Short synthesis of (R)- and (S)-4-amino-3-hydroxybutyric acid (GABOB)

Article abstract of DOI:10.1055/s-2005-861783

A simple and stereospecific synthesis of both (R)- and (S)-GABOB has been developed. The synthetic approach involves the conversion, through organoselenium intermediates, of commercially available ethyl (R)- and (S)-4-chloro-3-hydroxybutyrate into a protected 1,2-amino alcohol with retention of the original configuration.

Full text of DOI:10.1055/s-2005-861783

PAPER
579
Short Synthesis of (R)- and (S)-4-Amino-3-Hydroxybutyric Acid (GABOB)
S
hor
t
Synthesisof
(
R
)-
a
and(
S
)-4-A
r
mino-3
c
-Hydroxyb
e
utyric
A
cid
l
(G
A
BO
l
B) o Tiecco,* Lorenzo Testaferri, Andrea Temperini, Raffaella Terlizzi, Luana Bagnoli, Francesca Marini,
Claudio Santi
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, 06123 Perugia, Italy
Fax +39(075)5855116; E-mail: tiecco@unipg.it
Received 21 June 2004; revised 8 November 2004
Abstract: A simple and stereospecific synthesis of both (R)- and
(S)-GABOB has been developed. The synthetic approach involves
the conversion, through organoselenium intermediates, of commer-
cially available ethyl (R)- and (S)-4-chloro-3-hydroxybutyrate into
a protected 1,2-amino alcohol with retention of the original config-
uration.
Key words: selenium oxidation, ring closure, amino acids, b-hy-
droxyselenides, 1,3-oxazolidin-2-ones
4-Amino-3-hydroxybutyric acid (GABOB) is a com-
pound of great pharmacological importance due to its bio-
logical function as a neuromodulator in the mammalian
central nervous system and due to its hypotensive and an-
tiepileptic activity.1 The (R)-(–)-isomer 1 (Figure 1) has
been shown to have a greater biological activity than the
(S)-(+) isomer. Furthermore, the trimethylamino analogue
of GABOB, i.e. (R)-(–)-carnitine (2), plays a significant
role in the human energy metabolism via the transport of
Scheme 1
long chain fatty acids into the mitochondria.2 In recent
years, a large number of reports and patents dealing with
By reaction with benzoyl isocyanate in CH2Cl2 at room
temperature, this compound was converted into its N-ben-
zoyl-carbamate derivative 5. Treatment of this b-carbam-
oyloxyalkyl phenyl selenide with an excess of m-
chloroperoxybenzoic acid (m-CPBA) in THF,8 in the
presence of potassium hydrogenphosphate, afforded the
corresponding selenone intermediate 6. The N-benzoyl-
1,3-oxazolidin-2-one 7 was then obtained as a result of the
displacement of the selenonyl group by the nitrogen atom
of the carbamate. This new cyclization reaction, which
represents the crucial step of the entire process, is an in-
tramolecular nucleophilic substitution, which occurs eas-
ily because of the great leaving ability of the selenonyl
group. During this process no racemization occurred,9 as
demonstrated by HPLC analysis on chiral column. The
phenylseleno moiety, introduced in the first step is elimi-
nated as benzeneseleninic acid (8) in the oxidation/cy-
clization step. After addition of K2CO3 the water-soluble
potassium benzeneseleninate could be separated. From
this diphenyl diselenide was recovered10 in good yield. An
attempt to obtain (R)-GABOB by basic hydrolysis of 7
with NaOH in EtOH was unsuccessful because 7 under-
goes a rapid b-elimination,6e giving the ethyl N-benzoyl-
4-aminocrotonate as the sole reaction product. An optimi-
zation study revealed that the following two-steps se-
quence gave the best results (Scheme 2).
the synthesis of enantiomerically pure (R)-GABOB em-
ploying optical resolution of diastereoisomeric salts,3 en-
zymatic or microbial technique,4 and asymmetric
synthesis,5 have been published. Moreover, several syn-
theses which make use of chiral non-racemic starting ma-
terials have also appeared.6 Following our recently
proposed stereospecific transformation of b-hydroxyalkyl
phenyl selenides into N-benzoyl-1,3-oxazolidin-2-ones7
we now report a short synthesis of both (R)- and (S)-GA-
BOB.
