Efficient amide bond formation through a rapid and strong activation of carboxylic acids in a microflow reactor

Article abstract of DOI:10.1002/anie.201307987

The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less-toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74 %-quant.) without significant epimerization (≤3 %). Our process can be carried out at ambient temperature, and only CO₂ and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents. In the fast lane: The title reaction is described for the synthesis of peptides. Various carboxylic acids including easily epimerizable amino acids were rapidly converted into highly electrophilic species, and then reacted with various amines, including less nucleophilic N-methyl amino acids, to afford the desired peptides in high yields without significant epimerization. Copyright

Full text of DOI:10.1002/anie.201307987

Angewandte
Chemie
DOI: 10.1002/anie.201307987
Peptides
Efficient Amide Bond Formation through a Rapid and Strong
Activation of Carboxylic Acids in a Microflow Reactor**
Shinichiro Fuse,* Yuto Mifune, and Takashi Takahashi
Abstract: The development of highly efficient amide bond
forming methods which are devoid of side reactions, including
epimerization, is important, and such a method is described
herein and is based on the concept of rapid and strong
activation of carboxylic acids. Various carboxylic acids are
rapidly (0.5 s) converted into highly active species, derived
from the inexpensive and less-toxic solid triphosgene, and then
rapidly (4.3 s) reacted with various amines to afford the desired
peptides in high yields (74%–quant.) without significant
epimerization (ꢀ 3%). Our process can be carried out at
ambient temperature, and only CO2 and HCl salts of diiso-
propylethyl amine are generated. In the long history of peptide
synthesis, a significant number of active coupling reagents have
been abandoned because the highly active electrophilic species
generated are usually susceptible to side reactions such as
epimerization. The concept presented herein should renew
interest in the use of these reagents.
ment of highly efficient methods for the formation of amide
bonds without side reactions, including epimerization, is
regarded as a highly important endeavor.[3] The use of highly
electrophilic species such as acid chlorides and acid anhy-
drides has a long history in peptide synthesis,[4] as they are
useful for the couplings of less nucleophilic amines such as N-
methyl amino acids,[5] which have attracted great attention in
recent years because of their contributions to the improve-
ment of the metabolic stability of peptides.[2e] However,
applications of acid chlorides and anhydrides are somewhat
limited because their strong electrophilicity tends to cause
side reactions. The most conventional approach is the
condensation of amines with carboxylic acids by active
esters using coupling reagents such as carbodiimides or
phosphonium or uronium salts.[2] This method is based on
a concept that is referred to as the mild activation of
carboxylic acids, whereby epimerization is suppressed by the
mild electrophilicity of the active species (Scheme 1). Thus,
H
ighly active species are attractive in organic synthesis
because their reactivity allows rapid reaction of sterically and
electronically less-reactive substrates. In contrast, these tend
to cause undesired reactions and, therefore, suppression of
the side reactions is key to their utilization. Recent dramatic
progress in flash chemistry[1] has enabled the utilization of
highly active species without side reactions by precisely
controlling the reaction time (< 1 s) and temperature by the
utilization of microflow reactors.
Amide bonds are ubiquitous in nature, and are a key
method of linkage for peptides and proteins.[2] The develop-
[*] Dr. S. Fuse, Y. Mifune
Department of Applied Chemistry, Tokyo Institute of Technology
2-12-1, Ookayama, Meguro-ku, Tokyo 152-8552 (Japan)
E-mail: sfuse@apc.titech.ac.jp
Scheme 1. Amide bond formation based on a conventional concept of
the mild activation of carboxylic acids and our concept of rapid and
strong activation of carboxylic acids.
Homepage: http://www.apc.titech.ac.jp/~htanaka/index.html
Prof. T. Takahashi
Faculty of Pharmaceutical Sciences, Yokohama College of Pharmacy
601, Matana-cho, Totsuka-ku, Yokohama-shi 245-0066 (Japan)
the reaction time is usually long and it is sometimes difficult to
couple less-reactive substrates such as N-methyl amino acids.
Herein, we report an efficient amide bond formation
based on the concept of rapid and strong activation of
carboxylic acids (Scheme 1). Various carboxylic acids, which
included easily racemizable amino acids, were activated using
an inexpensive and less-toxic solid triphosgene,[6] and the
racemization was suppressed (ꢀ 3%) by reducing the resi-
dence time of the highly active species[1] (0.5 s) through
microflow synthesis.[7] The active species rapidly reacted
(4.3 s) with less nucleophilic amines, including N-methyl
amino acids, in good to excellent yields at ambient temper-
ature (208C).
