A short synthesis of γ-amino acids from nitrones; synthesis of Vigabatrin

Article abstract of DOI:10.1055/s-2001-9758

Treatment of the γ-N-hydroxylamino-α,β-acetylenic esters, obtained by the reaction of nitrones with alkyl 3-lithiopropiolates, with H₂ over Raney nickel, followed by in situ protection of the formed amines, gives N-Boc-γ-amino esters. This meth

Full text of DOI:10.1055/s-2001-9758

150
PAPER
A Short Synthesis of g-Amino Acids from Nitrones; Synthesis of Vigabatrin®
Christelle Dagoneau, Axel Tomassini, Jean-Noël Denis, Yannick Vallée*
L.E.D.S.S., CNRS - Université Joseph Fourier, B.P. 53, 38041 Grenoble, France
Fax +33(4)76514382; E-mail: Yannick.Vallee@ujf-grenoble.fr
Received 22 July 2000; revised 7 September 2000
(Scheme 2). Yields of isolated N-hydroxyamino com-
Abstract: Treatment of the g-N-hydroxylamino-a,b-acetylenic
pounds 3 are summarized in Table 1.
esters, obtained by the reaction of nitrones with alkyl 3-lithiopro-
piolates, with H2 over Raney nickel, followed by in situ protection
of the formed amines, gives N-Boc-g-amino esters. This method has
been applied to a synthesis of (S) and (R)-Vigabatrin®.
Key words: nitrones, g-amino acids, Vigabatrin,® 3-lithiopro-
piolates
g-Aminobutyric acid (GABA) is a major neurotransmit-
ter, known to have a beneficial effect against epilepsy. It
is degraded by the enzyme GABA-transaminase and
Scheme 2
when its concentration in the brain falls under a threshold
level, epileptic seizures appear.1 Various GABA-analogs
The direct reduction of g-N-hydroxyamino-a,b-acetylenic
have been synthesized and tested as GABA-transaminase
inhibitors, the most important being Vigabatrin® [(S)-4-
amino-5-hexenoic acid]2 and 4-amino-5-hexynoic acid.3
In this communication, we present a short synthesis of g-
amino esters, and its application to the synthesis of Vi-
gabatrin® and of its enantiomer.
esters into saturated amino esters requires the cleavage of
the N-O bond and the dihydrogenation of the C∫C triple
bond. Furthermore, if R3 is a benzyl group, it can be ex-
pected that the needed reductive conditions will also
cleave the N-R3 bond and liberate the free amine.
We found that the expected saturated amines were formed
when the acetylenic compounds 3 were treated with hy-
drogen (45-50 atmospheres) over Raney Nickel (Scheme
3). However, as these g-amino esters can readily undergo
self-condensations to lactams or polymerization, we pre-
ferred to isolate them as their N-Boc protected derivatives
4. The protection was effected in situ. Compounds 4 were
isolated in medium to good yields (Table 2).
We have recently reported that the reaction of alkyl
3-lithiopropiolates with nitrones leads to g-N-hy-
droxyamino-a,b-acetylenic esters (Scheme 1).4 These
compounds are efficient precursors for a,b-ethylenic and
a,b-dihydroxy-g-amino esters.4-6 We have now found
that they can be reduced in one pot into saturated g-amino
esters.
