Synthesis of 2-(5-Hydroxymethyl-2-formylpyrrol-1-yl)propionic acid lactone

Article abstract of DOI:10.1007/s10600-012-0202-8

2-(5-Hydroxymethyl-2-formylpyrrol-1-yl)propionic acid lactone was synthesized in six steps with a 17.0% overall yield, starting from L-alanine. The synthetic route involved the Clauson-Kaas reaction, Vilsmeier reaction, and transesterification. The transesterification was the key step in the formation of the target compound.

Full text of DOI:10.1007/s10600-012-0202-8

Chemistry of Natural Compounds, Vol. 48, No. 2, May, 2012 [Russian original No. 2, March–April, 2012]
SYNTHESIS OF 2-(5-HYDROXYMETHYL-2-FORMYLPYRROL-1-YL)PROPIONIC
ACID LACTONE
Xiaolin Bu, Yueqing Li, Jihong Liu, Debin Zeng, and Weijie Zhao*
UDC 547.595:547.23/24
2-(5-Hydroxymethyl-2-formylpyrrol-1-yl)propionic acid lactone was synthesized in six steps with a 17.0%
overall yield, starting from L-alanine. The synthetic route involved the Clauson-Kaas reaction, Vilsmeier
reaction, and transesterification. The transesterification was the key step in the formation of the target
compound.
Keywords: alkaloid, L-alanine, transesterification, lactone.
2-(5-Hydroxymethyl-2-formylpyrrol-1-yl)propionic acid lactone (1) was firstly reported by Shigematsu, who obtained
compound 1 via roasting DL-alanine and D-glucose at 200–250ꢀC ꢁ1ꢂ. Subsequently, compound 1 was isolated from
flue-cured tobacco and used to improve its flavor and aroma ꢁ2–5ꢂ. Recently, compound 1 was isolated from mature fruits of
Capparis spinosa ꢁ6, 7ꢂ, whose extract showed anti-inflammatory and pain-relieving activity. It is necessary that an appropriate
synthesis route be found to supply enough sample since there is only 1.5 mg compound 1 per 10 kg dry fruits of C. spinosa.
Obviously, it is not easy to get compound 1 by roasting DL-alanine and D-glucose. To the best of our knowledge, no
other total synthesis of compound 1 has been reported. In the present research, the retrosynthetic analysis of compound 1 is
outlined (Scheme 1). Two strategies for the present purpose were explored: i) synthesize lactone 7 by intramolecular esterification
of compound 5 and ii) synthesize lactone 7 by intramolecular transesterification of compound 6.
Starting from L-alanine, ethyl 2-(2-formyl-1H-pyrrol-1-yl)-propionate (3) was prepared according to the reference
procedure [8]. In pathway i, the ethyl ester protecting group was hydrolyzed by aqueous NaOH to afford compound 4. During
the reduction of compound 4, a problem appeared. Unfortunately, compound 5 was not obtainable. Compound 5 could be
monitored in the reaction solution when compound 4 was reduced by NaBH . Upon neutralization, the reaction mixture
4
immediately turned to violet, and a red-violet solid was generated from the aqueous phase. The target compound 5 no longer
existed. We speculate that polymerization between molecules of compound 5 occurred. Probably, the ꢃ-excessive characteristic
of the pyrrole ring caused the problem. Therefore the other strategy was carried out.
O
O
O
O
O
O
O
O
O
O
N
OH
H
N
O
N
N
N
O
O
O
6
L-alanine
HO
HO
H
1
7
3
2
N
O
N
OH
H
5
4
Scheme 1
School of Pharmaceutical Science and Technology, Dalian University of Technology, 2 Linggong Road, Ganjingzi
District, Dalian, 116024, P. R. China, e-mail: zyzhao@dlut.edu.cn. Published in Khimiya Prirodnykh Soedinenii, No. 2,
March–April, 2012, pp. 181–183. Original article submitted December 24, 2010.
