scheme 4 The reaction pathway leading to the 3,4-cis intermediate B2
for model compounds (3m + Al2Cl6). B3LYP/6-31G*-optimized struc-
tures of the model compounds are shown. The Gibbs free energies are
relative to A1 (R = Me) in Scheme 3.
B3LYP/6-31G* (without brackets) and [B3LYP/6-311+G(d,p) SCRF
(PCM, solvent = CH2Cl2)//B3LYP/6-31G*] (with square brackets [ ]).
=
from 3 and Al2Cl6 reversibly. The reaction may start from the
precursor A1 consisting of 3 and Al2Cl6. The C–C bond for-
mation and Cl–C bond formation from A1 may occur concert-
edly to yield the cyclized intermediate B1. The intermolecular
Cl− anti-attack leading to a 3,4-trans cyclized product can be
explained by a steric reason. One molecule of the Lewis acid
(AlCl3) may work as a catalyst and could be released after the
cyclization step. Protonation and removal of AlCl2(OH) yield
the product 4.
In order to support the proposed mechanism, the struc-
tures of the intermediates and transition states of model com-
pounds (the corresponding methyl esters and Al2Cl6) were
calculated using B3LYP/6-31G*.17,18 TS geometry was character-
ized by vibrational analysis, which checked whether the
obtained geometry has single imaginary frequencies (ν‡). From
TSs, reaction pathways were traced by the intrinsic reaction
coordinate (IRC) method19 to obtain the energy-minimum geo-
metries. Relative Gibbs free energies were refined by single-
point calculations of RB3LYP/6-311+G(d,p) SCRF = (PCM,
solvent = CH2Cl2)20 on the RB3LYP/6-31G* geometries and
their thermal corrections (T = 298.15 K, P = 1 atm). ΔG‡ for
TS1 leading to 3,4-trans tetrahydrofuran is found to be lower
than that of TS2 leading to 3,4-cis tetrahydrofuran (Schemes 3
and 4). Two conformational isomers, trans precursor A1 and
cis precursor A2, were obtained. A2 is 5.15 [1.28] kcal mol−1
more stable than A1. The energy difference may be small
enough and they are considered to exist as interconvert-
ing forms. Although the barrier for conformational change has
not been computed, the Curtin–Hammett principle21 may be
applicable in this case. The calculation results are similar to
those for allyl ester + Al2Cl6.11 Thus, formation of 3,4-trans
five-membered rings is a lower energy process than that of 3,4-
cis. The results support the assignment of 3,4-trans stereo-
chemistry for the products 4.
Calculations of the 1 : 1 complex of the substrate and AlCl3
were also examined (ESI†). Although the concerted formation
of both 3,4-cis and trans tetrahydrofuran rings by intramolecu-
lar Cl− attack was calculated, they have higher activation ener-
gies (ΔG‡) than the systems of the substrate and Al2Cl6. In
addition, the process to form the by-product, 3,4-cis-4-ethynyl-
tetrahydrofuran 5 (Table 1, entries 3–5) shown in Scheme 5,
was calculated using a model system (3m + AlCl3). The acti-
vation energy (ΔG‡) for formation of 5 with AlCl3 is also higher
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nyl
oxygen
and
nitrogen-containing
five-membered
heterocycles has been found. The reaction gave 3,4-trans sub-
stituted cyclized products stereoselectively. AlCl3 and AlBr3
gave 2-oxotetrahydrofurans, and AlCl3 and ZnX2 (X = Cl, Br, I)
gave 2-oxopyrrolidines efficiently. The haloalkenyl five-mem-
bered heterocycles generated in this reaction should be versa-
tile synthetic intermediates. Some transformations of the
products utilizing the haloalkenyl functionality have also been
demonstrated. Further elaboration of the products and studies
on various alkyl substitution patterns of allenyl groups includ-
ing chiral substrates are under investigation.
Scheme 5 Formation of the by-product 5.
than the systems of the substrate and Al2Cl6. Further mechan-
istic studies are underway.
Concerning the reactivity of the oxygen and nitrogen sub-
strates, relatively weak Lewis acids such as zinc halides
promote the cyclization of the amide substrates 11a,b. The
facile cyclization of amides compared to esters can be
explained as follows. The conformations of model compounds
of allenyl ester 3 and amide substrate 11 were calculated and
compared. The s-cis and s-trans conformations about the
2-ester or the amide carbonyl moiety are shown in Scheme 6.
Ester 3 is 8.98 [7.67] kcal mol−1 more stable in the s-cis confor-
mation, probably because of the steric repulsion. On the other
hand, the energy difference of s-cis and s-trans conformarions
of amide 11 is small. In order to cyclize, they must have s-trans
conformations. The different reactivities of esters and amides
may arise from their structural features.
Experimental section
General methods
1H chemical shifts are reported in ppm relative to Me4Si. 13C
chemical shifts are reported in ppm relative to CDCl3
(77.1 ppm). 13C multiplicities were determined by DEPT and
HSQC. Peak assignments are made from 2D COSY, HSQC,
NOESY, and HMBC spectra.
Allenyl alcohols 2a,b,c were prepared according to the
literature.5a,22,23
1,1-Diethyl 2-buta-2,3-dienyl ethene-1,1,2-tricarboxylate
(3a). To a solution of 1,1-diethyl 2-hydrogen ethenetricarboxy-
late (432 mg, 2 mmol) (prepared from 1,1-diethyl 2-tert-butyl
ethenetricarboxylate (545 mg, 2 mmol) upon treatment with
CF3CO2H) in ether (2 mL) were added diethyl azodicarboxylate
40% in toluene (0.91 mL, 2 mmol), PPh3 (525 mg, 2 mmol)
and 2a (210 mg, 3 mmol) at room temperature. The reaction
mixture was stirred overnight. After removal of the solvent
under reduced pressure, the residue was purified by column
chromatography over silica gel with hexane–ether as the eluent
to give 3a (333 mg, 62%).
In summary, a Lewis acid-promoted reaction of allenyl ethe-
netricarboxylates 3a,b and the amides 11a,b to give haloalke-
3a: Rf = 0.8 (ether); pale yellow oil; 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H),
4.30 (q, J = 7.1 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.69 (dt, J = 7.1,
2.3 Hz, 2H), 4.88 (dt, J = 6.6, 2.3 Hz, 2H), 5.30 (tt, J = 7.1, 6.6
Hz, 1H), 6.88 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm)
13.91 (q), 13.96 (q), 62.13 (t), 62.54 (t), 63.48 (t), 76.96 (t), 85.57
(d), 129.63 (d), 139.29 (s), 162.21 (s), 163.27 (s), 164.18 (s),
210.08 (s); IR (neat) 2984, 1958, 1728, 1652, 1259, 1178,
1067 cm−1; MS (EI) m/z 269 (M+, 29), 200 (90), 199 (93), 171
(95), 143 (100%); HRMS M+ 268.0945 (calcd for C13H16O6
268.0947); Anal. Calcd for C13H16O6: C, 58.20; H, 6.01. Found:
C, 58.05; H, 5.81.
3b: Rf = 0.8 (ether); pale yellow oil; 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H),
1.70 (d, J = 2.9 Hz, 6H), 4.30 (q, J = 7.1 Hz, 2H), 4.38 (q, J = 7.1
Hz, 2H), 4.62 (d, J = 7.0 Hz, 2H), 5.11 (m, 1H), 6.89 (s, 1H); 13
C
Scheme 6 The model compounds, dimethyl esters with allenyl group
3m and 11m optimized by B3LYP/6-31G* and their relative energies ΔG°.
ΔG° is the difference of Gibbs free energies (T = 298.15 K, P = 1 atom) of
NMR (100.6 MHz, CDCl3) δ (ppm) 13.98 (q), 14.01 (q), 20.19
(q), 62.13 (t), 62.54 (t), 64.73 (t), 83.99 (d), 97.73 (s), 129.98 (d),
139.10 (s), 162.33 (s), 163.36 (s), 164.30 (s), 203.87 (s); IR (neat)
B3LYP/6-31G* (without brackets) and [B3LYP/6-311+G(d,p) SCRF
=
2984, 1972, 1728, 1651, 1446, 1375, 1259, 1177, 1067 cm−1
;
(PCM, solvent = CH2Cl2)//B3LYP/6-31G*] (with square brackets [ ]), rela-
tive to that of s-cis conformations.
MS (EI) m/z 297 ((M + 1)+, 16), 296 (M+, 5.6), 269 (24), 251 (100%);
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HRMS M+ 296.1260 (calcd for C15H20O6 296.1260); Anal. Calcd 1179, 1032 cm−1; MS (CI) m/z 351, 349 [M + H]+; HRMS [M +
for C15H20O6: C, 60.80; H, 6.80. Found: C, 60.88; H, 6.98.
H]+ 349.0285, 351.0261 (calcd for C13H18BrO6 349.0287,
3c: Rf = 0.6 (hexane–ether = 1 : 1); pale yellow oil; H NMR 351.0266).