Figure 1
Thus, ethyl (R)-4-chloro-3-hydroxybutyrate (3) was re-
acted with phenylselenium anions to give the correspond-
ing b-hydroxyalkyl phenyl selenide 4 in excellent yield
(Scheme 1).
SYNTHESIS 2005, No. 4, pp 0579–0582
x
x
.
x
x
.2
0
0
5
Advanced online publication: 18.01.2005
DOI: 10.1055/s-2005-861783; Art ID: T06904SS
© Georg Thieme Verlag Stuttgart · New York

580
M. Tiecco et al.
PAPER
Ethyl (3R)-3-Hydroxy-4-(phenylseleno)butanoate (4)
To a solution of diphenyl diselenide (0.96 g, 3 mmol), in anhyd THF
(30 mL), sodium hydride (0.14 g, 6 mmol) was added. The suspen-
sion was refluxed for 2 h and then allowed to cool to 40 °C. HMPA
(6 mL) was then added. To the resulting orange-colored solution,
ethyl (R)-(+)-4-chloro-3-hydroxybutyrate (3; 1.0 g, 6 mmol) was
added. After 36 h the reaction was quenched with a 10% solution of
NH4Cl (10 mL). The reaction mixture was extracted with Et2O (3 ×
30 mL) and the combined organic layers were dried over Na2SO4
and evaporated. The reaction product was purified by column chro-
matography on a silica gel column using a mixture of Et2O and light
petroleum (4:6) as eluent. Pure compound 4 was obtained as a pale
yellow oil in 86% yield; [a]D25 +2.58 (c = 2.23, CHCl3).
Scheme 2
FT-IR (KBr): 3472 (br), 2981, 1730, 1186, 1022 cm–1.
1H NMR (CDCl3, 25 °C, TMS): d = 7.58–7.47 (m, 2 H, ArH), 7.30–
7.21 (m, 3 H, ArH), 4.14 (q, J = 7.2 Hz, 2 H, OCH2), 4.24–4.08 (m,
1 H, OCH), 3.24 (d, J = 4.0 Hz, 1 H, OH), 3.17–2.95 (m, 2 H,
SeCH2), 2.74–2.48 (m, 2 H, CH2), 1.25 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (CDCl3, 25 °C): d = 172.0 (CO), 132.8 (2 × CH), 129.2
(2 × CH), 127.2, 126.4, 67.1 (OCH), 60.8 (OCH2), 40.4 (CH2), 34.7
(SeCH2), 14.1 (CH3).
The N-benzoyl-1,3-oxazolidin-2-one 7 was first hydro-
lyzed to the corresponding acid 9 by treatment with 4 N
HCl at 70 °C. Treatment of 9 with refluxing 6 N HCl then
afforded the (R)-GABOB hydrochloride (10). Purification
of 10 by ion-exchange chromatography on a cation ex-
change resin afforded crude (R)-(–)-GABOB (1) in good
yield and with spectral data in good agreement with those
reported in the literature. The product was contaminated
by the corresponding dehydrated derivative, as demon-
strated by the 1H NMR spectrum. The enantiomeric purity
was determined by chiral HPLC after conversion into the
corresponding 4-hydroxy-2-pyrrolidinone as reported in
the literature.11 An enantiomeric ratio of 96:4 was thus de-
termined. Following the same procedure, the ethyl (S)-4-
chloro-3-hydroxybutyrate [ent-3] (97% ee) was trans-
formed into (S)-(+)-GABOB [ent-1] with practically the
same global yield. Chiral HPLC analysis was affected as
described above for the (R)-enantiomer. The measured
enantiomeric ratio was 96:4.