Scheme 3
Merino et al.6 and our team4 reported that the reaction of
lithiopropiolates with a-chiral nitrones is highly stereose-
lective. This was the case for the reactions presented in
entries 6-9 of Table 1. In each case, only one diastereoi-
somer was obtained. These compounds were attributed a
syn structure by comparison with Merino's results.6 Appli-
cation of the procedure described above to these com-
pounds gave the corresponding Boc-amino esters in good
yields (Table 2, entries 6-9). Interestingly, compound 5,
a diastereoisomer of 4af, has already been described as an
intermediate in a synthesis of Vigabatrin®.7,8 The overall
yield of 4ad from the nitrone 2d was 68%. The previously
Scheme 1
A series of g-N-hydroxyamino-a,b-acetylenic esters were
prepared by condensation of the lithiated anion of propi-
olate esters 1a,b with nitrones 2a-f at -78 °C in THF
Synthesis 2001, No. 1, 150–154 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Short Synthesis of g-Amino Acids from Nitrones; Synthesis of Vigabatrin“
151
Table 1 Synthesis of Compounds 3
Entry
Propiolate
R1
Nitrone
R2
R3
Time (h)
Product
Yield (%)
1
2
3
4
5
6
1a
1b
1a
1b
1b
1a
Me
But
Me
But
But
Me
2a
2a
2b
2b
2c
2d
Et
Bn
Bn
Bn
Bn
Bn
Bn
1.5
3
1
1.66
2.5
1.5
3aa
3ba
3ab
3bb
3bc
3adb
69
77
65
94
60
88
Et
Pri
Pri
Bui
7
8
9
1b
1b
1a
But
But
Me
2d
2e
2f
–
–
Bn
1.5
1.5
1.5
3bdb
3beb
3afb
88
50
94
2,4-DMBa
Bn
a 2,4-DMB: 2,4-dimethoxybenzyl.
b Only the syn isomer was obtained.
reported synthesis of 57 was done in 4 steps and in 45%
yield from the epoxy alcohol 6. Cleavage of the isopropyl-
idene protection followed by reductive elimination of the
two hydroxy groups of diol 7 gave the methyl ester of N-
Boc-(S)-Vigabatrin 8. The deoxygenation was effected by
a one pot procedure (PPh3, I2, imidazole) which we found
more convenient than the two steps protocol used by
Pericas et al.7 Compound 8 was deprotected under acidic
conditions to give (S)-Vigabatrin 9 (Scheme 4). A similar
synthetic sequence starting from nitrone 2d afforded
(R)-9.
Mps were obtained with a Büchi-Tottoli apparatus and are uncor-
rected. IR spectra were recorded (neat) on a Nicolet Impact 400
1
spectrophotometer. H and 13C NMR spectra were recorded on
Brucker AC200, AM300, Avance 300 spectrometers or a Varian
Unit+500 spectrometer using (unless otherwise stated) CDCl3 as
solvent and TMS as an internal standard. Chemical shifts (d) are re-
ported in ppm and coupling constants (J) are in Hz. Mass spectra
were carried out on a Nermag R10 mass spectrometer (CI or CDI).
Microanalyses were performed by the “ Service Central d’Analyse
du CNRS”.
Scheme 4
THF was distilled from sodium-benzophenone and CH2Cl2 on
CaH2. Raney Nickel was prepared as described in ref.9 It was
washed four times with H2O at reflux and then four times with THF
before use. Nitrones 2a-e were prepared according to a known pro-
cedure.10 Nitrones 2a-d4,6,10 were previously known.
Table 2 Synthesis of Compounds 4
Entry
Reactant
Time (h)
Product
Yield (%)
(Z)-N-(1-Deoxy-2,3-O-isopropylidene-D-glycero-1-yliden)-2,4-
dimethoxybenzylamine N-oxide (2e)
Yield: 85%.
1
2
3
4
5
6
7
8
9
3aa
24
24
24
24
16
24
24
40
24
4aa
67
79
71
75
69
77
80
65
67
3ba
3ab
3bb
3bc
4ba
4ab
4bb
4bc
Mp: 40-41 °C.
[a]D +72.5° (c 3.2, CHCl3).
3ada
3bda
3bea
3afa
4ada
4bda
4bda
4afa
IR (NaCl, film): 3100, 2995, 2840, 1615, 1590, 1510, 1470, 1440,
1415, 1380, 1375, 1335, 1295, 1265, 1205, 1160, 1135, 1060, 1035,
930, 850, 755 cm-1.
1H NMR (500 MHz): d = 1.36 (s, 3H, CH3), 1.38 (s, 3H, CH3), 3.82
(s, 3H, CH3O), 3.83 (s, 3H, CH3O), 3.86 (dd, 1H, J = 5.9, 8.6 Hz,
a Syn isomer.