1
(400 MHz, CDCl3) δ (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.35 (t, J =
Diethyl 2-(cis-4-ethynyl-2-oxotetrahydrofuran-3-yl)malonate
7.1 Hz, 3H), 2.37 (tdt, J = 6.8, 6.8, 3.1 Hz, 2H), 4.26 (t, J = 6.8 (5). Rf = 0.5 (hexane–ether = 1 : 1); pale yellow oil; 1H NMR
Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.73 (400 MHz, CDCl3) δ (ppm) 1.29 (t, J = 7.1 Hz, 3H), 1.32 (t, J =
(dt, J = 6.8, 3.1 Hz, 2H), 5.10 (tt, J = 6.8, 6.8 Hz, 1H), 6.87 (s, 7.1 Hz, 3H), 2.29 (d, J = 2.6 Hz, 1H), 3.55 (dd, J = 10.4, 8.3 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.98 (q), 14.02 (q), 1H), 3.76 (dddd, J = 8.3, 4.4, 3.4, 2.6 Hz, 1H), 3.87 (d, J = 10.4
27.44 (t), 62.16 (t), 62.57 (t), 64.81 (t), 75.84 (t), 85.55 (d), Hz, 1H), 4.22–4.33 (m, 4H), 4.40 (d, J = 4.4 Hz, 1H), 4.41 (d, J =
129.86 (d), 139.19 (s), 162.34 (s), 163.58 (s), 164.27 (s), 209.10 (s); 3.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.01 (q),
IR (neat) 2984, 1957, 1728, 1373, 1345, 1261, 1180, 1066, 14.04 (q), 31.58 (d), 42.70 (d), 50.94 (d), 62.28 (t), 62.30 (t),
1023 cm−1; MS (EI) m/z 282 (M+, 3.2), 236 (24), 208 (45), 71.19 (t), 74.57 (d), 79.22 (s), 167.07 (s), 167.13 (s), 174.14 (s);
171 (90), 143 (100%); HRMS M+ 282.1102 (calcd for C14H18O6 1H NMR (400 MHz, C6D6) δ (ppm) 0.890 (t, J = 7.1 Hz, 3H),
282.1103); Anal. Calcd for C14H18O6: C, 59.57; H, 6.43. Found: 1.06 (t, J = 7.1 Hz, 3H), 1.63 (d, J = 2.6 Hz, 1H), 3.15 (dddd, J =
C, 59.59; H, 6.55.
8.2, 5.7, 2.6, 1.5 Hz, 1H), 3.25 (dd, J = 8.9, 5.7 Hz, 1H), 3.42
Typical experimental procedure (eqn (3), Table 1, entry (dd, J = 10.8, 8.2 Hz, 1H), 3.68 (dd, J = 8.9, 1.5 Hz, 1H), 2.92 (q,
1). To a solution of 3a (148 mg, 0.55 mmol) in CH2Cl2 J = 7.1 Hz, 2H), 4.09 (d, J = 10.8 Hz, 1H), 4.11–4.25 (m, 2H).
(2.2 mL) was added AlCl3 (73 mg, 0.55 mmol). The mixture was Selected NOEs are between δ 3.15 (H-4) and δ 3.42 (H-3), 3.25
stirred at room temperature for 18 h. The reaction mixture was (H-5a) and between δ 3.42 (H-3) and δ 4.09 (CH(CO2Et)2); 13C
poured into saturated aqueous NaHCO3 solution. The mixture NMR (100.6 MHz, C6D6) δ (ppm) 13.83 (q), 13.93 (q), 31.79 (d),
was extracted with dichloromethane and the organic phase 43.07 (d), 51.41 (d), 61.92 (t), 62.12 (t), 70.46 (t), 74.16 (d), 79.
was dried (Na2SO4) and evaporated in vacuo. The residue was 65 (s), 167.38 (s), 167.44 (s), 173.81 (s). Selected HMBC corre-
filtered through Florisil eluting with dichloromethane to give lations are between δ 3.42 (H-3) and δ 51.41 (CH(CO2Et)2),
4a (126 mg, 75%).
31.79 (C-4), 79.65 (CuCH), between δ 3.15 (H-4) and δ 43.07
Diethyl 2-[trans-4-(1-chlorovinyl)-2-oxotetrahydrofuran-3-yl] (C-3), 79.65 (CuCH), 74.16 (CuCH), between δ 3.68 (H-5b)
malonate (4a). Rf = 0.7 (ether); pale yellow oil; 1H NMR and δ 31.79 (C-4), 43.07 (C-3), 79.65 (CuCH) and between
(400 MHz, CDCl3) δ (ppm) 1.29 (t, J = 7.1 Hz, 3H), 1.30 (t, J = δ 3.25 (H-5a) and δ 79.65 (CuCH); IR (neat) 3275, 2982, 1781,
7.1 Hz, 3H), 3.43 (dd, J = 9.9, 4.8 Hz, 1H), 3.97 (ddd, J = 9.9, 1734, 1467, 1447, 1370, 1283, 1249, 1163, 1096, 1029 cm−1
;
8.8, 8.8 Hz, 1H), 4.00 (d, J = 4.8 Hz, 1H), 4.13–4.28 (m, 5H), MS (EI) m/z 269 ([M + H]+, 83), 223 (100%); HRMS [M + H]+
4.52 (dd, J = 8.9, 8.9 Hz, 1H), 5.32 (dd, J = 1.6, 0.4 Hz, 1H), 5.38 269.1029 (calcd for C13H17O6 269.1025).
(d, J = 1.6 Hz, 1H). Selected NOEs are between δ 3.43 (H-3) and
6: Rf = 0.3 (hexane–ether = 1 : 1); pale yellow oil; 1H NMR
δ 5.38 (vCHH); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.93 (400 MHz, CDCl3) δ (ppm) 1.29 (t, J = 7.1 Hz, 3H), 1.30 (t, J =
(q), 13.97 (q), 41.85 (d), 46.09 (d), 49.68 (d), 62.06 (t), 62.17 (t), 7.1 Hz, 3H), 3.54 (d, J = 7.0 Hz, 1H), 3.96 (d, J = 4.1 Hz, 1H),
68.74 (t), 117.20 (t), 138.72 (s), 167.12 (s), 167.45 (s), 175.17 (s). 4.21–4.30 (m, 4H), 4.70 (dtd, J = 7.2, 2.3, 1.3 Hz, 1H), 4.74 (dd,
Selected HMBC correlations are between δ 3.97 (H-4) and J = 7.0, 4.1 Hz, 1H), 4.87 (dt, J = 6.6, 2.2 Hz, 2H), 5.29 (tt, J =
δ 41.85 (C-3), 68.74 (C-5), between δ 3.43 (H-3) and δ 46.09 (C-4), 7.0, 6.6 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.01
138.72 (CClv), δ 4.52 (H-5b) and δ 41.85 (C-3), 138.72 (CClv), (q), 14.04 (q), 55.14 (d), 62.05 (t), 62.09 (t), 63.89 (t), 69.75 (d),
and between δ 5.32, 5.38 (vCH2) and δ 46.09 (C-4), 138.72 76.92 (t), 85.67 (d), 166.99 (s), 167.19 (s), 171.45 (s), 210.13 (s);
(CClv); IR (neat) 2984, 1781, 1734, 1633, 1476, 1373, 1264, IR (neat) 3491, 2984, 1958, 1739, 1466, 1446, 1373, 1267, 1178,
1240, 1181, 1032 cm−1; MS (FAB) m/z 307, 305 [M + H]+; HRMS 1033 cm−1; MS (CI) m/z 287 [M + H]+; HRMS [M + H]+ 287.1130
[M + H]+ 305.0795 (calcd for C13H18ClO6 305.0792).
(calcd for C13H19O7 287.1131).
Diethyl 2-[trans-4-(1-bromovinyl)-2-oxotetrahydrofuran-3-yl]
Diethyl 2-[trans-4-(1-chloro-2-methylprop-1-enyl)-2-oxotetra-
malonate (4b). Rf = 0.5 (hexane–ether = 1 : 1); pale yellow oil; hydrofuran-3-yl]malonate (4c). Rf = 0.4 (hexane–ether = 1 : 1);
1
1H NMR (400 MHz, CDCl3) δ (ppm) 1.29 (t, J = 7.1 Hz, 3H), pale yellow oil; H NMR (400 MHz, CDCl3) δ (ppm) 1.28 (t, J =
1.30 (t, J = 7.1 Hz, 3H), 3.40 (dd, J = 9.8, 4.7 Hz, 1H), 3.87 (ddd, 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.79 (s, 3H), 1.86 (s, 3H),
J = 9.8, 8.8, 8.8 Hz, 1H), 4.00 (d, J = 4.7 Hz, 1H), 4.11–4.28 (m, 3.56 (dd, J = 10.4, 4.8 Hz, 1H), 3.96 (d, J = 4.6 Hz, 1H),
5H), 4.49 (dd, J = 9.0, 9.0 Hz, 1H), 5.57 (d, J = 2.0 Hz, 1H), 5.82 4.01–4.26 (m, 5H), 4.39 (dd, J = 8.6, 8.6 Hz, 1H), 4.49 (ddd, J =
(dd, J = 2.0, 0.4 Hz, 1H). Selected NOEs are between δ 3.40 10.4, 8.9, 8.9 Hz, 1H). Selected NOEs are between δ 4.49 (H-4)
(H-3) and 5.82 (vCHH); 13C NMR (100.6 MHz, CDCl3) δ (ppm) and δ 3.96 (CH(CO2Et)2); 13C NMR (100.6 MHz, CDCl3) δ (ppm)
14.00 (q), 42.87 (d), 47.42 (d), 49.65 (d), 62.08 (t), 62.19 (t), 13.94 (q), 14.01 (q), 20.82 (q), 22.65 (q), 41.08 (d), 42.53 (d),
69.62 (t), 121.67 (t), 131.71 (s), 167.13 (s), 167.48 (s), 175.08 (s). 49.28 (d), 61.98 (t), 62.03 (t), 68.53 (t), 123.71 (s), 134.30 (s),
Selected HMBC correlations are between δ 3.87 (H-4) and 167.51 (s), 167.70 (s), 175.61 (s). Selected HMBC correlations
δ 42.87 (C-3), 121.67 (vCH2), between δ 3.40 (H-3) and δ 47.42 are between δ 4.49 (H-4) and δ 42.53 (C-3), 68.53 (C-5), between
(C-4), 131.71 (CBrv), δ 4.49 (H-5b) and δ 42.87 (C-3), 131.71 δ 3.56 (H-3) and δ 41.08 (C-4), 123.71 (CClv), δ 4.39 (H-5b)
(CBrv), and between δ 5.57, 5.82 (vCH2) and δ 47.42 (C-4), and δ 42.53 (C-3), 68.53 (C-5), and between δ 1.79, 1.86
131.71 (CBrv); IR (neat) 2983, 1780, 1733, 1627, 1475, 1373, (vC(CH3)2) and δ 123.71 (CClv); IR (neat) 2983, 2920, 1782,
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1738, 1466, 1446, 1374, 1239, 1179, 1027 cm−1; MS (EI) m/z
Transformation of 8 to 7t. A solution of compound 811
334 (M+, 5.6), 332 (M+, 16), 173 (20), 160 (19), 85 (81), (113 mg, 0.37 mmol), Bu3SnH (215 mg, 199 μL, 0.74 mmol),
83 (100%); HRMS M+ 332.1026, 334.1010 (calcd for C15H21ClO6 and AIBN (12.2 mg, 0.074 mmol) in benzene (2.3 mL) was
332.1027, 334.0997).
