Towards a synthesis of vigabatrin using glycal chemistry

Article abstract of DOI:10.3390/10080871

Application of the Ferrier rearrangement led to a novel carbohydrate based synthetic route to 4-aminohexenoic acid viz. (R) and (S)-vigabatrin. The potential of D-glucose or D-galactose as the chiral starting materials for the synthesis of (R) and (S)-vig

Full text of DOI:10.3390/10080871

Molecules 2005, 10, 871-883
molecules
ISSN 1420-3049
http://www.mdpi.org
Towards a Synthesis of Vigabatrin Using Glycal Chemistry
Sobhana B. Boga, Jaimala S. Aidhen and Indrapal S. Aidhen*
Department of Chemistry, Indian Institute of Technology, Madras, Chennai-600 036, India, Tel. 2257
8263, Fax 2235 0509.
* Author to whom correspondence should be addressed; e-mail isingh@iitm.ac.in
Received: 24 October 2004; in revised form: 8 December 2004 / Accepted: 7 January 2005 /
Published: 31 August 2005
Abstract: Application of the Ferrier rearrangement led to a novel carbohydrate based
synthetic route to 4-aminohexenoic acid viz. (R) and (S)-vigabatrin. The potential of D-
glucose or D-galactose as the chiral starting materials for the synthesis of (R) and (S)-
vigabatrin has been explored.
Keywords: Vigabatrin, GABA-T, γ-aminobutyric acid, 4-amino-5-hexenoic acid, Ferrier
rearrangement, glycal.
Introduction
γ-Aminobutyric acid (GABA) is the vital inhibitory neurotransmitter in the mammalian central
nervous system [1]. It was found that 4-amino-5-hexenoic acid (γ-vinyl GABA, vigabatrin, 1) is one of
the most effective and selective catalytic inhibitors of GABA-T.
Inhibition of this enzyme results in an increase in the levels of GABA and could have therapeutic
applications in neurological disorders including epilepsy [2], Parkinson’s disease [3], Huntington’s
chorea [4] and Alzheimer’s disease [5]. Recently it has been found that an increase in GABA also
blocks the effect of drug addiction to nicotine and cocaine [6]. Vigabatrin (1), not a complex chiral
molecule, is already marketed in its racemic form as Sabril® in Europe [7], and has evoked
considerable interest among organic chemists and medicinal chemists as an attractive synthetic target.
Since vigabatrin has a chiral center at C-4, two enantiomers are possible viz. (R)-vigabatrin and
(S)-vigabatrin. It has been found that the (S)-enantiomer is pharmacologically active. Several methods
have been reported for the synthesis of enantiomerically pure 1 and most of these employ natural α-
amino acids viz., L-glutamic acid, regioselective ring opening of an enantiomerically enriched epoxy
alcohol (obtained through Sharpless epoxidation), the Pd(0)-catalyzed deracemization reaction and

Molecules 2005, 10
872
Sharpless asymmetric aminohydroxylation [8]. The vinyl moiety was then introduced by pyrolysis of
an N-oxide or an ester or through a Wittig reaction. While many syntheses of racemic and
enantiomerically pure vigabatrin are known, the potential of D-glucose or D-galactose as the chiral
starting materials for the synthesis of (R) and (S)-vigabatrin has not been explored. Herein we disclose
our results in this area.
1
1
3
3
5
5
4
γ4
2
α
2
α
CO2
CO2
β
NH3
β
NH3
γ
1
1
(S)-vigabatrin
(R)-vigabatrin
The synthesis of the target molecule vigabatrin (1) was visualized as starting from the 2,3-
unsaturated methylglycoside (3), obtained via Ferrier rearrangement of tri-O-acetyl-D-glucal (2) [9].
The 5-amino functionality could be introduced by a SN2 displacement of the mesylate by azide ion and
subsequently the vinyl group could be constructed by fragmentation of 6-bromo-6-deoxyglycosides
with Zn or n-BuLi - the Vasella reaction [10]. The complete retrosynthetic analysis of (R)-vigabatrin is
outlined in Scheme 1.
Scheme 1.
BOC
HN
Br
O
N3
Br
O
R2
R1
COO-
OCH3
OCH3
1
+
R1= NH3 ; R2=H; (R) vigabatrin
+
R1= H; R2=NH3 ; (S) vigabatrin
H
Br
O
Br
O
O
O
O
MsO
O
O
OCH3
O
OCH3
OCH3
OAc
O
OAc
O
HO
HO
AcO
AcO
AcO
OCH3
OCH3
Results and Discussion
Methyl-4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside (3), obtained from 3,4,6-tri-
O-acetylglucal 2 [9a] was hydrogenated using Pd/C in MeOH for 1h to afford the saturated derivative
4 in 90% yield. After purification and subsequent hydrolysis of 4, the diol obtained was directly
converted to the benzylidene derivative 5 in 76% yield using benzaldehyde dimethylacetal/cat. PTSA

