Stereoselective synthesis of (S)-oxiracetam and (S)-GABOB from (R)-glyceraldehyde acetonide

Article abstract of DOI:10.1016/j.tetlet.2013.03.035

Synthetic routes to (S)-oxiracetam and (S)-GABOB have been developed starting from (R)-glyceraldehyde acetonide through its conversion to an appropriate aldehyde intermediate followed by reductive amination using glycinamide hydrochloride/benzyl amine and subsequent chemical transformations.

Full text of DOI:10.1016/j.tetlet.2013.03.035

Tetrahedron Letters 54 (2013) 2637–2640
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Stereoselective synthesis of (S)-oxiracetam and (S)-GABOB from
(R)-glyceraldehyde acetonide
⇑
Ishita Sanyal, Brajesh Shukla, Piyali Deb Barman, Asish Kumar Banerjee
Department of Chemistry, CSIR – Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic routes to (S)-oxiracetam and (S)-GABOB have been developed starting from (R)-glyceraldehyde
acetonide through its conversion to an appropriate aldehyde intermediate followed by reductive amina-
tion using glycinamide hydrochloride/benzyl amine and subsequent chemical transformations.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 4 January 2013
Revised 5 March 2013
Accepted 7 March 2013
Available online 15 March 2013
Keywords:
Oxiracetam
GABOB
(R)-Glyceraldehyde acetonide
Glycinamide hydrochloride
Reductive amination
Oxiracetam (1) (Fig. 1) having a b-hydroxy-
c
-lactam core struc-
importances. We report herein, a divergent route toward the ster-
eoselective total synthesis of (S)-oxiracetam and (S)-GABOB start-
ing from easily available (R)-glyceraldehyde acetonide as chiral
synthon.
ture, is a highly effective nootropic drug used in the treatment of
Alzheimer’s disease.1 Clinical findings reveal that it enhances hip-
pocampal synaptic transmission2 due to the activation of excit-
atory amino acid receptors and has positive effects on logical
performance, attention/concentration, memory, and orientation
on chronic use.3 Patients suffering from exogenic post-concussion
syndrome and other dementias or organic brain syndromes feel
an improvement after treatment with oxiracetam without any side
effects.4 Considering the importance of the compound, several re-
ports5 on the synthesis of enantiomerically pure oxiracetam (1)
and analogues as well as some of their patents6 have been
documented.
In a retrosynthetic analysis (Scheme 1) we envisioned that (S)-
oxiracetam (1) could be obtained from the appropriately protected
carboxylic acid 3 by activation of the carboxylic acid group fol-
lowed by hydrogenation and spontaneous cyclization. The pro-
tected carboxylic acid, in turn, could be acquired from the alkene
4 through protection of the amine, dihydroxylation of the olefin
moiety, oxidative cleavage of the diol followed by oxidation of
the generated aldehyde. The alkene 4 could be realized by reduc-
tive amination of the intermediate aldehyde 5, which could be
derived from (R)-glyceraldehyde acetonide 6. On the other hand,
(S)-GABOB (2) could be achieved by hydrogenolysis of the
protected carboxylic acid 7, which is expected to be generated
from the alkene 8 by involving a similar procedure as described
for the synthesis of 3 from 4. Furthermore, the alkene 8 should
be obtained by reductive amination of the aldehyde 5.
The c-amino-b-hydroxybutyric acid (GABOB) (2) (Fig. 1) is an
unusual amino acid present in a family of marine cyclic peptides,
possessing antitumor and antifungal activities7 and behaves as
an agonist of
c-amino-butyric acid (GABA). It functions in the
mammalian central nervous system as a neuromodulator having
hypotensive and antiepileptic activity.8 It has also been used as a
precursor of some heterocycles, which act as GABA-receptor ago-
nists.9 Reported syntheses of enantiomerically pure GABOB involve
resolution of racemic substrates,10 enzymatic or microbial tech-
niques,11 and asymmetric syntheses involving the use of chiral cat-
alysts12 and chiral non-racemic starting materials.13 Nevertheless,
research interest for the synthesis of oxiracetam and GABOB con-
tinues unabated due to their biological and pharmacological
HO
O
H2N
COOH
N
OH
NH2
O
(S)-GABOB (2)
(S)-Oxiracetam (1)
⇑
Corresponding author. Tel./fax: +91 33 24292422.
E-mail address: ashisbanerjee@iicb.res.in (A.K. Banerjee).
Figure 1. Structure of (S)-oxiracetam (1) and (S)-GABOB (2).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.035

