Conversion of 4-oxoproline esters to 4-substituted pyrrole-2-carboxylic acid esters

Article abstract of DOI:10.1248/cpb.57.167

The Grignard, Wittig, Tebbe, Horner-Emmons, and Reformatsky reactions of the 4-oxoproline esters gave the corresponding 4-alylated or 4-alkylidenated products, respectively. The products were properly treated with bases to cause aromatization, giving 4-su

Full text of DOI:10.1248/cpb.57.167

February 2009
Chem. Pharm. Bull. 57(2) 167—176 (2009)
167
Conversion of 4-Oxoproline Esters to 4-Substituted Pyrrole-2-carboxylic
Acid Esters
Yasushi ARAKAWA,* Naomi YAGI, Yukimi ARAKAWA, Ken-ichi TANAKA, and Shigeyuki YOSHIFUJI
Faculty of Pharmaceutical Sciences, Hokuriku University; Kanagawa-machi Ho-3, Kanazawa 920–1181, Japan.
Received September 29, 2008; accepted November 28, 2008; published online December 1, 2008
The Grignard, Wittig, Tebbe, Horner–Emmons, and Reformatsky reactions of the 4-oxoproline esters gave
the corresponding 4-alylated or 4-alkylidenated products, respectively. The products were properly treated with
bases to cause aromatization, giving 4-substituted pyrrole-2-carboxylic acid esters such as methyl 4-methylpyr-
role-2-carboxylate, which is a trail pheromone of Atta texana.
Key words 4-oxoproline ester; Grignard reaction; Horner–Emmons reaction; Reformatsky reaction; aromatization; methyl 4-
methylpyrrole-2-carboxylate
During our study of the synthesis of several compounds proline 513) and 614) as substrates for the ketone reactions,
using 4-hydroxyproline (1) as a starting material,1) when a p- and synthesized them from 1 according to the previously re-
toluenesulfonyl (Ts, tosyl) group was introduced to the nitro- ported methods.2) Next, we attempted the base treatments of
gen atom of 1 by the Schotten–Baumann method employing 5 and 6 using appropriate bases to cause enolization and
TsCl and aqueous NaOH according to Portoghese’s method2) aromatization. As a result, 4-hydroxypyrrole-2-carboxylic
in order to obtain compound 2, thereby prolonging the reac- acid esters 8 and 9 were successfully obtained in 76% and
tion, we encountered a side reaction that caused the elimina- 60% yields, respectively. Only the benzyl ester of 4-hydroxy-
tion of sulfinic acid and aromatization, giving pyrrole-2-car- pyrrole-2-carboxylic acid15) has been reported previously; 8
boxylic acid (3) (Chart 1). We therefore considered that the and 9 are new compounds (Chart 3).
aromatization could be utilized for the synthesis of pyrrole-
The Grignard Reactions of N-Tosyl-4-oxoproline Ester
2-carboxylic acid derivatives such as methyl 4-methylpyr- and Conversion into the Pyrrole Derivatives Grignard re-
role-2-carboxylate (4), which is a trail pheromone of Atta actions were attempted with the tert-butyl ester of N-tosyl-4-
texana.3—6)
oxoproline 6, in order to prevent the reaction at the ester moi-
Although aromatizations of the N-tosylproline derivatives ety. When the Grignard reagent was employed without addi-
giving pyrrole-2-carboxylic acid derivatives,7—9) as well as tion of other reagent, the by-products were remarkably
other syntheses of the pyrrole-2-carboxylic acid deriva- formed and yields of the desired products were much lower
tives,10—12) have been reported by many workers, synthesis of (mixture of epimers ꢀ70%). In order to prevent the aldol re-
the pyrrole-2-carboxylic acid derivatives using 4-oxoproline action and the aromatization of 6, which seemed to be the
16,17)
derivatives has not been reported. Therefore, we performed side reactions, additions of CeCl3
into the reaction sys-
alkylation and alkylidenaion of N-tosyl-4-oxoproline ester, tems were examined. Consequently, the numbers of the com-
followed by aromatization of the products to give 4-substi-
tuted proline-2-carboxylic acid esters 7 (Chart 2). This
method made it possible to introduce not only a simple alkyl
group but also an alkyl possessing a functional group into 4-
position of the pyrrole-2-carboxylic acid derivatives.
Thus we report here the conversion of 4-oxoproline esters
5 and 6 to the 4-substituted proline-2-carboxylic acid esters
7.
Base Treatments of N-Tosyl-4-oxoproline Esters We
chose the methyl and/or tert-butyl esters of N-tosyl-4-oxo-
Chart 2
Chart 1
Fig. 1. Trail Pheromone of Atta texana
Chart 3
∗ To whom correspondence should be addressed. e-mail: ya-arakawa@hokuriku-u.ac.jp
© 2009 Pharmaceutical Society of Japan

168
Vol. 57, No. 2
Chart 4. The Grignard Reactions of Compound 6
Chart 5
Next, aromatizations of the compounds 10—13 were at-
tempted. In order to obtain methyl esters of 4-substituted pyr-
role-2-carboxylic acids, 10b—12b and 13 were treated with
SOCl2–MeOH, which should cause chlorination and transes-
terification, then treated with NaOMe in MeOH, affording
compounds 4, 14, 15, and 16 in 56%, 55%, 55%, and 79%
yields, respectively (Chart 5, route 1). Compounds 10a—12a
Fig. 2. Selected Decisive NOE Relationships of Compounds 10a and 10b
ponents of the reaction mixtures decreased in the TLC analy- were also treated similarly to 10b—12b, and similar results
ses and the yields of the desired products improved (Chart 4). were obtained.
The obtained products were the epimers in each alkylation,
Meanwhile, to obtain tert-butyl esters of 4-substituted pyr-
and the ratio of the epimers seemed to change by the size of role-2-carboxylic acids, 10b—12b and 13 were treated with
the alkyl (or phenyl) groups introduced to the 4-position. SOCl2-pyridine, which should cause chlorination and elimi-
When a phenyl group was introduced, a single epimer, nation, then treated with 1,8-diazabicyclo[5.4.0]undec-7-ene
(2S,4R)-form 13 was generated. Although, by the IUPAC (DBU) in refluxing toluene, affording compounds 17, 18, 19,
nomenclature, the absolute configuration of 13 is different and 20 in 77%, 82%, 60%, and 41% yields, respectively
from those of 10b—12b, which were (2S,4S)-forms, the (Chart 5, route 2).
structure of 13 should be similar to those of 10b—12b. The
Incidentally, the aromatizations are characteristic of N-to-
stereochemistries of the epimers were determined by differ- sylproline derivatives, and normally N-protected proline de-
1
ential nuclear Overhauser effect (NOE) experiments of H- rivatives (urethanes and amides) do not undergo aromatiza-
NMR (Fig. 2). As for 10a, ꢁNOEs were observed between a tion under the basic conditions. For example, treatment of N-
signal at d 1.74 assigned to the hydroxy proton and a signal tert-butoxycarbonyl-4-iodo-L-proline methyl ester with DBU
at d 4.33 assigned to 2-H, and between a signal at d 1.35 as- provided 3,4- and 4,5-dehydroproline derivatives without
signed to the 4-methyl protons and a signal at d 1.48 as- aromatization.18)
signed to methyl protons of the tert-butyl group. Therefore,
The Wittig, the Tebbe, and the Horner–Emmons Reac-
10a was proved to have a (2S,4R)-configuration. As for 10b, tions of N-Tosyl-4-oxoproline Esters and Conversion into
ꢁNOEs were observed between a signal at d 4.29 assigned the Pyrrole Derivatives We examined the Wittig reaction
to the hydroxy proton and signals at d 1.97 assigned to 3-Hb of 5 with methylenetriphenylphosphorane, which was gener-
and d 1.50 assigned to methyl protons of the tert-butyl ated by treatment of methyltriphenylphosphonium bromide
group. ꢁNOEs were also observed between a signal at d with phenyllithium in Et2O,19) at room temperature and the
2.06 assigned to 3-Ha and signals at d 4.16 assigned to 2-H expected 4-methyleneproline derivative 21 was obtained in
and d 1.29 assigned to 4-methyl protons. Therefore, 10b was only 10% yield. A similar reaction was examined by Cheng
proved to have a (2S,4S)-configuration. In the case of 11— et al., and they reported that the low yield of the reaction was
13, ꢁNOEs similar to those for compound 10 were observed, due to the propensity of the sulfonamide moiety to decom-
and the configurations of these compounds were confirmed.
Further, differences between the characteristics of the
pose under basic conditions.20)
We next examined the Tebbe reaction21) of 6, and the de-
epimers 10a—12a and 10b—12b were observed in TLC (sil- sired product 22 was obtained in 16% yield together with the
ica gel) analysis and IR spectra due to the probable intramo- dimethylated product 23 in 22% yield (Chart 6).
lecular hydrogen bondings between a hydroxy group and an
Meanwhile, the Horner–Emmons reactions22) of 5 and 6
ester carbonyl group of 10b—12b. The Rf values of 10b— gave satisfactory results, as shown in Table 1. However, the
12b were higher than those of the corresponding epimers expected products underwent rearrangement at olefin or
10a—12a in TLC analysis, because the intermolecular hy- aromatization under the basic reaction conditions to give the
drogen bondings between the hydroxy groups of 10b—12b secondary products, depending on the alkyl groups of esters
and silica gel seem to have been prevented. Concerning the 5 and 6, temperatures, and reagents. For example, the
characteristic absorption bands of carbonyl groups in the IR Horner–Emmons reaction of 6 and triethyl phosphonoacetate
spectra, those of 10b—12b (1707, 1720, 1718 cmꢂ1) were lo- at room temperature for 1 h (entry 3) gave exo-olefins 25a
cated at lower wavenumbers than those of 10a—12a (1728, (4E) and 25b (4Z), endo-olefins 25c (3-ene) and 25d (4-ene),
1751, 1730 cmꢂ1).
and pyrrole 29, in 17%, 14%, 33%, 9%, and 23% yields. A

February 2009
169
Chart 6
Fig. 3. Selected Decisive NOE Relationships of Compounds 25a—d
Table 1. The Horner–Emmons Reactions of Compounds 5 and 6
Substrate
Yields (%)
Entry
R2
Temp.
R1
Olefin
24
a (4E)
b (4Z)
Pyrrole
1
2
3
4
5
6
7
8
5
6
5
6
Me
t-Bu
Me
COOEt
r.t.
ꢂ40 °C
r.t.
0 °C
0 °C
ꢂ40 °C
15 °C
0 °C
2
48
17
37
—
37
—
48
—
44
14a)
30b)
4
33
—
36
28
29
30
31
86
—
23
—
56
3
25
CN
26
t-Bu
27
98
5
a) The isomers
and
were obtained. b) 25c 30%, 25d 2%. r.t.: room temperature.
similar reaction at 0 °C for 1 h (entry 4) gave 25a, 25b, 25c, side chain, and d 7.70 assigned to aromatic protons. In the
and 25d in 37%, 30%, 30%, and 2% yields without forma- case of 24, 26, and 27, discriminations of the (4E)-form from
tion of 29. In the case of the reactions using diethyl cyano- the (4Z)-form were done similarly (Fig. 3).
methylphosphonate (entry 5—8), aromatization occurred
more easily.
