Carboxylic Anhydride Synthesis from γ-Benzyl-L-glutamate and Dimethyl Carbonate

Article abstract of DOI:10.1021/acs.orglett.8b03984

A green, environmentally friendly, and nontoxic method was developed to synthesize carboxylic anhydrides (NCAs) from γ-benzyl-l-glutamate (BLG) and dimethyl carbonate (DMC) though two steps: synthesis of N-methoxycarbonyl-γ-benzyl-l-glutamate intermediate (NOM-BLG) and cyclization. The highest yields of NOM-BLG (up to 83.7%) and NCA-BLG (up to 66.7%) were obtained. Most importantly, the use of DMC will open an innovative door to synthesize NCAs.

Full text of DOI:10.1021/acs.orglett.8b03984

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Carboxylic Anhydride Synthesis from γ‑Benzyl‑L‑glutamate and
Dimethyl Carbonate
Zhao Zhang, Kunmei Su, and Zhenhuan Li*
State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on
Separation Membranes, School of Materials, Science and Engineering, School of Environment Science and Chemistry Engineering,
Tianjin Polytechnic University, Tianjin 300387, China
S
* Supporting Information
ABSTRACT: A green, environmentally friendly, and nontoxic
method was developed to synthesize carboxylic anhydrides
(NCAs) from γ-benzyl-L-glutamate (BLG) and dimethyl
carbonate (DMC) though two steps: synthesis of N-methox-
ycarbonyl-γ-benzyl-L-glutamate intermediate (NOM-BLG) and
cyclization. The highest yields of NOM-BLG (up to 83.7%) and
NCA-BLG (up to 66.7%) were obtained. Most importantly, the
use of DMC will open an innovative door to synthesize NCAs.
ith the development of protein-directed evolution
technology,1 the diversity of polypeptides and proteins
qualified as an environmental compound to synthesize various
chemicals such as polycarbonate,24 methyl benzoate, furazoli-
done,25 etc. DMC can also be considered as an effective
carbonylation reagent due to the following advantages
compared with bisarylcarbonates, methyl chloroformate, and
phosgene.26,27 (1) The structure of DMC contains some high
reactivity functional groups, such as −CH3, CH3O−, and
−CO, which are easy to synthesize intermediate products
with amino acid derivatives.28 (2) When the active center site
on the carbonyl group is attacked by a nucleophilic substance,
−CO will be broken and then recombine to a new
substance. After DMC carbonylation, the decomposition
byproduct methanol is convenient to handle.20,29 (3) DMC
is nontoxic, much more economical, safely stored, and utilized.
Therefore, the employment of DMC will open an innovative
door to the synthesis of NCAs.
Herein, we report our preliminary investigation on the
synthesis of NCAs of γ-benzyl-L-glutamate 1 from DMC in
tetrahydrofuran (THF), and a unique NCA synthetic method
that consisted of two steps (Scheme 1) was developed: The
first step is the synthesis of intermediate N-methoxycarbonyl-γ-
benzyl-L-glutamate 3, and then the pure intermediate was
obtained through extraction with hexane or petroleum ether.
The influences of various solvents, different temperatures, and
DMC/amino acids ratios on the yields of the intermediate
were investigated. The second step is the preparation of
corresponding NCA from the cyclization of the intermediate.
It turned out that THF was a good solvent for the following
cyclization reaction due to the poor solubility of NCAs and its
extreme sensitivity to water.
