Direct synthesis of polybenzylated glutamic acid monoesters: Disambiguation of N, N -dibenzylglutamic acid α- And γ-benzyl esters

Article abstract of DOI:10.1055/s-0034-1378532

In this study, we explored the regioselective benzylation of l-glutamic acid under substoichiometric amounts of the alkylating agent. Our results demonstrate unambiguously that N,N-dibenzylglutamic acid γ-benzyl ester was not obtained by direct benzylatio

Full text of DOI:10.1055/s-0034-1378532

2166▌
LETTER
lDettierrect Synthesis of Polybenzylated Glutamic Acid Monoesters:
Disambiguation of N,N-Dibenzylglutamic Acid α- and γ-Benzyl Esters
Direct Synthesis of Polybenzylated Glutamic Acid Monoesters
Gastón Silveira-Dorta, Víctor S. Martín, José M. Padrón*
Instituto Universitario de Bio-Orgánica ‘Antonio González’ (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN),
Universidad de La Laguna, C/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain
Fax +34(922)318571; E-mail: jmpadron@ull.es
Received: 15.05.2014; Accepted after revision: 25.06.2014
O
Abstract: In this study, we explored the regioselective benzylation
CO2Bn
CO2Bn
HO
of L-glutamic acid under substoichiometric amounts of the alkylat-
ing agent. Our results demonstrate unambiguously that N,N-diben-
zylglutamic acid γ-benzyl ester was not obtained by direct
benzylation of L-glutamic acid as reported by other authors. Instead,
under such reaction conditions N,N-dibenzylglutamic acid α-benzyl
ester was obtained.
H
NBn2
NBn2
4
3
ref. 6
ref. 3b
Key words: amino acids, benzylation, disambiguation, protecting
groups, regioselectivity
HO
OH
ref. 8
BnO2C
CO2Bn
NBn2
5
NBn2
Amino acids represent a natural source of enantiomerical-
ly pure building blocks useful in organic synthesis. In this
particular context, L-aspartic and L-glutamic acids are po-
tentially valuable providing that the two carboxyl groups
could be differentiated. Within our program directed at
the discovery of biologically active sphingosine ana-
logues,1 we have developed general methodologies for the
synthesis of saturated2 and unsaturated3 lipidic α-amino
acids. The latter method is based on the regioselective ω-
reduction of N,N-di-Boc-aspartic or glutamic dialkyl es-
ters. The resulting semialdehydes have proven to be ver-
satile intermediates in the synthesis of biologically
relevant substances.4
2
this work
ref. 6
BnO2C
CO2H
ref. 10
HO2C
CO2H
NH2
NBn2
7
X
L-glutamic acid (1)
this work
ref. 9
HO2C
CO2Bn
BnO2C
CO2H
NH2
NBn2
In addition to Boc, other suitable amino protecting groups
have been explored extensively, from which the benzyl
group remains as highly useful in synthetic organic chem-
istry.5 In the particular case of L-glutamic acid (1), meth-
ods have been reported to prepare diverse N,N-
dibenzylamino acid derivatives (Scheme 1). Thus, the
perbenzylation of L-glutamic acid (1) with excess of BnBr
under basic conditions is a commonly used process to ob-
tain derivative 2 in 61–96% yield.6 The regioselective re-
duction of perbenzylated L-glutamic acid 2 affords the
corresponding γ-aldehyde of N,N-dibenzylglutamic acid
α-benzyl ester (3).3b Although in less extent, the latter has
been used as intermediate for the preparation of biologi-
cally significant compounds.7 Additionally, perbenzylat-
ed L-glutamic acid 2 served also as the precursor of γ-
alcohol 46 and diol 58 (Scheme 1). Similarly, the γ-benzyl
ester of L-glutamic acid 6 is prepared typically under acid-
ic conditions in 84% yield.9
8
6
Scheme 1 Reported methods for the synthesis of (poly)benzylated
L-glutamic acid derivatives
Recently, the use of N,N-dibenzylglutamic acid γ-benzyl
ester (7) in the synthesis of schulzeines was reported.10
However, a complete experimental procedure for its
preparation and full characterization with relevant spec-
troscopic data were never reported in the literature. After
a thorough search, we found that the preparation of com-
pound 7 in 18% yield was described in a PhD thesis.11 The
low yield of the reaction together with the synthetic versa-
tility of intermediate 7 encouraged us to study the process
in more detail.