Aromatizations of the olefinic compounds 21 and 22 were
then examined (Table 2). In these cases, similarly to the
The structures of 24—27 were determined by differential aromatization process of 4-alkylated proline derivatives 10—
1
nuclear Overhauser effect (NOE) experiments of H-NMR 13, treatments of 21 and 22 with DBU in refluxing toluene
(Fig. 3). As for 25a, ꢁNOEs were observed between a signal for 12 h (entry 1 and 3) afforded pyrrole derivatives 4 and 17
at d 5.79 assigned to the olefinic proton and signals at d 4.22 in 97% and 99% yields, respectively. Without heating, the
and d 4.24 assigned to 5-Hs. For 25b, ꢁNOEs were ob- aromatization reaction hardly proceeded. Compounds 21 and
served between a signal at d 5.78 assigned to the olefinic 22 were also treated with potassium tert-butoxide in tetrahy-
proton and a signal at d 3.12 assigned to 3-Hb. For 25c, drofuran (THF) at room temperature for 1 h (entry 2 and 4),
ꢁNOEs were observed between a signal at d 5.53 assigned giving 4 and 17 in 77% and 85% yields, respectively.
to the olefinic 3-proton and signals at d 3.07 and d 3.12 as-
On the other hand, compounds 24—27 seemed to be more
signed to methylene protons of the side chain, and d 4.98 as- reactive (Table 3). Even at room temperature, treatments of
signed to 2-H. For 25d, ꢁNOEs were observed between a 24a and 26a with DBU in toluene (using concentrations sim-
signal at d 6.28 assigned to the olefinic 5-proton and signals ilar to that of 21) for 1 h (entry 1 and 3) gave the correspon-
at d 3.01 and d 3.03 assigned to methylene protons of the ding pyrrole derivatives 28 and 30 in 97% and 99% yields,

170
Vol. 57, No. 2
Table 2. Aromatization of Compounds 21 and 22
Table 3. Aromatization of Compounds 24—27
Reaction
conditions
Yield
(%)
Entry Substrate
R
Product
Yield
(%)
Entry Substrate
R1
R2
Temp.
r.t.
Product
1
2
3
4
21
22
Me
DBU, toluene, reflux, 12 h
t-BuOK, THF, r.t., 1 h
DBU, toluene, reflux, 12 h
t-BuOK, THF, r.t., 1 h
4
97
77
99
85
1
2
3
4
24a
25a
26a
27a
Me
t-Bu
Me
COOEt
COOEt Reflux
CN
CN
28
29
30
31
97
99
99
99
t-Bu
17
r.t.
Reflux
t-Bu
Table 4. The Reformatsky Reactions of Compound 6
Reaction conditions
Reagents
Yields (%)
Entry
R1
H
R2
H
Time (h)
a (4R)
b (4S)
1
2
3
4
Zn, (CH3O)3B
Zn–Cu
Zn, (CH3O)3B
Zn, (CH3O)3B
1
1
1.5
1
Complicated mixture
32
33
34
45
55
60
10
21
18
CH3
CH3
H
CH3
respectively. Compounds 24b and 26b were treated similarly
to 24a and 26a and similar results were obtained. In the case
of 25a and 27a, which have tert-butyl ester function, treat-
ments with DBU at room temperature caused the aromatiza-
tion, but slowly. So the reaction mixtures were heated under
reflux for 1 h (entry 2 and 4), giving 29 and 31 in 99% and
99% yields, respectively. We attributed the lower reactivities
of the tert-butyl esters to the steric hindrances around the 2-
hydrogens, which would be abstracted by DBU. Treatment of
the corresponding geometric isomers 25b and 27b in a man-
Fig. 4. Selected Decisive NOE Relationships of Compounds 32a and 32b
ner similar to 25a and 27a gave similar results. Similar treat- carbons of side chains; each separation of the epimers was
ment of the regioisomers 25c and 25d also afforded 29 quan- difficult and the ratios of epimers were estimated to be 56 : 44
1
titatively.
for 33a, and 66 : 34 for 33b, by H-NMR. The same result
The Reformatsky Reactions of N-Tosyl-4-oxoproline was obtained when optically active ethyl (R)-2-bromopropi-
Ester and Conversion into the Pyrrole Derivatives It onate or ethyl (S)-2-bromopropionate was employed for the
seems impossible that the Horner–Emmons reaction should reaction in place of racemic ethyl 2-bromopropionate.
induce a pyrrole derivative which has a tertiary alkyl group,
Meanwhile, a complicated mixture was obtained when
so we next attempted the Reformatsky reaction. As the usual ethyl bromoacetate was used (entry 1). We therefore at-
Reformatsky reaction condition (ketone, bromoacetate, and tempted the method using Zn–Cu couple24) for ethyl bro-
zinc) often generates side reactions such as an aldol reaction moacetate (entry 2), and compounds 32a and 32b were ob-
and a dehydration,23) addition of trimethyl borate into the re- tained in 45% and 10% yields.
action system was examined. Unfortunately, methyl ester 5
The stereochemistries of 32a and 32b were determined by
gave complicated mixtures under the conditions employed differential nuclear Overhauser effect (NOE) experiments of
for 6. As shown in Table 4, when ethyl 2-bromopropionate 1H-NMR (Fig. 4). As for 32a, ꢁNOE was observed between
and ethyl 2-bromoisobutyrate were used (entry 3 and 4), the a signal at d 4.34 assigned to the hydroxy proton and a signal
desired 4-alkylated products 33a, 33b, 34a, and 34b were at d 1.48 assigned to methyl protons of the tert-butyl group.
obtained in 55%, 21%, 60%, and 18% yields. Each of 33a Unfortunately, because the signals of 3-methylene protons
and 33b is a mixture of the epimers based on the asymmetric overlapped at d 2.16, no other effective information to deter-

February 2009
171
(s), 103.97 (d), 108.04 (d), 120.96 (s), 143.66 (s), 160.83 (s). IR nmneaaxt cmꢂ1
:
3415, 3315 (NH, OH), 1681 (CꢄO). HR-MS m/z: 183.0892 (Calcd for
C9H13NO3: 183.0895).
tert-Butyl (2S,4R)-4-Hydroxy-4-methyl-1-p-toluenesulfonylpyrroli-
dine-2-carboxylate (10a) and tert-Butyl (2S,4S)-4-Hydroxy-4-methyl-1-
p-toluenesulfonylpyrrolidine-2-carboxylate (10b) Under reduced pres-
sure, powdered CeCl3·7H2O (1.62 g, 4.4 mmol) was heated at 90 °C for 1 h,
then the temperature was slowly raised and kept at 140 °C for 2 h. After
cooling, the vessel was filled with argon. THF (15 ml) was added and the
vessel was irradiated with ultrasonic waves for 2 h. After the suspension was
cooled at ꢂ40 °C under an argon atmosphere, 3 M CH3MgBr in THF
(1.33 ml, 4.0 mmol) was added dropwise and the mixture was stirred for
1.5 h. A solution of compound 6 (679 mg, 2.00 mmol) in THF (3 ml) was
added dropwise to the suspension prepared as described above and stirred
for 1 h. The reaction was quenched with 3% CH3COOH (13 ml). The whole
was extracted with AcOEt (15 mlꢃ3) and the organic layer was washed with
brine (15 ml), dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residual white solid was subjected to column chromatography
on silica gel [benzene–AcOEt (10 : 1 then 8 : 1)] to give 10b (472 mg, 66%)
and then 10a (130 mg, 18%). These compounds were recrystallized from i-
Pr2O, respectively.
Chart 7
mine the stereochemistry at 4-position was obtained. There-
fore, 32a was proved to have a (2S,4R)-configuration. For
32b, ꢁNOEs were observed between a signal at d 4.21 as-
signed to 2-H, a signal at d 3.27 assigned to the hydroxy pro-
ton, and a signal at d 2.31 assigned to 3-Ha. ꢁNOEs were
also observed between a signal at d 1.90 assigned to 3-Hb
and signals at d 2.64 and d 2.65 assigned to 4-methylene
protons. Therefore, 32b was proved to have a (2S,4S)-config-
uration.
Aromatizations of compounds 32a—34a were done ac-
cording to those of the Grignard products 10—13, treated
with SOCl2-pyridine, then treated with DBU in refluxing
toluene, giving the desired pyrrole derivatives 29, 35, and 36
in 85%, 89%, and 90% yields, respectively. Enantiomeric
10a: Colorless prisms, mp 213—214 °C (dec.), [a]D30 ꢂ71.3° (cꢄ0.7,
CHCl3). 1H-NMR (CDCl3) d: 1.35 (3H, s, CH3), 1.48 (9H, s, C(CH3)3), 1.74
(1H, br s, OH), 1.90 (1H, dd, Jꢄ13.1, 9.6 Hz, 3-Hb), 2.25 (1H, ddd, Jꢄ13.1,
7.6, 2.0 Hz, 3-Ha), 2.41 (3H, s, Ar-CH3), 3.34 (1H, d, Jꢄ11.3 Hz, 5-Hb),
3.40 (1H, dd, Jꢄ2.0, 11.3 Hz, 5-Ha), 4.33 (1H, dd, Jꢄ7.6, 9.6 Hz, 2-H), 7.30
(2H, d, Jꢄ8.3 Hz, Ar-H), 7.79 (2H, d, Jꢄ8.3 Hz, Ar-H). 13C-NMR (CDCl3)
d: 21.56 (q), 24.15 (q), 27.92 (q), 44.74 (t), 60.82 (t), 61.03 (d), 76.79 (s),
KBr
compounds 32b—34b were also treated similarly to 32a— 81.85 (s), 127.81 (d), 129.58 (d), 135.33 (s), 143.66 (s), 171.19 (s). IR n
max
cmꢂ1: 3483 (OH), 1728 (CꢄO). MS (FAB) m/z: 356 (Mꢁꢁ1). Anal. Calcd
for C17H25NO5S: C, 57.44; H, 7.09; N, 3.94. Found: C, 57.38; H, 6.92; N,
4.01.
34a, and similar results were obtained (Chart 7).
In conclusion, we accomplished the conversion of 4-oxo-
proline esters to 4-substituted pyrrole-2-carboxylic acid es-
ters.
10b: Colorless prisms, mp 127—129 °C, [a]D30 ꢂ51.6° (cꢄ0.7, CHCl3).
1H-NMR (CDCl3) d: 1.29 (3H, s, CH3), 1.50 (9H, s, C(CH3)3), 1.97 (1H,
ddd, Jꢄ1.8, 2.8, 13.8 Hz, 3-Hb), 2.06 (1H, dd, Jꢄ10.3, 13.8 Hz, 3-Ha), 2.44
(3H, s, Ar-CH3), 3.06 (1H, d, Jꢄ9.5 Hz, 5-Ha), 3.46 (1H, dd, Jꢄ9.5, 2.8 Hz,
5-Hb), 4.16 (1H, dd, Jꢄ10.3, 1.8 Hz, 2-H), 4.29 (1H, s, OH), 7.33 (2H, d,
Jꢄ8.1 Hz, Ar-H), 7.75 (2H, d, Jꢄ8.1 Hz, Ar-H). 13C-NMR (CDCl3) d: 21.83
Experimental
Melting points were measured with a Yanagimoto micromelting point ap-
paratus and are uncorrected. Specific rotations were determined with a
JASCO DIP-370 polarimeter. NMR spectra, except for the amino acids,
were recorded in chloroform-d (CDCl3) on a JEOL JNM-ECP500 spectrom-
eter using tetramethylsilane as an internal standard. Infrared (IR) spectra
were recorded on a Hitachi 270-30 spectrophotometer. Mass spectra (MS)
and high resolution mass spectra (HR-MS) were obtained with a JEOL JMS-
DX300 instrument. TLC was performed on Silica gel 60 F254 plates
(0.25 mm; Merck). Column chromatography was performed on silica gel
(Kieselgel 60, 70—230 mesh; Merck). Flash chromatography was per-
formed on silica gel (Silica Gel 60, 230—400 mesh; Nacalai Tesque).