Molecules 2005, 10
873
in DMF. The benzylidene derivative was fully characterized by spectroscopic techniques. The signal
due to the benzylidene proton appeared as a singlet at δ 5.55 in the 1H-NMR spectrum and that of the
acetal carbon at δ 101.66 in the 13C-NMR spectrum. Compound 5 was subjected to the Hannesian-
Huller reaction [11] using NBS in refluxing CCl4, to furnish the bromobenzoate 6 in 70% yield
(Scheme 2).
Scheme 2.
R2
OAc
O
CH3OH, InCl3, 9a
CH3OH, LiBF4, 9b
OAc
O
R2
R1
OAc
O
Pd / C , H2
rt, 90%
R2
R1
R1
AcO
OCH3
OCH3
R1=OAc, R2=H; 2
R1=H, R2=OAc; 9
R1=OAc, R2=H; 3
R1=H, R2=OAc; 10
R1=OAc, R2=H; 4
R1=H, R2=OAc; 11
H
X
Br
O
R2
R1
1) Na2CO3 / MeOH, 90%
NBS, CCl4
O
O
reflux, 4 h, 70%
2) PhCH(OMe)2, PTSA
DMF, rt, 3 h, 76%
OCH3
OCH3
R1=OCOC6H5, R2=H; 6
R1=H, R2=OCOC6H5; 13
X=O(equatorial); 5
X=O(axial); 12
Br
O
Br
R2
R2
CH3SO2Cl, Et3N
0 oC to rt, 88%
Na2CO3 / MeOH
rt, 24 h, 90%
O
R1
R1
OCH3
OCH3
R1=OH, R2=H; 7
R1=H, R2=OH; 14
R1=OMs, R2=H; 8
R1=H, R2=OMs; 15
The benzoate 6 was hydrolyzed using Na2CO3/MeOH to give methyl-6-bromo-2,3-dideoxy-D-
1
erythro-hexopyranoside (7) in 80% yield as a homogeneous gum (by TLC). The H-NMR and
13C-NMR spectral data were in accordance with the proposed structure. An attempt was made to
introduce the azide group at C-4 with an inversion by a modified Mitsonobu reaction (Scheme 3) using
bis-(p-nitrophenyl)phosphorazidate as reagent [12], however, there was no reaction at either ambient
or elevated temperature (110 oC) and the starting material 7 was recovered.
Having failed to introduce the C-4 azido group by the above methodology, the bromo derivative 7
was converted to the mesylate using mesyl chloride in Et3N. The mesylate 8 was obtained as a viscous
liquid in 82% yield. Again considerable efforts were directed to effect exclusive displacement of the
mesylate group with azide ion to obtain 16, but all were in vain. These reactions were attempted at
different temperatures ranging from 0 oC to 110 oC, and in different solvents viz. DMF and DMSO, as
well as under phase transfer catalyst conditions, but without any success, as invariably, a mixture of
monoazide, diazide and other products was obtained (Scheme 3).

Molecules 2005, 10
874
Scheme 3.
Br
O
R2
R1
p- Nitro DPPA
OCH3
CH2Cl2 / C6H5CH3 / DMF
Br
O
R2
R1=OH, R2=H; 7
R1=H, R2=OH; 14
R1
OCH3
Br
O
R2
R1=H, R2=N3; 16
R1=N3, R2=H; 17
NaN3
R1
OCH3
DMF / DMSO /
C6H5CH2(C2H5)3NBF4, CH2Cl2
R1=OMs, R2=H; 8
R1=H, R2=OMs; 15
From the above observations, it was apparent that there was not much difference in the reactivity
of bromo as a leaving group at C-6 and mesylate at C-4 towards nucleophilic substitution with azide
ion. We then considered the synthesis of the C-4 epimer of the mesylate 8, in the hope that there would
be some steric hindrance for substitution of the Br at C-6 due to the axial mesylate group and this
would result in the selective displacement of the mesylate by azide furnishing the desired 17, a
potential precursor for pharmacologically active (S)-vigabatrin. We thus synthesized the epimeric
mesylate 15 via a similar synthetic sequence as described for the mesylate 8 (Scheme 2). The synthesis
proceeded well in an overall yield of 42% over six steps. All the intermediates leading to 15 were
characterized by IR, 1H-NMR and 13C-NMR spectroscopy. Unfortunately, our attempts to bring about
a selective displacement of the mesylate group in 15 by azide ion to form 17 were also unsuccessful.
Though TLC analysis revealed that the product was homogeneous, giving a close moving non-polar
1
spot but the H-NMR and 13C-NMR spectra indicated it to be a mixture of 4,6-diazide and 6-azide
derivatives.
In retrospect, we realized that selective displacement of the secondary mesylate with azide ion at
C-4, be it axial or equatorial, in the presence of the primary bromide was neither practical nor feasible.
Initial incorporation of the azido group at C-4 and later appropriate functionalisation for the Vasella
reaction [10] should serve as a viable alternative. Accordingly, the synthetic strategy was slightly
modified (Scheme 4).
In the proposed alternative route diacetate 4 was hydrolyzed and the C-6 hydroxyl was selectively
protected as the corresponding trityl ether using Ph3CCl/Et3N in DMF, thus furnishing compound 18 in
70% yield. The trityl ether 18 was again characterized using IR, 1H- and 13C-NMR spectroscopy. Since
we had learned from previous experience that bis (p-nitrophenyl)phophorazidate was not successful in
replacing the C4-OH by an azido group, we did not attempt this reaction on 18. Instead 18 was directly
converted to the mesylate 19 in 80% yield using methanesulfonyl chloride/Et3N in CH2Cl2. The
mesylate 19 underwent a smooth nucleophilic substitution reaction upon treatment with NaN3 in DMF

Molecules 2005, 10
875
o
o
at 110 C and afforded the crystalline (m.p. 69 C), methyl 4-azido-6-triphenylmethyl-2,3-dideoxy-D-
threo-hexopyranoside (20) in 90% yield.
Scheme 4.
OAc
O
OC(Ph)3
O
1) Na2CO3 / MeOH, 90%
CH3SO3Cl / Et3N
0 oC to rt, 87%
OCH3
AcO
HO
2) Ph3CCl / Et3N
DMF, 36 h,70%
OCH3
4
18
N3
OC(Ph)3
O
OC(Ph)3
O
O
S
O
NaN3, DMF
H3C
O
110 oC, 6 h, 90%
OCH3
OCH3
19
20
While the anomeric proton resonated at δ 4.67(d), the signal due to H-4 of 20 was shifted upfield δ
3.87(td). The stereochemistry at C-4 was established from the coupling constants of H-4. The signal
due to H-4 in 19 appeared as a triplet of doublets with J = 9.99Hz and 5.51Hz, whereas the signal due
to H-4 in the azide 20 appeared as a triplet of doublets with smaller coupling constants of 6.1 Hz and
1.47 Hz. The large coupling constant between J4,5 = J3a,4 = 9.99 Hz for H-4 in 19, due to the diaxial
nature of H3a and H5 at C-3 and C-5 disappeared, giving rise to a coupling constant J4,5 and J3a,4 = 6.1
Hz due to the vicinal axial-equatorial relationship existing in 20. Based on this, we infer that
nucleophilic substitution by the azide has taken place with complete inversion at C-4, thus leading to
the threo series.
Scheme 5.
BOC
N3
OC(Ph)3
O
HN
OC(Ph)3
O
10% Pd/ C, H2,
CH3COOH : H2O = 8 : 2
rt, 16 h, 90%
(BOC)2O, EtOAc
rt,12 h, 86%
OCH3
OCH3
20
21
BOC
BOC
HN
Br
+H3N
HN
OH
O
O
COO-
OCH3
OCH3
(R)-vigabatrin 1
22
23
Catalytic reduction of azide 20 over 10% Pd/C and in the presence of (BOC)2O/EtOAc furnished
the protected amine 21 in 86% yield as a semi solid (Scheme 5). Detritylation of 21 proceeded without