W
from ring-opening polymerization2,3 of carboxylic anhydrides
(NCAs) has been increasingly investigated for various
chemical and biomedical applications,4−6 such as drug delivery,
artificial tissues, etc.7,8 Therefore, it is extremely indispensable
to give more attention to the preparation of NCAs, which are
highly useful monomers for preparing polypeptides.9,10
The original synthesis methods of NCAs and their
applications in the construction of polypeptides were reported
by Leuchs11 in 1906. Subsequently, different synthetic
methods using amino acid derivatives and halogenating agents
(SOCl2, PBr3, PCl3) were developed.12 Other researchers13,14
made a breakthrough on direct NCA synthesis through the
reaction of amino acids with phosgene, triphosgene, or
diphosgene,15 and the various NCAs and well-defined
polypeptides can be obtained from amino acids and phosgene
compounds. However, those methods have many disadvan-
tages and limitations because of their lethal toxicity and highly
corrosive byproduct, HCl.16,17 In some other synthetic routes
to NCA, methyl chloroformate,18 NO/O2,19 and bis(2,4-
dinitrophenyl) carbonate (DNPC)20 were considered as good
cyclization reagents, but they also suffered from the similar
toxicity problems.21 In summary, plenty of restrictions on the
NCA synthetic process still exist, incluing being operationally
difficult, harmful to the human body, incapable of large-scale
production, difficult to obtain high purity products, and so on.
Therefore, it is especially necessary to develop an environ-
mentally friendly22 and nontoxic NCA synthetic route, which
will strongly benefit the technological development of
polypeptides and protein engineering.
Dimethyl carbonate (DMC) is a suitable and desirable
Received: December 13, 2018
candidate as an alternative to phosgene,23 and it is completely
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03984
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
DMSO, and THF, respectively. However, there was a
downward trend of the intermediate yield with an increase in
temperature. This tendency was consistent with the reactivity
of DMC functional groups (−CO, −CH3) at different
temperatures. Namely, carbonylation took place when a
nucleophilic substance mainly attacked the carbonyl carbon
of DMC at low temperature, whereas methylation occurred
when the nucleophilic reagent primarily attacked the methyl
group at high temperature (greater than 90 °C). The highest
reactivity of carbonyl carbon appeared at 100 °C, which was
conducive for reacting with the nitrogen atom in compound 1.
The relationship between intermediate yield and BLG/
DMC mole ratios is listed in Figure 2. When the BLG/DMC
Scheme 1. Reaction Process
The characterized results of 1H NMR, 13C NMR, and
elemental analysis (Supporting Information) were extremely
consistent with the molecular structure of compound 3, which
indicated that the intermediate was successfully synthesized,
and it would be applied to carry out the cyclization reaction to
synthesize NCA. During the conversion process of DMC, there
was the formation of other byproducts from the esterification
reaction of the carboxyl group, the methylation of the nitrogen
atom, and both (Scheme 2), which resulted in a relatively low
yield of the intermediate.
Scheme 2. Products in the Reaction
Figure 2. Relationship between the isolated yield (%) and BLG/
DMC mole ratios of compound 3 in two solvents.
molar ratio was 1:2, the highest yields achieved were 83.7 and
74.6% in DMF and DMSO, respectively. The slightly excess of
DMC was indispensable because it would partially volatilize at
100 °C (boiling point 90 °C). Theoretically, there was a
competitive reaction between methylation and carbonylation
of the nitrogen atom in compound 1. The electrophilicity of
carbonyl groups was much higher than that of methyl group;
therefore, the carbonyl groups had advantages to react with the
nitrogen atom. On the other hand, excess DMC probably
reacted with the carboxyl group in compound 1 to form the
corresponding ester, but it was detrimental to the cyclization
reaction in the next step. In addition, the unfavorable water
byproduct would cause the hydrolysis of DMC and BLG,
resulting in significant reduction in the yield of the
intermediate. Therefore, it turned out that the optimum
BLG/DMC mole ratio was 1:2.
As shown in Figure 1, there was no intermediate formation
in three solvents when the temperature was less than 70 °C.
The maximum yield reached 83.7, 73.4, and 60.3% in DMF,
The influence of various solvents on the intermediate yield
was investigated, as indicated in Table 1. The different reaction
effects were attributed to the consequence of solvent polarities
and solubility of compound 1. The order of the solvents’
polarity strength is as follows: DMSO, DMF, 1,4-dioxane,
THF, cyclohexanone, ethyl acetate, dichloromethane and
cyclohexane. The strongly polar DMF and DMSO could
significantly improve the solubility of compound 1 at the same
reaction temperature and time. The formation of a
homogeneous solution system promoted the formation of an
intermediate. However, compound 1 did not dissolve in these
solvents with lower polarity during the reaction, which resulted
in no intermediate being obtained in reaction systems. The
Figure 1. Relationship between the isolated yield (%) and
temperature (°C) of compound 3 in three solvents.
