Stereospecific synthesis of azetidine-cis-2,3-dicarboxylic acid

Article abstract of DOI:10.1248/cpb.51.96

Electrocyclic reaction product of 1-(methoxycarbonyl)-1,2-dihydropyridine was stereospecifically converted by RuO₄ oxidation into azetidine-cis-2,3-dicarboxylic acid.

Full text of DOI:10.1248/cpb.51.96

96
Notes
Chem. Pharm. Bull. 51(1) 96—97 (2003)
Vol. 51, No. 1
Stereospecific Synthesis of Azetidine-cis-2,3-dicarboxylic Acid
Yasushi ARAKAWA,* Tomoaki MURAKAMI, Yukimi ARAKAWA, and Shigeyuki YOSHIFUJI
Faculty of Pharmaceutical Sciences, Hokuriku University; Kanagawa-machi Ho-3, Kanazawa 920–1181, Japan.
Received September 19, 2002; accepted October 23, 2002
Electrocyclic reaction product of 1-(methoxycarbonyl)-1,2-dihydropyridine was stereospecifically converted
by RuO4 oxidation into azetidine-cis-2,3-dicarboxylic acid.
Key words azetidine-cis-2,3-dicarboxylic acid; 1,2-dihydropyridine; ruthenium tetroxide; 2-(methoxycarbonyl)-2-azabicy-
clo[2.2.0]hex-5-ene
We have previously reported a study of the synthesis of the N-methoxycarbonyl group for an N-tert-butoxycarbonyl
amino acids using Diels–Alder (D–A) adducts of dienes and (Boc) group.
N-containing dienophiles.1,2) Subsequently, our interests
Although removal of the methoxycarbonyl group from
turned to the synthesis of additional amino acids from other compound 3 by methyl lithium has been reported,5,6) we
N-containing olefins, which can be prepared by pericyclic re- newly executed a simple alkaline hydrolysis of 3 to achieve
action.
ease of handling. Compound 3 was heated with 2 M
In the present paper, we would like to report the synthesis NaOH–EtOH under reflux for 24 h and the reaction mixture
of azetidine-cis-2,3-dicarboxylic acid (1) using the electro- was treated with the ethereal solution of di-tert-butyl dicar-
cyclic reaction of 1,2-dihydropyridine followed by ruthenium bonate to give Boc form 5 in a 57% yield. The olefinic link-
tetroxide oxidation. Bridges et al. reported the first synthesis age of 5 was oxidized under similar conditions to those em-
of azetidine-2,3-dicarboxylic acids; their inhibition activities ployed for the oxidation of 3, but both the disappearance of 5
against the high affinity L-glutamate transporter were exam- and the completeness of the expected reaction appeared to be
ined, but the details of the synthetic procedure and the physi- faster than those of 3. We concluded that the difference be-
cal data of the compounds were not described.3)
tween the reaction rates was due to the solubilities of the in-
Bicyclic alkene 3, which can be transformed to certain termediate products in AcOEt. The generated dicarboxylic
useful compounds,4—11) is known to be easily prepared by a acid was treated with diazomethane to give dimethyl ester 6
photoinduced electrocyclic reaction of 1-methoxy-1,2-dihy- in a 67% yield (2 steps).
dropyridine.4—8) As variation among yields has been fre-
Compound 6 was heated with 6 M HCl–AcOH at 50 °C for
quently observed, depending on the irradiation conditions,12) 3 d and the salt of the target amino acid, which was obtained
compound 2 was exposed to UV rays using a high-pressure after concentration of the reaction mixture, and was desalted
mercury lamp through a Pyrex filter, basically according to simply by dissolving the residue in hot water to give free
Fowler’s method,4) to give bicyclic alkene 3 in 85% yield. amino acid 1 as colorless prisms in an 85% yield (Chart 2).
Oxidation of compound 3 by RuO4 was achieved at 0 °C for
The stereochemistry of 1 was confirmed by observation of
80 h, giving the corresponding dicarboxylic acid, which was the coupling constants and the nuclear Overhauser effects
1
treated with diazomethane and isolated as dimethyl ester 4 in (NOE) of the H-NMR analysis (Fig. 2). The coupling con-
a 58% yield. Attempts at the hydrolysis of 4 with hydrochlo- stant between H2 (d 5.39) and H3 (d 3.94) was 9.9 Hz, that
ric acid were made, but both treatments with 6 M HCl at
50 °C for 6 d and with 4 M HCl at 95 °C for 2 d afforded com-
plicated mixtures of products (Chart 1). As the failure of
these hydrolyses was attributed on one hand to the difficulty
of removing the N-methoxycarbonyl group and on the other
hand to the ease of epimerization, we planned to exchange
Fig. 1
Chart 1
Chart 2
∗ To whom correspondence should be addressed. e-mail: ya-arakawa@hokuriku-u.ac.jp
© 2003 Pharmaceutical Society of Japan