Molecules 2005, 10
876
any complications in aq. 80% acetic acid at ambient temperature to furnish methyl 4-(N-t-
butoxycarbonyl)-2,3-dideoxy-D-threo-hexopyranoside (22) in 90% yield.
After successful incorporation of the protected amino functionality at C-4, the conversion of 22 to
the bromo derivative 23 was necessary for effecting the Vasella reaction and arrive at (R)-vigabatrin
(1). This appears to be a straightforward reaction, but various attempts to convert the 6-OH to the
corresponding bromide by CBr4/PPh3 or PBr3/pyridine were all in vain. The lack of reactivity of the 6-
OH in the above reaction may be due to the presence of a bulky axial 4-(N-t-butoxycarbonyl) group at
C-4. The same steric hindrance should be absent in the erythro series, which therefore offers a
rationale and motivation to pursue the synthesis of pharmacologically active (S)-vigabatrin. These
synthetic efforts are currently underway.
Conclusions
Both methyl-4-methanesulfonyl-6-bromo-2,3-dideoxy-D-erythro-hex-2-eno-pyranoside (8) and
methyl-4-methanesulfonyl-6-bromo-2,3-dideoxy-D-threo-hex-2-eno-pyranoside (15) failed to undergo
exclusive mono nucleophilic substitution reaction at C-4 with azide under various conditions. The
successful incorporation of the amino group and arriving at 20 was finally achieved by adopting a
different synthetic sequence, wherein C6-OH is temporarily protected and its derivatization to bromo
derivative is postponed to a later stage. Completion of the synthesis of (R)-vigabatrin and (S)-
vigabatrin is currently underway.
Experimental
General
1H- and 13C-NMR spectra were obtained using a Varian Gemini 200 NMR and were recorded at
200 and 50 MHz respectively. All reagents and chemicals were obtained from Aldrich Chemical
Company (USA) and were used as received unless otherwise noted.
General procedure for the hydrogenation of methyl-4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-
enopyranosid (3) and methyl-4,6-di-O-acetyl-2,3-dideoxy-D-threo-hex-2-enopyranoside(10).
Compounds 3 or 10 (1 mmol) was placed in a 25 mL round bottomed flask. The substrate was
dissolved in methanol (5 mL) and a catalytic amount of 10% Pd/C catalyst was added. Hydrogen gas
was passed through the solution using a balloon. When there was no more uptake of hydrogen (5 h to 6
h), the reaction was stopped and the catalyst filtered. The solvent was evaporated in a rotary
evaporator under reduced pressure to afford methyl-4,6-di-O-acetyl-2,3-dideoxy-D-erythro-
hexopyranoside (4) and methyl-4,6-di-O-acetyl-2,3-dideoxy-D-threo-hexopyranoside (11).
Methyl-4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hexopyranoside (4). Semi-solid; TLC: Rf: 0.7 (hexane-
EtOAc = 7:3); IR (CHCl3) υ (cm-1): 2960, 2848, 1734, 1452, 1360, 1270, 1126, 1084, 1062, 995, 969,
956, 899, 857; 1H-NMR δ (ppm): 1.44-1.99 (m, 4H, H-2a, H-2e, H-3a, H-3e), 1.96 (s, 3H, OCOCH3),
1.98 (s, 3H, -OCOCH3), 3.26 (s, 3H, OCH3), 3.92-4.06 (m, 3H, H-5, H-6a, H-6b), β), 4.65-4.81 (m,