B
DOI: 10.1021/acs.orglett.8b03984
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
instability of compound 4. In addition, the benzyl ester
underwent hydrolysis, resulting in the formation of benzyl
alcohol byproduct.
A novel NCA synthetic technology has been developed by
employing DMC instead of phosgene as carbonyl reagent, and
this method was environmentally friendly and effortless to
operate. The new NCA synthetic method from DMC and
amino acid consisted of two steps.
For the carbonylation of DMC with amino acid, the
optimized synthesis conditions played a key role in the
intermediate product selectivity. When the ratio of BLG and
DMC was equal to 1:2, the reaction was carried out at 100 °C
for 5 h in aprotic polar solvents, in which the highest yield of
83.7% for compound 3 was obtained in DMF. In the
cyclization reaction of compound 3, glacial acetic acid was
employed as cyclization reagent to synthesize compound 4,
and a maximum yield of 66.7% was obtained after cyclization at
90 °C for 8 h.
Although there are still some disadvantages to this process,
such as low yield of intermediate and NCA, formation of some
byproducts, requirement of an anhydrous environment, etc.,
this method was indeed highly innovative. Furthermore, the
employment of DMC will open an innovative door to the
synthesis of NCAs. The power of this synthetic method may be
applicable to polypeptide preparation and protein evolution in
the near future.
Table 1. Relationship between the Isolated Yield (%) of
Compound 3 and Various Solvents
entry
temp (°C)
solvent
DMF
DMSO
time (h)
yield (%)
1
2
3
4
5
6
7
8
100
100
100
100
100
100
100
100
5
5
5
5
5
5
5
5
83.7
73.4
60.3
29.3
24.4
THF
1,4-dioxane
cyclohexanone
ethyl acetate
dichloromethane
cyclohexane
compound 3 formation reaction was significantly dependent
on the properties of solvents, and the weak tendency of the
self-transfer proton and the strong ability of dissolution would
improve the yield of compound 3.
The same peak positions and molecular fragments of NCA-
BLG 4 were detected in the reaction solution, which were
perfectly consistent with the standard sample. Therefore, it
could be confirmed that compound 4 has been successfully
prepared. Other peaks at 5.136 min were attributed to the
benzyl alcohol formation from the hydrolysis of compound 3,
which was further confirmed by mass spectrometry (Support-
ing Information).
To obtain the pure product compound 4, it was quite
essential to strictly control the reaction conditions. Some
challenges existed during the synthesis process, such as the
immense difficulties preparing a stable cyclic compound, the
extreme sensitivity to aqueous environments, and the strong
probability of ring-opening polymerization.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03984.
As described in Figure 3, the effect of different temperatures
on the efficiency of the cyclization reaction has been
Experimental procedures and compound characteriza-
tion data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhenhuanli1975@aliyun.com or lizhenhuan@tjpu.
edu.cn.
ORCID
Zhenhuan Li: 0000-0002-4797-6663
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support from the
National Natural Science Foundation of China (Nos.
21676202 and 21376177).
Figure 3. Relationship between the isolated yield (%) and reaction
time of compound 4 at different temperatures.
REFERENCES
■
(1) Dietert, R. R.; Dietert, J. M. Healthcare 2015, 3, 100−129.
(2) Hadjichristidis, N.; Iatrou, H.; Pitsikalis, M.; Sakellariou, G.
Chem. Rev. 2009, 109, 5528.
investigated. The results indicated that both low temperature
and high temperature were not conducive to the cyclization
reaction, and there was almost no compound 4 formation
under low-temperature and high-temperature conditions. After
8 h reaction at 90 °C, a maximum yield of 66.7% was detected.