194
0009-3130/12/4802-0194 02012 Springer Science+Business Media, Inc.

O
O
O
O
O
O
N
N
N
+ H
- H O
2
O
CH
2
OH
OH
OH
O
2
N
N
6
O
O
O
O
HO
O
O
O
O
N
N
N
O
8
Scheme 2
O
O
O
O
O
f
d, e
a, b, c
N
N
O
N
O
L-alanine
H
3
7
1
a. SOCl , EtOH, –5°C to room temperature to reflux, 7h; b. NaOAc, HOAc, 2,5-dimethoxytetrahydrofuran,
2
1h; c. 2, POCl , DMF, NaOAc, CH Cl , –5ꢀC to room temperature to reflux, 8h; d. NaBH , MeOH,
3
2
2
4
–15ꢀC, 2h; e. 6, DBU, toluene, 45ꢀC, 5h; f. POCl , DMF, NaOAc, CH Cl , –5ꢀC to room temperature to
3
2
2
reflux, 8h.
Scheme 3
In pathway ii, compound 3 was reduced by NaBH to afford compound 6 [9]. In general, such reaction is conducted
4
at room temperature and the yield is acceptable. However, we did not get the desired compound 6 when the reaction temperature
–
was –5ꢀC. Instead, a compound with [M + Cl] 190.1 analyzed by API-ES was generated, which was assumed to be
2-(2-hydroxymethylpyrrol-1-yl)-propan-1-ol. We found that the reaction must be kept at low temperature. Once the temperature
was higher than –8ꢀC, ethyl ester would be reduced too. Finally we conducted the reaction at –15ꢀC.
We tried three catalytic conditions to generate compound 7 ꢁ10–12ꢂ.
It has been reported that transesterification occurs when toluene is used as solvent [10]. However, transesterification
did not occur under the first conditions. In the second catalytic system using acidic ion-exchange resin Amberlyst-15,
polymerization occurred between two molecules of compound 6 to generate compound 8 (Scheme 2), as confirmed by
1
1
1
H NMR and H– H COSY. This indicated that acidic conditions were not suitable for the system. We speculate that a possible
mechanism may be bimolecular polymerization. Finally, DBU in toluene was chosen to catalyze transesterification between
ethyl and hydroxymethyl to afford the key intermediate compound 7. We also needed to concern with the reaction temperature
because side reactions occurred when the temperature reached 60°C. Finally, a formyl group was introduced at the
5-position of the pyrrole ring of compound 7 via the Vilsmeier reaction to afford target compound 1. Pathway ii was
successful (Scheme 3).
EXPERIMENTAL
Solvents and chemicals were reagent grade or better and were obtained from commercial sources. The petroleum
ether (PE) used was the fraction boiling in the range 60–90°C. Reactions were monitored by TLC on 0.25 mm silica gel plates
1
13
(60GF ) and visualized with ultraviolet light. The H and C NMR spectra were recorded on a Bruker AV 400MHz
254
1
13
spectrometer (400 MHz for H, 100 MHz for C). High-resolution mass spectra (HR-MS) were obtained on a Micromass
GCT-TOF mass spectrometer.
Ethyl (2S)-2-(1H-Pyrrol-1-yl)propionate (2). L-alanine (17.82 g, 0.2 mol) was added to EtOH (200 mL) at r.t. The
mixture was stirred at –5ꢀC for 10 min. SOCl (35.69 g, 0.3 mol) was added to the above mixture dropwise and stirred at r.t.
2
for 2 h. The mixture was then stirred under reflux for 5 h. The solvent was evaporated under vacuum, and the residue was
suspended in a solution of NaOAc (16.41 g, 0.2 mol) and 2,5-dimethoxytetrahydrofuran (26.43 g, 0.2 mol) in AcOH (150 mL).