2638
I. Sanyal et al. / Tetrahedron Letters 54 (2013) 2637–2640
HO
H2N
H2N
N
CO2H
N
H
O
N
O
Cbz OBn
O
OBn
NH2
3
4
O
(S)-Oxiracetam (1)
O
OHC
O
CHO
OBn
6
5
Bn
Bn
N
H
N
CO2H
H2N
CO2H
OBn
Cbz OBn
OH
8
7
(S)-GABOB (2)
Scheme 1. Retrosynthetic plan for (S)-oxiracetam and (S)-GABOB.
O
O
b
a
O
O
O
O
CHO
c
OH
OBn
6
9a : 9b = anti : syn = 95 : 5
10
HO
OHC
HO
d
OBn
OBn
5
11
H2N
H2N
e
f
N
N
H
O
Cbz OBn
O
OBn
12
4
HO
g
H2N
h
O
N
CO2H
N
O
Cbz OBn
NH2
3
O
(S)-Oxiracetam (1)
Scheme 2. Reagents and conditions: (a) allyl bromide, Zn dust, THF, rt, 4 h, overall yield 84%; (b) BnBr, NaH, DMF, 0 °C to rt, 14 h, 85%; (c) 80% AcOH, rt, 24 h, 90%; (d) NaIO4,
MeOH–H2O (4:1), rt, 2 h, 82%; (e) glycinamide HCl, Et3N, NaCNBH3, MeOH–Et2O, 0 °C to rt, 4 h, 80%; (f) CbzCl, NaHCO3, EtOH–H2O (2:1), 0 °C to rt, 3 h, 90%; (g) (i) OsO4, NMO,
acetone–H2O (3:1), rt, 14 h, (ii) NaIO4, MeOH–H2O (4:1), rt, 2 h, (iii) NaClO2, 20% NaH2PO4ꢀ2H2O, tBuOH, 0 °C to rt, 4 h (70% over three-steps); (h) (i) EDCꢀHCl, pentafluoro
phenol, DCM, rt, 14 h, (ii) H2, 10% Pd/C, MeOH, 12 h, 72%.
Following the above retrosynthetic analysis, (R)-glyceraldehyde
acetonide (6)14 was subjected to Zn-mediated allylation to furnish
the anti and syn hydroxyalkenes (9a and 9b) as a diastereomeric
mixture (dr = 95:5, 84% overall yield)15 (Scheme 2) and the major
isomer 9a was separated by flash chromatography in 78% yield.
Then, 9a was protected as its benzyl derivative 1015b followed by
treatment with 80% AcOH to furnish the diol 11,15b which upon
oxidative cleavage16a using NaIO4 generated the key aldehyde
intermediate 5.16a,b Reductive amination of 5 with glycinamide
hydrochloride17 using Et3N and NaCNBH3 furnished the amide 4.
Attempted Osmium-catalyzed dihydroxylation of the olefin 4 led
to an intractable mixture.18 However, the amino group was pro-
tected as its carbamate derivative with CbzCl, NaHCO3 in aqueous
EtOH15 to furnish 12 in 90% yield. The 1H and 13C NMR spectra of
12 revealed that the compound existed as a mixture of rotamers
due to the presence of the N-Cbz group. Similar kind of NMR spec-
tral characteristics was observed for the N-Cbz protected com-
pounds prepared in the subsequent steps. Efforts to convert 12
into the carboxylic acid 3 in a single step with RuCl3, NaIO4 sys-
tem19 afforded a mixture of unidentified products. An alternative
three-step procedure was carried out involving dihydroxylation
of the terminal double bond of 12 with OsO4, NMO in aqueous ace-
tone followed by oxidative cleavage using NaIO4 in MeOH–H2O
(4:1) affording the corresponding aldehyde and further oxidation
by NaClO2 in the presence of 20% aqueous NaH2PO4ꢀ2H2O in tBuOH
to produce 3 in 70% overall yield. Hydrogenolysis of 3 using
20 mol % of Pd/C (10%) catalyst under 1 atm pressure failed to af-
ford the desired cyclized product (S)-oxiracetam (1). However,
activation of the acid group as its pentafluorophenyl ester20 fol-
lowed by catalytic hydrogenolysis using H2 over Pd/C (10%) re-
sulted in spontaneous lactamization to afford the target
compound (S)-oxiracetam (1). The spectral data and optical rota-
tion value of 1 were in good accordance with those of the reported
values.21
For the synthesis of (S)-GABOB (2), the aldehyde 5 was sub-
jected to reductive amination22 with benzylamine using sodium