January 2003
97
neat
max
52.52 (q), 52.67 (q), 62.66 (d), 156.18 (s), 169.19 (s), 169.99 (s). IR n
cmꢀ1: 1750, 1718 (CꢂO). MS m/z: 231 (Mꢃ).
tert-Butyl 2-Azabicyclo[2.2.0]hex-5-ene-2-carboxylate (5) A solution
of 3 (1.00 g, 7.19 mmol) in EtOH (8.0 ml) and 2 M NaOH (8.0 ml) was re-
fluxed for 24 h. After cooling, a solution of di-tert-butyl dicarbonate (1.88 g,
8.61 mmol) in ether (10 ml) was added to the reaction mixture and the whole
mixture was vigorously stirred for 2 d. The ether layer was separated and the
aqueous layer was extracted with ether (100 mlꢁ3). The combined ethereal
solution was dried over anhydrous MgSO4 and concentrated under reduced
pressure to give an orange oil, which was then subjected to column chro-
matography on alumina (ether) to give 5 (746 mg, 57%) as a colorless oil.
1H-NMR (CDCl3) d: 1.44 (9H, s, C(CH3)3), 3.33—3.37 (1H, s, 4-H), 3.44
(1H, d, Jꢂ8.4 Hz, 3-Ha), 3.87—3.91 (1H, m, 3-Hb), 4.72 (1H, br, 1-H), 6.43
and 6.50 (2H, br, olefinic H). 13C-NMR (CDCl3) d: 28.43 (q), 37.93 (d),
49.26 (t), 50.27 (t), 64.92 (d), 65.77 (d), 79.31 (s), 140.16 (d), 140.82 (d),
143.15 (d), 156.95 (s). IR n nmeaaxt cmꢀ1: 1704 (CꢂO), 1551 (CꢂC). MS m/z:
182 (Mꢃꢃ1).
Dimethyl 1-(tert-Butoxycarbonyl)azetidine-cis-2,3-dicarboxylate (6)
A solution of 5 (651 mg, 3.59 mmol) in AcOEt (30 ml), RuO2·xH2O (5 mg)
and a 10% NaIO4 solution (43 ml) were mixed and then vigorously stirred at
0 °C for 23 h. The AcOEt layer was separated and the aqueous layer was sat-
urated with NaCl, then extracted with AcOEt (50 mlꢁ5). Isopropyl alcohol
(2 ml) was added to the combined AcOEt layers and the solution was left to
stand for 2 h. The precipitated RuO2 was filtered off and the solution was
concentrated under reduced pressure. The residue was dissolved in MeOH
(10 ml) and treated with diazomethane. The solution was concentrated under
reduced pressure and the residual black oil was dissolved in CHCl3 (30 ml).
The solution was then washed with 2% aqueous NaS2O3 and dried over an-
hydrous Na2SO4, then concentrated under reduced pressure to give a black
oil, which was then subjected to column chromatography on silica gel
(ether : hexaneꢂ3 : 2) to give 6 (660 mg, 67%) as a colorless oil. 1H-NMR
(CDCl3) d: 1.42 (9H, s, C(CH3)3), 3.63—3.70 (1H, m, 3-H), 3.70 (3H, s,
OCH3), 3.77 (3H, s, OCH3), 4.03 (1H, t, Jꢂ8.4 Hz, 4-Ha), 4.29 (1H, dd,
Jꢂ8.4, 6.6 Hz, 4-Hb), 4.79 (1H, d, Jꢂ9.5 Hz, 2-H). 13C-NMR (CDCl3) d:
28.23 (q), 35.52 (d), 49.50-51.08 (br, t), 52.30 (q), 52.52 (q), 62.16—63.16
(d), 80.66 (s), 155.12 (s), 169.49 (s), 170.17 (s). IR n nmeaaxt cmꢀ1: 1754, 1712
(CꢂO). MS m/z: 273 (Mꢃ).
Fig. 2. Coupling Constants and NOE Relationships of the Target Amino
Acid 1 in 1 M DCl
between H3 and H4a (d 4.31) was 9.9 Hz, and that between H3
and H4b (d 4.11) was 5.9 Hz. No NOE was observed between
H3 and H4b, which implies that the relative configuration be-
tween 2- and 3-position is cis.
Thus, we accomplished the stereospecific synthesis of aze-
tidine-cis-2,3-dicarboxylic acid (1).
Experimental
Melting points were measured with a Yanagimoto micromelting point ap-
paratus and are uncorrected. NMR spectra were recorded in chloroform-d
(CDCl3), except for those of the amino acid on a GSX-400 spectrometer
with tetramethylsilane as an internal standard. For the amino acid, analysis
was performed in 1 M deuterium chloride (DCl) with 1,4-dioxane as an inter-
1
nal standard (d: 3.7 for H-NMR and d: 67.4 for 13C-NMR). Infrared (IR)
spectra were recorded on a Hitachi 270-30 spectrophotometer. Mass spectra
(MS) were obtained with a JEOL JMS-DX300 instrument. Column chro-
matography was performed on silica gel (Kieselgel 60, 70—230 mesh,
Merck) or alumina (Aluminium oxide 90, 70—230 mesh, Merck).