195

The mixture was stirred at 80ꢀC for an appropriate time (0.5 h, TLC monitoring). After the AcOH was evaporated, the residue
was dissolved in water (200 mL) and extracted with EtOAc (200 mLꢄ 3). The combined organic layer was dried over anhydrous
Na SO , filtered, and concentrated. The residue was purified by silica gel chromatograph (PE–EtOAc, 6:1) to give 2 (28.0 g,
2
4
20
–1
83.7%) as colorless oil, [ꢅ] –15.0ꢀ (c 5.78, CHCl ). IR (neat, , cm ): 3102, 724 (=C–H), 2985, 2939, 1449, 1376 (CH,
D
3
1
CH , CH ), 1740 (C=O), 1550, 1491 (C=C), 1189 (C-O). H NMR (400 MHz, CDCl , ꢆ, ppm, J/Hz): 1.25 (3H, t, J = 7.2,
2
3
3
OCH CH ), 1.71 (3H, d, J = 7.2, CHCH ), 4.17 (2H, q, J = 7.2, OCH ), 4.74 (q, 1H, J = 7.2, CHCH ), 6.19 (2H, s, H-3ꢇ, 4ꢇ),
2
3
3
2
3
13
6.76 (2H, s, H-2ꢇ, 5ꢇ). C NMR (100 MHz, CDCl , ꢆ, ppm, J/Hz): 171.3 (s, C-1), 119.7 (s, C-2ꢇ, 5ꢇ), 108.6 (s, C-3ꢇ, 4ꢇ), 61.6
3
(s, C-2), 57.1 (s, OCH CH ), 18.4 (s, C-3), 14.1 (s, OCH CH ). TOF-MS (EI, m/z): 167.0943 (calcd for C H NO , 167.0946).
2
3
2
3
9
13
2
Ethyl 2-(2-Formyl-1H-pyrrol-1-yl)propionate (3). POCl (12.27 g, 80 mmol) was added dropwise to DMF (6.97 g,
3
80 mmol) in 15 min at –5ꢀC, and the whole was stirred for another 20 min. A solution of compound 2 (13.38 g, 80 mmol) in
CH Cl (40 mL) was added dropwise to the mixture in 30 min. The mixture was allowed to warm to r.t., stirred for 2 h, and
2
2
then poured into a solution of NaOAc (26.24 g, 0.32 mol) in water (100 mL). The mixture was heated to reflux for 5 h. Later,
the reaction solution was diluted with water (100 mL) and extracted with CH Cl (200 mL ꢄ 3). The combined extracts were
2
2
dried over anhydrous Na SO and evaporated. The residue was purified by silica gel chromatograph (PE–EtOAc, 5:1) to give
2
4
20
–1
3 (13.35 g, 85.5%) as colorless oil, [ꢅ] –59.1ꢀ (c 5.78, CHCl ). IR (neat, , cm ): 3116, 778, 755 (=C-H), 2985, 2941, 2810,
1410, 1371 (CH, CH , CH ), 1740, 1655 (C=O), 1529, 1474 (C=C), 1202 (C-O). H NMR (400 MHz, CDCl , ꢆ, ppm, J/Hz):
D
3
1
2
3
3
1.25 (3H, t, J = 7.2, OCH CH ), 1.74 (3H, d, J = 7.2, CHCH ), 4.19 (2H, q, J = 7.2, OCH ), 5.87 (1H, q, J = 7.2, CHCH ), 6.31
2
3
3
2
3
13
(1H, t, J = 3.2, H-4ꢇ), 6.97–6.99 (1H, m, H-3ꢇ), 7.18 (1H, m, H-5ꢇ), 9.51 (1H, s, CHO). C NMR (100 MHz, CDCl , ꢆ, ppm,
3
J/Hz): 179.5 (s, CHO), 171.0 (s, C-1), 131.6 (s, C-2ꢇ), 128.9 (s, C-5ꢇ), 125.4 (s, C-3ꢇ), 110.1 (s, C-4ꢇ), 61.5 (s, C-2), 55.5 (s,
OCH CH ), 17.7 (s, C-3), 14.0 (s, OCH CH ). TOF-MS (EI, m/z): 195.0902 (calcd for C H NO , 195.0895).