Molecules 2005, 10
877
1H, H-4), 5.20 (bs, 1H, H-1); 13C-NMR δ (ppm): 20.60 (q, -OCOCH3), 20.77 (q, -OCOCH3), 22.51 (t,
C-3), 24.16 (t, C-2), 54.70 (q, -OCH3), 63.61 (t, C-6), 66.67 (d, C-5), 66.96 (d, C-4), 97.88 (d, C-1),
170.48 (s, -OCOCH3), 170.65 (s, -OCOCH3).
Methyl-4,6-di-O-acetyl-2,3-dideoxy-D-threo-hexopyranoside (11). Semi solid; TLC: Rf: 0.7 (hexane-
EtOAc = 7:3); IR (CHCl3) υ (cm-1): 2962, 2848, 1735, 1458, 1368, 1272, 1124, 1088, 1060, h992,
1
966; H-NMR δ (ppm): 1.50-2.00 (m, 4H, H-2a, H-2e, H-3a, H-3e), 2.06 (s, 3H, OCOCH3), 2.11 (s,
3H, -OCOCH3), 3.38 (s, 3H, OCH3), 4.00-4.25 (m, 3H, H-5, H-6a, H-6b), 4.78 (apparent d, J =
1.18Hz, H-4), 4.93 (bs, 1H, H-1); 13C-NMR δ (ppm): 20.53 (q, -OCOCH3), 20.82 (q, -OCOCH3),
22.24 (t, C-3), 23.89 (t, C-2), 54.46 (q, -OCH3), 63.37 (t, C-6), 66.42 (d, C-5), 66.69 (d, C-4), 97.67 (d,
C-1), 170.23 (s, -OCOCH3), 170.41 (s, -OCOCH3).
General procedure for the hydrolysis and subsequent benzylidene protection of methyl-4,6-di-O-
acetyl-2,3-dideoxy-D-erythro-hexopyranoside (4) and methyl-4,6-di-O-acetyl-2,3-dideoxy-D-threo-
hexopyranoside (11) to obtain the corresponding benzylidene acetals
Compounds 4 or 11 (1 mmol) was dissolved in absolute methanol (50 mL) and stirred for 3h at
room temperature with anhydrous sodium carbonate (3 mol). The solids were removed by filtration
and the filtrate was evaporated under reduced pressure to give the crude product, which can be used as
such for benzylidene protection with out any purification. Diols were dissolved in dry DMF (5 mL) in
a two necked round bottomed flask. To this was added benzaldehyde dimethylacetal (1.2 mmol), a
catalytic amount of p-toluene-sulfonic acid (15-25 mg) and the contents stirred at room temperature
(for 3 h in the case of gluco-4, 14 h in the case of galacto-11). The reaction mixture was poured into
cold water (5 mL), stirred for an additional 10 min and the product extracted with hexane (3 x 25 mL),
dried over anhydrous sodium sulphate and concentrated. The residue was purified by flash column
chromatography on silica gel to obtain methyl 4,6-O-benzylidene-2,3-dideoxy-D-erythro-
hexopyranoside (5) and methyl-4,6-O-benzylidene-2,3-dideoxy-D-threo-hexopyranoside (12).
o
Methyl-4,6-O-benzylidene-2,3-dideoxy-D-erythro-hexopyranoside (5). Solid (m.p. = 63 C); TLC: Rf:
0.7 (hexane-EtOAc = 7:3); IR (CHCl3) υ (cm-1): 2944, 2864, 1452, 1369, 1315, 1289, 1126, 1097,
1
1052, 995, 976, 915; H-NMR δ (ppm): 1.64-2.12 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.36 (s, 3H,
OCH3), 3.44-3.70 (m, 3H, H-5, H-6a, H-6b), 4.19-4.22 (m, 1H, H-4), 4.67 (d, J1,2a = 2.55Hz, 1H, H-1),
5.55 (s, 1H, ArCHO2), 7.23-7.49 (m, 3H, Ar-H), 7.61-7.88 (m, 2H, Ar-H); 13C-NMR δ (ppm): 23.97 (t,
C-3), 29.45 (t, C-2), 55.30 (q, -OCH3), 64.00 (t, C-6), 67.00 (d, C-5), 67.63 (d, C-4), 96.92 (d, C-1),
101.66 (d, -CH-Ar), 124.96 (d, Ar-CH), 127.01 (d, Ar-CH), 127.36 (d, Ar-CH), 137.71 (s, Ar-C).
Methyl-4,6-O-benzylidene-2,3-dideoxy-D-threo-hexopyranoside (12). Semi-solid; TLC: Rf: 0.7
(hexane-EtOAc = 7:3); IR (CHCl3) υ (cm-1): 2948, 2866, 1458, 1366, 1310, 1288, 1128, 1086, 1057,
998; 1H-NMR δ (ppm): 1.62-2.15 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.39 (s, 3H, OCH3), 3.31-3.59 (m,
2H, H-6a, H-6b), 3.83-4.24 (m, 2H, H-4, H-5), 4.83 (bs, 1H, H-1), 5.54 (s, 1H, PCHO2), 7.24-7.62 (m,
4H, Ar-H), 7.85 (d, J = 7.27Hz, 1H, Ar-H); 13C-NMR δ (ppm): 22.18 (t, C-3), 24.69 (t, C-2), 55.30 (q,
-OCH3), 64.00 (t, C-6), 67.63 (d, C-5), 67.92 (d, C-4), 98.25 (d, C-1), 101.52 (d, -O2CHAr), 126.25 (d,
Ar-CH), 127.66 (d, Ar-CH), 128.92 (d, Ar-CH), 138.30 (s, Ar-C).

Molecules 2005, 10
878
General procedure for the opening of benzylidene acetals of methyl-4,6-O-benzylidene-2,3-dideoxy-D-
erythro-hexopyranoside (5) and methyl-4,6-O-benzylidene-2,3-dideoxy-D-threo-hexopyranoside (12)
using N-bromosuccinimide
Compound 5 or 12 (1 mmol) was dissolved in dry CCl4 (5 mL) in a two necked round bottomed
flask. To this solution, N-bromosuccinimide (1.2 mmol) and barium carbonate (0.55 mol) were added.
The reaction mixture is heated to reflux for the required period (4 h in the case of 5, 2.5 h in the case of
12). During the initial period of heating, a reddish orange color developed but faded before completion
of the reaction. The yellowish gummy residue was washed with CCl4 (2 x 25 mL), and the filtrate and
washings were evaporated under reduced pressure. The residue was dissolved in ether (50 mL) and the
solution washed with water (3 x 25 mL), dried over anhydrous sodium sulphate and concentrated. The
residue was purified by flash column chromatography on silica gel to obtain methyl-4-O-benzoyl-6-
bromo-2,3-dideoxy-D-erythro-hexopyranoside (6) and methyl-4-O-benzoyl-6-bromo-2,3-dideoxy-D-
threo-hexopyranoside (13).
Methyl-4-O-benzoyl-6-bromo-2,3-dideoxy-D-erythro-hexopyranoside (6). Viscous liquid; TLC: Rf: 0.8
(hexane-EtOAc = 7:3); IR (CHCl3) υ (cm-1): 2944, 1718, 1596, 1446, 1360, 1312, 1267, 1126, 1113,
1
1062, 1027, 998, 944 ; H-NMR δ (ppm): 1.69-2.13 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.39 (s, 3H,
OCH3), 3.42-3.62 (m, 2H, H-6a, H-6b), 4.03-4.09 (m, 1H, H-5), 4.76 (bs, 1H, H-1), 4.86-4.94 (m, 1H,
H-4), 7.39-7.57 (m, 3H, Ar-H), 7.99 (d, J = 7.22Hz, 2H, Ar-H); 13C-NMR δ (ppm): 24.01 (t, C-3),
28.76 (t, C-2), 32.95 (t, C-6), 54.80 (q, -OCH3), 70.07 (d, C-5), 70.98 (d, C-4), 97.63 (d, C-1), 128.43
(d, Ar-CH), 129.60 (d, Ar-CH), 129.72 (d, Ar-CH), 133.25 (s, Ar-C), 165.37 (s, -OCO-Ar).
Methyl-4-O-benzoyl-6-bromo-2,3-dideoxy-D-threo-hexopyranoside (13). Viscous liquid; TLC: Rf: 0.8
(hexane-EtOAc = 7:3); IR (CHCl3) υ (cm-1): 2948, 1712, 1603, 1444, 1366, 1312, 1276, 1171, 1126,
1120, 1072, 1024, 979, 951, 905; 1H-NMR δ (ppm): 1.57-2.16 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.35
(s, 3H, OCH3), 3.32-3.60 (m, 2H, H-6a, H-6b), 4.14 (t, J5,6a = J5,6b = 6.81Hz, 1H, H-5), 4.84 (bs, 1H,
H-1), 5.25 (bs, 1H, H-4), 7.24-7.58 (m, 3H, Ar-H), 8.04 (d, J = 7.38Hz, 2H, Ar-H); 13C-NMR δ (ppm):
21.81 (t, C-3), 24.15 (t, C-2), 31.28 (t, C-6), 55.44 (q, -OCH3), 69.26 (d, C-5), 70.18 (d, C-4), 97.99 (d,
C-1), 128.42 (d, Ar-CH), 129.30 (d, Ar-CH), 129.94 (d, Ar-CH), 133.19 (s, Ar-C), 165.68 (s, -
OCOAr).
General procedure for the hydrolysis of methyl-4-O-benzoyl-6-bromo-2,3-dideoxy-D-erythro-
hexopyranoside (6) and Methyl-4-O-benzoyl-6-bromo-2,3-dideoxy-D-threo-hexopyranoside (13).
Compounds 6 or 13 (1 mmol) were dissolved in absolute methanol (50 mL) and stirred for 3h at
room temperature with anhydrous sodium carbonate (3 mol). The solids were removed by filtration
and the filtrate was evaporated under reduced pressure. The residue was further purified by flash
column chromatography on silica gel to obtain methyl-6-bromo-2,3-dideoxy-D-erythro-
hexopyranoside (7) and methyl-6-bromo-2,3-dideoxy-D-threo-hexopyranoside (14).