GC–MS: m/z (%) = 288 (100) [M+], 270 (32), 183 (23), 157 (63),
131 (59), 103 (63), 91 (58), 77 (29).
Anal. Calcd for C12H16O3Se (287.2): C, 50.18; H, 5.61. Found: C,
50.42; H, 5.33.
Ethyl (3S)-3-Hydroxy-4-(phenylseleno)butanoate (ent-4)
This compound was prepared as 4. Yield: 89%; pale yellow oil;
[a]D26 –2.63 (c = 4.59, CHCl3).
Anal. Calcd for C16H16O3Se (287.2): C, 50.18; H, 5.11. Found: C,
50.04; H, 5.50.
Ethyl (3R)-3-{[(Benzoylamino)carbonyl]oxy}-4-(phenylsele-
no)butanoate (5)
Under an inert atmosphere, benzoyl isocyanate (0.83 g, 5.6 mmol)
was added to a solution of the b-hydroxyalkyl phenyl selenide 4
(1.48 g, 5.1 mmol) in anhyd CH2Cl2 (30 mL) and the reaction was
stirred at r.t. until TLC analysis showed that the starting alcohol was
completely consumed (14–15 h). The solvent was evaporated and
the crude benzoyl carbamate was purified by column chromatogra-
phy on silica gel with Et2O–light petroleum (6:4) as eluent. Com-
pound 5 was obtained as an oil in 89% yield; [a]D25 –24.70 (c = 1.65,
CHCl3).
In summary, starting from commercially available chiral
building blocks, optically active (R)- and (S)-GABOB
were synthesized by simple chemical reactions promoted
by the versatile organoselenium intermediates. The key
step of our synthesis is the ring-closure reaction, which
occurs by intramolecular nucleophilic substitution of the
selenone group by the nitrogen atom of the carbamate.
FT-IR (KBr): 3271 (br), 2982, 1757, 1737, 1508, 1184 cm–1.
1H NMR spectra were recorded in CDCl3 or D2O at 200 MHz on a
Bruker Avance DR 200 spectrometer and TMS or HOD was used
as internal reference. 13C NMR spectra were recorded at 50.3 MHz
with a Bruker Avance DR 200 spectrometer in CDCl3 or D2O using
the resonance of CDCl3 or dioxane (dC = 67.4 ppm), respectively, as
internal reference. FT-IR spectra were recorded with a Jasco model
410 spectrometer equipped with a diffuse reflectance accessory.
GC–MS analyses were performed on an HP-6890 gas chromato-
graph (dimethyl silicone column; 12.5 m) equipped with an HP-
5973 mass selective detector at an ionizing voltage of 70 eV. HPLC
analyses were performed on an HP 1100 instrument equipped with
chiral columns and an UV detector. Melting points are uncorrected.
Optical rotations were measured in a 50 mm cell with a Jasco DIP-
1000 digital polarimeter. Elemental analyses were carried out on a
Carlo Erba 1106 elemental analyzer. Commercial grade Et2O,
CH2Cl2, CCl4 and THF were used without purification and were
dried, if necessary. Column chromatography was performed with
Merck silica gel 60 (70–230 mesh). Ethyl (R)-(+)-4-chloro-3-hy-
droxybutyrate (97% ee) and ethyl (S)-(–)-4-chloro-3-hydroxybu-
tyrate (97% ee) were purchased from Sigma-Aldrich Chemical Co.