[**] We thank Prof. Dr. Jun-ichi Yoshida and Dr. Aiichiro Nagaki, Kyoto
University, and Prof. Dr. Takayuki Doi, Tohoku University, for kindly
giving us valuable suggestions. We also thank The Grants-in-Aid for
Scientific Research on Innovative Areas “Organic Synthesis Based
on Reaction Integration. Development of New Methods and
Creation of New Substances” (No. 2105) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307987.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial and no
modifications or adaptations are made.
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851

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Table 1: Microflow amide bond formation with various solvents and
bases.[a]
Entry
Solvent
Base
DIEA
Yield [%]
A
B
C
3
4
1
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
31
–
1
–
2
–
3
[b]
1,4-dioxane 1,4-dioxane 1,4-dioxane DIEA
Figure 1. Microflow synthesis of peptides based on the concept of
rapid and strong activation of carboxylic acids using triphosgene.
MeCN
iPrOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DIEA
DIEA
MeCN/H2O DIEA
(1:1)
48
[c]
–
52
6
7
8
NMP
DMF
MeCN/H2O MeCN
(9:1)
MeCN/DMF MeCN
(9:1)
DMF/H2O
(9:1)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
H2O
MeCN
MeCN
MeCN
MeCN
MeCN
DIEA
DIEA
DIEA
<55 <10
The microflow reactor that was used to test our concept is
shown in Figure 1. We connected two T-shape mixers with
Teflonꢀ tubing and immersed them in a water bath (208C). A
solution of carboxylic acid and base in solvent A was
introduced into the first mixer with a syringe pump. The
solution of triphosgene in solvent B was also introduced into
the first mixer with a syringe pump. We speculated that the
phosgene, generated in situ by the reaction between the base
and triphosgene, converted the carboxylic acid into the
corresponding acid chloride.[6,3n,w] We anticipated that the
epimerization was suppressed by reducing the residence time
of the highly electrophilic active species to less than one
second. To accomplish amidation, a solution of the amine in
solvent C was then introduced into the second mixer with
a syringe pump. The reaction was quenched by pouring the
mixture into a saturated aqueous solution of NH4Cl and
CHCl3. In principle, this method only emits CO2 and the HCl
salts of a base other than the substrate.
Initially, solvents were examined as shown in Table 1
(entries 1–10). N-Boc-O-benzyl-l-serine (1) and l-phenyl-
alanine allyl ester (2) were employed as substrates since they
have bulky side chains at the a-position. The serine 1 has an
acid-labile Boc group on the amino group, and N-Boc serine is
susceptible to epimerization. The combination of DMF for
solvent A, and MeCN for solvents B and C afforded the best
results (entry 7). Interestingly, the use of H2O as either
solvent A or C afforded comparable results (entries 5, 8, and
10). Bases were examined in combination with an optimal
solvent system (DMF/MeCN; Table 1, entries 7 and 11–17).
As shown, DIEA afforded the best results (entry 7).
62
56
9
15
9
MeCN
MeCN
DIEA
DIEA
Et3N
Me2NEt 52
Cy2NMe 63
lutidine 48
collidine
DBU
DABCO
LiOH
55
58
2
9
10
MeCN
[b]
11
12
13
14
15
16
17
18
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
–
–
10
15
1
[b]
–
–
24
9
–
–
[b]
–
[b]
–
[a] Flow rate A: 2000 mLminÀ1, flow rate B: 1200 mLminÀ1, flow rate C:
2000 mLminÀ1. [b] Insoluble salts were generated. [c] A complex mixture
was obtained. Boc=tert-butoxycarbonyl, DABCO=1,4-diazabicyclo-
[2,2,2]octane, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DIEA=N,N-
diisopropylethylamine, DMF=N,N-dimethylformamide, NMP=N-
methylpyrrolidone.
Table 2: Optimization of quantities of carboxylic acid 1 and DIEA in
microflow amide bond formation.[a]
Entry
X
Y
Yield [%]
Quantities of 1 and DIEA were optimized (Table 2). The
yield of the desired dipeptide 3 was improved with an increase
in the amount of 1 (entries 1–3). In contrast, the yield of the
epimer 4 decreased with a decreasing amount of DIEA
(entries 3–5). The best results were obtained by employing
2.5 equivalents of 1, and 3.0 equivalents of DIEA (entry 5).