heated at reflux for 3 h and cooled to room temperature. The
Diethyl 2-[trans-4-(1-bromo-2-methylprop-1-enyl)-2-oxotetra- reaction mixture was concentrated under reduced presure. The
hydrofuran-3-yl]malonate (4d). Rf = 0.5 (hexane–ether = 1 : 1); residue was purified by column chromatography over silica gel
1
pale yellow oil; H NMR (400 MHz, CDCl3) δ (ppm) 1.29 (t, J = with hexane–ether as the eluent to give 7t (89 mg, 89%). 1H
7.1 Hz, 6H), 1.82 (s, 3H), 1.89 (s, 3H), 3.58 (dd, J = 9.9, 4.7 Hz, NMR spectra of the product are identical to those of 7t
1H), 3.96 (d, J = 4.7 Hz, 1H), 4.01–4.27 (m, 5H), 4.35–4.43 (m, obtained from 4a.
2H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.98 (q), 14.02 (q),
Diethyl
2-(cis-4-ethyl-2-oxotetrahydrofuran-3-yl)malonate
21.36 (q), 26.41 (q), 42.17 (d), 43.81 (d), 49.22 (d), 62.00 (t), (7c). A mixture of 5 (146 mg, 0.54 mmol) and 10% Pd–C
62.03 (t), 69.49 (t), 119.05 (s), 137.31 (s), 167.51 (s), 167.73 (s), (58 mg, 10 mol%) in methanol (5.5 mL) was stirred in a hydro-
1
175.52 (s); H NMR (400 MHz, C6D6) δ (ppm) 0.892 (t, J = 7.1 gen atmosphere for 18 h at room temperature. The catalyst was
Hz, 3H), 0.907 (t, J = 7.1 Hz, 3H), 1.53 (s, 3H), 1.57 (s, 3H), 3.51 removed by filtration (Celite) and washed with methanol. The
(dd, J = 10.7, 4.9 Hz, 1H), 3.69–4.00 (m, 6H), 4.08 (d, J = 4.9 Hz, filtrate was concentrated in vacuo. The residue was purified by
1H), 4.44 (ddd, J = 10.7, 8.9, 8.9 Hz, 1H). Selected NOEs are column chromatography over silica gel with hexane–ether as
between δ 4.44 (H-4) and δ 4.08 (CH(CO2Et)2); 13C NMR the eluent to give 7c (115 mg, 78%).
(100.6 MHz, C6D6) δ (ppm) 13.77 (q), 13.78 (q), 21.06 (q), 25.78
7c: Rf = 0.3 (hexane–ether = 1 : 1); colorless oil; 1H NMR
(q), 42.35 (d), 44.01 (d), 49.55 (d), 61.61 (t), 61.78 (t), 69.89 (t), (400 MHz, CDCl3) δ (ppm) 0.951 (t, J = 7.3 Hz, 3H), 1.19–1.33
119.68 (s), 136.80 (s), 167.66 (s), 168.00 (s), 174.81 (s). Selected (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H),
HMBC correlations are between δ 3.51 (H-3) and δ 49.55 (CH- 1.34–1.44 (m, 1H), 2.63–2.70 (m, 1H), 3.57–3.58 (m, 2H),
(CO2Et)2), 42.35 (C-4), between δ 4.44 (H-4) and δ 49.55 (CH- 4.19–4.32 (m, 6H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 11.36
(CO2Et)2), 44.01 (C-3), 69.89 (C-5), between δ 4.08 (CH(CO2Et)2) (q), 13.97 (q), 14.04 (q), 20.34 (t), 39.63 (d), 43.83 (d), 49.37 (d),
and δ 44.01 (C-3), 42.35 (C-4), and between δ 1.53, 1.57 62.16 (t), 70.13 (t), 167.28 (s), 167.38 (s), 175.86 (s); 1H NMR
(vC(CH3)2) and δ 119.68 (CBrv); IR (neat) 2983, 2913, 1781, (400 MHz, C6D6) δ (ppm) 0.451 (t, J = 7.4 Hz, 3H), 0.698–0.814
1735, 1446, 1373, 1297, 1265, 1236, 1187, 1027 cm−1; MS (EI) (m, 1H), 0.881 (t, J = 7.1 Hz, 3H), 0.918–1.02 (m, 1H), 1.06 (t,
m/z 378 (M+, 9.3), 376 (M+, 9.3), 333 (14), 331 (14), 297 (100%); J = 7.1 Hz, 3H), 2.18 (m, 1H), 3.49 (ddd, J = 9.3, 5.3, 1.1 Hz,
HRMS M+ 376.0519, 378.0499 (calcd for C15H21BrO6 376.0522, 1H), 3.56 (dd, J = 11.4, 7.3 Hz, 1H), 3.57 (dd, J = 9.3, 1.3 Hz,
378.0501).
1H), 3.65 (d, J = 11.4 Hz, 1H), 3.86–3.93 (m, 2H), 4.10–4.23 (m,
Diethyl 2-(trans-4-ethyl-2-oxotetrahydrofuran-3-yl)malonate 2H). Selected NOEs are between δ 3.65 (CH(CO2Et)2) and
(7t). A mixture of 4a (168 mg, 0.55 mmol) and 10% Pd–C δ 0.698–0.814, 0.918–1.02 (CH2CH3); 13C NMR (100.6 MHz,
(59 mg, 10 mol%) in methanol (5.5 mL) was stirred in a hydro- C6D6) δ (ppm) 11.08 (q), 13.86 (q), 13.96 (q), 20.27 (t), 39.60
gen atmosphere for 18 h at room temperature. The catalyst was (d), 44.11 (d), 49.76 (d), 61.78 (t), 61.97 (t), 69.47 (t), 167.51 (s),
removed by filtration (Celite) and washed with methanol. The 167.61 (s), 175.46 (s). Selected HMBC correlations are between
filtrate was concentrated in vacuo. The residue was purified by δ 3.65 (CH(CO2Et)2), 3.49 (H-5) and δ 44.11 (C-3), between
column chromatography over silica gel with hexane–ether as δ 0.451 (CH2CH3), 0.698–0.814 (CHHCH3) and δ 39.60 (C-4),
the eluent to give 7t (76 mg, 51%).
and between δ 0.698–0.814, 0.918–1.02 (CH2CH3) and δ 69.47
7t: Rf = 0.4 (hexane–ether = 1 : 1); colorless oil; 1H NMR (C-5); IR (neat) 2979, 1777, 1752, 1737, 1465, 1369, 1284, 1166,
(400 MHz, CDCl3) δ (ppm) 0.917 (t, J = 7.5 Hz, 3H), 1.29 (t, J = 1030 cm−1; MS (EI) m/z 272 (M+, 1.9), 271 (11), 226 (100%);
7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.37–1.50 (m, 1H), HRMS M+ 272.1273 (calcd for C13H20O6 272.1260).
1.61–1.71 (m, 1H), 2.60 (dddd, J = 9.2, 9.0, 8.4, 7.9, 4.6 Hz, 1H),
2.87 (dd, J = 9.0, 4.8 Hz, 1H), 3.90 (d, J = 4.8 Hz, 1H), 3.92 (dd, 10b was prepared according to the literature procedure.