Methyl 4-Hydroxypyrrole-2-carboxylate (8) Under an argon atmos-
phere, compound 5 (1.00 g, 3.36 mmol) was suspended in MeOH (10 ml),
and then 28% NaOMe (10 ml) was added at room temperature and the mix-
ture was stirred for 1 h. A sufficient amount of carbon dioxide was bubbled
into the mixture and the mixture was concentrated under reduced pressure.
Water (25 ml) was added to the residue at 0 °C and the whole was extracted
with AcOEt (25 mlꢃ2). The organic layer was washed with water (25 ml),
dried over anhydrous Na2SO4, and concentrated under reduced pressure. The
residual brown oil was subjected to column chromatography on silica gel
(AcOEt) to give 8 (360 mg, 76%) as a pale yellow oil. 1H-NMR (CDCl3) d:
3.83 (3H, s, CH3), 5.39 (1H, s, OH), 6.51 (1H, dd, Jꢄ2.8, 1.8 Hz, 3-H), 6.58
(1H, dd, Jꢄ3.0, 1.8 Hz, 5-H), 8.84 (1H, s, NH). 13C-NMR (CDCl3) d: 51.63
(q), 23.50 (q), 28.00 (q), 43.90 (t), 60.72 (d), 61.34 (t), 77.00 (s), 83.51 (s),
KBr
max
127.96 (d), 130.03 (d), 134.76 (s), 144.21 (s), 173.53 (s). IR n
cmꢂ1
:
3410 (OH), 1707 (CꢄO). MS (FAB) m/z: 356 (Mꢁꢁ1). Anal. Calcd for
C17H25NO5S: C, 57.44; H, 7.09; N, 3.94. Found: C, 57.38; H, 6.89; N, 4.14.
tert-Butyl (2S,4R)-4-Ethyl-4-hydroxy-1-p-toluenesulfonylpyrrolidine-
2-carboxylate (11a) and tert-Butyl (2S,4S)-4-Ethyl-4-hydroxy-1-p-tolue-
nesulfonylpyrrolidine-2-carboxylate (11b) Compounds 11a (128 mg,
17%) and 11b (475 mg, 64%) were obtained from 6 (679 mg, 2.00 mmol) in
a manner similar to that described for 10, but using 2 M EtMgCl in Et2O
(2.0 ml, 4.0 mmol) and a reaction time of 1.5 h. These compounds were re-
crystallized from i-Pr2O, respectively.
11a: Colorless prisms, mp 114—115 °C, [a]D30 ꢂ77.2° (cꢄ0.6, CHCl3).
1H-NMR (CDCl3) d: 0.92 (3H, t, Jꢄ7.6 Hz, CH2CH3), 1.48 (9H, s,
C(CH3)3), 1.61 (2H, q, Jꢄ7.6 Hz, CH2CH3), 1.85 (1H, dd, Jꢄ13.0, 9.6 Hz,
3-Ha), 1.85 (1H, s, OH), 2.22 (1H, ddd, Jꢄ13.0, 7.5, 1.8 Hz, 3-Hb), 2.41
(3H, s, Ar-CH3), 3.33 (1H, d, Jꢄ11.5 Hz, 5-Hb), 3.39 (1H, dd, Jꢄ11.5,
1.8 Hz, 5-Ha), 4.32 (1H, dd, Jꢄ9.6, 7.5 Hz, 2-H), 7.31 (2H, d, Jꢄ8.4 Hz, Ar-
H), 7.80 (2H, d, Jꢄ8.4 Hz, Ar-H). 13C-NMR (CDCl3) d: 8.48 (q), 21.56 (q),
27.92 (q), 30.52 (t), 42.84 (t), 59.80 (t), 61.00 (d), 79.81 (s), 81.82 (s),
KBr
max
127.80 (d), 129.57 (d), 135.34 (s), 143.64 (s), 171.35 (s). IR n
cmꢂ1
:
3502 (OH), 1751 (CꢄO). MS (FAB) m/z: 370 (Mꢁꢁ1). Anal. Calcd for
C18H27NO5S: C, 58.51; H, 7.37; N, 3.79. Found: C, 58.56; H, 7.24; N, 3.78.
11b: Colorless prisms, mp 126—127 °C, [a]D26 ꢂ48.9° (cꢄ1.0, CHCl3).
1H-NMR (CDCl3) d: 0.94 (3H, t, Jꢄ7.4 Hz, CH2CH3), 1.50 (9H, s,
C(CH3)3), 1.56 (2H, q, Jꢄ7.4 Hz, CH2CH3), 1.94 (1H, dt, Jꢄ13.7, 1.6 Hz, 3-
Ha), 2.02 (1H, dd, Jꢄ13.7, 10.3 Hz, 3-Hb), 2.44 (3H, s, Ar-CH3), 3.05 (1H,
d, Jꢄ9.4 Hz, 5-Hb), 3.45 (1H, dd, Jꢄ9.4, 1.6 Hz, 5-Ha), 4.17 (1H, s, OH),
4.19 (1H, d, Jꢄ1.6 Hz, 2-H), 7.33 (2H, d, Jꢄ8.1 Hz, Ar-H), 7.76 (2H, d,
Jꢄ8.1 Hz, Ar-H). 13C-NMR (CDCl3) d: 8.67 (q), 21.56 (q), 27.81 (q), 30.32
(q), 104.47 (d), 108.98 (d), 119.22 (s), 143.81 (s), 161.79 (s). IR nmneaaxt cmꢂ1
3403, 3134 (NH, OH), 1685 (CꢄO). HR-MS m/z: 141.0428 (Calcd for
C6H7NO3: 141.0426).
:
tert-Butyl 4-Hydroxypyrrole-2-carboxylate (9) Under an argon atmos-
phere, compound 6 (1.00 g, 2.95 mmol) was dissolved in DMSO (5 ml), and
then t-BuOK (800 mg) was added at room temperature and the mixture was
stirred for 1 h. A sufficient amount of carbon dioxide was bubbled into the
mixture and the mixture was concentrated under reduced pressure. Water
(25 ml) was added to the residue at 0 °C and the whole was extracted with
AcOEt (25 mlꢃ2). The organic layer was washed with water (25 ml), dried
over anhydrous Na2SO4, and concentrated under reduced pressure. The
residual brown oil was subjected to column chromatography on silica gel
[hexane–Et2O (1 : 1)] to give 9 (325 mg, 60%) as a pale yellow oil. 1H-NMR
(CDCl3) d: 1.54 (9H, s, C(CH3)3), 5.30 (1H, br s, OH), 6.45 (1H, s, 3-H),
6.53 (1H, s, 5-H), 8.78 (1H, s, NH). 13C-NMR (CDCl3) d: 28.36 (q), 81.17
(t), 42.05 (t), 59.96 (t), 60.31 (d), 79.57 (s), 83.17 (s), 127.68 (d), 129.76
neat
(d), 134.57 (s), 143.91 (s), 173.29 (s). IR n
cmꢂ1: 3465 (OH), 1720
max
(CꢄO). MS (FAB) m/z: 370 (Mꢁꢁ1). Anal. Calcd for C18H27NO5S: C,
58.51; H, 7.37; N, 3.79. Found: C, 58.61; H, 7.31; N, 3.74.
tert-Butyl (2S,4R)-4-Butyl-4-hydroxy-1-p-toluenesulfonylpyrrolidine-
2-carboxylate (12a) and tert-Butyl (2S,4S)-4-Butyl-4-hydroxy-1-p-tolue-
nesulfonylpyrrolidine-2-carboxylate (12b) Compounds 12a (136 mg,

172
Vol. 57, No. 2
17%) and 12b (588 mg, 74%) were obtained from 6 (679 mg, 2.0 mmol) in a
manner similar to that described for 10, but using 2 M BuMgCl in Et2O
(2.0 ml, 4.0 mmol), a reaction time of 2 h, and column chromatography on
silica gel [benzene–AcOEt (15 : 1 then 10 : 1)]. These compounds were re-
Methyl 4-Butylpyrrole-2-carboxylate (15) Compound 15 (56 mg,
55%) was obtained from 12b (223 mg, 0.56 mmol) in a manner similar to
that described for 4 but with column chromatography on silica gel
[hexane–AcOEt (2 : 1)]. It was recrystallized from hexane to give colorless
1
crystallized from i-Pr2O, respectively.
needles, mp 63—64 °C, (lit.11) mp 59—60 °C). H-NMR (CDCl3) d: 0.91
12a: Colorless oil, [a]D26 ꢂ45.8° (cꢄ0.8, CHCl3). H-NMR (CDCl3) d: (3H, t, Jꢄ7.3 Hz, (CH2)3CH3), 1.31—1.39 (2H, m, (CH2)2CH2CH3), 1.51—
0.88 (3H, t, Jꢄ7.1 Hz, (CH2)3CH3), 1.23—1.30 (2H, m, CH2CH2CH2CH3), 1.57 (2H, m, CH2CH2CH2CH3), 2.46 (2H, t, Jꢄ7.3 Hz, benzylic H), 3.83
1.48 (11H, s, C(CH3)3 and CH2(CH2)2CH3), 1.51—1.58 (4H, m, (3H, s, CO2CH3), 6.73 (1H, s, 3-H), 6.75 (1H, s, 5-H), 8.95 (1H, br s, NH).
1
CH2CH2CH2CH3), 1.78 (1H, s, OH), 1.86 (1H, dd, Jꢄ13.1, 9.9 Hz, 3-Ha), 13C-NMR (CDCl3) d: 13.92 (q), 22.30 (t), 26.36 (t), 33.12 (t), 51.34 (q),
2.22 (1H, ddd, Jꢄ13.1, 7.3, 1.8 Hz, 3-Hb), 2.42 (3H, s, Ar-CH3), 3.33 (1H, d, 115.04 (d), 120.65 (d), 122.14 (s), 126.81 (s), 161.63 (s). IR n
KBr
cmꢂ1
:
max
Jꢄ11.5 Hz, 5-Ha), 3.40 (1H, dd, Jꢄ11.5, 1.8 Hz, 5-Hb), 4.32 (1H, dd, 3300 (NH), 1693 (CꢄO). MS m/z: 181 (Mꢁ).
Jꢄ9.9, 7.3 Hz, 2-H), 7.31 (2H, d, Jꢄ8.3 Hz, Ar-H), 7.80 (2H, d, Jꢄ8.3 Hz,
Methyl 4-Phenylpyrrole-2-carboxylate (16) Compound 16 (89 mg,
Ar-H). 13C-NMR (CDCl3) d: 13.93 (q), 21.57 (q), 22.96 (t), 26.39 (t), 27.93 79%) was obtained from 13 (234 mg, 0.56 mmol) in a manner similar to that
(q), 37.47 (t), 43.31 (t), 60.05 (t), 60.89 (d), 79.55 (s), 81.82 (s), 127.81 (d),
described for 4. It was recrystallized from i-Pr2O to give colorless prisms,
mp 197—198 °C, (lit.26) mp 176—180 °C). 1H-NMR (CDCl3) d: 3.89 (3H, s,
OCH3), 7.20—7.25 (3H, m, Ar-H), 7.36 (2H, m, Ar-H), 7.52 (2H, m, 3-H
and 5-H), 9.17 (1H, br s, NH). 13C-NMR (CDCl3) d: 51.61 (q), 112.55 (d),
neat
129.58 (d), 135.37 (s), 143.66 (s), 171.29 (s). IR n
cmꢂ1: 3485 (OH),
max
1730 (CꢄO). MS (FAB) m/z: 398 (Mꢁꢁ1).