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152
C. Dagoneau et al.
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Table 3 Physical and Spectroscopic Data of Compounds 3 and 4a
Pro- Mp
duct (°C)
IR (neat)
1H NMR (300 MHz, 400 MHz or 500 13C NMR (CDCl3, TMS) d
MHz, CDCl3, TMS) d, J (Hz)
MS (DCI, NH3 + [a]D
n (cm-1)
i-C4H12) m/z
(c, solvent)
3aad 73–
3485 (NOH), 1.01 (t, 3 H, J = 7.4, CH3), 1.65-1.85 10.7 (CH3), 25.8 (CH2), 52.7
248 (MH+), 229
(M+-H2O), 217
(MH+-MeO)
–
74
2235 (C∫C),
(m, 2 H, CH2), 3.48 (t, 1 H, J = 7.4,
(OCH3), 60.3 (CHN), 61.6
1715 (CO2)
CHN), 3.79 (s, 3 H, CO2Me), 3.93
(CH2Ph), 78.2 and 85.4 (C∫C),
(ABq, 2 H, JAB = 12.8, dA-dB = 56.8, 127.6 (CH), 128.4 (CH), 129.6
CH2), 5.53 (s, 1 H, OH), 7.20-7.48 (m, (CH), 136.7 (C), 153.8 (CO2)
5 H)
3abe Oil
3475 (NOH), 1.02 (d, 3 H, J = 6.9, CH3), 1.06 (d, 3 H, 19.7 (CH3), 19.8 (CH3), 30.5 (CH), 262 (MH+)
–
2230 (C∫C),
1715 (CO2)
J = 6.9, CH3), 2.00-2.13 [m, 1 H,
CH(CH3)2], 3.20 (d, 1 H, J = 8.9,
52.6 (CH3O), 61.8 (CH2), 65.4
(CH), 78.8 and 85.0 (C∫C), 127.5
CHN), 3.79 (s, 3 H, OCH3), 3.95 (ABq, (CH), 128.3 (CH), 129.4 (CH),
2H, JAB = 12.8, dA-dB = 105.5, CH2Ph), 137.0 (C), 153.9 (CO2)
5.01 (br s, 1 H, NOH), 7.22-7.42 (m, 5
H)
3bad 92–
3250 (NOH), 1.05 (t, 3 H, J = 7.4, CH3), 1.52 (s, 9 H, 10.8 (CH3), 26.0 (CH2), 28.0
290 (MH+), 274, –
93
2225 (C∫C),
1705 (CO2)
t-Bu), 1.82-1.89 (m, 2 H, CH2), 3.58 [(CH3)3C], 60.4 (CHN), 61.8
(t, 1 H, J = 7.4, CHN), 3.99 (ABq, 2 H, (CH2Ph), 79.9, 82.4 and 83.4
JAB = 13.0, dA-dB = 79.0, CH2Ph), 4.59 [C(CH3)3 and C∫C], 127.5 (CH),
272, 250, 234
(s, 1 H, NOH), 7.27-7.41 (m, 5 H)
128.4 (CH), 129.4 (CH), 137.1 (C),
152.5 (CO2)
3bbf 114
3bcf Oil
3adf Oil
3480 (NOH), 1.04 (d, 3 H, J = 6.8, CH3), 1.07 (d, 3 H, 19.8 [(CH3)2C], 28.0 [(CH3)3C],
304 (MH+), 248
–
–
2235 (C∫C),
1715 (CO2)
J = 7.2, CH3), 1.52 (s, 9 H, t-Bu), 1.97- 30.6 (CH), 61.9 (CH2), 65.5 (CH),
2.20 [m, 1 H, CH(CH3)2], 3.23 (d, 1 H, 80.6, 81.8 and 83.3 [C(CH3)3 and
J = 8.9, CHN), 3.98 (ABq, 2 H, JAB
=
C∫C], 127.4 (CH), 128.4(CH),
13.0, dA-dB = 58.6, CH2Ph), 4.74 (br s, 129.3 (CH), 137.1 (C), 152.5 (CO2)