J = 9.0, 7.9 Hz, 1H), 4.20–4.30 (m, 4H), 4.52 (dd, J = 9.0, 8.4 Hz,
10b: pale yellow oil; bp. 43 °C/50 mmHg; 1H NMR
Allenylamine 10a was prepared according to the literature.24
1H). Selected NOEs are between δ 2.87 (H-3) and δ 0.917 (400 MHz, CDCl3) δ (ppm) 0.925 (t, J = 7.3 Hz, 3H), 1.38 (bs,
(CH2CH3), 1.37–1.50, 1.61–1.71 (CH2CH3), and between δ 2.60 1H), 1.52 (qt, J = 7.3, 7.3 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 3.25
(H-4) and
δ
3.90 (CH(CO2Et)2, overlapped); 13C NMR (dt, J = 6.4, 3.1 Hz, 2H), 4.76 (dt, J = 6.6, 3.1 Hz, 2H), 5.22 (tt,
(100.6 MHz, CDCl3) δ (ppm) 11.12 (q), 14.01 (q), 14.05 (q), J = 6.6, 6.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 11.87
26.23 (t), 39.34 (d), 44.79 (d), 51.04 (d), 62.01 (t), 62.07 (t), (q), 23.22 (t), 47.92 (t), 51.19 (t), 75.92 (t), 89.44 (d), 208.35 (s);
71.91 (t), 167.49 (s), 167.71 (s), 176.76 (s). Selected HMBC cor- IR (neat) 3301, 2958, 2931, 2874, 1955, 1458, 1127, 842 cm−1
;
relations are between δ 1.37–1.50, 1.61–1.71 (CH2CH3) and MS (CI) m/z 112 [M + H]+; HRMS [M + H]+ 112.1132 (calcd for
δ 44.79 (C-3), 39.34 (C-4), 71.91 (C-5) and between δ 0.917 C7H14N 112.1126).
(CH2CH3) and δ 39.34 (C-4); IR (neat) 2980, 1778, 1733, 1465,
Preparation of substrates 11a–b. To a solution of 1,1-diethyl
1372, 1300, 1264, 1235, 1178, 1026 cm−1; MS (EI) m/z 273 2-hydrogen ethenetricarboxylate (432 mg, 2 mmol) (prepared
([M + H]+, 3.8), 272 (M+, 1.9), 227 (51), 160 (100%); HRMS [M + H]+ from 1,1-diethyl 2-tert-butyl ethenetricarboxylate (545 mg,
273.1331 (calcd for C13H21O6 273.1338), M+ 272.1259 (calcd for 2 mmol) upon treatment with CF3CO2H) in THF (2.8 mL) were
C13H20O6 272.1260).
added allenylamine 10a (326 mg, 2 mmol), Et3N (0.28 mL,
3970 | Org. Biomol. Chem., 2014, 12, 3964–3975
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202 mg, 2 mmol), HOBt (1-hydroxybenzotriazole) (540 mg, NaHCO3. The mixture was extracted with dichloromethane and
4 mmol) and EDCI (1-[3-(dimethylamino)propyl]-3-ethylcarbo- the organic phase was dried (Na2SO4), and evaporated
diimide hydrochloride) (399 mg, 2.08 mmol) at 0 °C. The reac- in vacuo. The crude product included impurities (possibly non-
tion mixture was stirred for 1 h at 0 °C, and was allowed to cyclized water-adducts). To a solution of the crude product in
warm to room temperature and stirred overnight. The reaction CH2Cl2 (2 mL) was added ZnCl2 (68.2 mg, 0.5 mmol). The
mixture was concentrated under reduced pressure and the mixture was stirred at room temperature for 18 h. The reaction
residue was diluted with CH2Cl2. The organic phase was mixture was quenched with water and then with saturated
washed with saturated aqueous NaHCO3 solution,
2
M
aqueous NaHCO3. The mixture was extracted with dichloro-
aqueous citric acid, saturated aqueous NaHCO3 and water, methane and the organic phase was dried (Na2SO4), and evap-
dried (Na2SO4), and evaporated in vacuo. The residue was puri- orated in vacuo. The residue was purified by column
fied by column chromatography over silica gel eluting with chromatography over silica gel with hexane–ether (1 : 2) as the
hexane–ether (1 : 1) to give 11a (375 mg, 53%).
11a: Rf = 0.3 (hexane–ether = 1 : 1); pale yellow oil; H NMR
eluent to give 12a (148 mg, 76%).
Diethyl 2-(1-benzyl-trans-4-(1-chlorovinyl)-2-oxopyrrolidin-3-
1
(400 MHz, CDCl3) (2 rotamers, ratio 1.5 : 1) δ (ppm) 1.29 (t, J = yl)malonate (12a). Rf = 0.3 (hexane–ether = 1 : 1); pale yellow
7.1, 3H × 0.4, minor rotamer) 1.31 (t, J = 7.1 Hz, 3H × 0.6, oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.275 (t, J = 7.1 Hz,
major rotamer), 1.32 (t, J = 7.1 Hz, 3H × 0.6), 1.35 (t, J = 7.1 Hz, 3H), 1.279 (t, J = 7.1 Hz, 3H), 3.29 (dd, J = 9.7, 7.1 Hz, 1H), 3.36
3H × 0.4), 3.85 (dt, J = 6.0, 3.1 Hz, 1H × 0.6), 4.00 (dt, J = 6.8, (dd, J = 9.0, 4.7 Hz, 1H), 3.36 (dd, J = 9.0, 4.7 Hz, 1H), 3.41 (dd,
2.5 Hz, 1H × 0.4), 4.24–4.39 (m, 4H), 4.57 (s, 2H × 0.4), 4.65 (s, J = 9.7, 9.4 Hz, 1H), 3.72 (ddd, J = 9.4, 9.0, 7.1 Hz, 1H), 4.06 (d,
2H × 0.6), 4.78 (dt, J = 6.6, 2.6 Hz, 2H × 0.4), 4.88 (dt, J = 6.6, J = 4.7 Hz, 1H), 4.11–4.25 (m, 4H), 4.40 (d, J = 14.9 Hz, 1H),
3.1 Hz, 2H × 0.6), 5.07 (tt, J = 6.6, 6.0 Hz, 1H × 0.6), 5.15 (tt, J = 4.58 (d, J = 14.9 Hz, 1H), 5.19 (d, J = 1.5 Hz, 1H), 5.25 (d, J = 1.5
6.8, 6.6 Hz, 1H × 0.4), 7.22–7.43 (m, 5H), 7.34 (s, 1H × 0.4), Hz, 1H), 7.24–7.36 (m, 5H). Selected NOEs are between δ 3.36
7.36 (s, 1H × 0.6); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.01 (H-3) and δ 5.25 (vCHH) and between δ 3.72 (H-4) and δ 4.06
(q), 14.03 (q), 14.05 (q), 14.10 (q), 43.85 (t), 45.88 (t), 48.37 (t), (CH(CO2Et)2); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.98 (q),
51.01 (t), 61.95 (t), 62.25 (t), 76.58 (t), 78.11 (t), 85.59 (d), 86.58 (d), 14.04 (q), 42.64 (d), 44.58 (d), 46.76 (t), 48.64 (t), 50.09 (d),
127.22 (d), 127.75 (d), 128.10 (d), 128.57 (d), 128.72 (d), 61.67 (t), 61.69 (t), 115.41 (t), 127.72 (d), 128.05 (d), 128.76 (d),
129.05 (d), 134.19 (d), 134.28 (d), 135.20 (s), 135.54 (s), 135.71 135.80 (s), 141.52 (s), 167.98 (s), 168.14 (s), 171.88 (s). Selected
(s), 136.46 (s), 162.97 (s), 163.08 (s), 164.26 (s), 164.34 (s), HMBC correlations are between δ 3.36 (H-3) and δ 50.09 (CH-
164.52 (s), 164.59 (s), 208.90 (s), 209.69 (s); IR (neat) 2983, (CO2Et)2), 42.64 (C-4), between δ 3.72 (H-4) and δ 50.09 (CH-
1956, 1732, 1652, 1496, 1446, 1373, 1255, 1199, 1069, (CO2Et)2), 44.58 (C-3), between δ 3.29, 3.41 (H-5a,5b) and
1022 cm−1; MS (EI) m/z 357 (M+, 67), 312 (24), 158 (30), 143 (73), δ 141.52 (CClvCH2), and between δ 4.06 (CH(CO2Et)2) and
91 (100%); HRMS M+ 357.1577 (calcd for C20H23NO5 δ 44.58 (C-3), 42.64 (C-4); IR (neat) 2982, 2935, 1732, 1697, 1632,
357.1576).
1491, 1446, 1373, 1261, 1175, 1032 cm−1; MS (EI) m/z 395 (M+,
11b (82%): Rf = 0.3 (hexane–ether = 1 : 1); pale yellow oil; 1H 8.8), 393 (M+, 26), 234 (54), 91 (100%); HRMS M+ 393.1341,
NMR (400 MHz, CDCl3) (2 rotamers, ratio 1 : 1) δ (ppm) 0.909 395.1317 (calcd for C20H24ClNO5 393.1345, 395.1314).