12b: Colorless needles, mp 116—117 °C, [a]D30 ꢂ41.8° (cꢄ1.0, CHCl3).
1H-NMR (CDCl3) d: 0.87 (3H, t, Jꢄ7.1 Hz, (CH2)3CH3), 1.25—1.31 (2H, 119.51 (d), 123.42 (s), 125.31 (d), 126.34 (d), 126.94 (s), 128.79 (d), 134.48
m, CH2CH2CH2CH3), 1.32—1.39 (2H, m, CH2CH2CH2CH3), 1.50 (11H, s, (s), 161.56 (s). IR nmKaBxr cmꢂ1: 3280 (NH), 1677 (CꢄO). MS m/z: 201 (Mꢁ).
C(CH3)3 and CH2(CH2)2CH3), 1.95 (1H, ddd, Jꢄ13.7, 1.8, 1.6 Hz, 3-Hb), Anal. Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.46; H,
2.02 (1H, dd, Jꢄ13.7, 10.3 Hz, 3-Ha), 2.44 (3H, s, Ar-CH3), 3.04 (1H, d, 5.64; N, 6.97.
Jꢄ9.5 Hz, 5-Ha), 3.45 (1H, dd, Jꢄ9.5, 1.6 Hz, 5-Hb), 4.16 (1H, dd, Jꢄ10.3,
tert-Butyl 4-Methylpyrrole-2-carboxylate (17) Thionyl chloride
1.8 Hz, 2-H), 4.18 (1H, s, OH), 7.32 (1H, d, Jꢄ8.3 Hz, Ar-H), 7.75 (2H, d, (4.0 ml, 55 mmol) was added dropwise to a solution of compound 10b
Jꢄ8.3 Hz, Ar-H). 13C-NMR (CDCl3) d: 13.95 (q), 21.57 (q), 23.05 (q), (200 mg, 0.56 mmol) in pyridine (12 ml) and the whole was stirred at room
26.52 (t), 27.81 (q), 37.29 (t), 42.46 (t), 60.18 (t), 60.21 (d), 79.28 (s), 83.21
(s), 127.70 (d), 129.76 (d), 134.55 (s), 143.91 (s), 173.29 (s). IR nmKaBxr cmꢂ1
temperature for 2 h. The reaction mixture was concentrated under reduced
pressure. Toluene (12 ml) was added and the solution was concentrated
:
3467 (OH), 1718 (CꢄO). MS (FAB) m/z: 398 (Mꢁꢁ1). Anal. Calcd for under reduced pressure. This operation was repeated once. Water (20 ml)
C18H27NO5S: C, 60.43; H, 7.86; N, 3.52. Found: C, 60.51; H, 7.71; N, 3.38.
was added to the residue and the whole was extracted with benzene
tert-Butyl(2S,4R)-4-Hydroxy-4-phenyl-1-p-toluenesulfonylpyrrolidine- (20 mlꢃ2). The organic layer was washed with brine (20 ml), dried over an-
2-carboxylate (13) Compound 13 (762 mg, 91%) was obtained from 6 hydrous Na2SO4, and concentrated under reduced pressure. The residue was
(679 mg, 2.0 mmol) in a manner similar to that described for 10, but using
1 M PhMgBr in THF (4.0 ml, 4.0 mmol), a reaction time of 2 h, and column
chromatography on silica gel [benzene–Et2O (40 : 1)]. The resulting white
dissolved in toluene (6 ml) and DBU (0.5 ml, 3.3 mmol), and the solution
was refluxed for 12 h. The mixture was concentrated under reduced pressure
and the residue was subjected to column chromatography on silica gel
solid was recrystallized from i-PrOH to give colorless needles, 166— [hexane–AcOEt (10 : 1)] to give 17 (79 mg, 77%) as a white solid. It was re-
168 °C, [a]D29 ꢂ80.9° (cꢄ1.0, CHCl3). 1H-NMR (CDCl3) d: 1.54 (9H, s, crystallized from hexane to give colorless prisms, mp 113—114 °C. 1H-
C(CH3)3), 2.25 (1H, dd, Jꢄ14.0, 1.6 Hz, 3-Hb), 2.44 (3H, s, Ar-CH3), 2.55 NMR (CDCl3) d: 1.59 (9H, s, C(CH3)3), 2.10 (3H, s, CH3), 6.66 (1H, s, 3-
(1H, dd, Jꢄ14.0, 10.6 Hz, 3-Ha), 3.44 (1H, d, Jꢄ9.6 Hz, 5-Ha), 3.71 (1H, H), 6.68 (1H, s, 5-H), 9.08 (1H, br s, NH). 13C-NMR (CDCl3) d: 11.69 (q),
dd, Jꢄ9.6, 1.6 Hz, 5-Hb), 4.35 (1H, dd, Jꢄ10.6, 1.6 Hz, 2-H), 4.75 (1H, s,
28.39 (q), 80.57 (s), 115.40 (d), 120.55 (d), 120.64 (s), 123.98 (s), 160.82
KBr
OH), 7.30 (5H, m, Ph), 7.38 (2H, d, Jꢄ7.6 Hz, Ar-H), 7.80 (2H, d, (s). IR n
cmꢂ1: 3323 (NH), 1676 (CꢄO). MS (FAB) m/z: 182 (Mꢁꢁ1).
max
Jꢄ7.6 Hz, Ar-H). 13C-NMR (CDCl3) d: 21.59 (q), 27.85 (q), 44.01 (t), 60.27 Anal. Calcd for C10H15NO2: C, 66.27; H, 8.34; N, 7.73. Found: C, 66.36; H,
(d), 61.67 (t), 79.91 (s), 83.51 (s), 125.24 (d), 127.78 (d), 127.91 (d), 128.46 8.40; N, 7.70.
(d), 129.84 (s), 134.44 (d), 140.18 (s), 144.08 (s), 173.12 (s). IR nmKaBxr cmꢂ1
:
tert-Butyl 4-Ethylpyrrole-2-carboxylate (18) Compound 18 (90 mg,
3398 (OH), 1703 (CꢄO). MS (FAB) m/z: 418 (Mꢁꢁ1). Anal. Calcd for 82%) was obtained from 11b (207 mg, 0.56 mmol) in a manner similar to
C22H27NO5S: C, 63.29; H, 6.52; N, 3.35. Found: C, 63.16; H, 6.45; N, 3.37. that described for 17. It was recrystallized from hexane to give colorless
Methyl 4-Methylpyrrole-2-carboxylate (4) Thionyl chloride (0.61 ml, prisms, mp 75—76 °C. 1H-NMR (CDCl3) d: 1.19 (3H, t, Jꢄ7.6 Hz,
7.9 mmol) was added dropwise to MeOH (5 ml) at ꢂ10 °C. After 30 min,
compound 10b (200 mg, 0.56 mmol) was added to the solution. The whole
was stirred at room temperature for 24 h and the reaction mixture was con-
centrated under reduced pressure. MeOH (15 ml) was added to the residue 160.79 (s). IR n
and the solution was concentrated under reduced pressure. This operation
was repeated 3 times. The residual oil was dissolved in MeOH (3 ml) and 67.89; H, 8.72; N, 7.14.
CH2CH3), 1.55 (9H, s, C(CH3)3), 2.49 (2H, q, Jꢄ7.6 Hz, CH2CH3), 6.69
(2H, s, 3-H and 5-H), 9.03 (1H, br s, NH). 13C-NMR (CDCl3) d: 15.28 (q),
19.91 (t), 28.40 (q), 80.57 (s), 113.89 (d), 119.41 (d), 123.97 (s), 128.07 (s),
KBr
cmꢂ1: 3319 (NH), 1672 (CꢄO). MS (FAB) m/z: 196
max
(Mꢁꢁ1). Anal. Calcd for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C,
28% NaOMe solution (3 ml) was added. Then the mixture was stirred at
tert-Butyl 4-Butylpyrrole-2-carboxylate (19) Compound 19 (75 mg,
room temperature for 1.5 h. A sufficient amount of carbon dioxide was bub- 60%) was obtained from 12b (223 mg, 0.56 mmol) in a manner similar to
bled into the mixture and the mixture was concentrated under reduced pres- that described for 17. It was recrystallized from hexane to give colorless
sure. Water (20 ml) was added to the residue at 0 °C and the whole was ex- prisms, mp 70—71 °C. 1H-NMR (CDCl3) d: 0.92 (3H, t, Jꢄ7.4 Hz,
tracted with AcOEt (20 mlꢃ2). The organic layer was washed with brine (CH2)3CH3), 1.33 (2H, m, (CH2)2CH2CH3), 1.55 (11H, s, C(CH3)3 and
(20 ml), dried over anhydrous Na2SO4, and concentrated under reduced pres-
CH2CH2CH2CH3), 2.45 (2H, t, Jꢄ7.7 Hz, CH2(CH2)2CH3), 6.67 (2H, s, 3-H
sure. The residue was subjected to column chromatography on silica gel and 5-H), 8.87 (1H, br s, NH). 13C-NMR (CDCl3) d: 13.93 (q), 22.36 (t),
(AcOEt) to give 4 (43 mg, 56%) as a white solid. It was recrystallized from 26.43 (t), 28.41 (q), 33.22 (t), 80.56 (s), 114.35 (d), 119.79 (d), 123.96 (s),
cyclohexane to give colorless needles, mp 73—74 °C, (lit.25) mp 73—74 °C). 126.55 (s), 160.69 (s). IR n
cmꢂ1: 3315 (NH), 1676 (CꢄO). MS (FAB)
KBr
max
1H-NMR (CDCl3) d: 2.10 (3H, s, CH3), 3.84 (3H, s, OCH3), 6.72 (2H, s, 3-
m/z: 224 (Mꢁꢁ1). Anal. Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27.
H and 5-H), 9.20 (1H, br s, NH). 13C-NMR (CDCl3) d: 11.67 (q), 51.36 (q), Found: C, 69.94; H, 9.29; N, 6.15.
neat
max
116.12 (d), 120.94 (s), 121.50 (d), 122.16 (s), 161.79 (s). IR n
cmꢂ1
:
tert-Butyl 4-Phenylpyrrole-2-carboxylate (20) Compound 20 (56 mg,
41%) was obtained from 13 (234 mg, 0.56 mmol) in a manner similar to that
described for 17. It was recrystallized from hexane to give a white powder,
mp 94—95 °C. 1H-NMR (CDCl3) d: 1.60 (9H, s, C(CH3)3), 7.12 (1H, m, Ar-
H), 7.20 (2H, s, 3-H and 5-H), 7.35 (2H, t, Jꢄ8.0 Hz, Ar-H), 7.52 (2H, d,
3283 (NH), 1673 (CꢄO). MS m/z: 139 (Mꢁ).
Methyl 4-Ethylpyrrole-2-carboxylate (14) Compound 14 (47 mg,
55%) was obtained from 11b (207 mg, 0.56 mmol) in a manner similar to
that described for 4 but with column chromatography on silica gel
[hexane–AcOEt (1 : 1)]. It was recrystallized from hexane to give colorless Jꢄ8.0 Hz, Ar-H), 9.45 (1H, br s, NH). 13C-NMR (CDCl3) d: 28.41 (q),
1
needles, mp 56—57 °C, (lit.11) mp 56—57 °C). H-NMR (CDCl3) d: 1.19 81.14 (s), 111.95 (d), 118.88 (d), 125.13 (s), 125.30 (d), 126.15 (d), 126.61
KBr
max
(3H, t, Jꢄ7.6 Hz, CH2CH3), 2.50 (2H, q, Jꢄ7.6 Hz, CH2CH3), 3.84 (3H, s, (s), 128.72 (d), 134.77 (s), 160.79 (s). IR n
cmꢂ1: 3300 (NH), 1678
CO2CH3), 6.76 (2H, s, 3-H and 5-H), 8.87 (1H, br s, NH). 13C-NMR
(CꢄO). HR-MS (FAB) m/z: 243.1260 (Calcd for C15H17NO2: 243.1259).