1 H, NOH), 7.21-7.43 (m, 5 H)
3420 (NOH), 0.89 (d, 3 H, J = 6.5, CH3), 0.91 (d, 3 H, 22.2 (CH3), 22.4 (CH3), 24.9
318 (MH+)
320 (MH+)
2230 (C∫C),
1720 (CO2)
J = 6.5, CH3), 1.40-2.02 (m, 3 H, CH [(CH3)3C], 28.3 (CH), 41.3 (CH2),
and CH2), 1.52 (s, 9 H), 3.74 (psuedo t, 56.9 (CHN), 61.7 (CH2), 79.8, 82.6
1 H, J = 7.2 and 7.8, CHN), 3.98 (ABq, and 83.3 [C(CH3)3 and C∫C], 127.5
2 H, JAB = 13.0, dA-dB = 48.7, CH2Ph), (CH), 128.4 (CH), 129.4 (CH),
4.63 (s, 1 H, NOH), 7.22-7.45 (m, 5 H) 137.0 (C), 152.5 (CO2)
3405 (NOH), 1.33 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 25.5 (CH3), 26.6 (CH3), 52.9
–46.3
(1.3,
2235 (C∫C),
1725 (CO2)
3.76 (M of ABMX, d, 1 H, J = 6.9,
CH), 3.81 (s, 3 H, MeO), 4.01 (ABq, 67.1 (CH2), 75.3 (CH), 79.5 and
2 H, JAB = 12.5, dA-dB = 50, CH2Ph, 81.6 (C∫C), 109.9 [(CH3)2C], 127.9
4.06 (AB of ABMX, 2 H, JAB = 8.9, JAM (CH), 128.6 (CH), 129.6 (CH),
(CH3O), 60.6 (CH), 62.6 (CH2),
CHCl3)b
= 5.5, JBM = 6.2, CH2O), 4.44 (X of
ABMX, psuedo q, 1 H, Jobs = 5.8 and
13, CHO), 5.60 (s, 1 H, NOH), 7.20-
7.46 (m, 5 H)
135.7 (C), 153.4 (CO2)
3bdg Oil
3400 (NOH), 1.34 (s, 6 H, 2CH3), 1.50 (s, 9 H, t-Bu), 25.6 (CH3), 26.6 (CH3), 28.0
362 (MH+), 344, –41
2235 (C∫C),
1705 (CO2)
3.77 (M of ABMX, d, 1 H, J = 5.0,
[(CH3)3C], 60.6 (CH), 62.5 (CH2), 239, 220
(1.0,
CHCl3)
CH), 4.05 (ABq, 2 H, JAB = 12.7, dA-dB 67.2 (CH2), 75.3 (CH), 78.6, 81.2
= 134.3, CH2Ph), 4.06 (AB of ABMX, and 83.7 [C(CH3)3 and C∫C], 109.9
2 H, JAB = 8.9, JAM = 5.9, JBM = 6.2,
[(CH3)2C], 127.8 (CH), 128.5
CH2), 4.40 (X of ABMX, psuedo q,
(CH), 129.6 (CH), 135.8 (C), 152.1
1 H, Jobs = 6.2 and 12.8, CHO), 4.97 (s, (CO2)
1 H, NOH), 7.23-7.38 (m, 5 H)
3bed 46–
3495 (NOH), 1.26 (s, 6 H, 2CH3), 1.44 (s, 9 H, t-Bu), 25.7 (CH3), 26.5 (CH3), 28.0
422 (MH+), 151 –47.7
47
2240 (C∫C),
1705 (CO2)
3.71 (s, 3 H, CH3O), 3.73 (s, 3 H,
CH3O), 3.70-3.77 (m, 1 H, CHN),
[(CH3)3C], 56.6 (2 CH3O), 57.8
(CH2), 60.5 (CH2), 67.2 (CH2),
(1.5,
CHCl3)
3.97 (ABq, 2 H, JAB = 13, dA-dB = 33.6, 79.3, 81.0 and 83.4 [C(CH3)3 and
CH2Ph), 3.92-3.97 (m, 1 H, CH2O),
C∫C], 98.5 (CH), 104.1 (CH),