Molecules 2005, 10
879
Methyl-6-bromo-2,3-dideoxy-D-erythro-hexopyranoside (7). Viscous liquid; TLC: Rf: 0.3 (hexane-
EtOAc = 7:3); IR (CHCl3) υ (cm-1): 3408,2928, 2864, 1372, 1340, 1315, 1123, 1094, 1014, 982, 956,
902, 864 ; 1H-NMR δ (ppm): 1.69-2.01 (m, 4H, H-2a, H-2e, H-3a, H-3e), 2.20 (bs, 1H, 4-OH), 3.40 (s,
3H, OCH3), 3.50-3.70 (m, 3H, H-5, H-6a, H-6b), 3.77 (d, J4,5 = 9.09 Hz, H-4), 4.75 (bs, 1H, H-1); 13C-
NMR δ (ppm): 27.45 (t, C-3), 29.13 (t, C-2), 34.21 (t, C-6), 54.64 (q, -OCH3), 68.38 (d, C-4), 72.41 (d,
C-5), 97.50 (d, C-1).
Methyl-6-bromo-2,3-dideoxy-D-threo-hexopyranoside (14). Viscous liquid; TLC: Rf: 0.3 (hexane-
EtOAc = 7:3); IR (CHCl3) υ (cm-1): 3410, 2928, 2866, 1376, 1343, 1316, 1128, 1098, 1017, 986, 962;
1H-NMR δ (ppm): 1.67-2.10 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.42 (s, 3H, OCH3), 3.37-3.55 (m, 3H,
4-OH, H-6a, H-6b), 3.90 (bs, 1H, H-4), 3.99 (distorted t, J = 6.20Hz, 1H, H-5), 4.76 (bs, 1H, H-1);
13C-NMR δ (ppm): 23.37 (t, C-3), 25.68 (t, C-2), 31.87 (t, C-6), 54.94 (q, -OCH3), 65.04 (d, C-4),
70.58 (d, C-5), 98.45 (d, C-1).
General procedure for the mesitylation of methyl-6-bromo-2,3-dideoxy-D-erythro-hexopyranoside (7)
and methyl-6-bromo-2,3-dideoxy-D-threo-hexopyranoside (14).
Compound 7 (or 14) (1 mmol) was dissolved in dry dichloromethane (5 mL) in a two-necked
round-bottomed flask. To this solution, methansesulfonyl chloride (1.2 mmol) and triethyl amine (2
o
mmol) were added at 0 C. The reaction mixture was stirred for 3 h at ambient temperature. The
reaction mixture was diluted with CH2Cl2 (2 x 25 mL), washed with water (3 x 25 mL), dried over
anhydrous sodium sulphate and concentrated. The residue was purified by flash column
chromatography on silica gel to obtain methyl-4-O-methanesulfonyl-6-bromo-2,3-dideoxy-D-erythro-
hexopyranoside (8) and methyl-4-O-methanesulfonyl-6-bromo-2,3-dideoxy-D-threo-hexopyranoside
(15).
Methyl-4-O-methanesulfonyl-6-bromo-2,3-dideoxy-D-erythro-hexopyranoside (8). Viscous liquid;
TLC: Rf: 0. 7 (hexane-EtOAc = 1:1); IR (CHCl3) υ (cm-1): 2944, 2864, 1356, 1174, 1129, 1094, 905,
960, 908, 889, 867, 832 ; 1H-NMR δ (ppm): 1.72-2.15 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.06 (s, 3H, -
SO2CH3), 3.36 (s, 3H, OCH3), 3.45-3.70 (m, 2H, H-6a, H-6b), 3.87 (d, J = 2.5Hz, 1H, H-5), 4.51 (d, J
= 5.5Hz, 1H, H-4), 4.70 (bs, 1H, H-1); 13C-NMR δ (ppm): 25.32 (t, C-3), 28.89 (t, C-2), 32.68 (t, C-6),
38.98 (q, -OSO2CH3), 54.94 (q, -OCH3), 68.97 (d, C-5), 76.61 (d, C-4), 97.43 (d, C-1).
Methyl-4-O-methanesulfonyl-6-bromo-2,3-dideoxy-D-threo-hexopyranoside (15). Vscous liquid; TLC:
Rf: 0. 5 (hexane-EtOAc = 7:3); IR (CHCl3) υ (cm-1): 2948, 2864, 1358, 1176, 1123, 1098, 908, 958,
1
908; H-NMR δ (ppm): 1.72-2.24 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.10 (s, 3H, -SO2CH3 of α), 3.15
(s, 3H, -SO2CH3 of β), 3.41 (s, 3H, OCH3 of α), 3.44 (s, 3H, OCH3 of β), 3.28-3.70 (m, 2H, H-6a, H-
6b), 4.06 (t, J5,6a = J5,6b = 6.07Hz, 1H, H-5), 4.78 (bs, 1H, H-1), 4.92 (bs, 1H, H-4); 13C-NMR δ (ppm):
23.35 (t, C-3), 23.85 (t, C-2), 30.34 (t, C-6), 38.65 (q, -OSO2CH3), 54.94 (q, -OCH3), 69.12 (d, C-5),
74.53 (d, C-4), 98.05 (d, C-1).
Methyl-6-O-triphenylmethyl-2,3-dideoxy-D-erythro-hexopyranoside (18). Methyl-2,3-dideoxy-D-
erythro-hexopyranoside (4) (1 mmol) was dissolved in dry DMF (5 mL) in a two necked round
bottomed flask. To this solution, triphenylmethyl chloride (1.1 mmol), triethyl amine (2 mmol) and