Methyl (2S)-4-Methylene-1-p-toluenesulfonylpyrrolidine-2-carboxy-
(CDCl3) d: 15.17 (q), 19.86 (t), 51.35 (q), 114.56 (d), 120.08 (d), 122.23 (s),
128.42 (s), 161.57 (s). IR nmKaBxr cmꢂ1: 3292 (NH), 1685 (CꢄO). MS m/z: 153 late (21) Ph3P–CH3Br (2.20 g, 6.2 mmol) was heated at 120 °C under re-
(Mꢁ).
duced pressure for 1 h, then heated in a stream of dry N2 at 120 °C. Under an

February 2009
173
argon atmosphere, Et2O (15 ml) and 1.9 M PhLi (1.8 ml, 3.4 mmol) were
added and stirred at room temperature for 4 h. A solution of 5 (893 mg,
3.00 mmol) in THF (5 ml) was added and the mixture was stirred at room
Jꢄ7.1 Hz, CH2CH3), 2.43 (3H, s, Ar-CH3), 2.82 (1H, br d, Jꢄ17.4 Hz, 3-
Hb), 2.94 (1H, ddd, Jꢄ17.4, 8.9, 1.1 Hz, 3-Ha), 3.62 (3H, s, COOCH3), 4.15
(2H, q, Jꢄ7.1 Hz, CH2CH3), 4.46—4.58 (3H, m, 2-H and 5-H), 5.78 (1H, s,
temperature for 30 h. The mixture was cooled at 0 °C and neutralized with olefinic H), 7.32 (2H, d, Jꢄ8.3 Hz, Ar-H), 7.32 (2H, d, Jꢄ8.3 Hz, Ar-H).
10% aqueous citric acid. The whole was extracted with AcOEt (30 ml) and 13C-NMR (CDCl3) d: 14.21 (q), 21.56 (q), 37.91 (t), 52.03 (t), 52.47 (q),
water (20 ml). The aqueous layer was extracted with AcOEt (20 mlꢃ3) and
the combined organic layer was dried over anhydrous MgSO4, and concen-
trated under reduced pressure. The residual reddish brown oil was subjected HR-MS m/z: 367.1092 (Calcd for C17H21NO6S: 367.1090).
59.03 (d), 60.34 (t), 114.29 (d), 127.52 (d), 129.77 (d), 134.99 (s), 143.96
neat
(s), 155.74 (s), 165.40 (s), 171.18 (s). IR n
cmꢂ1: 1745, 1711 (CꢄO).
max
to flash chromatography on silica gel [hexane–CHCl3 (1 : 1), then hexane–
tert-Butyl (2S,4E)-4-Ethoxycarbonylmethylene-1-p-toluenesulfonyl-
Et2O (3 : 1)] to give 21 (91 mg, 10%) as a colorless oil. Colorless oil, [a]D23 pyrrolidine-2-carboxylate (25a), tert-Butyl (2S,4Z)-4-Ethoxycarbonyl-
1
ꢂ30.8° (cꢄ0.7, CHCl3). H-NMR (CDCl3) d: 2.42 (3H, s, Ar-CH3), 2.62 methylene-1-p-toluenesulfonylpyrrolidine-2-carboxylate (25b), tert-Butyl
(1H, d, Jꢄ14.2, 3.5 Hz, 3-Hb), 2.75 (1H, m, 3-Ha), 3.65 (3H, s, CO2CH3), (2S)-4-Ethoxycarbonylmethyl-1-p-toluenesulfonyl-3-pyrroline-2-car-
4.02 (2H, s, 5-H), 4.45 (1H, dd, Jꢄ9.2, 3.5 Hz, 2-H), 4.96 (2H, s, olefinic
boxylate (25c), and tert-Butyl (2S)-4-Ethoxycarbonylmethyl-1-p-toluene-
H), 7.31 (2H, d, Jꢄ8.4 Hz, Ar-H), 7.73 (2H, d, Jꢄ8.4 Hz, Ar-H). 13C-NMR sulfonyl-4-pyrroline-2-carboxylate (25d) THF (10 ml) was added to 60%
(CDCl3) d: 21.56 (q), 36.92 (t), 51.75 (t), 52.44 (q), 60.45 (d), 108.65 NaH in oil (168 mg, 4.2 mmol), which was washed beforehand with hexane
(t), 127.49 (d), 129.72 (d), 134.99 (s), 141.94 (s), 143.85 (s), 171.80 (s). to remove the oil. Under an argon atmosphere, triethyl phosphonoacetate
neat
IR n
cmꢂ1: 1741 (CꢄO). HR-MS (FAB) m/z: 296.0957 (Calcd for
(1.12 g, 5.00 mmol) was added and the whole was stirred at room tempera-
ture for 2 h. After the mixture was cooled at 0 °C, a solution of 6 (339 mg,
max
C14H18NO4S: 296.0957).
tert-Butyl (2S)-4-Methylene-1-p-toluenesulfonylpyrrolidine-2-car- 1.00 mmol) in THF (5 ml) was added dropwise and the whole was stirred for
boxylate (22) Under an argon atmosphere, 0.5 M Tebbe reagent in toluene
1 h. A sufficient amount of carbon dioxide was bubbled into the mixture and
(4.0 ml, 2.0 mmol) was added dropwise to a solution of 6 (339 mg, the mixture was concentrated under reduced pressure. Water (20 ml) was
1.00 mmol) in THF (10 ml) and the mixture was stirred at ꢂ70 °C for 4 h,
added to the residue at 0 °C and the whole was extracted with benzene
then at 0 °C for 1 h. Water (5 ml) was added and the insoluble material was (20 mlꢃ3). The organic layer was washed with brine (20 ml), dried over an-
filtered out using Hyflo Super-Cel®. The filtrate was extracted with AcOEt hydrous Na2SO4, and concentrated under reduced pressure. The residual yel-
(80 mlꢃ2). The organic layer was washed with water (50 ml), dried over an- low oil was subjected to column chromatography on silica gel [hexane–Et2O
hydrous Na2SO4, and concentrated under reduced pressure. The residual
(4 : 1)] to give 25a (152 mg, 37%) as a colorless oil, then 25b (123 mg, 30%)
reddish brown oil was subjected to flash chromatography on silica gel as a colorless oil, then 25d (9 mg, 3%) as a pale yellow oil, and then 25c
[hexane–AcOEt (6 : 1), then hexane–CHCl3 (1 : 3)] to give 22 (54 mg, 16%) (124 mg, 30%) as a pale yellow oil.
as a pale yellow oil and 23 (78 mg, 22%) as a white solid, which was recrys-
25a: [a]D21 ꢂ9.2° (cꢄ0.72, CHCl3). 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jꢄ7.1 Hz, CH2CH3), 1.40 (9H, s, C(CH3)3), 2.42 (3H, s, Ar-CH3), 3.11 (1H,
tallized from hexane to give a white powder, mp 76—77 °C.
22: [a]D31 ꢂ38.8° (cꢄ0.4, CHCl3). 1H-NMR (CDCl3) d: 1.41 (9H, s, ddd, Jꢄ19.0, 9.2, 0.9 Hz, 3-Ha), 3.28 (1H, br d, Jꢄ 19.0 Hz, 3-Hb), 4.14
C(CH3)3), 2.42 (3H, s, Ar-CH3), 2.55 (1H, dd, Jꢄ15.8, 3.2 Hz, 3-Hb), 2.76 (2H, q, Jꢄ7.1 Hz, CH2CH3), 4.22 (1H, d, Jꢄ16.5 Hz, 5-Ha), 4.24 (1H, d,
(1H, dd, Jꢄ15.8, 9.0 Hz, 3-Ha), 4.02 (2H, s, olefinic H), 4.35 (1H, dd,
Jꢄ16.5 Hz, 5-Hb), 4.42 (1H, dd, Jꢄ9.2, 3.2 Hz, 2-H), 5.79 (1H, m, olefinic
Jꢄ3.2, 9.0 Hz, 2-H), 4.96 (2H, m, 5-H), 7.30 (2H, d, Jꢄ8.1 Hz, Ar-H), 7.74 H), 7.32 (2H, d, Jꢄ8.0 Hz, Ar-H), 7.73 (2H, d, Jꢄ8.0 Hz, Ar-H). 13C-NMR
(2H, d, Jꢄ8.1 Hz, Ar-H). 13C-NMR (CDCl3) d: 21.53 (q), 27.83 (q), 37.29 (CDCl3) d: 14.23 (q), 21.55 (q), 27.81 (q), 36.06 (t), 53.15 (t), 60.20 (t),
(t), 51.72 (t), 61.22 (d), 81.96 (s), 108.20 (t), 127.46 (d), 129.64 (d), 135.73 61.41 (d), 82.31 (s), 113.59 (d), 127.49 (d), 129.76 (d), 135.32 (s), 143.91
neat
max
neat
max
(s), 142.54 (s), 143.56 (s), 170.45 (s). IR n
cmꢂ1: 1743 (CꢄO). HR-MS (s), 156.05 (s), 165.65 (s), 170.18 (s). IR n
cmꢂ1: 1736, 1712 (CꢄO).
(FAB) m/z: 338.1424 (Calcd for C17H23NO4S: 338.1426).
HR-MS (FAB) m/z: 410.1634 (Calcd for C20H28NO6S: 410.1637).
23: [a]D25 ꢂ85.7° (cꢄ0.4, CHCl3). 1H-NMR (CDCl3) d: 0.75 (3H, s,
25b: [a]D17 ꢂ16.6° (cꢄ0.70, CHCl3). H-NMR (CDCl3) d: 1.25 (3H, t,
1
CH3), 1.07 (3H, s, CH3), 1.48 (9H, s, C(CH3)3), 1.76 (1H, dd, Jꢄ8.2, Jꢄ7.1 Hz, CH2CH3), 1.40 (9H, s, C(CH3)3), 2.42 (3H, s, Ar-CH3), 3.12 (1H,
17.6 Hz, 3-Ha), 1.95 (1H, dd, Jꢄ8.2, 17.6 Hz, 3-Hb), 2.42 (3H, s, Ar-CH3), dd, Jꢄ19.0, 9.2 Hz, 3-Hb), 3.28 (1H, d, Jꢄ19.0 Hz, 3-Ha), 4.13 (2H, q,
3.13 (2H, m, 5-H), 4.17 (1H, t, Jꢄ8.2 Hz, 2-H), 7.30 (2H, d, Jꢄ8.1 Hz, Ar- Jꢄ7.1 Hz, CH2CH3), 4.23 (2H, d, Jꢄ3.3 Hz, 5-H), 4.42 (1H, dd, Jꢄ9.2,
H), 7.79 (2H, d, Jꢄ8.1 Hz, Ar-H). 13C-NMR (CDCl3) d: 21.53 (q), 25.78 3.3 Hz, 2-H), 5.78 (1H, s, olefinic H), 7.30 (2H, d, Jꢄ8.3 Hz, Ar-H), 7.73
(q), 27.91 (q), 38.74 (s), 44.57 (t), 60.52 (t), 61.24 (d), 81.56 (s), 127.62 (d),
(2H, d, Jꢄ8.3 Hz, Ar-H). 13C-NMR (CDCl3) d: 14.23 (q), 21.55 (q), 27.81
KBr
129.51 (d), 135.64 (s), 143.39 (s), 171.56 (s). IR n
cmꢂ1: 1745 (CꢄO).