1-(Methoxycarbonyl)-1,2-dihydropyridine (2) This compound was
prepared according to the cited method4) with little modification. A solution
of methyl chlorocarbonate (18.9 g, 0.200 mol) in ether (25 ml) was added to
a mixture of sodium borohydride (8.00 g, 0.211 mol), pyridine (15.8 g,
0.200 mol), and MeOH (150 ml) cooled in Dry Ice-acetone. The rate of addi-
tion was controlled such that the temperature of the reaction mixture did not
exceed ꢀ73 °C. The reaction mixture was stirred for an additional 1 h and
was then poured into ice water (200 ml). After all of the ice melted, the mix-
ture was extracted with ether (100 mlꢁ4). The ether layer was washed with
water (100 mlꢁ4) and dried over MgSO4. Removal of the solvent in vacuo
gave compound 2 (24.0 g), which was contaminated by small amounts of im-
purities, but was used for the next step without further purification. 1H-NMR
(CDCl3) d: 3.62 (3H, m, OCH3), 4.15—4.32 (2H, m, CH2), 4.88—4.98 (3H,
m, 3-,4-,5-H), 6.57 (1H, d, Jꢂ7.5 Hz, 2-H).
Azetidine-cis-2,3-dicarboxylic Acid (1) Compound
6
(100 mg,
0.366 mmol) was heated in AcOH (10 ml) and 6 M HCl (10 ml) at 50 °C for
3 d. The reaction mixture was concentrated under reduced pressure. Addi-
tion of water (10 ml) to the residue and concentration of the solution were
repeated three times. The residual solid was recrystallized from water to give
1
amino acid 1 (45 mg, 85%) as colorless prisms, mp 187 °C (dec.). H-NMR
(1 M DCl) d: 3.94 (1H, ddd, Jꢂ9.9, 9.9, 5.9 Hz, 3-H), 4.11 (1H, dd, Jꢂ11.0,
5.9 Hz, 4-Hb), 4.31 (1H, dd, Jꢂ11.0, 9.9 Hz, 4-Ha), 5.39 (1H, d, Jꢂ9.9 Hz,
2-H). 13C-NMR (1 M DCl) d: 36.20 (d), 43.12 (t), 55.81 (d), 165.33 (s),
neat
169.38 (s). IR n
cmꢀ1: 3100 (N–H), 1746, 1640, 1590 (CꢂO). MS (FAB)
max
m/z: 146 (Mꢃꢃ1). Anal. Calcd for C5H7NO4: C, 41.38; H, 4.86; N, 9.65.
Methyl 2-Azabicyclo[2.2.0]hex-5-ene-2-carboxylate (3) This com-
pound was also prepared according to the cited method4) with minor modifi-
cation. A solution of 2 (10.0 g, 71.9 mmol) in dichloromethane (1500 ml)
was irradiated using a high-pressure mercury lamp (Ushio UM452, 450W,
Pyrex filter, under Ar) for 48 h. Removal of the solvent gave a yellow oil,
which was subjected to column chromatography on alumina (ether) to give
3 (8.50 g, 85%) as a pale yellow oil. 1H-NMR (CDCl3) d: 3.67 (3H, m,
OCH3), 3.27—4.17 (3H, m, CH2, 4-H), 4.73—4.93 (1H, m, 1-H), 6.43—
6.63 (2H, m, olefinic H).
Found: C, 41.08; H, 4.78; N, 9.47.
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mg, 3.59 mmol) in AcOEt (30 ml), RuO2·xH2O (5 mg), and a 10% NaIO4
solution (43 ml) were mixed and then vigorously stirred at 0 °C for 80 h. The
AcOEt layer was separated and the aqueous layer was saturated with NaCl,
then extracted with AcOEt (50 mlꢁ10). Isopropyl alcohol (2 ml) was added
to the combined AcOEt layers and the solution was left to stand for 2 h. The
precipitated RuO2 was filtered off and the solution was concentrated under
reduced pressure. The residue was dissolved in MeOH (10 ml) and treated
with diazomethane. The solution was concentrated under reduced pressure
and the residual yellow oil was dissolved in CHCl3 (30 ml). The solution was
washed with 2% aqueous NaS2O3 and dried over anhydrous Na2SO4, then
concentrated under reduced pressure to give a colorless oil. This oil was then
subjected to column chromatography on silica gel (ether : hexaneꢂ1 : 1—
1
2 : 1) to give 4 (482 mg, 58%) as a colorless oil. H-NMR (CDCl3) d: 3.69
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(3H, s, OCH3), 3.72 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.71—3.80 (1H, m,
3-H), 4.11 (1H, t, Jꢂ8.6 Hz, 4-Ha), 4.32 (1H, dd, Jꢂ8.6, 6.6 Hz, 4-Hb), 4.87
(1H, d, Jꢂ9.5 Hz, 2-H). 13C-NMR (CDCl3) d: 36.04 (d), 50.49 (t), 52.49 (q),