In this study, we investigated the benzylation reaction of
L-glutamic acid and the unexpected results obtained when
we tried to repeat the procedure reported for the synthesis
of 7.
1
A direct comparison of the H NMR spectra of com-
SYNLETT 2014, 25, 2166–2170
Advanced online publication: 13.08.2014
DOI: 10.1055/s-0034-1378532; Art ID: st-2014-b0423-l
© Georg Thieme Verlag Stuttgart · New York
pounds 2 and 3 was reported earlier by us,3b and the
1H NMR spectrum for compound 7 was described by
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Direct Synthesis of Polybenzylated Glutamic Acid Monoesters
2167
Akkarasamiyo11 that showed marked differences in the In order to synthesize compound 7, we envisioned a strat-
signals of the benzyl ester protons PhCH2O (Figure 1). In- egy based on the widely known process to prepare deriv-
deed, the 1H NMR spectrum reported for 7 showed the ap- ative 6 (Scheme 3). Our first attempt to prepare 7 was the
pearance of the α-ester derivative and not the γ-ester benzylation of 6 under basic conditions. However, the de-
analogue. The same typical 1H NMR signal was found for sired compound could not be obtained. Alternatively,
the reported intermediate in the synthesis of schulzeines.10 compound 2 was treated under saponification conditions
to give diacid 9 in high yield. Selective benzylation of 9
under acidic conditions led to the expected compound 7 in
1
70% yield. This time the H NMR spectrum was consis-
tent, as shown in Figure 2.
a
BnO2C
CO2H
NH2
BnO2C
CO2H
NBn2
X
b
7
6
2
Figure 1 1H NMR signals of benzylic protons (PhCH2O) in L-glu-
tamic acid benzyl esters. (a) 2; (b) compound 43 in ref. 11; (c) com-
pound 11 in ref. 10a (Supporting Information); d) compound 13 in ref.
10b (Supporting Information).
c
BnO2C
CO2Bn
NBn2
HO2C
CO2H
NBn2
9
8
At this point, we suspected that the compound resulting
from the experimental conditions described by Ak-
karasamiyo was N,N-dibenzylglutamic acid α-benzyl es-
ter (8). This subtle difference was unnoticed for the
authors since the N,N-dibenzylglutamic acid monobenzyl
ester was transformed into a 3-amino-2,6-piperidinedione
intermediate. The reaction conditions are leading to the
synthesis, and the undoubtedly identification of com-
pounds 7 and 8 will be discussed below.
d
HO2C
CO2Bn
NBn2
Scheme 3 Reagents and conditions: (a) BnCl (2.5 equiv), K2CO3,
KOH, MeOH–H2O (1:1), Δ, overnight; (b) NaOH, MeOH, Δ, 20 h,
90%; (c) CH3SO3H, BnOH, toluene, Δ, 5 h, 70%; (d) BnBr (1.1 equiv),
K2CO3, KOH, MeOH–H2O (1:1), 70 °C, 5 h, 25%.
As shown in Scheme 2, when we repeated the benzylation
of L-glutamic acid (1) under the experimental conditions
described by Akkarasamiyo,10 N,N-dibenzylglutamic acid
α-benzyl ester (8) was obtained in 20% yield (Table 1, en-
try 1). As a byproduct of the reaction, the perbenzylated
derivative 2 was isolated in 1% yield. More important,
compound 7 was not obtained. Subsequent selective re-
duction of the carboxylic acid group of 8 using standard
methods allowed us to obtain compound 4. The spectro-
scopic data was in full agreement with that reported in the
literature. Consequently, the compound synthesized using
the reported protocol is the α-benzyl ester 8 and not the γ-
benzyl ester 7.