(q), 36.06 (t), 53.15 (t), 60.21 (t), 61.42 (d), 82.31 (s), 113.60 (d), 127.49
max
MS (FAB) m/z: 354 (Mꢁꢁ1). Anal. Calcd for C18H27NO4S: C, 61.16; H, (d), 129.77 (d), 135.31 (s), 143.91 (s), 156.05 (s), 165.65 (s), 170.18 (s). IR
neat
max
7.70; N, 3.96. Found: C, 61.14; H, 7.56; N, 4.01.
Methyl (2S,4E)-4-Ethoxycarbonylmethylene-1-p-toluenesulfonyl- C20H28NO6S: 410.1637).
pyrrolidine-2-carboxylate (24a) and Methyl (2S,4Z)-4-Ethoxycarbonyl-
methylene-1-p-toluenesulfonylpyrrolidine-2-carboxylate (24b) THF (10
n
cmꢂ1: 1736, 1712 (CꢄO). HR-MS (FAB) m/z: 410.1635 (Calcd for
1
25c: [a]D23 ꢂ138.7° (cꢄ0.7, CHCl3). H-NMR (CDCl3) d: 1.22 (3H, t,
Jꢄ7.2 Hz, CH2CH3), 1.47 (9H, s, C(CH3)3), 2.42 (3H, s, Ar-CH3), 3.07 (1H,
ml) was added to 60% NaH in oil (168 mg, 4.2 mmol), which was washed d, Jꢄ16.3 Hz, CH2COOEt), 3.12 (1H, d, Jꢄ16.3 Hz, CH2COOEt), 4.11 (2H,
beforehand with hexane to remove the oil. Under an argon atmosphere, tri- q, Jꢄ7.1 Hz, CH2CH3), 4.17 (1H, br dd, Jꢄ13.7, 5.7 Hz, 5-Ha), 4.22 (1H, d,
ethyl phosphonoacetate (1.12 g, 5.00 mmol) was added and the whole was Jꢄ13.7 Hz, 5-Hb), 4.98 (1H, d, Jꢄ2.1 Hz, 2-H), 5.53 (1H, dd, Jꢄ5.7,
stirred at room temperature for 2 h. After the mixture was cooled at ꢂ40 °C,
a solution of 5 (297 mg, 1.00 mmol) in THF (5 ml) was added dropwise and
the whole was stirred for 1 h. A sufficient amount of carbon dioxide was 61.15 (t), 68.97 (d), 82.26 (s), 122.23 (d), 127.59 (d), 129.68 (d), 134.80 (s),
bubbled into the mixture and the mixture was concentrated under reduced 135.51 (s), 143.63 (s), 168.79 (s), 169.20 (s). IR n
pressure. Water (20 ml) was added to the residue at 0 °C and the whole was HR-MS (FAB) m/z: 410.1639 (Calcd for C20H28NO6S: 410.1637).
2.1 Hz, 3-H), 7.31 (2H, d, Jꢄ8.1 Hz, Ar-H), 7.79 (2H, d, Jꢄ8.1 Hz, Ar-H).
13C-NMR (CDCl3) d: 14.09 (q), 21.55 (q), 27.96 (q), 34.57 (t), 56.54 (t),
neat
max
cmꢂ1: 1738 (CꢄO).
1
extracted with benzene (20 mlꢃ3). The organic layer was washed with brine
(20 ml), dried over anhydrous Na2SO4, and concentrated under reduced pres-
25d: [a]D23 ꢂ120.9° (cꢄ0.3, CHCl3). H-NMR (CDCl3) d: 1.22 (3H, t,
Jꢄ7.1 Hz, CH2CH3), 1.49 (9H, s, C(CH3)3), 2.43 (3H, s, Ar-CH3), 2.62 (1H,
sure. The residual yellow oil was subjected to column chromatography on dd, Jꢄ16.0, 7.1 Hz, 3-Hb), 2.79 (1H, dd, Jꢄ16.0, 11.5 Hz, 3-Ha), 3.01 (1H,
silica gel [hexane–AcOEt (4 : 1)] to give 24a (177 mg, 48%) as a colorless
oil, and then 24b (163 mg, 44%) as a colorless oil.
d, Jꢄ16.5 Hz, CH2COOEt), 3.03 (1H, d, Jꢄ16.5 Hz, CH2COOEt), 4.10 (2H,
q, Jꢄ7.2 Hz, CH2CH3), 4.15 (1H, dd, Jꢄ11.5, 7.1 Hz, 2-H), 6.28 (1H, s, 5-
24a: [a]D29 ꢂ6.8° (cꢄ1.0, CHCl3). 1H-NMR (CDCl3) d: 1.25 (3H, t, H), 7.31 (2H, d, Jꢄ8.2 Hz, Ar-H), 7.70 (2H, d, Jꢄ8.2 Hz, Ar-H). 13C-NMR
Jꢄ7.1 Hz, CH2CH3), 2.43 (3H, s, Ar-CH3), 3.13 (1H, dd, Jꢄ19.0, 9.4 Hz, (CDCl3) d: 14.12 (q), 21.59 (q), 27.90 (q), 33.55 (t), 37.61 (t), 60.88 (t),
3-Ha), 3.32 (1H, br d, Jꢄ19.0 Hz, 3-Hb), 3.64 (3H, s, COOCH3), 4.13 (2H, 61.31 (d), 82.19 (s), 116.56 (s), 127.44 (s), 127.75 (s), 129.74 (d), 133.70
q, Jꢄ7.1 Hz, CH2CH3), 4.22 (1H, d, Jꢄ16.0 Hz, 5-Hb), 4.24 (1H, d, (s), 144.04 (s), 169.84 (s), 169.92 (s). IR n
neat
max
cmꢂ1: 1738 (CꢄO). HR-MS
Jꢄ16.0 Hz, 5-Ha), 4.54 (1H, dd, Jꢄ9.0, 2.9 Hz, 2-H), 5.80(1H, br s, olefinic
H), 7.32 (2H, d, Jꢄ7.9 Hz, Ar-H), 7.72 (2H, d, Jꢄ7.9 Hz, Ar-H). 13C-NMR
(CDCl3) d: 14.22 (q), 21.55 (q), 35.89 (t), 52.45 (q), 53.11 (t), 60.24 (t),
m/z: 409.1557 (Calcd for C20H27NO6S: 409.1559).
Methyl (2S,4E)-4-Cyanomethylene-1-p-toluenesulfonylpyrrolidine-2-
carboxylate (26a) and Methyl (2S,4Z)-4-Cyanomethylene-1-p-toluenesul-
60.57 (d), 113.83 (d), 127.48 (d), 129.84 (d), 134.70 (s), 144.14 (s), 155.42 fonylpyrrolidine-2-carboxylate (26b) Compound 5 (297 mg, 1.00 mmol)
neat
(s), 165.54 (s), 171.39 (s). IR n
cmꢂ1: 1743, 1712 (CꢄO). HR-MS m/z: was treated in a manner similar to that described for 24, but using diethyl
max
367.1093 (Calcd for C17H21NO6S: 367.1090).
cyanomethylphosphonate (886 mg, 5.00 mmol) and column chromatography
24b: [a]D29 ꢂ12.5° (cꢄ1.1, CHCl3). 1H-NMR (CDCl3) d: 1.27 (3H, t, on silica gel [hexane–Et2O (1 : 1)], giving pyrrole derivative 28 (5 mg, 3%),

174
Vol. 57, No. 2
then 26a (118 mg, 37%) as a white solid, and then 26b (107 mg, 33%) as a
bled into the mixture and the mixture was concentrated under reduced pres-
white solid. Compounds 26a and 26b were recrystallized from i-Pr2O- sure. Water (15 ml) was added to the residue at 0 °C and the whole was ex-
AcOEt, respectively.
tracted with CHCl3 (15 mlꢃ2). The organic layer was washed with water
26a: Colorless needles, mp 80—82 °C, [a]D21 ꢁ9.4° (cꢄ0.8, CHCl3). H- (5 ml), dried over anhydrous Na2SO4, and concentrated under reduced pres-
NMR (CDCl3) d: 2.44 (3H, s, Ar-CH3), 2.98—3.02 (2H, m, 3-H), 3.66 (3H, sure. The residue was subjected to column chromatography on silica gel
1
s, COOCH3), 4.23 (1H, d, Jꢄ16.5 Hz, 5-Ha), 4.27 (1H, d, Jꢄ16.5 Hz, 5-Hb),
4.60 (1H, t, Jꢄ6.1 Hz, 2-H), 5.34 (1H, m, olefinic H), 7.34 (2H, d, Jꢄ8.3
Hz, Ar-H), 7.71 (2H, d, Jꢄ8.3 Hz, Ar-H). 13C-NMR (CDCl3) d: 21.60 (q),
[hexane–AcOEt (3 : 1)] to give 17 (44 mg, 85%).
Methyl 4-(Ethoxycarbonylmethyl)pyrrole-2-carboxylate (28) DBU
(0.21 ml, 1.4 mmol) was added to a solution of 24a (72 mg, 0.20 mmol) in
36.70 (t), 52.14 (q), 52.73 (t), 59.81 (d), 93.73 (d), 115.31 (s), 127.44 (d), toluene (1 ml) and the mixture was stirred at room temperature for 1 h. It
KBr
129.95 (d), 134.62 (s), 144.50 (s), 161.30 (s), 170.62 (s). IR n
cmꢂ1
:
was concentrated under reduced pressure and the residual brown oil was
max
2216 (CN), 1736 (CꢄO). MS m/z: 320 (M+). Anal. Calcd for C15H16N2O4S: subjected to column chromatography on silica gel (AcOEt) to give 28
C, 56.24; H, 5.03; N, 8.74. Found: C, 56.10; H, 5.04; N, 8.72.