1H NMR (CDCl3, 25 °C, TMS): d = 8.15 (s, 1 H, NH), 7.91–7.80
(m, 2 H, ArH), 7.60–7.40 (m, 5 H, ArH), 7.32–7.10 (m, 3 H, ArH),
5.48–5.30 (m, 1 H, OCH), 4.11 (q, J = 7.2 Hz, 2 H, OCH2), 3.35–
3.15 (m, 2 H, SeCH2), 2.88 (dd, J = 16.1, 5.5 Hz, 1 H, CH2), 2.76
(dd, J = 16.1, 7.1 Hz, 1 H, CH2), 1.24 (t, J = 7.2 Hz, 3 H, CH3)
13C NMR (CDCl3, 25 °C, TMS): d = 169.6 (CO), 164.8 (CO), 146.8
(CO), 132.7 (CH), 132.6 (CH), 132.5 (CH), 132.4 (CH), 129.0 (2 ×
CH), 128.4 (2 × CH), 127.5 (2 × CH), 127.0 (2 × CH), 71.7 (OCH),
60.6 (OCH2), 38.0 (CH2), 30.0 (SeCH2), 13.8 (CH3).
Anal. Calcd for C20H21NO5Se (434.3): C, 55.30; H, 4.87; N, 3.22.
Found: C, 55.62; H, 5.13; N, 3.04.
Ethyl (3S)-3-{[(Benzoylamino)carbonyl]oxy}-4-(phenylsele-
no)butanoate (ent-5)
26
This compound was prepared as 5. Yield: 88%; oil; [a]D +19.74
(c = 1.70, CHCl3).
Anal. Calcd for C20H21NO5Se (434.3): C, 55.30; H, 4.87; N, 3.22.
Found: C, 55.07; H, 5.19; N, 3.11.
Synthesis 2005, No. 4, 579–582 © Thieme Stuttgart · New York

PAPER
Short Synthesis of (R)- and (S)-4-Amino-3-Hydroxybutyric Acid (GABOB)
581
Ethyl [(5R)-3-Benzoyl-2-oxo-1,3-oxazolidin-5-yl]acetate (7)
To a solution of N-benzoyl carbamate 5 (1.96 g, 4.5 mmol) in THF
(100 mL) at 0 °C powdered potassium hydrogenphosphate (3.81 g,
22.5 mmol) and meta-chloroperoxybenzoic acid (3.10 g, 18 mmol)
were added. The reaction mixture was allowed to slowly reach r.t.
and was stirred until TLC analysis showed that the starting selenide
was completely converted into the corresponding selenone (4 h).
The solvent was evaporated in vacuo and the residue was suspended
in reagent grade acetone (160 mL). Powdered K2CO3 (3.10 g, 22.5
mmol) was then added at r.t. The consumption of the selenone was
monitored by TLC (20 h). The mixture was then concentrated in
vacuo, poured into water (100 mL) and extracted with Et2O (3 × 60
mL). The organic layer was dried over Na2SO4 and evaporated. The
reaction product was purified by column chromatography on silica
gel using a mixture of Et2O and light petroleum (6:4) as eluent.
Yields, physical and spectral data of pure 7 and ent-7 are reported
below.
Anal. Calcd for C5H7NO4 (145.1): C, 41.38; H, 4.86; N, 9.65.
Found: C, 41.49; H, 5.11; N, 9.77.
(3R)-4-Amino-3-hydroxybutanoic Acid (1)
The pure acid 9 (0.23 g, 1.6 mmol) was dissolved in 6 N HCl (3 mL)
and then refluxed (110–120 °C) for 7 h. Evaporation of the acid
gave (R)-GABOB hydrochloride (10) which was dissolved in dis-
tilled water (2 mL), and passed through a column containing Dowex
50WX2-100 mesh (H+ form) cation exchange resin (4 g). The col-
umn was washed with distilled water (60 mL) until the pH of the
elute was neutral. The column was eluted with 25% aq NH3 (20 mL)
and the ammoniacal elute was evaporated under vacuum to afford
crude (R)-(–) GABOB (1).
Yield of the crude product 73%; white solid; mp 208–210 °C (Lit,6f
mp 213–214 °C); [a]D21 –17.51 (c = 0.96, H2O). The value reported
in the literature6f is [a]D25 = –20.5 (c = 1.75 in H2O), after recrystal-
lization from aq EtOH. Analytical HPLC of the 4-hydroxy-2-pyrro-
lidinone derivative: Chirapak AD-H column (250 × 4 mm, Daicel),
eluent: EtOH–hexane (5:95), flow rate: 1.0 mL/min, UV detection
at 210 nm; tR 75.97 min; er = 96:4.