2
3
2
3
10 13
3
Ethyl 2-(2-Hydroxymethyl-1H-pyrrol-1-yl)propionate (6). Compound 3 (2.93 g, 15 mmol) was dissolved in MeOH
(60 mL) and chilled in an ice-salt bath. When the temperature was reduced to –15ꢀC, NaBH (0.57 g, 15 mmol) was added to
4
the solution. The reaction temperature was kept below –10ꢀC for 2 h. The reaction mixture was quenched with saturated
aqueous NaHCO (60 mL). The solution was extracted with CH Cl (80 mL ꢄ 3). The combined extract was dried over
3
2
2
Na SO . The solvent was removed under vacuum, and the residue was purified by silica gel chromatograph (PE–EtOAc, 4:1)
2
4
20
–1
to give 6 (2.40 g, 81.0%) as colorless oil, [ꢅ] –24.0ꢀ (c 1.86, CHCl ). IR (neat, , cm ): 3404 (OH), 2985, 2940, 2876, 1429,
1378 (CH, CH , CH ), 1736 (C=O), 1552, 1482 (C=C), 1202 (C-O), 716 (=C-H). H NMR (400 MHz, CDCl , ꢆ, ppm, J/Hz):
D
3
1
2
3
3
1.24 (3H, t, J = 7.2, OCH CH ), 1.71 (3H, t, J = 7.2, CHCH ), 2.14 (1H, s, OH), 4.16 (2H, q, J = 7.2, OCH ), 4.52 (2H, s,
2
3
3
2
13
CH OH), 5.05 (1H, q, J = 7.2, CHCH ), 6.08–6.12 (2H, m, H-3ꢇ, 4ꢇ), 6.81 (1H, t, J = 2.4, H-5ꢇ). C NMR (100 MHz, CDCl ,
2
3
3
ꢆ): 171.9 (s, C-1), 131.8 (s, C-2ꢇ), 119.7 (s, C-5ꢇ), 109.1 (s, C-4ꢇ), 107.8 (s, C-3ꢇ), 61.7 (s, C-2), 56.6 (s, OCH CH ), 53.7 (s,
2
3
CH OH), 18.1 (s, C-3), 14.1 (s, OCH CH ). TOF-MS (EI, m/z): 197.1056 (calcd for C H NO , 197.1052).
2
2
3
10 15
3
2-(2-Hydroxymethylpyrrol-1-yl)propionic Acid Lactone (7). To a solution of 6 (2.37 g, 12 mmol) in toluene
(100 mL), DBU (9.13 g, 60 mmol) was added. The mixture was stirred at 45ꢀC for 5 h. The solution was washed with saturated
aqueous NH Cl (100 mL ꢄ 3). The combined organic layer was dried over Na SO , filtered, and concentrated. The residue was
4
2
4
20
purified by silica gel chromatograph (PE–acetone, 8:1) to give 7 (1.18 g, 65.3%) as colorless oil, [ꢅ] –8.0ꢀ (c 0.81, CHCl ).
IR (neat, , cm ): 3105, 801, 779, 765, 712 (=C-H), 2990, 2941, 1372 (CH, CH , CH ), 1751 (C=O), 1479 (C=C), 1205 (C-O).
H NMR (400 MHz, CDCl , ꢆ, ppm, J/Hz): 1.78 (3H, d, J = 7.2, CHCH ), 4.76 (1H, q, J = 7.2, CHCH ), 5.36 (1H, d, J = 14.4,
OCH ), 5.39 (1H, d, J = 14.4, OCH ), 6.11 (1H, d, J = 2.8, H-3ꢇ), 6.22 (1H, m, H-4ꢇ), 6.72 (1H, s, H-5ꢇ). C NMR (100 MHz,
D
3
–1
2
3
1
3
3
3
13
2
2
CDCl , ꢆ, ppm): 169.3 (s, C-1), 122.1 (s, C-2ꢇ), 117.6 (s, C-5ꢇ), 109.6 (s, C-4ꢇ), 104.8 (s, C-3ꢇ), 64.4 (s, C-2), 53.6 (s, CH O),
3
2
17.0 (s, C-3). TOF-MS (EI, m/z): 151.0639 (calcd for C H NO , 151.0633).