(40 mg, 97%) as a white solid. It was recrystallized from hexane–AcOEt to
26b: Colorless needles, mp 102—104 °C, [a]D21 ꢂ21.7° (cꢄ0.7, CHCl3). give colorless needles, mp 66—68 °C, (lit.27) mp 64—65 °C). 1H-NMR
1H-NMR (CDCl3) d: 2.43 (3H, s, Ar-CH3), 2.82 (1H, dd, Jꢄ17.6, 1.1 Hz, 3- (CDCl3) d: 1.26 (3H, t, Jꢄ7.1 Hz, CH2CH3), 3.49 (2H, s, CH2CO2Et), 3.84
Hb), 2.96 (1H, dd, Jꢄ17.6, 8.9 Hz, 3-Ha), 3.63 (3H, s, COOCH3), 4.30 (1H, (3H, s, CO2CH3), 4.16 (2H, q, Jꢄ7.1 Hz, CH2CH3), 6.85 (1H, s, 3-H), 6.91
d, Jꢄ16.6 Hz, 5-Ha), 4.36 (1H, d, Jꢄ16.6 Hz, 5-Hb), 4.61 (1H, dd, Jꢄ8.9,
3.0 Hz, 2-H), 5.33 (1H, s, olefinic H), 7.35 (2H, d, Jꢄ8.2 Hz, Ar-H), 51.45 (q), 60.83 (t), 115.73 (d), 117.74 (s), 122.13 (d), 122.54 (s), 161.63
(1H, s, 5-H), 9.41 (1H, s, NH). 13C-NMR (CDCl3) d: 14.21 (q), 32.82 (t),
7.73(2H, d, Jꢄ8.2 Hz, Ar-H). 13C-NMR (CDCl3) d: 21.60 (q), 37.25 (t),
(s), 171.91 (s). IR nmKaBxr cmꢂ1: 3325 (NH), 1736, 1689 (CꢄO). MS m/z: 211
51.83 (t), 52.67 (q), 60.15 (d), 93.56 (d), 115.04 (s), 127.50 (d), 129.94 (d), (Mꢁ). Anal. Calcd for C10H13NO4: C, 56.86; H, 6.20; N, 6.63. Found: C,
KBr
134.65 (s), 144.44 (s), 161.53 (s), 170.60 (s). IR n
cmꢂ1: 2222 (CN),
56.87; H, 6.15; N, 6.59.
tert-Butyl 4-(Ethoxycarbonylmethyl)pyrrole-2-carboxylate (29) DBU
(0.21 ml, 1.4 mmol) was added to a solution of 25a (82 mg, 0.20 mmol) in
max
1753 (CꢄO). MS m/z: 320 (Mꢁ). Anal. Calcd for C15H16N2O4S: C, 56.24;
H, 5.03; N, 8.74. Found: C, 56.22; H, 5.11; N, 8.68.
tert-Butyl (2S,4E)-4-Cyanomethylene-1-p-toluenesulfonylpyrrolidine- toluene (1 ml) and the mixture was refluxed for 1 h. After cooling, the mix-
2-carboxylate (27a) and tert-Butyl (2S,4Z)-4-Cyanomethylene-1-p-tolu- ture was concentrated under reduced pressure and the residual brown oil was
enesulfonylpyrrolidine-2-carboxylate (27b) Compound 6 (339 mg, 1.00 subjected to column chromatography on silica gel [benzene–Et2O (5 : 1)] to
1
mmol) was treated in a manner similar to that described for 25, but using di-
give 29 (50 mg, 99%) as a colorless oil. H-NMR (CDCl3) d: 1.27 (3H, t,
ethyl cyanomethylphosphonate (886 mg, 5.00 mmol) and column chroma- Jꢄ7.1 Hz, CH2CH3), 1.55 (9H, s, C(CH3)3), 3.48 (2H, s, benzylic H), 4.16
tography on silica gel [hexane–Et2O (2 : 1)], giving pyrrole derivative 29
(4 mg, 5%), then 27a (174 mg, 48%) as a white solid, and then 27b (131 mg,
36%) as a white solid. Compounds 27a and 27b were recrystallized from (t), 80.85 (s), 115.03 (d), 117.44 (s), 121.24 (d), 124.35 (s), 160.71 (s),
(2H, q, Jꢄ7.1 Hz, CO2CH2CH3), 6.77 (1H, s, 3-H), 6.86 (1H, s, 5-H), 9.29
(1H, br s, NH). 13C-NMR (CDCl3) d: 14.21 (q), 28.37 (q), 32.84 (t), 60.79
neat
max
hexane–AcOEt, respectively.
172.00 (s). IR n
cmꢂ1: 3311 (NH), 1738, 1678 (CꢄO). HR-MS m/z:
1
27a: Colorless needles, mp 96—97 °C, [a]D17 ꢁ9.9° (cꢄ0.7, CHCl3). H- 253.1315 (Calcd for C13H19NO4S: 253.1314).
NMR (CDCl3) d: 1.41 (9H, s, C(CH3)3), 2.44 (3H, s, Ar-CH3), 2.94 (1H,
br d, Jꢄ17.9 Hz, 3-Hb), 2.98 (1H, ddd, Jꢄ17.9, 8.5, 1.6 Hz, 3-Ha), 4.24 (1H, mmol) was added to a solution of 26a (65 mg, 0.20 mmol) in toluene (1 ml)
Methyl 4-Cyanomethylpyrrole-2-carboxylate (30) DBU (0.21 ml, 1.4
dd, Jꢄ16.5, 1.1 Hz, 5-Ha), 4.26 (1H, dd, Jꢄ16.5, 1.8 Hz, 5-Hb), 4.49 (1H,
dd, Jꢄ8.5, 3.2 Hz, 2-H), 5.32 (1H, m, olefinic H), 7.32 (2H, d, Jꢄ8.1 Hz,
and the mixture was stirred at room temperature for 1 h. It was concentrated
under reduced pressure and the residual brown oil was subjected to column
Ar-H), 7.72 (2H, d, Jꢄ8.1 Hz, Ar-H). 13C-NMR (CDCl3) d: 21.58 (q), 27.80 chromatography on silica gel [hexane–Et2O (4 : 1)] to give 30 (33 mg, 99%)
(q), 37.03 (t), 52.15 (t), 60.70 (d), 82.95 (s), 93.46 (d), 115.37 (s), 127.44 as a white solid. It was recrystallized from hexane–AcOEt to give colorless
(d), 129.90 (d), 135.16 (s), 144.29 (s), 161.90 (s), 169.36 (s). IR nmneaaxt cmꢂ1
:
prisms, mp 92—93 °C. 1H-NMR (CDCl3) d: 3.60 (2H, s, CH2CN), 3.86 (3H,
2222 (CN), 1739 (CꢄO). MS (FAB) m/z: 363 (Mꢁꢁ1). Anal. Calcd for s, CO2CH3), 6.85 (1H, s, 3-H), 6.70 (1H, s, 5-H), 9.74 (1H, s, NH). 13C-
C18H22N2O4S: C, 59.65; H, 6.12; N, 7.73. Found: C, 59.56; H, 6.18; N, 7.77.
NMR (CDCl3) d: 15.76 (t), 51.75 (q), 113.95 (s), 114.48 (d), 118.25 (s),
KBr
27b: Colorless needles, mp 120—121 °C, [a]D17 ꢂ37.2° (cꢄ0.6, CHCl3).
121.51 (d), 123.34 (s), 161.47 (s). IR n
cmꢂ1: 3303 (NH), 2249 (CN),
max
1H-NMR (CDCl3) d: 1.38 (9H, s, C(CH3)3), 2.44 (3H, s, Ar-CH3), 2.75 (1H, 1685 (CꢄO). MS m/z: 164 (Mꢁ). Anal. Calcd for C8H8N2O2: C, 58.53; H,
br d, Jꢄ17.6 Hz, 3-Hb), 2.96 (1H, dd, Jꢄ17.6, 9.0 Hz, 3-Ha), 4.34 (1H, br d, 4.91; N, 17.06. Found: C, 58.50; H, 5.02; N, 17.04.
Jꢄ16.6 Hz, 5-Hb), 4.37 (1H, dd, Jꢄ16.6, 1.1 Hz, 5-Ha), 4.49 (1H, ddd,
Jꢄ9.0, 2.5, 1.6 Hz, 2-H), 5.33 (1H, m, olefinic H), 7.33 (2H, d, Jꢄ8.1 Hz,
tert-Butyl 4-Cyanomethylpyrrole-2-carboxylate (31) DBU (0.21 ml,
1.4 mmol) was added to a solution of 27a (73 mg, 0.20 mmol) in toluene
Ar-H), 7.74 (2H, d, Jꢄ8.1 Hz, Ar-H). 13C-NMR (CDCl3) d: 21.56 (q), 27.76 (1 ml) and the mixture was refluxed for 1 h. After cooling, the mixture was
(q), 37.59 (t), 51.85 (t), 61.08 (d), 82.88 (s), 93.19 (d), 115.07 (s), 127.47 concentrated under reduced pressure and the residual brown oil was sub-
(d), 129.90 (d), 135.22 (s), 144.23 (s), 162.21 (s), 169.32 (s). IR nmKaBxr cmꢂ1
:
jected to column chromatography on silica gel [benzene–Et2O (5 : 1)] to give
2220 (CN), 1743 (CꢄO). MS (FAB) m/z: 363 (Mꢁꢁ1). Anal. Calcd for 31 (41 mg, 99%) as a white solid. It was recrystallized from hexane–AcOEt
1
C18H22N2O4S: C, 59.65; H, 6.12; N, 7.73. Found: C, 59.65; H, 6.14; N, 7.72.
Treatments of 21 with Bases Method a: DBU (0.21 ml, 1.4 mmol) was s, C(CH3)3), 3.59 (2H, s, CH2CN), 6.78 (1H, s, 3-H), 6.90 (1H, s, 5-H), 9.61
added to a solution of 21 (59 mg, 0.20 mmol) in toluene (1 ml) and the mix-
to give colorless needles, mp 112—113 °C. H-NMR (CDCl3) d: 1.57 (9H,
(1H, s, NH). 13C-NMR (CDCl3) d: 15.80 (t), 28.34 (q), 81.45 (s), 113.64 (s),
KBr
max
ture was refluxed for 12 h. After cooling, the mixture was concentrated 113.89 (d), 118.28 (s), 120.63 (d), 125.16 (s), 160.50 (s). IR n
cmꢂ1
:
under reduced pressure and the residual brown oil was subjected to column 3300 (NH), 2252 (CN), 1662 (CꢄO). MS (FAB) m/z: 207 (Mꢁꢁ1). Anal.
chromatography on silica gel (AcOEt) to give 4 (27 mg, 97%).
Method b: To a solution of 21 (86 mg, 0.29 mmol) in THF (2 ml), 1 M t-
BuOK in THF (0.7 ml) was added and the resulting solution was stirred at
Calcd for C11H14N2O2: C, 64.06; H, 6.84; N, 13.58. Found: C, 64.20; H,
6.85; N, 13.67.
tert-Butyl (2S,4R)-4-Ethoxycarbonylmethyl-4-hydroxy-1-p-toluenesul-
room temperature for 1 h. A sufficient amount of carbon dioxide was bub- fonylpyrrolidine-2-carboxylate (32a) and tert-Butyl (2S,4S)-4-Ethoxy-
bled into the mixture and the mixture was concentrated under reduced pres- carbonylmethyl-4-hydroxy-1-p-toluenesulfonylpyrrolidine-2-carboxylate
sure. Water (15 ml) was added to the residue at 0 °C and the whole was ex- (32b) A mixture of granulated zinc (0.15 g), copper(II) acetate hydrate
tracted with CHCl3 (15 mlꢃ2). The organic layer was washed with water (15 mg), and acetic acid (1 ml) was stirred at room temperature for 12 h. The
(5 ml), dried over anhydrous Na2SO4, and concentrated under reduced pres-
sure. The residue was subjected to column chromatography on silica gel (1 mlꢃ3) and benzene (1 ml). To the Zn–Cu couple, THF (2 ml) was added
[hexane–AcOEt (3 : 1)] to give 4 (31 mg, 77%). with stirring, then a solution of compound 6 (339 mg, 1.00 mmol) and ethyl
Treatments of 22 with Bases Method a: DBU (0.21 ml, 1.4 mmol) was bromoacetate (334 mg, 2.0 mmol) in THF (2 ml) was added dropwise. The
added to a solution of 22 (68 mg, 0.20 mmol) in toluene (1 ml) and the mix- mixture was heated under reflux for 1 h. After cooling, AcOEt (5 ml) and
acetic acid was then decanted and the Zn–Cu couple was washed with Et2O
ture was refluxed for 12 h. After cooling, the mixture was concentrated concentrated ammonium hydroxide (5 ml) were added at 0 °C and the mix-
under reduced pressure and the residual brown oil was subjected to column ture was stirred for 10 min. The whole was filtered and the organic layer was
chromatography on silica gel [hexane–AcOEt (3 : 1)] to give 17 (36 mg,
99%).