4.00-4.06 (m, 1 H, CH2O), 4.28 (psue- 109.5 [(CH3)2C], 116.4 (C), 132.4
do q, 1 H, CHO), 6.00 (s, 1 H, NOH), (CH), 152.2 (CO2), 159.1 (C),
6.34-6.36 (m, 2 H), 7.16-7.20 (m,
1 H)
160.1 (C)
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A Short Synthesis of g-Amino Acids from Nitrones; Synthesis of Vigabatrin“
153
Table 3 (continued)
Pro- Mp
duct (°C)
IR (neat)
1H NMR (300 MHz, 400 MHz or 500 13C NMR (CDCl3, TMS) d
MHz, CDCl3, TMS) d, J (Hz)
MS (DCI, NH3 + [a]D
n (cm–1)
i-C4H12) m/z
(c, solvent)
4aad 39–
3360 (NH),
1740 and
0.92 (pst, 3 H, J = 7.2 and 7.5, CH3), 10.0 (CH3), 28.2 [(CH3)3C], 28.3
1.26-1.97 (m, 4 H, 2 CH2), 1.44 (s, 9 H, (CH2), 29.9 (CH2), 30.6 (CH2), 51.3 190, 146, 116
246 (MH+), 207, –
40
1690 (2 CO2) t-Bu), 2.38 (t, 2 H, J = 7.5, CH2), 3.38– (CH3O), 51.6 (CH), 78.6 [(CH3)3C],
3.60 (m, 1 H, CHN), 3.67 (s, 3 H,
155.6 (NHCO2), 173.8 (CO2)
MeO), 4.28 (d, 1 H, J=9.2, NH)
4abf 64–
3350 (NH),
1730 and
0.89 (d, 3 H, J = 6.9, CH3), 0.91 (d, 3 17.7 (CH3), 18.9 (CH3), 27.5 (CH2), 260 (MH+), 204, –
65
H, J = 6.9, CH3), 1.43 (s, 9 H, t-Bu), 28.3 [(CH3)3C], 31.1 (CH2), 32.5
160, 128, 116
1695 (2 CO2) 1.50–1.96 (m, 3 H, CH and CH2), 2.38 (CH), 51.5 (CH3O), 55.3 (CHN),
(t, 2 H, J = 7.5, CH2), 3.30–3.54 (m, 1 78.8 [(CH3)3C], 155.9 (NHCO2),
H, CHN), 3.68 (s, 3 H, MeO), 4.30 (d, 174.1 (CO2)
1 H, J = 9.6, NH)
4baf 66-–
3340 (NH),
1730 and
0.91 (pst, 3 H, J = 7.2 and 7.5, CH3), 10.1 (CH3), 28.0 [(CH3)3C], 28.3
1.35–1.90 (m, 4 H, 2 CH2), 1.44 (s, 9H, [(CH3)3C], 28.5 (CH2), 29.7 (CH2), 193, 176, 130,
114, 102
288 (MH+), 232, –
67
1690 (2 CO2) t-Bu), 1.45 (s, 9 H, t-Bu), 2.28 (t, 2 H, 32.2 (CH2), 51.7 (CH), 78.7
J = 7.5, CH2), 3.30–3.60 (m, 1 H,
CHN), 4.32 (d, 1 H, J = 9.2, NH)
[(CH3)3C], 80.1 [(CH3)3C], 155.7
(NHCO2), 172.9 (CO2)
4bbf 62–
3345 (NH),
1710 and
0.88 (d, 3 H, J = 6.9, CH3), 0.91 (d, 3 17.8 (CH3), 18.9 (CH3), 27.2 (CH2), 302 (MH+), 277, –
63
H, J = 6.9, CH3), 1.40–1.90 (m, 3 H, 28.1 [(CH3)3C], 28.4 [(CH3)3C],
246, 190, 128,
102
1695 (2 CO2) CH and CH2), 1.43 (s, 9 H, t-Bu), 1.45 32.6 (CH and CH2), 55.5 (CHN),
(s, 9 H, t-Bu), 2.28 (pst, 2 H, J = 7.2