(t, J = 7.4 Hz, 3H × 0.5), 0.930 (t, J = 7.4 Hz, 3H × 0.5), 1.318 (t,
Diethyl 2-(1-benzyl-trans-4-(1-bromovinyl)-2-oxopyrrolidin-3-
J = 7.1 Hz, 3H × 0.5), 1.320 (t, J = 7.1 Hz, 3H × 0.5), 1.322 (t, J = yl)malonate (12b). Rf = 0.6 (ether); pale yellow oil; 1H NMR
7.1 Hz, 3H × 0.5), 1.324 (t, J = 7.1 Hz, 3H × 0.5), 1.55–1.68 (m, (400 MHz, CDCl3) δ (ppm) 1.28 (t, J = 7.1 Hz, 3H), 1.29 (t, J =
2H), 3.30 (dd, J = 7.6, 7.6 Hz, 2H × 0.5), 3.34–3.38 (m, 2H × 7.1 Hz, 3H), 3.26 (dd, J = 9.8, 7.1 Hz, 1H), 3.34 (dd, J = 8.7, 4.7
0.5), 3.94 (ddd, J = 6.1, 3.1, 3.1 Hz, 2H × 0.5), 4.02 (ddd, J = 6.6, Hz, 1H), 3.39 (dd, J = 9.8, 9.1 Hz, 1H), 3.63 (ddd, J = 9.1, 8.7,
2.7, 2.7 Hz, 2H × 0.5), 4.26–4.36 (m, 4H), 4.80 (dt, J = 6.6, 2.7 7.1 Hz, 1H), 4.07 (d, J = 4.7 Hz, 1H), 4.11–4.25 (m, 4H), 4.40 (d,
Hz, 2H × 0.5), 4.89 (dt, J = 6.6, 3.1 Hz, 2H × 0.5), 5.12–5.20 (m, J = 14.9 Hz, 1H), 4.59 (d, J = 14.9 Hz, 1H), 5.43 (d, J = 1.8 Hz,
1H), 7.32 (s, 1H × 0.5), 7.33 (s, 1H × 0.5); 13C NMR (100.6 MHz, 1H), 5.70 (d, J = 1.8 Hz, 1H), 7.25–7.36 (m, 5H). Selected NOEs
CDCl3) δ (ppm) 11.21 (q), 11.36 (q), 13.95 (q × 2), 14.01 (q), are between δ 3.34 (H-3) and δ 5.70 (vCHH) and between
14.03 (q), 20.68 (t), 22.12 (t), 44.37 (t), 47.01 (t), 47.73 (t), 49.59 δ 3.63 (H-4) and δ 4.07 (CH(CO2Et)2); 13C NMR (100.6 MHz,
(t), 61.78 (t × 2), 62.11 (t), 62.19 (t), 76.47 (t), 78.06 (t), 86.07 CDCl3) δ (ppm) 14.01 (q), 14.04 (q), 43.97 (d), 45.50 (d), 46.76
(d), 87.08 (d), 133.94 (d), 134.55 (d), 134.60 (s), 135.05 (s), (t), 49.54 (t), 49.99 (d), 61.68 (t), 61.70 (t), 119.86 (t), 127.71 (d),
163.08 (s), 163.11 (s), 163.62 (s), 163.91 (s), 164.58 (s), 164.62 128.06 (d), 128.75 (d), 134.80 (s), 135.77 (s), 168.00 (s), 168.11
(s), 208.74 (s), 209.33 (s); IR (neat) 2967, 2937, 1956, 1729, (s), 171.78 (s). Selected HMBC correlations are between δ 3.34
1652, 1466, 1445, 1430, 1374, 1256, 1210, 1068 cm−1; MS (EI) (H-3) and δ 43.97 (C-4), between δ 3.63 (H-4) and δ 49.99 (CH
m/z 309 (M+, 43), 199 (48), 171 (63), 143 (100%); HRMS M+ (CO2Et)2), 45.50 (C-3), between δ 3.26, 3.39 (H-5a,5b) and
309.1581 (calcd for C16H23NO5 309.1576).
δ 134.80 (CBrvCH2), and between δ 4.07 (CH(CO2Et)2) and
Experimental procedure (eqn (5), Table 2, entry 2). To a δ 45.50 (C-3), 43.97 (C-4); IR (neat) 2982, 1733, 1699, 1627, 1490,
solution of 11a (179 mg, 0.5 mmol) in CH2Cl2 (2 mL) was 1446, 1373, 1290, 1263, 1176, 1030 cm−1; MS (EI) m/z 439 (M+,
added ZnCl2 (68.2 mg, 0.5 mmol). The mixture was stirred at 34), 437 (M+, 38), 358 (23), 239 (34), 205 (62), 91 (100%); HRMS
room temperature for 18 h. The reaction mixture was M+ 437.0835, 439.0826 (calcd for C20H24BrNO5 437.0838,
quenched with water and then with saturated aqueous 439.0817).
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Diethyl 2-(1-benzyl-trans-4-(1-iodovinyl)-2-oxopyrrolidin-3-yl)- 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.57 (qt, J = 7.3, 7.3 Hz,
malonate (12c). Rf = 0.6 (hexane–ether = 1 : 4); yellow oil; 1H 1H), 3.20–3.34 (m, 3H), 3.38 (dd, J = 9.7, 6.8 Hz, 1H), 3.53 (dd,
NMR (400 MHz, CDCl3) δ (ppm) 1.28 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 9.7, 8.7 Hz, 1H), 3.65 (ddd, J = 8.7, 8.7, 6.8 Hz, 1H), 4.01 (d,
J = 7.1 Hz, 3H), 3.10–3.17 (m, 2H), 3.21 (dd, J = 8.6, 4.5 Hz, J = 4.6 Hz, 1H), 4.09–4.25 (m, 4H), 5.47 (d, J = 1.8 Hz, 1H), 5.74
1H), 3.35 (m, 1H), 4.06 (d, J = 4.5 Hz, 1H), 4.08–4.25 (m, 4H), (dd, J = 1.8, 0.4 Hz, 1H). Selected NOEs are between
4.39 (d, J = 14.8 Hz, 1H), 4.59 (d, J = 14.8 Hz, 1H), 5.74 (d, J = δ 3.20–3.34 (H-3, overlapped) and δ 5.74 (vCHH) and between
1.6 Hz, 1H), 6.19 (dd, J = 1.6, 0.4 Hz, 1H), 7.25–7.30 (m, 3H), δ 3.65 (H-4) and δ 4.01 (CH(CO2Et)2); 13C NMR (100.6 MHz,
7.32–7.36 (m, 2H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.02 CDCl3) δ (ppm) 11.18 (q), 13.98 (q × 2), 20.31 (t), 43.90 (d),
(q), 14.06 (q), 46.08 (d), 46.72 (t), 47.11 (d), 49.87 (d), 51.12 (t), 44.36 (t), 45.63 (d), 50.04 (d), 50.08 (t), 61.55 (t), 61.61 (t),
61.64 (t), 61.66 (t), 115.84 (s), 127.69 (d), 128.08 (d), 128.54 (t), 119.64 (t), 135.10 (s), 167.96 (s), 168.17 (s), 171.53 (s). Selected
128.70 (d), 135.73 (s), 167.98 (s), 168.03 (s), 171.63 (s); 1H NMR HMBC correlations are between δ 3.20–3.34 (H-3, overlapped)
(400 MHz, C6D6) δ (ppm) 0.934 (t, J = 7.1 Hz, 3H), 0.955 (t, J = and δ 50.04 (CH(CO2Et)2), between δ 3.65 (H-4) and δ 50.04
7.1 Hz, 3H), 2.86 (dd, J = 9.8, 7.1 Hz, 1H), 2.98 (dd, J = 9.8, 8.8 (CH(CO2Et)2), 45.63 (C-3), between δ 3.38, 3.53 (H-5a,5b) and δ
Hz, 1H), 3.20 (ddd, J = 8.8, 8.8, 7.1 Hz, 1H), 3.30 (dd, J = 8.8, 135.10 (CBrvCH2), and between δ 4.01 (CH(CO2Et)2) and δ
4.9 Hz, 1H), 3.83–4.08 (m, 4H), 4.06 (d, J = 15.0 Hz, 1H), 4.31 45.63 (C-3), 43.90 (C-4); IR (neat) 2966, 2935, 1733, 1698, 1627,
(d, J = 4.9 Hz, 1H), 4.51 (d, J = 15.0 Hz, 1H), 5.41 (d, J = 1.6 Hz, 1490, 1446, 1372, 1287, 1264, 1160, 1043 cm−1; MS (EI) m/z
1H), 5.81 (dd, J = 1.6, 0.6 Hz, 1H), 7.04–7.09 (m, 1H), 7.14–7.21 391 (M+, 38), 389 (M+, 36), 346 (27), 344 (29), 310 (100) 232
(m, 4H). Selected NOEs are between δ 3.30 (H-3) and δ 5.81 (96), 230 (99%); HRMS M+ 389.0836, 391.0811 (calcd for
(vCHH) and between δ 3.20 (H-4) and δ 4.31 (CH(CO2Et)2); 13
NMR (100.6 MHz, C6D6) δ (ppm) 13.90 (q), 13.95 (q), 46.45 (d),
C
C16H24BrNO5 389.0838, 391.0817).