Interestingly, we found that upon treatment of 9 under the
conditions reported by Akkarasamiyo, but using instead
1.1 equivalents of benzyl bromide, the α-benzyl ester 8
was obtained in 25% yield (Scheme 3). This intriguing re-
sult, due to the similarity with that obtained by the direct
benzylation of L-glutamic acid (1) with 3.5 equivalents of
benzyl bromide, together with the low yield obtained led
us to explore the influence of the reaction conditions.
The reaction conditions for the perbenzylation of 1 de-
scribed in the literature uses indistinctly benzyl chloride
or benzyl bromide as alkylating agents and NaOH or
KOH as base (together with K2CO3). In addition, some
methods described the use of MeOH as cosolvent. As ad-
ditional factors in our study, we selected time and tem-
perature. With these premises we ran a set of reactions,
and the results are given in Table 1.
HO2C
CO2Bn
NBn2
HO2C
CO2H
NH2
a
8
1
X
b
a
We speculated that under the aforementioned perbenzyla-
tion conditions the partial hydrolysis of 2 might occur.
This might be an explanation for the low yields obtained
by Akkarasamiyo. Thus, initially, we studied the benzyla-
tion process at shorter reaction times (5 h) and lower tem-
perature (70 °C). The results (Table 1, entries 2 and 3)
showed that lower reaction times and temperature benefit
the process since compounds 8 and 2 are obtained in
slightly higher yields, while compound 7 is obtained as
minor compound. Under these conditions, the base KOH
seems to increase the overall yield while the halide BnBr
CO2Bn
NBn2
BnO2C
CO2H
NBn2
HO
4
7
Scheme 2 Reagents and conditions: (a) ref. 10 [BnCl (3.5 equiv),
K2CO3, KOH, MeOH–H2O (1:1), Δ, overnight], 20%; (b) BH3–SMe2,
THF, 0 °C, 4 h, 86%.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2166–2170

2168
G. Silveira-Dorta et al.
LETTER
Figure 2 Partial 1H NMR spectra of compounds 2, 7, and 8
favors the formation of 2. However, at longer reaction no improvement in yield is obtained, regardless of the oth-
times the effect on the outcome of the reaction was inde- er reaction conditions. Similarly, a MeOH–H2O (3:1)
pendent of the base or halide used (Table 1, entries 7–10). mixture (Table 1, entries 12 and 13) produced 8 in low
The reduction of the amount of alkylating agent (Table 1, yields at low reaction times. To our surprise, when we in-
entry 4) is concomitant with a decrease in yield. Another creased the reaction time (Table 1, entry 14), the benzyla-
point of attention is the solvent. When reducing the per- tion of 1 to give 8 proceeded in 73% yield giving N,N-
centage of MeOH in the mixture (Table 1, entries 5–11) dibenzylglutamic acid α-methyl ester as side product of
Table 1 Effect of the Reaction Conditions in the Polybenzylation of L-Glutamic Acid (1)
Entry
Reaction conditionsa
Yield (%)
Base (2.3 equiv) 8
MeOH (%) Time (h)
Temp (°C)
BnX (equiv)
X
2
7
1b
2
50
50
50
50
25
25
25
25
25
25
0
overnight
reflux
70
3.5
3.5
3.5
3
Cl
Cl
Br
Cl
Br
Br
Br
Cl
Cl
Br
Cl
Br
Br
Br
NaOH
KOH
KOH
NaOH
KOH
KOH
NaOH
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
20
25
30
12
n.d.
19
12
12
17
13
9
1
7
n.d.c
1
5
3
5
70
20
2
4
4
5
70
n.d.
n.d.
1
5
2
50
3
n.d.