1H NMR (D2O, 25 °C): d = 3.99 (ddt, J = 9.6, 8.9, 3.2 Hz, 1 H,
OCH), 2.96 (dd, J = 13.1, 3.2 Hz, 1 H, NCH2), 2.73 (dd, J = 13.1,
9.6 Hz, 1 H, NCH2), 2.23 (d, J = 8.9 Hz, 2 H, CH2).
[Lit.5d 1H NMR (250 MHz, D2O): d = 4.13–4.00 (m, 1 H, OCH),
3.03 (dd, J = 13.1, 3.3 Hz, 1 H, NCH2), 2.81 (dd, J = 13.1, 9.4 Hz,
1 H, NCH2), 2.29 (d, J = 6.6 Hz, 2 H, CH2)].
24
Yield: 90%; white solid; mp 81–82 °C; [a]D –46.68 (c = 3.36,
CHCl3). Analytical HPLC: Chiracel OD-H column (250 × 4 mm,
Daicel), eluent: i-PrOH–hexane (20:80), flow rate: 0.8 mL/min, UV
detection at 240 nm; tR 50.8 min; er > 99:1.
FT-IR (KBr): 2982, 1788, 1736, 1682, 1328, 1205 cm–1.
1H NMR (CDCl3, 25 °C, TMS): d = 7.70–7.62 (m, 2 H, ArH), 7.55–
7.30 (m, 3 H, ArH), 5.01 (dddd, J = 8.2, 7.2, 6.9, 6.0 Hz, 1 H, OCH),
4.32 (dd, J = 11.2, 8.2 Hz, 1 H, NCH2), 4.18 (q, J = 7.1 Hz, 2 H,
OCH2), 3.90 (dd, J = 11.2, 7.2 Hz, 1 H, NCH2), 2.89 (dd, J = 16.7,
6.0 Hz, 1 H, CH2), 2.76 (dd, J = 16.7, 6.9 Hz, 1 H, CH2), 1.28 (t,
J = 7.1 Hz, 3 H, CH3).
13C NMR (CDCl3, 25 °C, TMS): d = 169.5 (CO), 168.7 (CO), 152.4
(CO), 132.9 (CH), 132.7 (CH), 129.0 (2 × CH), 127.8 (2 × CH),
70.0 (OCH), 61.2 (OCH2), 48.4 (NCH2), 38.6 (CH2), 14.4 (CH3).
13C NMR (D2O, 25 °C): d = 178.1 (CO), 65.3 (OCH), 44.0 (NCH2),
41.9 (CH2).
[Lit.5d 13C NMR (100 MHz, D2O): d = 179.5 (CO), 66.4 (OCH),
45.0 (NCH2), 43.2 (CH2)].
Anal. Calcd for C4H9NO3 (119.1): C, 40.33; H, 7.62; N, 11.76.
Found: C, 40.98; H, 7.38; N, 12.14.
Anal. Calcd for C14H15NO5 (277.3): C, 60.64; H, 5.45; N, 5.05.
Found: C, 60.82; H, 5.60; N, 5.21.
(3S)-4-Amino-3-hydroxybutanoic Acid (ent-1)
Ethyl [(5S)-3-Benzoyl-2-oxo-1,3-oxazolidin-5-yl]acetate (ent-7)
This compound was prepared as 7. Yield: 90%; white solid; mp 79–
81 °C; [a]D30 +43.74 (c = 1.83, CHCl3). Analytical HPLC: Chiracel
OD-H column (250 × 4 mm, Daicel), eluent: i-PrOH–hexane
(20:80), flow rate: 0.8 mL/min, UV detection at 240 nm; tR 61.6
min; er > 99:1.