Molecules 2005, 10
880
catalytic amount DMAP (25 mg) were added. The reaction mixture was stirred for 36 h at room
temperature. The solution was poured in to ice water (25 mL) and extracted with dichloromethane (3x
25 mL). The organic layer was washed successively with saturated ammonium chloride solution (3 x
25 mL) and water (3 x 25 mL), dried over anhydrous sodium sulphate and concentrated. The residue
was purified by flash column chromatography on silica gel to obtain (18). Semi solid; TLC: Rf: 0.5
(hexane-EtOAc = 7:3); IR (CHCl3) υ (cm-1): 3504(b), 2928, 2862, 1600, 1484, 1443, 1369, 1321,
1
1126, 1081, 988, 944, 899; H-NMR δ (ppm): 1.69-1.83 (m, 4H, H-2a, H-2e, H-3a, H-3e), 2.74 (bs,
1H, 4-OH), 3.41 (s, 3H, OCH3), 3.43-3.60 (m, 4H, H-4, H-5, H-6a, H-6b), 4.61 (bs, 1H, H-1), 7.20-
7.32 (m, 9H, Ar-H), 7.43-7.46 (m, 6H, Ar-H); 13C-NMR δ (ppm): 28.79 (t, C-3), 29.96 (t, C-2), 54.39
(q, -OCH3), 66.05 (t, C-6), 69.05 (d, C-5), 70.88 (d, C-4), 87.48 (s, -OC(Ph)3), 97.18 (d, C-1), 127.15
(d, Ar-CH), 127.92 (d. Ar-CH), 128.56 (d, Ar-CH), 143.38 (s, Ar-C), 143.57 (s, Ar-C).
Methyl-4-O-methanesulfonyl-6-triphenylmethyl-2,3-dideoxy-D-erythro-hexopyranoside (19). Methyl-
6-O-triphenylmethyl-2,3-dideoxy-D-erythro-hexopyranoside (18) (1 mmol) was dissolved in dry
dichloromethane (5 mL) in a two-necked round-bottomed flask. To this solution, methansesulfonyl
o
chloride (1.2 mmol) and triethyl amine (2 mmol) were added at 0 C. The reaction mixture was
brought to room temperature over a period of 1.5 h. The reaction mixture was diluted with CH2Cl2 (2 x
25 mL), washed with water (3 x 25 mL), dried over anhydrous sodium sulphate and concentrated. The
residue was purified by flash column chromatography on silica gel to obtain (19). Semi solid; TLC: Rf:
0.6 (hexane-EtOAc = 8:2); IR (CHCl3) υ (cm-1): 2928, 1600, 1488, 1446, 1356, 1174, 1129, 972, 956;
1H-NMR δ (ppm): 1.69-2.27 (m, 4H, H-2a, H-2e, H-3a, H-3e), 2.55 (s, 3H, 4-OSO2CH3), 3.40 (s, 3H,
OCH3), 3.26-3.57 (m, 2H, H-6a, H-6b), 3.86 (dd, J4,5 = 9.7Hz, J5,6a = 2.96Hz, 1H, H-5), 4.64 (td, J4,5
=
J3a,4 = 9.99Hz, J3e,4 = 5.51Hz, 1H, H-4), 4.77 (s, 1H, H-1), 7.05-7.28 (m, 9H, Ar-H), 7.45-7.48 (m, 6H,
Ar-H); 13C-NMR δ (ppm): 25.89 (t, C-3), 28.81 (t, C-2), 37.93 (q, -OSO2CH3), 54.50 (q, -OCH3),
62.57 (t, C-6), 69.28 (d, C-5), 75.61 (d, C-4), 86.58 (s, -OC(Ph)3), 97.14 (d, C-1), 125.73 (d, Ar-CH),
127.04 (d, Ar-CH), 127.74 (d, Ar-CH), 128.70 (d, Ar-CH), 143.57 (s, Ar-C).
Methyl-4-azido-6-O-triphenylmethyl-2,3-dideoxy-D-threo-hexopyranoside
(20).
Methyl-4-O-
methanesulfonyl-6-triphenylmethyl-2,3-dideoxy-D-erythro-hexopyranoside (19) (1 mmol) was
dissolved in dry DMF (3 mL) in a two necked round bottomed flask. To this solution were added
sodium azide (1.2 mmol) and one or two drops of water, just to solubilise the azide. The reaction
o
mixture was heated at 110 C for 6 h, then poured in to ice water (25 mL) and extracted with
dichloromethane (5 x 25 mL). The organic layer was dried over anhydrous sodium sulphate and
concentrated. The residue was purified by flash column chromatography on silica gel to obtain (20).
o
Solid (m.p. = 69 C); TLC: Rf: 0.6 (hexane-EtOAc = 8:2); IR (CHCl3) υ (cm-1): 3056, 2928, 2112,
1484, 1443, 1366, 1331, 1264, 1206, 1180, 1126, 1078, 1033, 995, 953, 921, 899, 707, 630; 1H-NMR
δ (ppm): 1.69-2.13 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.15 (dd, J6a,6b = 13.18Hz, J5,6a = 5.86Hz, 1H, H-
6a), 3.20-3.39 (m, 1H, H-6b), 3.33 (s, 3H, OCH3), 3.73 (s, 1H, H-5), 3.87 (td, J4,5 = J3a,4 = 6.1Hz, J3e,4
= 1.47Hz, 1H, H-4), 4.67 (d, J1,2e = 2.93Hz, 1H, H-1), 7.20-7.31 (m, 9H, Ar-H), 7.42-7.82 (m, 6H, Ar-
H); 13C-NMR δ (ppm): 22.60 (t, C-3), 24.40 (t, C-2), 54.67 (q, -OCH3), 56.77 (d, C-4), 63.67 (t, C-6),
68.13 (d, C-5), 86.91 (s, -OC(Ph)3), 97.07 (d, C-1), 127.06 (d, Ar-CH), 127.82 (d, Ar-CH), 128.64 (d,
Ar-CH), 128.74 (d, Ar-CH), 143.91 (s, Ar-C).