I. Sanyal et al. / Tetrahedron Letters 54 (2013) 2637–2640
2639
Bn
Bn
Bn
b
c
N
CO2H
a
N
N
H
5
Cbz OBn
Cbz OBn
OBn
7
13
8
Scheme 3. Reagents and conditions: (a) BnNH2, Na(OAc)3BH, ClCH2CH2Cl, rt, 4 h, 78%; (b) CbzCl, NaHCO3, EtOH–H2O (2:1), 0 °C to rt, 3 h, 92%; (c) (i) OsO4, NMO, acetone–H2O
(3:1), rt, 14 h, (ii) NaIO4, MeOH–H2O (4:1), rt, 2 h, (iii) NaClO2, 20% NaH2PO4ꢀ2H2O, tBuOH, 0 °C to rt, 4 h, 77% over three-steps.
Table 1
Formation of different products on hydrogenolysis
BnO
HO
H2, 10% Pd/C
EtOAc, 12 h
Bn
N
CO2H
or
H2N
CO2H
or
O
O
N
Bn
14
N
Bn
15
Cbz OBn
OH
7
(S)-2
Entry
Mol % of 10% Pd/C
Product
Yielda (%)
1
2
3
10
40
80
14
14,15
(S)-2
95
40,45
87
The significance of bold values indicates the product numbers.
a
Isolated yield.
triacetoxyborohydride in ClCH2CH2Cl to afford 8 in 78% yield
(Scheme 3). Carbamate protection of the amine group was fol-
lowed to generate 13 in 92% yield. The olefin 13 was transformed
to the carboxylic acid 7 (77%) involving a three-step procedure
using OsO4, NMO catalyzed dihydroxylation, oxidative cleavage
of the intermediate diol with NaIO4 in MeOH–H2O followed by fur-
ther oxidation with NaClO2 in the presence of 20% aqueous NaH2-
References and notes
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t
PO4ꢀ2H2O in BuOH.
Deprotection of the tri-protected carboxylic acid 7 was carried
out in different conditions. The product formation depends on
the mol % of Pd/C (10%) catalyst used under 1 atm pressure. On
using 10 mol % catalyst, only the Cbz group was deprotected giving
rise to the cyclized product 14,23 whereas hydrogenolysis with
40 mol % catalyst, resulted in the mixture of the cyclized products
14 and 15.5f Finally, using 80 mol % of the catalyst our desired
product (S)-GABOB (2) was obtained. The spectral data and optical
rotation value of 2 were in good accordance with those of the re-
ported values.21 The results have been summarized in Table 1.
In conclusion, the stereoselective syntheses of (S)-oxiracetam
and (S)-GABOB starting from (R)-glyceraldehyde acetonide in-
volved operationally simple and high-yielding steps. Reductive
amination of the aldehyde followed by generation of the carboxylic
acid group from the olefin moiety, activation of the carboxylic acid
group, deprotection, and concomitant cyclization led to the forma-
tion of (S)-oxiracetam. However, the (S)-GABOB was obtained,
when the carboxylic acid group was unactivated and hydrogenoly-
sis of the protecting groups was carried out using 80 mol % of Pd/C
catalyst.
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Acknowledgment
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The authors (I.S. and P.D.B.) acknowledge the Council of Scien-
tific and Industrial Research (CSIR), Govt. of India for providing Se-
nior Research Fellowship to them.
Supplementary data
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1996, 7, 2411–2416; (b) Song, C. E.; Lee, J. K.; Kim, I. O.; Choi, J. H. Synth.
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Supplementary data (experimental procedure, characterization
data, 1H and 13C NMR spectra for all important compounds) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.03.035.