The residence time of the active species and reaction temper-
ature were examined (see the Supporting Information). As
a result, 0.5 seconds for the residence time and 208C for the
reaction temperature proved to be the optimal combination.
The results of the scope and limitations of the established
reaction conditions were examined and are shown in Table 3.
The comparative batch reactions were carried out under the
same reaction conditions as microflow reactions except for
3
4
1
2
3
4
5
1.5
2.0
2.5
2.5
2.5
7.0
7.0
7.0
5.0
3.0
62
73
77
72
92
9
7
4
2
1
[a] Flow rate A: 2000 mLminÀ1, flow rate B: 1200 mLminÀ1, flow rate C:
2000 mLminÀ1
.
reaction times (activation: 30 s, amidation: 30 s). This modi-
fication was necessary because it was difficult to safely
perform batch experiments (caution: large amounts of CO2
and phosgene evolved) and obtain reproducible results when
852
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Table 3: Microflow amide bond formation with various substrates.
epimerization did not occur even when batch conditions were
used (entries 1, 2, and 4). However, a reduction in the yield
was observed under batch conditions probably because of the
acidic removal of Boc or triphenylmethyl (Trt) groups. The
desired dipeptides 3, 5, and 7 were, however, obtained in
excellent yields (92%, quant., and 94%, respectively) under
the microflow conditions (entries 1, 2, and 4). In the case of
easily racemizable l-histidine, the generation of 17% of the
epimer was observed under batch conditions, but microflow
conditions suppressed the epimerization to 2% (entry 3). To
our delight, highly racemizable d-phenylglycine was success-
fully coupled with l-phenylalanine in an excellent yield
(97%) accompanied by only 3% of epimer (entry 5) under
microflow conditions. In this case, it was necessary to perform
the reaction at 108C using MeCN as solvent A instead of
DMF. A decreased yield (74%) with a substantial generation
of the epimer (18%) was observed by employing the batch
conditions (entry 5). Less-nucleophilic bulky amines such as
l-isoleucine, l-proline, and sarcosine were coupled with l-
serine in good yields (89, 80, and 74%, respectively) without
detectable epimerization (entries 6–8). The corresponding
batch reactions resulted in a reduction in yields (47, 58 and
53%, respectively). Unexpectedly, l-lactic acid was coupled
with l-phenylalanine in an excellent yield (98%) without
detectable epimerization, although a secondary alcohol in the
lactic acid remained unprotected (entry 9). A severe reduc-
tion in yield (< 28%) was observed when the same reaction
was performed under batch conditions (entry 9). It should be
noted that although an excess amount (2.5–3.0 equiv) of
carboxylic acid was employed under our established reaction
conditions, unreacted carboxylic acid could be readily recov-
ered using a simple acid-base extraction and phase-separation
techniques during the workup process. In the case of the
microflow synthesis of the dipeptide 3, 74% of unreacted
1 was recovered without detectable epimerization (< 1%).
This proved the feasibility of our concept of a rapid and strong
activation of carboxylic acids for highly efficient amide bond
formation.
Next, we turned our attention to the identification of the
actual active species. We utilized an in situ IR detection
system (Mettler-Toledo React IR 15 Microflow cell) to
identify the active species. A DMF solution of an l-valine
derivative, DIEA, and a MeCN solution of triphosgene were
introduced to the T-shape mixer, and the reaction mixture,
after 0.5 seconds of the mixing of the two solutions, was
analyzed by the in situ IR detection system (see the
Supporting Information). Unexpectedly, comparisons
between the observed IR spectra and separately prepared
reference compounds indicated that the symmetric anhydride
was the actual active species.[8] This result means that a highly
electrophilic anhydride was generated quantitatively in only
0.5 seconds, although the detailed pathway was unclear.
Finally, we tried to synthesize a tetrapeptide moiety of the
depsipeptidic natural product auliride (13)[9] to extend the
range of applications for our established process. Tetrapep-
tide contains two N-methyl amino acids (Scheme 2). The
esterification of 14 was followed by the removal of the Fmoc
group in the batch reactor because a long reaction time was
required, and careful control of the reaction conditions
Entry
1
Structure of
desired product
Cond.
Yield [%]
(desired)
(epimer)
flow A[a]
batch[d]
92
57
1
2
flow B[b]
batch[d]
quant.