and 7.5, CH2), 3.30–3.51 (m, 1 H,
CHN), 4.33 (d, 1 H, J = 11.0, NH)
78.9 [(CH3)3C], 80.2 [(CH3)3C],
156.0 (NHCO2), 173.1 (CO2)
4bcf 50–
3350(NH),
1730 and
0.91 (d, 6 H, J = 6.5, 2CH3), 1.15–1.35 22.3 (CH3), 23.0 (CH3), 24.9 (CH), 316 (MH+), 260, –
(m, 2 H, CH2), 1.35–1.90 (m, 3 H, CH 28.1 [(CH3)3C], 28.4 [(CH3)3C], 221, 204, 158,
52
1695 (2 CO2) and CH2), 1.43 (s, 9 H, t-Bu), 1.44 (s, 9 31.0 (CH2), 32.2 (CH2), 45.2 (CH2), 142, 102
H, t-Bu), 2.27 (pst, 2 H, J = 7.2 and 7.5, 48.5 (CHN), 78.8 [(CH3)3C], 80.1
CH2), 3.48-3.76 (m, 1 H, CHN), 4.23 [(CH3)3C], 155.6 (NHCO2), 173.0
(d, 1 H, J=9.6, NH)
(CO2)
4adg 62–
3370 (NH),
1740 and
1.31 (s, 3 H, CH3), 1.40 (s, 3 H, CH3), 25.0 (CH3), 26.2 (CH3), 28.3
1.41 (s, 9 H, t-Bu), 1.80–1.91 (m, 2 H, [(CH3)3C], 28.7 (CH2), 30.7 (CH2), 262, 218, 116
318 (MH+), 279, +38.6
63
(1.02,
1705 (2 CO2) CH2), 2.40 (t, 2 H, J = 7.5, CH2CO2), 50.2 (CH), 51.6 (CH3O), 66.3
3.63 (pst, 1 H, J = 7.5 and 7.9, CH2O), (CH2), 77.4 (CH), 79.5 [(CH3)3C],
3.61–3.72 (m, 1 H, CHN), 3.65 (s, 3 H, 109.2 [(CH3)2C], 156.1 (NHCO2),
CHCl3)c
MeO), 3.98 (dd, 1 H, J = 6.8, 9.1,
CH2O), 4.12 (t, 1 H, J = 6.3, CHO),
4.63 (d, 1 H, J = 9.8, NH)
173.6 (CO2)
4bdg 78–
3420 (NH),
1725 and
1.31 (s, 3 H, CH3), 1.39 (s, 3 H, CH3), 25.0 (CH3), 26.2 (CH3), 28.1
1.41 (s, 9 H, t-Bu), 1.42 (s, 9 H, t-Bu), [(CH3)3C], 28.3 [(CH3)3C], 28.5
360 (MH+), 304, +34
79
248, 102
(0.55,
1700 (2 CO2) 1.74–1.85 (m, 2 H, CH2), 2.29 (t, 2 H, (CH2), 32.1 (CH2), 50.1 (CH), 66.3
CHCl3)
J = 7.5, CH2), 3.60–3.70 (m, 1 H,
CHN), 3.63 (dd, 1 H, J = 7.2, 8.2,
CH2O), 3.97 (dd, 1 H, J = 6.7, 8.2,
CH2O), 4.11 (psuedo t, 1 H, J = 5.9 and
6.5, CHO), 4.63 (d, 1 H, J = 9.7, NH)
(CH2), 77.4 (CH), 79.4 and 80.3
[(CH3)3C], 109.1 [(CH3)2C], 156.1
(NHCO2), 172.6 (CO2)
a Satisfactory microanalyses obtained: C 0.42; H, 0.31; N 0.23 or HRMS obtained (for compounds 3bd and 4bd): 0.0008 amu.
b Similar data obtained for 3af, [a]D +44.8° (c 1.25, CHCl3).
c Similar data obtained for 4af, [a]D –34.8° (c 1.0, CHCl3).
d Data obtained at 300 MHz.
e Data obtained at 400 MHz.
f Data obtained at 200 MHz.
g Data obtained at 500 MHz.