26
19
14
16
19
13
10
10
n.d.
6
2
reflux
80
4
7
12
3.25
3.25
3.25
3.25
3
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
7
8
12
80
9
12
80
10
11
12
13
14d
12
80
overnight
70
75
75
75
2
2
8
reflux
50
3
14
23
73
4
reflux
4
1
a 1 (1 equiv), K2CO3 (2.3 equiv), solvent (H2O–MeOH for 0.23 M).
b Reaction conditions of ref. 11.
c n.d. = not detected.
d The α-methyl ester was obtained in 10% yield as a byproduct.
Synlett 2014, 25, 2166–2170
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Synthesis of Polybenzylated Glutamic Acid Monoesters
2169
was extracted with EtOAc (3 × 50 mL). The organic extracts were
combined, and the solvent was removed under reduced pressure.
The solid residue was recrystallized from MeOH to give 9 as a white
the process (10% yield). For processes where the α-ester
should be transformed and thus transesterification is not
an inconvenience, the yield adds up to 83%.
solid (5.8 g, 90% yield): mp 228–229 °C; [α]25 –71.3 (c 1.03,
D
DMSO). 1H NMR (400 MHz, DMSO-d6): δ = 1.84–1.90 (m, 2 H),
2.13–2.21 (m, 1 H), 2.29–2.36 (m, 1 H), 3.12–3.16 (m, 1 H), 3.59
(d, J = 14.2, 2 H), 3.80 (d, J = 14.2, 2 H), 7.20–7.32 (m, 10 H) ppm.
13C NMR (100 MHz, DMSO-d6): δ = 24.2, 30.6, 50.0, 59.86, 126.3,
128.2, 128,4, 139.6, 173.6, 174.05 ppm. IR: νmax = 3340.3–2750.4,
2672.3–2172.5, 1729.3, 1612.6, 1452.6, 1245.5 cm–1. ESI-HRMS:
m/z calcd for C19H20NO4 [M + 2Na]+ 372.1188; found: 372.1180.
In summary, we have described a methodology to obtain
both N,N-dibenzylglutamic acid monobenzyl esters 7 and
8 from commercially available L-glutamic acid (1). Both
1
compounds can be differentiated in terms of their H
NMR spectra. The unprecedented compound 7 is reported
and characterized for the first time. The preferred method
to obtain 7 from L-glutamic acid is the three-step process
reported herein. We explored the reaction conditions lead-
ing to the formation of 8. A not optimized 73% yield was
achieved plus 10% yield of the N,N-dibenzylglutamic acid
α-methyl ester.
Acknowledgment
Cofinanced by the EU Research Potential (FP7-REGPOT-2012-
CT2012-31637-IMBRAIN), the European Regional Development
Fund (FEDER), the Spanish Ministerio de Educación (Programa
Campus de Excelencia Internacional CEI10/00018), the Spanish
MINECO (CTQ2011-28417-C02-01 and Instituto de Salud Carlos
III PI11/00840). G.S.-D. thanks the EU Social Fund (FSE) and the
Canary Islands ACIISI for a predoctoral grant.
(2S)-5-(Benzyloxy)-2-(dibenzylamino)-5-oxopentanoic Acid (7)
Methane sulfonic acid (3.6 mmol, 0.2 mL) was added dropwise to a
suspension of 9 (1.0 g, 3 mmol) and benzyl alcohol (4.8 mmol, 0.5
mL) in dry toluene (30 mL). The resulting mixture was heated at re-
flux in a Dean–Stark system for 5 h, after which time it was allowed
to cool to r.t. Then, the solvent was evaporated under reduced pres-
sure. The residue was diluted with H2O (30 mL) and extracted with
Et2O (2 × 20 mL). The combined organic extracts were washed with
brine (30 mL) and dried over MgSO4, filtered, and the solvent was
removed under reduced pressure. The residue was purified by flash
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
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Synlett 2014, 25, 2166–2170
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