Molecules 2005, 10
881
Methyl-4-(N-t-butoxycarbonyl)-6-O-triphenylmethyl-2,3-dideoxy-D-threo-exopyranoside
(21).
Methyl-4-azido-6-O-triphenylmethyl-2,3-dideoxy-D-threo-hexopyranoside (20) (1 mmol) was
dissolved in EtOAc (5 mL) in a two necked round bottomed flask. To this solution, a catalytic amount
of 10% Pd / C catalyst (25mg) and di-t-butylcarbonate (1.2 mmol) were added. Hydrogen gas was
passed through the solution using a balloon. When there was no more uptake of hydrogen (~ 12h), the
reaction was stopped and the catalyst filtered. The solvent was evaporated in a rotary evaporator under
reduced pressure and the residue was purified by flash column chromatography on silica gel to obtain
pure product (21). Semi solid; TLC: Rf: 0.5 (hexane-EtOAc = 8:2); IR (CHCl3) υ (cm-1): 3440(s),
2992, 2960, 1708, 1484, 1449, 1385, 1356, 1328, 1161, 1116, 1068, 1030, 1001, 905, 630; 1H-NMR δ
(ppm): 1.36 (s, 9H, C(CH3)3), 1.60-2.03 (m, 4H, H-2a, H-2e, H-3a, H-3e), 3.09-3.17 (m, 2H, H-6a, H-
6b), 3.42 (s, 3H, OCH3), 3.71 (bs, 1H, H-5), 4.05 (bs, H-4), 4.72 (bs, 1H, H-1), 5.13 (d, J 8.3Hz, 1H, -
13
NH), 7.20-7.30 (m, 9H, Ar-H), 7.44-7.84 (m, 6H, Ar-H); C-NMR δ (ppm): 23.87 (t, C-3), 24.49 (t,
C-2), 28.35 (q, -OC(CH3)3), 45.88 (d, C-4), 54.62 (q, -OCH3), 64.54 (t, C-6), 69.00 (d, C-5), 79.11 (s,
OC(CH3)3 of α), 86.65 (s, OC(CH3)3 of β), 98.07 (d, C-1), 126.95 (d, Ar-CH), 127.77 (d, Ar-CH),
128.68 (d, Ar-CH), 143.98 (s, Ar-C), 155.35 (s, -OCO(CH3)3).
Methyl-4-(N-t-butoxycarbonyl)-2,3-dideoxy-D-threo-hexopyranoside (22). To methyl-4-(N-t-
butoxycarbonyl)-6-O-triphenylmethyl-2,3-dideoxy-D-threo-exopyranoside (21) (1 mmol) taken in a
round bottomed flask, was added a solution of aq. 80% acetic acid (2 mL) and the contents stirred for
16 h at room temperature. The reaction mixture was poured into cold water (10 mL) and extracted with
chloroform (5x 25 mL). The organic layer was washed repeatedly with water (3 x 25 mL), saturated
hydrogen carbonate (3 x 25 mL) and again with water (3 x 25 mL). The organic layer was evaporated
in a rotary evaporator under reduced pressure and the residue was purified by flash column
chromatography on silica gel to obtain pure product (22). Viscous liquid; TLC: Rf: 0.2 (hexane-EtOAc
= 7:3); IR (CHCl3) υ (cm-1): 3540(bs), 2992, 2960, 1706, 1488, 1449, 1386, 1361, 1328, 1164, 1110,
1066, 1028, 908; 1H-NMR δ (ppm): 1.36 (s, 9H, C(CH3)3), 1.67-2.17 (m, 4H, H-2a, H-2e, H-3a, H-3e),
3.19-3.70 (m, 2H, H-6a, H-6b), 3.35 (s, 3H, OCH3), 3.83-3.98 (m, 2H, H-4, H-5), 4.76 (bs, 1H, H-1),
5.15 (d, J = 8.68Hz, 1H, -NH); 13C-NMR δ (ppm): 23.06 (t, C-3), 24.70 (t, C-2), 28.23 (q, -OC(CH3)3),
44.33 (d, C-4), 54.67 (q, -OCH3), 61.75 (t, C-6), 69.33 (d, C-5), 80.17 (s, -OC(CH3)3), 97.74 (d, C-1),
157.03 (s, -OCO(CH3)3).
References and Notes
1. (a) Krogsgaard-Larsen, P.; Scheel-Kruger, J.; Kotid, H. GABA-Neurotransmitters; Munksgard:
Copenhagen, 1979; (b) Lippert, B.; Metcalf, B. W.; Jung, M. J.; Casara, P. 4-amino-hex-5-enoic
acid, a selective catalytic inhibitor of 4-aminobutyric-acid aminotransferase in mammalian brain.
Eur. J. Biochem. 1977, 74, 441-445; (c) Nanavati, S. M.; Silverman, R. B. Mechanisms of
inactivation of γ-aminobutyric acid aminotransferase by the antiepilepsy drug γ-vinyl GABA
(vigabatrin). J. Am. Chem. Soc 1991, 113, 9341-9349.
2. Gale, K. GABA in epilepsy: the pharmacologic basis. Epilepsia 1989, 30, S1-11.
3. Hornykiewicz, O.; Lloyd, K. G.; Davidson, L. The GABA system, function of the basal ganglia,
and Parkinson's disease. (GABA in Nervous System Function); Roberts, E., Chase, T. N., Tower,
D. B., Eds.; Raven Press: New York, 1976; pp. 479-485.