40
<1
<1
2
3
flow B[b]
batch[d]
92
75
2
17
flow A[a]
batch[d]
94
71
<1
1
4
5
flow C[c]
batch[d]
97
74
3
18
flow B[b]
batch[d]
89
47
<1
1
6
7
flow A[a]
batch[d]
80
58
<1
1
flow A[a]
batch[d]
74
53
<1
<1
8
9
flow A[a]
batch[d]
98
<1
<28
[a] Carboxylic acid: 2.5 equiv, triphosgene: 0.4 equiv. [b] Carboxylic acid:
3.0 equiv, triphosgene: 0.5 equiv. [c] Carboxylic acid: 2.5 equiv, triphos-
gene: 0.4 equiv, DIEA: 2.5 equiv, solvent A: MeCN, reaction temper-
ature: 108C. [d] Reaction time for the activation of carboxylic acid and the
amidation: 30 s. Fmoc=9-fluorenylmethyloxycarbonyl.
shorter reaction times were used (< 30 s). However, micro-
flow experiments were performed safely, and reproducible
results were obtained regardless of the short reaction times
(activation: 0.5 s, amidation: 4.3 s). Although CO2 must be
generated in the first T-shape mixer, neither bubbles nor gas
plug flow was observed in the Teflon tubes. In the case of the
coupling reactions between l-serine, l-tyrosine, or l-cysteine,
as carboxylic acids, and l-phenylalanine as an amine, severe
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usually highly susceptible to side reactions such as epimer-
ization.[2c] Our concept should prompt a renewal of interest in
the use of these reagents. The wise use of microflow synthesis
should dramatically increase the value of highly active
reagents.
Received: September 11, 2013
Published online: December 2, 2013
Keywords: amides · amino acids · continuous flow ·
.
natural products · peptides
Scheme 2. Synthesis of the tetrapeptide 17, a substructure of aurilide
(13). a) Batch, AllylBr, K2CO3, DMF, RT, 19 h, 93%. b) Batch, Et2NH,
CH2Cl2, RT, 2.5 h. c) Flow A, N-Fmoc-sarcosine, 2 steps 87%.
d) Flow A, N-Fmoc-N-methyl-d-leucine, 2 steps 83%, epimer <1%.
e) Flow and batch, N-Fmoc-l-valine, 2 steps 60%, epimer <1%.
[1] a) J.-i. Yoshida, Flash Chemistry—Fast Organic Synthesis in Micro
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Yoshida, Chem. Rec. 2010, 10, 332 – 341.
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unnecessary. Removal of the Fmoc group meant that the
CH2Cl2 solvent and Et2NH were also removed after the
completion of the reaction, and that the residue was dissolved
in MeCN. The resultant solution was removed by syringe and
was used for microflow amidation with N-Fmoc sarcosine.
The desired dipeptide 15 was obtained in an excellent yield
(2 steps 87%). In this reaction, 2.6 grams of 15 were obtained
by continuous running of the microflow reactor for
24 minutes. Thus, the productivity of the established process
was satisfactory. To our delight, the subsequent coupling of N-
Fmoc-N-methyl-d-leucine with the less-nucleophilic dipep-
tide 15 afforded the desired tripeptide 16 in a good yield
(2 steps 83%) without detectable epimerization. The final
coupling of the tripeptide 16 with N-Fmoc-l-valine was
somewhat slow and therefore, the crude reaction mixture
obtained from the microflow reactor was collected in a dried
batch reactor and stirred for 10 minutes before the reaction
was quenched. The desired tetrapeptide 17 was obtained in
a good yield (2 steps 60%) without detectable epimerization.
Moreover, our developed process could be used for the
coupling of dipeptides (see the Supporting Information). The
desired tetrapeptide 17 was obtained in a satisfactory yield
without detectable epimerization.
In summary, we demonstrated highly efficient amide bond
formation based on our concept of rapid and strong activation
of carboxylic acids. The various carboxylic acids were rapidly
(0.5 s) converted into highly active species using inexpensive,
less-toxic solid triphosgene, and they were rapidly (4.3 s)
reacted with various amines to afford the desired peptides in
high yields (74%–quant.) without severe epimerization (ꢀ
3%). Moreover, our developed process was applicable to the
synthesis of a tetrapeptide moiety in the depsipeptidic natural
product aurilide. Our process was carried out at an ambient
temperature (208C), and it generated only CO2 and HCl salts
of DIEA, with the exception of recovered carboxylic acid.
These excellent results could not be achieved under the
conventional batch conditions because the precise control of
temperature and time is difficult. In the long history of
peptide synthesis, a significant number of active coupling
reagents have been abandoned because the highly electro-
philic active species generated by the active reagents were
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