Diethyl 2-(trans-4-(1-iodovinyl)-1-propyl-2-oxopyrrolidin-3-yl)-
46.54 (t), 47.24 (d), 50.23 (d), 50.83 (t), 61.39 (t), 61.48 (t), malonate (12f). Rf = 0.6 (hexane–ether = 1 : 4); yellow oil; 1H
116.56 (s), 127.69 (d), 128.31 (d), 128.38 (t), 128.81 (d), 136.69 NMR (400 MHz, CDCl3) δ (ppm) 0.921 (t, J = 7.3 Hz, 3H), 1.27
(s), 168.15 (s), 168.29 (s), 171.23 (s). Selected HMBC corre- (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.57 (qt, J = 7.3, 7.3
lations are between δ 3.30 (H-3) and δ 50.23 (CH(CO2Et)2), Hz, 2H), 3.11–3.34 (m, 5H), 3.49 (ddd, J = 9.4, 8.4, 1.0 Hz, 1H),
46.45 (C-4), between δ 3.20 (H-4) and δ 50.23 (CH(CO2Et)2), 4.01 (d, J = 4.4 Hz, 1H), 4.08–4.25 (m, 4H), 5.77 (d, J = 1.6 Hz,
47.24 (C-3), between δ 2.86, 2.98 (H-5a,5b) and δ 116.56 1H), 6.23 (dd, J = 1.6, 0.5 Hz, 1H); 13C NMR (100.6 MHz,
(CIvCH2), and between δ 4.31 (CH(CO2Et)2) and δ 47.24 (C-3), CDCl3) δ (ppm) 11.24 (q), 13.98 (q), 14.04 (q), 20.32 (t), 44.36
46.45 (C-4); IR (neat) 2980, 2934, 1733, 1699, 1612, 1488, 1445, (t), 46.00 (d), 47.26 (d), 49.92 (d), 51.71 (t), 61.56 (t), 61.62 (t),
1
1372, 1287, 1261, 1175, 1030 cm−1; MS (FAB) m/z 508 [M + 116.18 (s), 128.36 (t), 167.99 (s), 168.14 (s), 171.43 (s); H NMR
Na]+, 486 [M + H]+; HRMS [M + H]+ 486.0779 (calcd for (400 MHz, C6D6) δ (ppm) 0.758 (t, J = 7.3 Hz, 3H), 0.914 (t, J =
C20H25INO5 486.0778).
7.1 Hz, 3H), 0.945 (t, J = 7.1 Hz, 3H), 1.27 (qt, J = 7.3, 7.3 Hz,
Diethyl 2-(trans-4-(1-chlorovinyl)-1-propyl-2-oxopyrrolidin-3- 2H), 2.92 (dd, J = 9.7, 6.8 Hz, 1H), 3.01–3.10 (m, 3H), 3.22 (dd,
yl)malonate (12d). Rf = 0.5 (hexane–ether = 1 : 2); pale yellow J = 8.4, 4.8 Hz, 1H), 3.27 (dddd, J = 8.4, 8.1, 6.8, 0.5 Hz, 1H),
oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 0.912 (t, J = 7.3 Hz, 3.84–4.04 (m, 4H), 4.28 (d, J = 4.8 Hz, 1H), 5.47 (d, J = 1.6 Hz,
3H), 1.27 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.57 (qt, J = 1H), 5.93 (dd, J = 1.6, 0.5 Hz, 1H). Selected NOEs are between
7.3, 7.3 Hz, 2H), 3.21–3.33 (m, 3H), 3.40 (dd, J = 9.7, 7.0 Hz, δ 3.22 (H-3, overlapped) and δ 5.93 (vCHH) and between δ 3.27
1H), 3.54 (dd, J = 9.7, 9.4 Hz, 1H), 3.74 (ddd, J = 8.8, 8.8, 7.0 (H-4, overlapped) and
δ
4.28 (CH(CO2Et)2); 13C NMR
Hz, 1H), 4.01 (d, J = 4.6 Hz, 1H), 4.09–4.25 (m, 4H), 5.22 (d, J = (100.6 MHz, C6D6) δ (ppm) 11.26 (q), 13.88 (q), 13.95 (q), 20.50
1.5 Hz, 1H), 5.30 (d, J = 1.5 Hz, 1H). Selected NOEs are (t), 44.18 (t), 46.33 (d), 47.42 (d), 50.29 (d), 51.48 (t), 61.36 (t),
between δ 3.21–3.33 (H-3, overlapped) and δ 5.30 (vCHH) and 61.39 (t), 117.08 (s), 128.11 (t), 168.27 (s), 168.29 (s), 171.10 (s).
between δ 3.74 (H-4) and δ 4.01 (CH(CO2Et)2); 13C NMR Selected HMBC correlations are between δ 3.22 (H-3) and
(100.6 MHz, CDCl3) δ (ppm) 11.18 (q), 13.95 (q), 13.99 (q), δ 50.29 (CH(CO2Et)2), 117.08 (CIvCH2), between δ 3.27 (H-4)
20.32 (t), 42.57 (d), 44.37 (t), 44.71 (d), 49.15 (t), 50.12 (d), and δ 51.48 (C-5), between δ 2.92, 3.01–3.10 (H-5a,5b) and
61.56 (t), 61.62 (t), 115.22 (t), 141.81 (s), 167.97 (s), 168.22 (s), δ 46.33 (C-4), and between δ 4.28 (CH(CO2Et)2) and δ 47.42 (C-3),
171.63 (s). Selected HMBC correlations are between δ 3.21–3.33 46.33 (C-4); IR (neat) 2966, 2934, 1733, 1695, 1612, 1489, 1446,
(H-3, overlapped) and δ 50.12 (CH(CO2Et)2), 42.57 (C-4), 1372, 1287, 1175, 1112, 1043 cm−1; MS (EI) m/z 437 (M+, 38),
between δ 3.74 (H-4) and δ 50.12 (CH(CO2Et)2), 44.71 (C-3), 392 (38), 310 (100%); HRMS M+ 437.0697 (calcd for
between δ 3.40, 3.54 (H-5a,5b) and δ 141.81 (CClvCH2), and C16H24INO5 437.0699).
between δ 4.01 (CH(CO2Et)2) and δ 44.71 (C-3), 42.57 (C-4); IR
trans-3-(Di(ethoxycarbonyl)methyl)-2-oxotetrahydrofuran-4-
(neat) 2966, 2936, 1733, 1696, 1632, 1491, 1446, 1373, 1264, carboxylic acid (13). Compound 4a (84 mg, 0.28 mmol) was
1175, 1034 cm−1; MS (FAB) m/z 370 [M + Na]+, 368 [M + Na]+, dissolved in a mixture of CH3CN (1.4 mL), CCl4 (1.4 mL), and
348 [M + H]+, 346 [M + H]+; HRMS [M + H]+ 346.1421, 348.1392 H2O (1.4 mL). NaIO4 (385 g, 1.8 mmol) was then added fol-
(calcd for C16H25ClNO5 346.1421, 348.1392).
lowed by RuCl3·xH2O (5.2 mg, ca. 0.025 mmol). After 1 h of
Diethyl 2-(trans-4-(1-bromovinyl)-1-propyl-2-oxopyrrolidin-3- stirring at room temperature, the solution was diluted with
yl)malonate (12e). Rf = 0.6 (ether); pale yellow oil; 1H NMR CH2Cl2. The layers were separated, and the aqueous layer was
(400 MHz, CDCl3) δ (ppm) 0.915 (t, J = 7.3 Hz, 3H), 1.27 (t, J = extracted with CH2Cl2 three times. The combined organic
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layers were dried (Na2SO4) and concentrated in vacuo. The rated aqueous NaHCO3 and water, dried (Na2SO4), and then
residue was filtered through a short plug of Celite that was evaporated in vacuo. The residue was purified by column
washed with ether to give 13 (78 mg, 98%).
chromatography over silica gel eluting with hexane–ether (1 : 4)
13: Rf = 0.4 (hexane–ether = 1 : 4); colorless oil; 1H NMR to give 15a (110 mg, 58%).
(400 MHz, CDCl3) δ (ppm) 1.28 (t, J = 7.1 Hz, 3H), 1.29 (t, J =
15a: Rf = 0.3 (hexane–ether = 1 : 4); colorless needles; mp
7.1 Hz, 3H), 3.52 (dd, J = 9.2, 4.4 Hz, 1H), 3.82 (ddd, J = 9.2, 119–121 °C (AcOEt–hexane); 1H NMR (400 MHz, CDCl3)
9.2, 7.9 Hz, 1H), 4.07 (d, J = 4.4 Hz, 1H), 4.18–4.27 (m, 4H), δ (ppm) 1.24 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 3.51
4.37 (dd, J = 9.2, 7.9 Hz, 1H), 4.69 (dd, J = 9.7, 9.2 Hz, 1H), 9.10 (dd, J = 8.7, 4.0 Hz, 1H), 3.61 (ddd, J = 8.9, 8.7, 7.5 Hz, 1H),
(bs, 1H). Selected NOEs are between δ 3.82 (H-4) and δ 4.07 4.00–4.21 (m, 5H), 4.42 (d, J = 5.9 Hz, 2H), 4.45 (dd, J = 8.8, 7.5
(CH(CO2Et)2); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.89 (q), Hz, 1H), 4.52 (dd, J = 8.9, 8.8 Hz, 1H), 6.48 (br, 1H), 7.26–7.35
13.91 (q), 41.82 (d), 42.66 (d), 50.56 (d), 62.39 (t), 62.50 (t), (m, 5H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.94 (q), 42.64
67.75 (t), 167.25 (s), 167.47 (s), 175.04 (s), 176.02 (s). Selected (d), 44.10 (t), 44.14 (d), 50.35 (d), 62.38 (t), 68.88 (t), 127.74 (d),
HMBC correlations are between δ 3.52 (H-3) and δ 176.02 127.89 (d), 128.81 (d), 137.65 (s), 167.54 (s), 168.28 (s), 170.14 (s),
(CO2H), 42.66 (C-4), between δ 3.82 (H-4) and δ 50.56 (CH 175.52 (s). Selected HMBC correlations are between δ 3.51
(CO2Et)2), 41.82 (C-3), between δ 4.37, 4.69 (H-5a,5b) and (H-3) and δ 170.14 (CONH), 44.14 (C-4), between δ 3.61 (H-4)
δ 176.02 (CO2H), and between δ 4.07 (CH(CO2Et)2) and δ 41.82 and δ 50.35 (CH(CO2Et)2), 42.64 (C-3), and between δ 4.45, 4.52
(C-3), 42.66 (C-4); IR (neat) 3536, 2985, 1774, 1739, 1469, 1447, (H-5a,5b) and δ 170.14 (CONH); IR (KBr) 3302, 2979, 1783,
1373, 1207, 1032 cm−1; MS (EI) m/z 288 (M+, 8.9), 270 (13), 243 1770, 1731, 1646, 1540, 1371, 1258, 1189, 1142, 1044, 1012,
(100), 197 (94), 160 (91), 125 (70%); HRMS M+ 288.0842 (calcd 701 cm−1; MS (EI) m/z 377 (M+, 15), 279 (28), 200 (67), 149 (77),
for C12H16O8 288.0845).