CH2O), 4.40 (dd, 1H, J = 7.1, 8.6 Hz, CH2O), 4.83 (s, 2H, CH2Ph),
5.14 (pseudo tq, 1H, J = 4.7, 5.9, 7.1 Hz, CHO), 6.47 (d, 1H, J = 2.4
Hz, ArH), 6.50 (dd, !H, J = 2.4, 8.3 Hz, ArH), 6.74 (d, 1H, J = 4.7
Hz, CHN), 7.25 (d, 1H, J = 8.3 Hz, ArH).
13C NMR (75.5 MHz): d = 24.5 (CH3), 25.5 (CH3), 54.8 (CH3O),
54.8 (CH3O), 62.9 (CH2), 67.3 (CH2), 71.6 (CH), 98.2 (CH arom.),
104.2 (CH arom.), 109.0 [(CH3)2C], 112.5 (C arom.), 132.2 (CH
arom.), 137.6 (CHN), 158.4 (C arom.), 161.5 (C arom.).
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Anal. Calcd for C15H21NO5: C, 61.00; H, 7.17; N, 4.74. Found: C,
60.92; H, 7.07; N, 4.79.
CH2Cl2/Et2O, 9:1) to afford compound 8 (56 mg, 0.229 mmol, 88%
yield) as a white solid. The obtained NMR and IR spectra were in
agreement with the data reported for N-Boc-(S)-Vigabatrin methyl
ester.7 [a]D +12.5° (c 1, CHCl3), [Lit.7: [a]D +11.4° (c 1, CHCl3)].
g-N-Hydroxyamino-a,b-acetylenic Esters 3; General Procedure
A solution of n-BuLi in hexane (1.33-1.6 M, 1.4 mmol) was added
to a magnetically stirred solution of alkyl propiolate 1 (1.5 mmol)
in dry THF (10 mL) at -78 °C under Ar. The reaction mixture was
stirred for 1 h at that temperature and a solution of nitrone 2
(1 mmol) in dry THF (1 mL) was then slowly added. The evolution
of the reaction was monitored by TLC (EtOAc). After stirring for
1-3 h at -78 °C, the reaction was quenched with H2O and was al-
lowed to warm to r.t. The aqueous phase was extracted three times
with CH2Cl2. The organic layer was washed with brine, dried
(MgSO4), filtrated, and the solvents were evaporated under reduced
pressure. The crude product was purified by column chromatogra-
phy (silica gel, EtOAc/pentane, 1:9) to yield hydroxylamine 3 (Ta-
bles 1, 3).
(S)-Vigabatrin 9
N-Boc-(S)-Vigabatrin (35 mg, 0.144 mmol) was stirred into a mix-
ture of glacial HOAc (0.4 mL) and 37% HCl (0.5 mL) at 60 °C for
12 h. The mixture was then concentrated under vacuum and the re-
sulting material was passed through a column of Dowex 50W ion
exchange resin (4 g, 50/100 mesh, H+ form), eluting with H2O (dis-
carded) and then 2 N NH4OH. Evaporation of the latter provided
(S)-Vigabatrin (12 mg, 65% yield). The NMR and IR spectra were
in agreement with the literature data.2
Acknowledgement
We thank Mrs Pascale Cividino for her help in the hydrogenation
procedure.
g-Amino Esters 4; General Procedure
In a steel reactor were added Raney Nickel (approx. 1 g) as a sus-
pension in anhyd THF (70 mL), g-N-hydroxyamino-acetylenic ester
3 in THF (5 mL) and di-tert-butyldicarbonate (1.1 equiv) in THF
(5 mL). The reactor was purged with H2 during 10 min. The mixture
was placed under pressure (45-50 atm.), warmed to 90 °C, and
stirred for a period of time (16-40 h, Table 2). After removal of the
catalyst by decantation and evaporation of THF under reduced pres-
sure, the resulting crude product was purified by column chroma-
tography (silica gel, EtOAc/pentane, 1:9) to yield pure g-amino
esters 4 (Tables 2, 3).