8
9
2
2-(2-Formylpyrrol-1-yl)propionic Acid (4). To a stirred solution of compound 3 (1.95 g, 10 mmol) in methanol (20
mL), a solution of NaOH (0.80 g, 20 mmol) in water (10 mL) was added dropwise. The reaction mixture was stirred for 3 h at r.t.
(TLC monitoring). The reaction mixture was then diluted with water (10 mL) and acidified with HCl (5%) to pH 3–4. The
product was extracted with EtOAc (30 mL ꢄ 2). The combined organic extracts were dried over Na SO . The EtOAc was
2
4
1
removed in vacumm to give 4 (1.5 9 g, 95.1%) as light pink solid. H NMR (400 MHz, CDCl , ꢆ, ppm, J/Hz): 1.74 (3H, d,
3
J = 7.6, CHCH ), 5.79 (1H, d, J = 7.6, CHCH ), 6.31 (1H, t, J = 2.8, H-4ꢇ), 6.99–7.00 (1H, m, H-3ꢇ), 7.18 (1H, s, H-5ꢇ), 9.45
3
3
(1H, s, CHO).
2-(5-Hydroxymethyl-2-formylpyrrol-1-yl)propionic Acid Lactone (1). POCl (0.35 g, 2.3 mmol) was added
3
dropwise to DMF (0.30 g, 3.5 mmol) in 15 min at –5ꢀÑ and stirred for another 20 min. A solution of compound 7 (0.35 g,
2.3 mmol) in CH Cl (8 mL) was added dropwise to the mixture in 30 min. The mixture was allowed to warm to r.t. and stirred
2
2
196

for 2 h. Then the reaction mixture was poured into a solution of NaOAc (0.75 g, 9.2 mmol) in water (10 mL). The mixture was
heated to reflux for 5 h, then diluted with water (10 mL) and extracted with CH Cl (20mL ꢄ 3). The combined extracts were
2
2
dried over anhydrous Na SO . The solvent was removed under vacuum, and the residue was purified by silica gel chromatograph
2
4
20
–1
(PE–EtOAc, 6:1) to give 1 (0.19 g, 45.0%) as white solid, [ꢅ] 0ꢀ (c 0.57, CHCl ). IR (neat, , ñm ): 3101, 830, 785, 746,
718 (=C-H), 2995, 2977, 1401, 1386 (CH, CH , CH ), 1751, 1650 (C=O), 1501, 1466 (C=C), 1196 (C-O). H NMR
D
3
1
2
3
(400 MHz, CDCl , ꢆ, ppm, J/Hz): 1.72 (3H, d, J = 7.2, CHCH ), 5.39 (1H, d, J = 14.8, OCH ), 5.48 (1H, d, J = 14.8, OCH ),
3
3
2
2
13
5.85 (1H, q, J = 7.2, CHCH ), 6.21 (2H, d, J = 4.0, H-4ꢇ), 6.97 (2H, d, J = 4.0, H-3ꢇ), 9.54 (1H, s, CHO). C NMR (100 MHz,
3
CDCl , ꢆ, ppm): 179.2 (s, CHO), 168.2 (s, C-1), 130.8 (s, C-5ꢇ), 130.3 (s, C-2ꢇ), 124.5 (s, C-4ꢇ), 106.5 (s, C-3ꢇ), 63.3 (s, C-2),
3
53.8 (s, CH O), 19.1 (s, C-3). TOF-MS (EI, m/z): 179.0591 (calcd for C H NO , 179.0582).
2
9
9
3
ACKNOWLEDGMENT
This work was supported by the Fundamental Research Funds of the Central Universities of China.
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