There was a downward tendency as the reaction time
increased. The cyclization reaction was limited at low
temperature, whereas the ring-opening polymerization reaction
was prone to occur at high temperature due to the extreme
(3) Wang, C.; Ma, Y.; Su, K.; Li, Z. Mater. Lett. 2018, 231, 201−204.
(4) Lu, T. C.; Sun, J.; Dong, X.; Chen, X.; Wang, Y.; Jing, X. Sci.
China, Ser. B: Chem. 2009, 52, 2033−2037.
(5) Deming, T. J. Prog. Polym. Sci. 2007, 32, 858−875.
(6) Kricheldorf, H. R. Angew. Chem., Int. Ed. 2006, 45, 5752−5784.
(7) Appoh, F. E.; Thomas, D. S. Macromolecules 2006, 39, 5629−
5638.
C
DOI: 10.1021/acs.orglett.8b03984
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
̈
(8) Smeenk, J. M.; Schon, P.; Otten, M. B. J.; Speller, S.;
Stunnenberg, H. G.; van Hest, J. C. M. Macromolecules 2006, 39,
2989−2997.
(9) Fan, Y.; Chen, G.; Tanaka, J.; Tateishi, T. Biomacromolecules
2005, 6, 3051.
(10) Haruma, K.; Kamada, T.; et al. J. Gastroenterol. Hepatol. 2000,
15, 277−283.
(11) Leuchs, H. J. Ber. Dtsch. Chem. Ges. 1906, 39, 857−861.
(12) Kricheldorf, H. R. α-Aminoacid-N-Carboxy-Anhydrides and
Related Heterocycles; Springer: Berlin, 1987.
(13) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Amino
Acids 1999, 16, 321.
(14) Takaki, M.; Asami, R.; Hanada, Y.; Ochiai, N. Polym. Bull.
1987, 18, 105−110.
(15) Daly, W. H.; Poche, D. Tetrahedron Lett. 1988, 29, 5859−5862.
(16) Habraken, G. J. M.; Wilsens, K. H.; Koning, C. E.; Heise, A.
Polym. Chem. 2011, 2, 1322−1330.
(17) Vayaboury, W.; Giani, O.; Cottet, H.; Deratani, A.; Schue, F.
Macromol. Rapid Commun. 2004, 25, 1221−1224.
(18) Kricheldorf, H. R.; v. Lossow, C.; Schwarz, G. Macromol. Chem.
Phys. 2005, 206, 282−290.
(19) Vayaboury, W.; Giani, O.; Collet, H.; Commeyras, A.; Schue, F.
Amino Acids 2004, 27, 161−167.
(20) Fujita, Y.; Koga, K.; et al. J. Polym. Sci., Part A: Polym. Chem.
2007, 45, 5365−5370.
(21) Yamada, S.; Koga, K.; Endo, T. J. Polym. Sci., Part A: Polym.
Chem. 2012, 50, 2527−2532.
́
(22) Terrasson, V.; Guenin, E. Novel Magnetic Nanostructures 2018,
333−371.
(23) Tundo, P.; Selva, M. J. Acc. Chem. Res. 2002, 35, 706−716.
(24) Song, M.; Yang, X.; Wang, G. RSC Adv. 2018, 8, 35014−35022.
(25) Tundo, P.; Musolino, M.; Arico, F. Green Chem. 2018, 20, 28−
85.
(26) Tundo, P.; Anastas, P.; et al. Pure Appl. Chem. 2000, 72, 1207.
(27) Tundo, P.; Anastas, P.; et al. Pure Appl. Chem. 2000, 72, 1207−
1228.
(28) Anastas, P. T.; Lankey, R. L. Green Chem. 2000, 2, 289.
(29) Kim, H. K.; Wang, X. S.; et al. Macromol. Rapid Commun. 2005,
26, 1032−1036.
D
DOI: 10.1021/acs.orglett.8b03984
Org. Lett. XXXX, XXX, XXX−XXX