References and Notes
(1) Delgado-Escueta, A. V.; Ward, A. A., Jr.; Woodbury, D. M.;
Porter, R. J. Basic Mechanisms of the Epilepsies; Raven Press,
New York, 1986; pp 365-378.
(2) Wei, Z. -Y.; Knaus, E. E. Tetrahedron 1994, 50, 5569.
(3) Burke, J. R.; Silverman, R. B. J. Am. Chem. Soc. 1991, 113,
9329.
(4) Denis, J. -N.; Tchertchian, S.; Tomassini, A.; Vallée, Y.
Tetrahedron Lett. 1997, 38, 5503.
(5) Dagoneau, C.; Denis, J. -N.; Vallée, Y. Synlett 1999, 602.
(6) Merino, P.; Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1998, 9, 1759.
(7) Alcòn, M.; Poch, M.; Moyano, A.; Pericàs, M. A.; Riera, A.
Tetrahedron: Asymmetry 1997, 8, 2967.
Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synlett
2000, 442.
(8) Other syntheses of Vigabatrin: Trost, B. M.; Lemoine, R. C.
Tetrahedron Lett. 1996, 37, 9161.
(R)-N-Boc-4-amino-5-hexenoic Acid Methyl Ester (8)
To a magnetically stirred solution of compound 4af (177 mg,
0.558 mmol) in MeOH (6 mL) was added p-toluene sulfonic acid
(21 mg, 0.112 mmol). After 30 min at r.t., sat. NaHCO3 (2 mL) was
added and MeOH was eliminated in vacuo. The resulting aqueous
solution was extracted with CH2Cl2. The combined organic phases
were washed with brine, dried (MgSO4), and concentrated in vacuo.
The crude product was purified by column chromatography
(silica gel, EtOAc/pentane, 4:1) to afford compound 7 (110 mg,
0.396 mmol, 71% yield) as an oil.
Wei, Z. -Y.; Knaus, E. E. Synlett 1994, 345.
Margolin, A. L. Tetrahedron Lett. 1993, 34, 1239.
Wei, Z. -Y.; Knaus, E. E. J. Org. Chem. 1993, 58, 1586.
Kwon, T. W.; Keusenkothen, P. F.; Smith, M. B. J. Org.
Chem. 1992, 57, 6169.
7:
1H NMR (CDCl3, 200 MHz): d = 1.44 (s, 9H, t-Bu), 1.80-2.00 (m,
2H, CH2), 2.44 (t, 2H, J = 7.5 Hz, CH2), 2.71 (br s, 1H, OH), 3.12
(br s, 1H, OH), 3.40-3.70 (m, 7H), 4.83 (d, 1H, J = 9.9 Hz,
NHBoc).
Synthesis of racemic Vigabatrin: Casara, P. Tetrahedron Lett.
1994, 35, 3049.
To a magnetically stirred solution of diol 7 (71 mg, 0.26 mmol) in
anhyd toluene (10 mL) was added imidazole (71 mg, 1.04 mmol)
and Ph3P (272 mg, 1.04 mmol). The resulting mixture was refluxed
and I2 (66 mg, 0.261 mmol) was added in portions. The mixture was
refluxed for 3 h, whereupon it was allowed to cool to r.t. and was
treated with I2 (66 mg, 0.26 mmol) and NaOH (1.4 M, 1.5 mL). Af-
ter the disappearance of the red solid, H2O was added to the mixture.
The organic phase was washed with an aqueous solution of sodium
thiosulfate, dried (MgSO4), and concentrated in vacuo. The crude
product was purified by column chromatography (silica gel,
(9) Sane, S.; Bonnier, J. M.; Damon, J. P.; Masson, J. Appl. Catal.
1984, 9, 69.
(10) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.; Merino,
P.; Tejero, T. Synth. Commun. 1994, 24, 2537.
Article Identifier:
1437-210X,E;2001,0,01,0150,0154,ftx,en;Z06500SS.pdf
Synthesis 2001, No. 1, 150–154 ISSN 0039-7881 © Thieme Stuttgart · New York