Methyl trans-3-(di(ethoxycarbonyl)methyl)-2-oxotetrahydro- 377.1475).
furan-4-carboxylate (14). To solution of 13 (200 mg, 15b: Rf = 0.5 (hexane–ether = 1 : 4); colorless needles; mp
91 (100%); HRMS M+ 377.1479 (calcd for C19H23NO7
a
0.69 mmol) in methanol (0.28 mL)–benzene (1.1 mL) was 118–120 °C (benzene); 1H NMR (400 MHz, CDCl3) δ (ppm)
added (CH3)3SiCHN2 (ca. 10% hexane solution, 1.5 mL) at 1.240 (t, J = 7.1 Hz, 3H), 1.244 (t, J = 7.1 Hz, 3H), 3.51 (dd, J =
room temperature. The mixture was stirred for 30 min at room 8.6, 4.0 Hz, 1H), 3.63 (ddd, J = 8.9, 8.6, 7.6 Hz, 1H), 3.99–4.19
temperature and concentrated. The residue was purified by (m, 5H), 4.35 (dd, J = 14.9, 5.8 Hz, 1H), 4.39 (dd, J = 14.9, 6.0
column chromatography over silica gel with hexane–ether as Hz, 1H), 4.39 (dd, J = 8.8, 7.6 Hz, 1H), 4.52 (dd, J = 8.9, 8.8 Hz,
the eluent to give 14 (149 mg, 71%).
1H), 6.73 (broad t, J = 5.8 Hz, 1H), 7.20–7.23 (m, 2H), 7.27–7.31
14: Rf = 0.4 (hexane–ether = 1 : 1); colorless oil; 1H NMR (m, 2H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.89 (q), 42.48 (d),
(400 MHz, CDCl3) δ (ppm) 1.28 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 43.27 (t), 44.09 (d), 50.31 (d), 62.36 (t), 62.39 (t), 68.85 (t),
7.1 Hz, 3H), 3.53 (dd, J = 9.5 Hz, 4.4 Hz, 1H), 3.76 (s, 3H), 3.80 128.83 (d), 129.23 (d), 133.43 (s), 136.33 (s), 167.53 (s), 168.22
(ddd, J = 9.7, 9.5, 8.2 Hz, 1H), 4.05 (d, J = 4.4 Hz, 1H), (s), 170.24 (s), 175.62 (s). Selected HMBC correlations are
4.17–4.27 (m, 4H), 4.28 (dd, J = 9.2, 8.2 Hz, 1H), 4.65 (dd, J = between δ 3.51 (H-3) and δ 170.24 (CONH), 44.09 (C-4),
9.7, 9.2 Hz, 1H). Selected NOEs are between δ 3.80 (H-4) and between δ 3.63 (H-4) and δ 50.31 (CH(CO2Et)2), 42.48 (C-3), and
δ 4.05 (CH(CO2Et)2); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.94 between δ 4.39, 4.52 (H-5a,5b) and δ 170.24 (CONH); IR (KBr)
(q), 41.97 (d), 42.75 (d), 50.48 (d), 52.81 (q), 62.23 (t), 62.32 (t), 3291, 2979, 1784, 1771, 1744, 1645, 1541, 1370, 1261, 1189,
67.86 (t), 167.23 (s), 167.38 (s), 171.72 (s), 174.96 (s). Selected 1016 cm−1; MS (EI) m/z 413 (M+, 4.3), 411 (M+, 13), 366 (13),
HMBC correlations are between δ 3.53 (H-3) and δ 171.72 243 (44), 140 (100%); HRMS M+ 411.1084, 413.1062 (calcd for
(CO2CH3), 42.75 (C-4), between δ 3.80 (H-4) and δ 50.48 (CH C19H22ClNO7 411.1085, 413.1055); Anal. Calcd for
(CO2Et)2), 41.97 (C-3), between δ 4.28, 4.65 (H-5a,5b) and C19H22ClNO7: C, 55.41; H, 5.38; N, 3.40. Found: C, 55.26; H,
δ 171.72 (CO2CH3), and between δ 4.05 (CH(CO2Et)2) and δ 41.97 5.15; N, 3.32.
(C-3), 42.75 (C-4); IR (neat) 2986, 1784, 1741, 1439, 1372, 1248,
Preparation of 16a–b (eqn (6)). To a mixture of phenylboro-
1210, 1179, 1032 cm−1; MS (EI) m/z 302 (M+, 7.5), 271 (17), 257 nic acid (39 mg, 0.323 mmol), 12c (155 mg, 0.307 mmol), and
(64), 160 (100%); HRMS M+ 302.1001 (calcd for C13H18O8 K2CO3 (106 mg, 0.769 mmol) were added acetone (0.61 mL),
302.1002); Anal. Calcd for C13H18O8: C, 51.65; H, 6.00. Found: water (0.77 mL), and Pd(OAc)2 (4.0 mmol L−1 acetone solution,
C, 51.44; H, 5.88.
0.31 mL, 1.24 μmol), successively. The mixture was heated at
Preparation of 15a–b. To
a
solution of 13 (144 mg, 65 °C for 18 h. The reaction mixture was extracted with dichloro-
0.5 mmol) in THF (0.7 mL) were added benzylamine (54 mg, methane (4 × 20 mL) and the organic phase was washed with
0.5 mmol), Et3N (70 μL, 54 mg, 0.5 mmol), HOBt (1-hydroxy- brine, dried (Na2SO4), and then evaporated in vacuo. The
benzotriazole) (135 mg, 1 mmol) and EDCI (1-[3-(dimethyl- residue was purified by column chromatography over silica gel
amino)propyl]-3-ethylcarbodiimide hydrochloride) (100 mg, eluting with hexane–ether to give 16a (78 mg, 58%).
1
0.52 mmol) at 0 °C. The reaction mixture was allowed to warm
16a: Rf = 0.6 (hexane–ether = 1 : 4); pale yellow oil; H NMR
to room temperature and stirred for 18 h. The reaction mixture (400 MHz, CDCl3) δ (ppm) 1.19 (t, J = 7.1 Hz, 3H), 1.25 (t, J =
was concentrated under reduced pressure and the residue was 7.1 Hz, 3H), 3.00 (dd, J = 9.6, 7.6 Hz, 1H), 3.40 (dd, J = 9.2, 5.1
diluted with CH2Cl2. The organic phase was washed with satu- Hz, 1H), 3.48 (dd, J = 9.6, 9.2 Hz, 1H), 3.77 (dddd, J = 9.2, 9.2,
rated aqueous NaHCO3 solution, 2 M aqueous citric acid, satu- 7.6, 0.9 Hz, 1H), 3.96 (d, J = 5.1 Hz, 1H), 4.07–4.25 (m, 4H),
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4.40 (d, J = 14.8 Hz, 1H), 4.51 (d, J = 14.8 Hz, 1H), 5.13 (d, J =
0.9 Hz, 1H), 5.27 (s, 1H), 7.22–7.33 (m, 10H). Selected NOEs
are between δ 3.40 (H-3) and δ 5.13 (vCHH), and between
δ 3.77 (H-4) and δ 3.96 (CH(CO2Et)2); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) 13.97 (q), 14.02 (q), 39.38 (d), 45.71 (d), 46.82 (t),
51.01 (d), 51.75 (t), 61.65 (t × 2), 113.10 (t), 126.74 (d),
127.63 (d), 127.93 (d), 128.14 (d), 128.54 (d), 128.71 (d), 136.04 (s),
140.62 (s), 148.69 (s), 168.08 (s), 168.23 (s), 172.77 (s).
Selected HMBC correlations are between δ 3.40 (H-3) and
δ 51.01 (CH(CO2Et)2), 39.38 (C-4), between δ 3.77 (H-4) and
δ 51.01 (CH(CO2Et)2), 45.71 (C-3), between δ 3.00, 3.48 (H-5a,5b)
and δ 148.69 (CPhvCH2), and between δ 3.96 (CH(CO2Et)2)
and δ 45.71 (C-3), 39.38 (C-4); IR (neat) 2982, 2936, 1732, 1695,
1495, 1444, 1370, 1261, 1176, 1030 cm−1; MS (EI) m/z 435 (M+,
5), 276 (11), 220 (26), 205 (100%); HRMS M+ 435.2042 (calcd
for C26H29NO5 435.2046).