Molecules 2005, 10
882
4. Perry, T. L.; Hansen, S.; Kloster, M. Huntington's chorea. Deficiency of gamma-aminobutyric
acid in brain. New Eng. J. Med. 1973, 288, 337-342.
5. Aoyage, T.; Wada, T.; Nagai, M.; Kojima, F.; Harada, S.; Takeuchi, T.; Takahashi, H.; Kirokawa,
K.; Tsumita, T. Increased gamma-aminobutyrate aminotransferase activity in brain of patients
with Alzheimer's disease. Chem. Pharm. Bull. 1990, 38, 1748-1749.
6. (a) Kushner, S. A.; Dewey, S. L.; Kornetsky, C. J. The irreversible γ-aminobutyric acid (GABA)
transaminase inhibitor γ-vinyl-GABA blocks cocaine self-administration in rats. Pharmacol. Exp.
Ther. 1999, 290, 797-802; (b) Dewey, S. L.; Morgan, A. E.; Ashby, C. R., Jr.; Horan, B.;
Kushner, S. A.; Logan, J.; Volkow, N. D.; Fowler, J. S.; Gardner, E. L.; Brodie, J. D. A novel
strategy for the treatment of cocaine addiction. Synapse 1998, 30, 119-129; (c) Brennan, M.
Epilepsy drug could treat nicotine addiction. C&EN, December 7, 1998, p.13
7. Delgado-Escueta, A. V.; Ward, A. A. Jr.; Woodbury, D. M.; Porter, R. J. Basic Mechanisms of the
Epilepsies; Raven Press: New York, 1986; p. 365.
8. (a) Kwon, T. W.; Keusenkothen, P. F.; Smith, M. B. Asymmetric synthesis of (S)-4-aminohex-5-
enoic acid: a potent inhibitor of 4-aminobutyrate-2-oxoglutarate aminotransferase. J. Org.Chem.
1992, 57, 6169-6173; (b) Margolin, A. L. Synthesis of optically pure mechanism-based inhibitors
of γ-aminobutyric acid aminotransferase (GABA-T) via enzyme-catalyzed resolution Tetrahedron
Lett. 1993, 34, 1239-1242; (c) Wei, Z. Y.; Knaus, E. E. A short efficient synthesis of (S)-4-amino-
5-hexenoic acid [(S)-vigabatrin]. J. Org. Chem. 1993, 58, 1586-1588; (d) Wei, Z. Y.; Knaus, E. E.
Asymmetric synthesis of (S)-vigabatrin. An approach using methionine as the chiral pool. Synlett
1993, 295-296; (e) Wei, Z.Y.; Knaus, E. E. One-step reduction-Wittig olefination of methyl
pyroglutamate: chiral syntheses of (5S)-5-alkenyl-2-pyrrolidinones and (S)-vigabatrin.
Synlett.1994, 345-346; (f) Wei, Z.-Y.; Knaus, E. E. Asymmetric synthesis of both enantiomers of
vigabatrin: an approach using methionine as the chiral pool. Tetrahedron 1994, 50, 5569-5578; (g)
Trost, B. M.; Lemonine, R. C. An asymmetric synthesis of vigabatrin. Tetrahedron Lett. 1996, 37,
9161-9164; (h) Alcon, M.; Poch, M.; Moyano, A.; Pericas, M. A.; Riera, A. Enantioselective
synthesis of (S)-vigabatrin. Tetrahedron: Asymmetry 1997, 8, 2967; (i) Chandrasekhar, S.;
Mohapatra, S. Asymmetric synthesis of anti-convulsive drug (S)-vigabatrin. Tetrahedron Lett.
1998, 39, 6415-6418; (j) Dagoneau, C.; Tomassini, A.; Denis, J.-N.; Vallée, Y. A short synthesis
of γ-amino acids from nitrones; synthesis of vigabatrin. Synthesis 2001, 1, 150-154.
9. (a) Sobhana Babu, B.; Balasubramanian, K. K. Indium trichloride Catalyzed Glycosidation: An
expeditious synthesis of 2,3-unsaturated glycopyranosides. Tetrahedron Lett. 2000, 41, 1271-1274;
(b) Sobhana Babu, B.; Balasubramanian, K. K. Lithium tetrafluoborate catalyzed Ferrier
rearrangement – Facile synthesis of alkyl 2,3-unsaturated glycopyranosides. Synth. Commun.
1999, 29, 4299-4305.
10. Bernet, B.; Vasella, A. Fragmentation of 6-deoxy-6-halohexono-1,5-ortholactones: a concerted,
nonstereospecific process. Helv. Chim. Acta. 1984, 67, 1328-47.
11. Hanessian, S.; Plessas, N. R. The reactions of O-benzylidene sugars with N-bromosuccinimide. II.
Scope and synthetic utility in the methyl 4,6-O-benzylidenehexopyranoside series. J. Org. Chem.
1969, 34, 1035-1044.
12. Mizuno, M.; Shiori, T. Efficient method for the one-pot azidation of alcohols using bis(p-
nitrophenyl)phosphorazidate. Chem. Commun. 1997, 2165-2166

Molecules 2005, 10
883
Sample availability: Contact the authors.
© 2005 by MDPI (http://www.mdpi.org). Reproduction is permitted for non commercial purposes.