Method b: To a solution of 22 (96 mg, 0.29 mmol) in THF (2 ml), 1 M t-
BuOK in THF (0.7 ml) was added and the resulting solution was stirred at
separated. The aqueous layer was extracted with AcOEt (5 mlꢃ2) and the
combined organic layer was washed with water (10 ml), then brine (10 ml). It
was dried over anhydrous Na2SO4, and concentrated under reduced pressure.
The residual yellow oil was subjected to flash chromatography on silica gel
room temperature for 1 h. A sufficient amount of carbon dioxide was bub- [hexane–AcOEt (4 : 1)], then column chromatography on silica gel [ben-

February 2009
175
7.31 (2H, d, Jꢄ8.2 Hz, Ar-H), 7.79 (2H, d, Jꢄ8.2 Hz, Ar-H). 13C-NMR
(CDCl3) d: 14.04 (q), 21.76 (q), 21.90 (q), 27.78 (q), 31.60 (s), 38.90 (t),
zene–AcOEt (10 : 1)], giving 32a (192 mg, 45%) as a white solid and 32b
(43 mg, 10%) as a colorless oil. Compound 32a was recrystallized from
hexane–AcOEt.
47.19 (s), 56.93 (t), 61.04 (d), 61.37 (t), 81.82 (s), 82.47 (s), 127.91 (d),
32a: Colorless prisms (hexane–AcOEt) : mp 73—74 °C, [a]D17 ꢂ37.4°
(cꢄ0.93, CHCl3). 1H-NMR (CDCl3) d: 1.25 (3H, t, Jꢄ7.1 Hz, CH2CH3),
1.48 (9H, s, C(CH3)3), 2.16 (2H, m, 3-H), 2.43 (3H, s, Ar-CH3), 2.52 (1H, d,
Jꢄ15.4 Hz, CH2CO2Et), 2.56 (1H, d, Jꢄ15.4 Hz, CH2CO2Et ), 3.28 (1H, d,
Jꢄ9.9 Hz, 5-Ha), 3.58 (1H, dd, Jꢄ9.9, 0.8 Hz, 5-Hb), 4.14 (2H, q, Jꢄ7.1 Hz,
CH2CH3), 4.27 (1H, dd, Jꢄ8.9, 3.2 Hz, 2-H), 4.34 (1H, s, OH), 7.32 (2H, d,
Jꢄ8.3 Hz, Ar-H), 7.77 (2H, d, Jꢄ8.3 Hz, Ar-H). 13C-NMR (CDCl3) d: 14.12
(q), 21.56 (q), 27.83 (q), 41.93 (t), 42.40 (t), 59.44 (t), 59.98 (d), 60.95 (t),
neat
129.52 (d), 134.64 (s), 143.59 (s), 171.18 (s), 177.12 (s). IR n
cmꢂ1
:
max
3506 (OH), 1736, 1728 (CꢄO). HR-MS (FAB) m/z: 456.2054 (Calcd for
C22H34NO7S: 456.2056).
Aromatization of Compound 32 Giving 29 Thionyl chloride (1.0 ml,
14 mmol) was added dropwise to a solution of compound 32a (129 mg,
0.30 mmol) in pyridine (3.0 ml) at 0 °C and the whole was stirred at room
temperature for 2 h. The reaction mixture was concentrated under reduced
pressure. Toluene (12 ml) was added and the solution was concentrated
under reduced pressure. This operation was repeated once. Water (20 ml)
was added to the residue and the whole was extracted with benzene
(20 mlꢃ2). The organic layer was washed with brine (20 ml), dried over an-
hydrous Na2SO4, and concentrated under reduced pressure. The residue was
dissolved in toluene (2 ml) and DBU (0.30 ml, 2.0 mmol), and the solution
was refluxed for 3 h. The mixture was concentrated under reduced pressure
and the residue was subjected to column chromatography on silica gel
[hexane–AcOEt (1 : 1)] to give 29 (65 mg, 85%) as a colorless oil.
76.31 (s), 82.96 (s), 127.68 (d), 129.74 (d), 135.01 (s), 143.87 (s), 170.61
KBr
(s), 172.36 (s). IR n
cmꢂ1: 3438 (OH), 1736, 1714 (CꢄO). MS (FAB)
max
m/z: 428 (Mꢁꢁ1). Anal. Calcd for C20H29NO7S: C, 56.19; H, 6.84; N, 3.28.
Found: C, 56.20; H, 6.75; N, 3.21.
32b: [a]D26 ꢂ54.6° (cꢄ0.40, CHCl3). H-NMR (CDCl3) d: 1.26 (3H, t,
1
Jꢄ7.2 Hz, CH2CH3), 1.50 (9H, s, C(CH3)3), 1.90 (1H, dd, Jꢄ13.0, 9.0 Hz, 3-
Hb), 2.31 (1H, ddd, Jꢄ13.0, 7.7, 1.8 Hz, 3-Ha), 2.42 (3H, s, Ar-CH3), 2.64
(1H, d, Jꢄ16.9 Hz, CH2CO2Et), 2.65 (1H, d, Jꢄ16.9 Hz, CH2CO2Et), 3.27
(1H, s, OH), 3.41 (1H, d, Jꢄ11.5 Hz, 5-Hb), 3.52 (1H, dd, Jꢄ11.5, 1.8 Hz,
5-Ha), 4.15 (2H, q, Jꢄ7.2 Hz, CH2CH3), 4.21 (1H, dd, Jꢄ9.0, 7.7 Hz, 2-H),
7.32 (2H, d, Jꢄ8.1 Hz, Ar-H), 7.78 (2H, d, Jꢄ8.1 Hz, Ar-H). 13C-NMR
(CDCl3) d: 14.09 (q), 21.57 (q), 27.92 (q), 41.30 (t), 42.98 (t), 59.59 (t),
tert-Butyl 4-[1-(Ethoxycarbonyl)ethyl]pyrrole-2-carboxylate (35)
Compound 35 (72 mg, 89%) was obtained as a pale yellow oil from 33a
(133 mg, 0.30 mmol) in a manner similar to that described for 29 from 32,
1
but using column chromatography on silica gel [benzene–Et2O (5 : 1)]. H-
60.79 (d), 61.25 (t), 79.14 (s), 81.96 (s), 127.88 (d), 129.55 (d), 134.63 (s),
NMR (CDCl3) d: 1.24 (3H, t, Jꢄ7.1 Hz, CH2CH3), 1.46 (3H, d, Jꢄ7.1 Hz,
benzylic CH3), 1.56 (9H, s, C(CH3)3), 3.64 (1H, q, Jꢄ7.1 Hz, benzylic H),
4.13 (2H, q, Jꢄ7.1 Hz, CH2CH3), 6.78 (1H, s, 3-H), 6.83 (1H, s, 5-H), 9.77
(1H, br s, NH). 13C-NMR (CDCl3) d: 14.16 (q), 18.44 (q), 28.38 (q), 38.07
neat
max
143.66 (s), 171.02 (s), 171.98 (s). IR n
cmꢂ1: 3506 (OH), 1738, 1732
(CꢄO). HR-MS (FAB) m/z: 428.1744 (Calcd for C20H30NO7S: 428.1743).
An Epimeric Mixture of tert-Butyl (2S,4R)-4-[1-(Ethoxycarbonyl)-
ethyl]-4-hydroxy-1-p-toluenesulfonylpyrrolidine-2-carboxylates (33a)
and an Epimeric Mixture of tert-Butyl (2S,4S)-4-[1-(Ethoxycarbonyl)
ethyl]-4-hydroxy-1-p-toluenesulfonylpyrrolidine-2-carboxylates (33b)
Under an argon atmosphere, ethyl 2-bromopropionate (905 mg, 5.0 mmol)
was added to a mixture of 6 (679 mg, 2.00 mmol), zinc powder (260 mg,
4.00 mg-atoms), trimethyl borate (1.04 g, 10.0 mmol), and THF (10 ml). The
whole was stirred for a while at room temperature and heated under reflux
for 1.5 h. After cooling, AcOEt (10 ml), concentrated ammonium hydroxide
(10 ml), and glycerin (10 ml) were added at 0 °C and the mixture was stirred
for 10 min. The whole was filtered and the organic layer was separated. The
aqueous layer was extracted with AcOEt (10 mlꢃ2) and the combined or-
ganic layer was washed with water (20 ml), then brine (20 ml). It was dried
over anhydrous Na2SO4, and concentrated under reduced pressure. The
residual brown oil was subjected to column chromatography on silica gel
[hexane–AcOEt (3 : 1)] to give 33a (486 mg, 55%) as a pale yellow oil and
33b (186 mg, 21%) as a pale yellow oil.
(d), 60.66 (t), 80.87 (s), 113.45 (d), 120.19 (d), 124.11 (s), 124.69 (s),
neat
128.33 (d), 161.03 (s), 175.02 (s). IR n
cmꢂ1: 3112 (NH), 1736, 1676
max
(CꢄO). HR-MS m/z: 267.1469 (Calcd for C14H21NO4S: 267.1471).
tert-Butyl 4-[2-(Ethoxycarbonyl)propan-2-yl]pyrrole-2-carboxylate
(36) Compound 36 (76 mg, 90%) was obtained as a white solid from 34a
(137 mg, 0.30 mmol) in a manner similar to that described for 29 from 32,
but using column chromatography on silica gel [hexane–AcOEt (10 : 1)]. It
1
was recrystallized from hexane to give colorless prisms, mp 88—89 °C H-
NMR (CDCl3) d: 1.22 (3H, t, Jꢄ7.1 Hz, CH2CH3), 1.52 (6H, s, benzylic
CH3), 1.56 (9H, s, C(CH3)3), 4.12 (2H, q, Jꢄ7.1 Hz, CH2CH3), 6.80 (1H, s,
3-H), 6.83 (1H, s, 5-H), 9.43 (1H, s, NH). 13C-NMR (CDCl3) d: 14.09 (q),
26.65 (q), 28.39 (q), 41.54 (s), 60.75 (t), 80.85 (s), 112.71 (d), 119.28 (d),
KBr
123.98 (s), 130.38 (s), 160.88 (s), 176.70 (s). IR n
cmꢂ1: 3311 (NH),
max
1738, 1678 (CꢄO). MS m/z: 281 (Mꢁ). Anal. Calcd for C15H23NO4: C,
64.03; H, 8.24; N, 4.98. Found: C, 64.19; H, 8.08; N, 4.68.
tert-Butyl (2S,4R)-4-[2-(Ethoxycarbonyl)propan-2-yl]-4-hydroxy-1-p-
toluenesulfonylpyrrolidene-2-carboxylate (34a) and tert-Butyl (2S,4S)-4-
[2-(Ethoxycarbonyl)propan-2-yl]-4-hydroxy-1-p-toluenesulfonylpyrroli-
Acknowledgement This work was supported in part by the Special Re-
search Fund of Hokuriku University.
dene-2-carboxylate (34b) Under an argon atmosphere, ethyl 2-bro- References
moisobutyrate (975 mg, 5.0 mmol) was added to a mixture of 6 (679 mg,
2.00 mmol), zinc powder (260 mg, 4.00 mg-atoms), trimethyl borate (1.04 g,
10.0 mmol), and THF (10 ml). The whole was stirred for a while at room
temperature and heated under reflux for 1 h. After cooling, AcOEt (10 ml),
concentrated ammonium hydroxide (10 ml), and glycerin (10 ml) were added
at 0 °C and the mixture was stirred for 10 min. The whole was filtered and
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(20 ml), then brine (20 ml). It was dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. The residual brown oil was subjected
to flash chromatography on silica gel [hexane–Et2O (2 : 1)] to give 34a
(550 mg, 60%) as a colorless oil and 34b (164mg, 18%) as a pale yellow oil.
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