Springer, Berlin, Germany, 2005, pp. 183–210; (d) S. Ma,
Acc. Chem. Res., 2009, 42, 1679; (e) R. Zimmer,
C. U. Dinesh, E. Nandanan and F. A. Khan, Chem. Rev.,
2000, 100, 3067; (f) S. Ma, Chem. Rev., 2005, 105, 2829;
(g) S. Ma, Acc. Chem. Res., 2003, 36, 701; (h) L. K. Sydnes,
Chem. Rev., 2003, 103, 1133; (i) H. H. A. M. Hassan, Curr.
Org. Synth., 2007, 4, 413.
2 For some recent examples, see: (a) K. M. Brummond,
H. Chen, K. D. Fisher, A. D. Kerekes, B. Rickards, P. C. Sill
and S. J. Geib, Org. Lett., 2002, 4, 1931; (b) C. Mukai,
I. Nomura, K. Yamanishi and M. Hanaoka, Org. Lett., 2002,
4, 1755; (c) M. A. Tarselli and M. R. Gagné, J. Org. Chem.,
2008, 73, 2439; (d) K. M. Brummond and D. Chen, Org.
Lett., 2008, 10, 705; (e) H. Tsukamoto and Y. Kondo, Org.
Lett., 2008, 10, 2633; (f) J. Mo and P. H. Lee, Org. Lett.,
2010, 12, 2570; (g) M. Murakami, S. Kadowaki and
T. Matsuda, Org. Lett., 2005, 7, 3953.
3 (a) M. Bertrand, M.-L. Roumestant and P. Sylvestre-Panthet,
J. Chem. Soc., Chem. Commun., 1979, 529; (b) R. Hayashi,
J. B. Feltenberger and R. P. Hsung, Org. Lett., 2010, 12,
1152; (c) A. Padwa, H. Lipka, S. H. Watterson and
S. S. Murphree, J. Org. Chem., 2003, 68, 6238.
4 (a) W. G. Dauben, G. Shapiro and L. Luders, Tetrahedron
Lett., 1985, 26, 1429; (b) B. T. B. Hue, J. Dijkink, S. Kuiper,
K. K. Larson, F. S. Guziec Jr., K. Goubitz, J. Fraanje,
H. Schenk, J. H. van Maarseveen and H. Hiemstra, Org.
Biomol. Chem., 2003, 1, 4364; (c) M. S. Shepard and
E. M. Carreira, J. Am. Chem. Soc., 1997, 119, 2597.
5 (a) G. A. Molander and E. P. Cormier, J. Org. Chem., 2005,
70, 2622; (b) L. Xu and X. Huang, Tetrahedron Lett., 2008,
49, 500.
16b: Rf = 0.4 (hexane–ether = 1 : 4); colorless oil; 1H NMR
(400 MHz, CDCl3) δ (ppm) 0.877 (t, J = 7.4 Hz, 3H), 1.19 (t,
J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.51 (qt, J = 7.4, 7.4 Hz,
2H), 3.10 (dd, J = 9.3, 7.4 Hz, 1H), 3.23 (t-like, J = 7.4 Hz, 2H),
3.36 (dd, J = 9.1, 5.3 Hz, 1H), 3.59 (dd, J = 9.3, 9.2 Hz, 1H), 3.79
(dddd, J = 9.2, 9.1, 7.4, 0.9 Hz, 1H), 3.92 (d, J = 5.3 Hz, 1H),
4.06–4.24 (m, 4H), 5.16 (d, J = 0.9 Hz, 1H), 5.30 (s, 1H),
7.28–7.35 (m, 5H). Selected NOEs are between δ 3.36 (H-3) and
δ 5.16 (vCHH), 7.28–7.35 (Ph), and between δ 3.79 (H-4) and
δ 3.92 (CH(CO2Et)2); 13C NMR (100.6 MHz, CDCl3) δ (ppm)
11.24 (q), 13.96 (q), 14.00 (q), 20.39 (t), 39.37 (d), 44.46 (t),
45.86 (d), 51.09 (d), 52.32 (t), 61.56 (t), 61.60 (t), 112.85 (t),
126.75 (d), 127.95 (d), 128.57 (d), 140.79 (s), 149.01 (s),
168.09 (s), 168.32 (s), 172.57 (s). Selected HMBC correlations
are between δ 3.36 (H-3) and δ 51.09 (CH(CO2Et)2), 39.37 (C-4),
between δ 3.79 (H-4) and δ 51.09 (CH(CO2Et)2), 45.85 (C-3),
and between δ 3.92 (CH(CO2Et)2) and δ 45.85 (C-3), 39.37
(C-4); IR (neat) 2965, 2934, 1732, 1695, 1493, 1444, 1370,
1264, 1177, 1148, 1033 cm−1; MS (EI) m/z 387 (M+, 16), 342
(9.3), 228 (100%); HRMS M+ 387.2036 (calcd for C22H29NO5
387.2046).
6 S. Kitagaki, S. Teramoto and C. Mukai, Org. Lett., 2007, 9,
2549.
7 S.-K. Kang, Y.-M. Kim, Y.-H. Ha, C.-M. Yu, H. Yang and
Y. Lim, Tetrahedron Lett., 2002, 43, 9105.
8 G. Lemière, B. Cacciuttolo, E. Belhassen and E. Duñach,
Org. Lett., 2012, 14, 2750.
9 B. B. Snider and D. M. Roush, J. Org. Chem., 1979, 44, 4229.
10 S. Yamazaki, K. Yamada, S. Yamabe and K. Yamamoto,
J. Org. Chem., 2002, 67, 2889.
11 S. Yamazaki, K. Fujinami, Y. Maitoko, K. Ueda and
K. Kakiuchi, J. Org. Chem., 2013, 78, 8405.
Acknowledgements
This work was supported by the Ministry of Education,
Culture, Sports, Science, and Technology of the Japanese 12 (a) S. Yamazaki and M. Takebayashi, J. Org. Chem., 2011,
Government. We thank the Nara Institute of Science and
Technology (NAIST) and Prof. K. Kakiuchi (NAIST) for mass
spectrometry.
76, 6432; (b) S. Yamazaki, M. Takebayashi and K. Miyazaki,
J. Org. Chem., 2010, 75, 1188; (c) S. Morikawa, S. Yamazaki,
M. Tsukada, S. Izuhara, T. Morimoto and K. Kakiuchi,
J. Org. Chem., 2007, 72, 6459; (d) S. Yamazaki and Y. Iwata,
J. Org. Chem., 2006, 71, 739.
13 S. Yamazaki, Y. Yamamoto, Y. Fukushima, M. Takebayashi,
T. Ukai and Y. Mikata, J. Org. Chem., 2010, 75, 5216.
References
1 (a) The Chemistry of Allenes, ed. S. R. Landor, Academic, 14 Preliminary results were presented at the 13th Tetrahedron
London, 1982, vol. 1; (b) Modern Allene Chemistry, ed.
N. Krause and A. S. K. Hashmi, Wiley-VCH, Weinheim,
Germany, 2004, vol. 1 and 2; (c) S. Ma, Palladium-Catalyzed
Conference Asia Edition, Taipei, 2012 and at the 93rd
Annual Meeting of the Chemical Society of Japan, Shiga,
2013.
Two- or Three-Component Cyclization of Functionalized 15 S.-K. Kang, S.-W. Lee, J. Jung and Y. Lim, J. Org. Chem.,
Allenes in Palladium in Organic Synthesis, ed. J. Tsuji,
2002, 67, 4376.
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Paper
16 M. Hudlicky, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon Press, Oxford, U.K.,
1991, vol. 8, p. 895.
17 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648; (b) C. Lee,
W. Yang and R. G. Parr, Phys. Rev. B: Condens. Matter, 1998,
37, 785.
P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith,
M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe,
P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong,
C. Gonzalez and J. A. Pople, Gaussian 03, Revision C.02,
Gaussian, Inc., Wallingford, CT, 2004.
19 (a) K. Fukui, J. Phys. Chem., 1970, 74, 4161; (b) C. Gonzalez
and H. B. Schlegel, J. Phys. Chem., 1989, 90, 2154.
18 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., 20 (a) E. Cancès, B. Mennucci and J. Tomasi, J. Chem. Phys.,
T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam,
S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi,
G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji,
1997, 107, 3032; (b) M. Cossi, V. Barone, B. Mennucci and
J. Tomasi, Chem. Phys. Lett., 1998, 286, 253; (c) B. Mennucci
and J. Tomasi, J. Chem. Phys., 1997, 106, 5151.
M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, 21 (a) D. Y. Curtin, Rec. Chem. Prog., 1954, 15, 111;
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts,
(b) L. P. Hammett, Physical Organic Chemistry, McGraw-Hill,
New York, 1970, ch. 5; (c) J. I. Seeman, Chem. Rev., 1983,
83, 83.
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, 22 L. Brandsma, Synthesis of Acetylenes, Allenes and Cumu-
C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma,
G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski,
lenes: Methods and Techniques, Elsevier, Amsterdam,
2004.
S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, 23 B. M. Trost, A. B. Pinkerton and M. Seidel, J. Am. Chem.
D. K. Malick, A. D. Rabuck, K. Raghavachari, Soc., 2001, 123, 12466.
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, 24 C. Sahlberg, S. B. Ross, I. Fagervall, A. L. Ask and
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko,
A. Claesson, J. Med. Chem., 1983, 26, 1036.
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