This compound was prepared as 1. Yield of the crude product: 78%;
mp 198–201 °C; [a]D17 +16.7 (c = 0.41 in H2O) {Lit.6g [a]D22 +20.1
(c = 1.7 in H2O)}. Analytical HPLC of the 4-hydroxy-2-pyrrolidi-
none derivative: Chirapak AD-H column (250 × 4 mm, Daicel),
eluent: EtOH–hexane (5:95), flow rate: 1.0 mL/min, UV detection
at 210 nm; tR 85.1 min; er = 96:4.
Anal. Calcd for C14H15NO5 (277.3): C, 60.64; H, 5.45; N, 5.05.
Found: C, 60.87; H, 5.71; N, 5.22.
Anal. Calcd for C4H9NO3 (119.1): C, 40.33; H, 7.62; N, 11.76.
Found: C, 41.03; H, 7.30; N, 12.17.
[(5R)-2-Oxo-1,3-oxazolidin-5-yl]acetic Acid (9)
Recovery of Diphenyl Diselenide
The N-benzoyl-1,3-oxazolidin-2-one 7 (0.46 g, 1.6 mmol) was heat-
ed at 70 °C with 4 N HCl (6 mL) for 5 h. After cooling the mixture
was extracted with CH2Cl2 (3 × 10 mL) to remove benzoic acid and
then evaporated to yield almost pure 9. Yield 99%; colorless vis-
cous oil; [a]D21 +35.89 (c = 2.02, H2O).
1H NMR (D2O, 25 °C): d = 4.97 (ddt, J = 8.9, 6.6, 6.3 Hz, 1 H,
OCH), 3.71 (dd, J = 9.3, 8.9 Hz, 1 H, NCH2), 3.29 (dd, J = 9.3, 6.6
Hz, 1 H, NCH2), 2.78 (d, J = 6.3 Hz, 2 H, CH2).
The alkaline aqueous extract from the oxidation/cyclization proce-
dure (containing the benzeneseleninate anion) was neutralized with
concd HCl and then acidified by further addition of the acid. The re-
sulting suspension was evaporated and the residue was suspended
in MeOH (50 mL). Hydrazine monohydrate (14.5 mmol, 0.65 mL)
was added gradually to the suspension. Stirring was continued until
diphenyl diselenide was formed, as indicated by the yellow color.
The mixture was then concentrated in vacuo, poured into water (60
mL) and extracted with Et2O (3 × 30 mL). The organic layer was
dried over Na2SO4 and evaporated. Diphenyl diselenide was recov-
ered as a pure compound in 62% yield.
[Lit.6f 1H NMR (90 MHz, D2O): d = 4.85 (m, 1 H, OCH), 3.85 (dd,
J = 9.0 Hz, 1 H, NCH2), 3.40 (dd, J = 9.0, 6.5 Hz, 1 H, NCH2), 2.70
(d, J = 6.0 Hz, 2 H, CH2)].
13C NMR (D2O, 25 °C): d = 173.8 (CO), 161.3 (CO), 73.6 (OCH),
44.9 (NCH2), 38.4 (CH2).
Acknowledgment
Anal. Calcd for C5H7NO4 (145.1): C, 41.38; H, 4.86; N, 9.65.
Found: C, 41.57; H, 5.01; N, 9.49.
Financial support from MIUR, National Project ‘Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni’, FIRB Project
‘Progettazione, Preparazione e Valutazione Biologica e Farmacolo-
gica di Nuove Molecole Organiche Quali Potenziali Farmaci Inno-
vativi’, Consorzio CINMPIS and the University of Perugia, Progetti
di Ateneo, is gratefully acknowledged.
[(5R)-2-Oxo-1,3-oxazolidin-5-yl]acetic Acid (ent-9)
This compound was prepared as 9. Yield: 99%; colorless viscous
oil; [a]D27 –35.51 (c = 1.36, H2O).
Synthesis 2005, No. 4, 579–582 © Thieme Stuttgart · New York

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M. Tiecco et al.
PAPER
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