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I. Sanyal et al. / Tetrahedron Letters 54 (2013) 2637–2640
Marini, F.; Santi, C. Synthesis 2005, 579–582; (f) Shioiri, T.; Sasaki, S.; Hamada,
After stirring for 10 min, pentafluoro phenol (310 mg, 1.69 mmol) was added
and the mixture was stirred for 14 h at room temperature. It was washed
subsequently with 1 N HCl (10 mL), brine (2 ꢁ 10 mL), and dried (Na2SO4) and
the solvent was evaporated under reduced pressure. To a solution of this crude
ester in MeOH (15 mL) was added 10% Pd/C (244 mg, 20 mol %). The mixture
was degassed and hydrogenated under 1 atm pressure for 12 h. The catalyst
was filtered off and the solvent was concentrated under reduced pressure. The
crude product was purified by column chromatography over silica gel (60–120
mesh) using MeOH–CHCl3 (1:4) as eluent to yield (S)-oxiracetam (1) (128 mg,
Y. Arkivoc 2003, II, 103–122; (g) Sasaki, S.; Hamada, Y.; Shioiri, T. Synlett 1999,
453–455; (h) Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980, 102, 6304–6311; For
9
a review see: (i) Ordoñez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3–
99.
14. Prepared from D-Mannitol, see: Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.;
Phillips, J. L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J. Org. Chem.
1991, 56, 4056–4058.
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9871–9880; (c) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104–6107; (d)
Kamal, A.; Vangala, S. R. Tetrahedron 2011, 67, 1341–1347; (e) Kamal, A.;
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2589–2593; (f) Nagaiah, K.; Srinivasu, K.; Kumar, S. P.; Basha, J.; Yadav, J. S.
Tetrahedron: Asymmetry 2010, 21, 885–889.
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DeBaillie, A. C. J. Am. Chem. Soc. 2006, 128, 4936–4937.
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2001, 3, 791–794.
18. Dihydroxylation of 4 was tried with OsO4, NMO, acetone, H2O or with OsO4,
(DHQD)2PYR, K2CO3, K3Fe(CN)6, tBuOH, H2O system. The reason for obtaining
intractable mixture may be due to oxidation of the free amino group, indicating
possible requirement of the NH-protection.
19. Reagents used were RuCl3, NaIO4, CH3CN–H2O–EtOAc, see: Zimmermann, F.;
Meux, E.; Mieloszynski, J.-L.; Lecuire, J.-M.; Oget, N. Tetrahedron Lett. 2005, 46,
3201–3203.
72%) as white solid. Mp 134–135 °C, {lit.5c mp 135–136 °C};½a 2D5
ꢃ35.6 (c 0.28,
ꢂ
H2O), {lit.5c
[a
]
D
ꢃ38.5 (c 1.0, H2O)}; IR (KBr): 3420, 3345, 1672, 1485, 1395,
1306, 1081 cmꢃ1 1H NMR (600 MHz, DMSO-d6): d 2.06 (dd, J = 2.4, 16.8 Hz,
;
1H), 2.55 (dd, J = 6.6, 16.8 Hz, 1H), 3.14 (dd, J = 1.8, 9.6 Hz, 1H), 3.62 (dd, J = 5.4,
10.2 Hz, 1H), 3.65 (d, J = 16.8 Hz, 1H), 3.85 (d, J = 16.8 Hz, 1H), 4.29 (m, 1H),
5.22 (d, J = 4.2 Hz, 1H), 7.11 (s, 1H), 7.31 (s, 1H); 13C NMR (150 MHz, DMSO-d6):
d 40.3, 44.7, 56.7, 63.3, 169.7, 172.8; HRMS (ESI): m/z [M+Na]+ calcd for
C6H10N2NaO3: 181.0589; found: 181.0626. For 2: To a solution of 7 (400 mg,
0.92 mmol) in EtOAc (20 mL) was added 10% Pd/C (785 mg, 0.74 mmol,
80 mol %) and the mixture was degassed and hydrogenated under 1 atm
pressure of H2 gas for 12 h. The catalyst was filtered off and the solvent was
concentrated under reduced pressure to yield (S)-GABOB (2) (95 mg, 87%) as
white solid, which was recrystallized from EtOH–H2O. Mp 200–202 °C, {lit.13e
mp 198–201 °C};½a D27
ꢂ
+17.2 (c 1.23, H2O), {lit.13e};½a D25
ꢂ
+16.7 (c 0.41, H2O)}; 1
H
NMR (600 MHz, D2O): d 2.44 (d, J = 6.6 Hz, 2H), 3.97 (dd, J = 13.2, 9.6 Hz, 1H),
3.18 (dd, J = 13.2, 3.0 Hz, 1H), 4.19–4.23 (m, 1H); 13C NMR (150 MHz, D2O): d
42.3, 44.1, 65.5, 178.6; HRMS (ESI): m/z [M+Na]+ calcd for C4H9NNaO3:
142.0480; found: 142.0462.
20. Ghorai, A.; Gayen, A.; Kulsi, G.; Padmanaban, E.; Laskar, A.; Achari, B.;
Mukhopadhyay, C.; Chattopadhyay, P. Org. Lett. 2011, 13, 5512–5515.
22. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J.
Org. Chem. 1996, 61, 3849–3862.
21. Experimental and spectral data for 1: To
a stirred solution of 3 (450 mg,
1.13 mmol) in DCM (60 mL) at 0 °C was added EDCꢀHCl (258 mg, 1.35 mmol).
23. Chen, Z.; Chen, Z.; Jiang, Y.; Hu, W. Tetrahedron 2005, 61, 1579–1586.