Rapid and Mild Synthesis of Amino Acid N-Carboxy Anhydrides: Basic-to-Acidic Flash Switching in a Microflow Reactor

Article abstract of DOI:10.1002/anie.201803549

Polymerization of N-carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid-labile substrates unusable and results in an undesired ring opening of NCAs. Basic-to-acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid-labile functional groups. The basic-to-acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid-labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods.

Full text of DOI:10.1002/anie.201803549

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Accepted Article
Title: Rapid and Mild Synthesis of Amino Acid N-Carboxy Anhydrides
Using Basic-to-Acidic Flash Switching in a Micro-flow Reactor
Authors: Yuma Otake, Hiroyuki Nakamura, and Shinichiro Fuse
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803549
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10.1002/anie.201803549
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Rapid and Mild Synthesis of Amino Acid N-Carboxy Anhydrides
Using Basic-to-Acidic Flash Switching in a Micro-flow Reactor
Yuma Otake,[a,b] Hiroyuki Nakamura,[a] and Shinichiro Fuse*[a]
Abstract: Polymerization of N-carboxy anhydrides (NCAs) is the
primary process used to prepare polypeptides. The synthesis of
various pure NCAs is a key to the efficient synthesis of polypeptides.
The only practical method that can be used to synthesize NCAs
requires harsh acidic conditions that make acid-labile substrates
unusable and results in an undesired ring opening of NCAs. We used
“basic-to-acidic flash switching” and subsequent “flash dilution”
technology in a micro-flow reactor to demonstrate synthesis of NCAs
that is both rapid (0.1 s) and mild (20 °C) and includes versions
containing acid-labile functional groups. The basic-to-acidic flash
switching enabled both an acceleration of the desired NCA formation
and an avoidance of the undesired ring opening of NCAs. The flash
dilution avoided the undesired decomposition of acid-labile functional
groups. The developed process allowed us to synthesize various
NCAs that cannot be readily synthesized using conventional batch
methods.
solution) is used in this process, which requires harsh conditions
(ca. 40-50 oC, 2-5 h, pH <1).[5b, 7] These conditions prohibit the use
of amino acids with acid-labile side chains. Moreover, the
extended heating of NCAs with HCl sometimes causes an
undesired ring opening of NCAs to generate acid chloride
(Scheme 1, upper scheme), and this leads to a decrease in
purity.[6a, 8]
Several approaches have been proposed to overcome these
disadvantages: use of an acid scavenger,[9] use of urethane-
protected amino acids[10] and diphenyl carbonate,[11] nitrosation of
N-carbamoyl amino acids,[12] and vacuum or N2 flow conditions.[13]
However, those approaches have other drawbacks such as
decreases in purity, increases in the number of reaction steps,
and process complications. Therefore, the Fuchs-Farthing
method has not been replaced for almost 100 years.
If NCA formation is carried out under basic conditions, both
NH2 and CO2- groups in amino acids will rapidly attack phosgene
at ambient temperatures (Scheme 1, middle scheme). However,
deprotonation of the NH groups in the produced NCAs causes
their undesired polymerization.[14] In addition, amino acids with
N-Carboxy anhydrides (NCAs) are important as -amino acid
building blocks for the synthesis of oligopeptides[1] and non-
peptide compounds,[2] and for the synthesis of polypeptides.[2c, 3]
In particular, the latter use is important because the
polymerization of NCAs is the main process for preparing
polypeptides. Polymerization of proteinogenic and/or non-
proteinogenic amino acid-derived NCAs readily affords various
polypeptides with desired properties that can be used as
biocompatible materials, biodegradable polymers, drugs, and
drug carriers.[3b, 4] In addition to the structure of the side chains in
NCAs, their purity significantly influences the properties of the
polypeptides. Therefore, the preparation of various pure NCAs is
a key to polypeptide synthesis. The Fuchs-Farthing method[5] was
first reported in 1922 and remains the only practical method for
NCA synthesis, which is the reason it is also used in industrial
processing (Scheme 1, upper scheme).[6] In this process, amino
acids are coupled with phosgene to afford the intended NCAs with
the generation of HCl. This one-step process only emits CO2 and
HCl; the NCAs that are produced are relatively stable under acidic
conditions, and there is no undesired polymerization of NCAs.
Both NH2 and CO2H groups, however, have their nucleophilicity
reduced under strong acidic conditions. In addition, a biphasic
system that employs solids (amino acids) and liquid (phosgene
-
NH2 and CO2 groups are usually only soluble in water, and the
use of an aqueous solvent under basic conditions tends to cause
an undesired hydrolytic ring opening in NCAs.[15] Therefore, NCA
synthesis under basic conditions has never been reported.
Micro-flow technology enables control of a short reaction time
(<1 s) via flash mixing due to a shortening of the diffusion
length.[16] The reaction rate of organic-aqueous biphasic reactions
[a]
[b]
Y. Otake, Prof. Dr. H. Nakamura, Dr. S. Fuse
Laboratory for Chemistry and Life Science, Institute of Innovative
Research, Tokyo Institute of Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503 (Japan)
E-mail: sfuse@res.titech.ac.jp
Y. Otake
School of Life Science and Technology, Tokyo Institute of
Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503 (Japan)
Scheme 1. NCA synthesis under acidic conditions (conventional approach,
upper scheme), basic conditions (unreported approach, middle scheme), and
basic-to-acidic conditions (this work, lower scheme).
Supporting information for this article is given via a link at the end of
the document.
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is enhanced by increasing the interfacial area between two
phases.[17] We have demonstrated an efficient peptide synthesis
based on the strong and rapid (0.5 s) activation of carboxylic
acids.[18] A rapid pH change in the reaction solution using micro-
flow technology was expected to enable the rapid and mild
formation of NCAs with an avoidance of undesired polymerization
and/or hydrolysis of the produced NCAs (Scheme 1, lower
scheme). Herein, we wish to report a rapid (0.1 s), mild (20 °C),
and scalable (up to gram scale) NCA synthesis based on basic-
to-acidic flash switching in micro-flow reactors. In addition, flash
dilution was also performed to avoid the undesired decomposition
of acid-labile functional groups.
Bases were examined as shown in Table S-3 in the supporting
information. Pyridine (pKa = 5.2) and NMM (pKa = 7.4) afforded
good yields due to
dimethylamine (pKa = 10.0), N-methyl piperidine (pKa = 10.1), and
diethyl methylamine (pKa 10.3) caused undesired
a moderate level of basicity. Ethyl
=
polymerization. NMM can be readily removed by aqueous workup,
therefore it was selected as the optimal base. Quantities of
triphosgene and NMM were then optimized, and the best result
was obtained from a combination of 1.0 equiv. of triphosgene and
4.5 equiv. of NMM. Comparative batch reactions were carried out
under the same reaction conditions with the exception of reaction
time (10 s), because it was impossible to perform the batch
reaction in 0.1 s. Although the reaction mixture was vigorously
stirred during the batch NCA formation, reproducible results were
not observed due to batch-to-batch differences in the mixing
efficiency. This clearly indicates the advantage of micro-flow
conditions for biphasic reactions compared with batch conditions.
Although the merits of using micro-flow technology to enhance
mixing efficiency in a liquid/liquid biphasic reaction are frequently
proposed, there has been no report of reactions that cannot be
performed reproducibly using a batch reactor.[17b] As far as we
could ascertain, these are the first successful results of such
reactions.
The details of a working hypothesis for NCA synthesis based
on basic-to-acidic flash switching are shown in Figure 1. Amino
acid sodium salt (1 equiv.) and base (>1 equiv.) in water and
phosgene (>1 equiv.) with an organic solvent are independently
injected into a micromixer. In order to achieve rapid mixing in the
water/organic solvent biphasic system, a V-shape mixer was
utilized because Nagaki, Yoshida, and coworkers used the V-
shaped mixer and achieved highly efficient mixing in the
nucleophilic addition of aryl lithium compounds against
difunctional electrophiles.[19] The first nucleophilic attack by the
-
CO2 group most reactive to phosgene and the subsequent
intramolecular nucleophilic attack by the NH2 group both occur
rapidly to afford NCA and 1 equiv. of base·HCl (step 1). The
unreacted phosgene is then decomposed by water along with the
generation of HCl (step 2), and the remaining base is completely
protonated to afford base · HCl. Thus, the reaction mixture
becomes acidic (step 3) and the undesired polymerization and/or
hydrolysis of the produced NCAs is avoided.
NCA formation was examined using phenylalanine as a model
amino acid (for details, see supporting information). N-Methyl
morpholine (NMM) was employed as a base because this mild
organic base (pKa = 7.4) can rapidly trap the protons of HCl, but
the deprotonation of NCA (pKa = 11.3)[1e] by NMM is a very slow
process. A safely handled triphosgene was used as a phosgene
equivalent. Initially, organic solvent was optimized as shown in
Table S-2 in the supporting information. Nonpolar organic
solvents caused a precipitation of the insoluble solids in the micro-
flow reactor. Polar solvents, however, generated no precipitation
and afforded the desired product. In particular, the use of
acetonitrile afforded the best yield.
We performed micro-flow NCA formation and a subsequent
isolation of the desired product, 2a (Figure 2), based on the
optimized conditions. The goal of this work was the synthesis of
various pure NCAs including those with acid-labile functional
groups. After basic-to-acidic flash switching, the desired NCA 2a
was in an acetonitrile and water mixed solvent under acidic
conditions. In order to avoid the undesired decomposition of acid-
labile functional groups, a new technology referred to as flash
dilution was used in the micro-flow reactor. The reaction mixture
obtained by the basic-to-acidic flash switching was rapidly diluted
by ethyl acetate in the second micromixer. This flash dilution
reduced the concentration of HCl and water in the organic phase.
It was a simple procedure to separate the obtained acidic biphasic
solution, and the organic layer was dried over MgSO4 and
concentrated. In this case, pure NCA 2a was obtained in a
quantitative yield without recrystallization. In order to confirm the
optical purity of the synthesized NCA 2a, it was reacted with an
excess amount of L-alanine methyl ester. HPLC analysis of an
obtained amide indicated that no racemization of the NCA had
occurred (for details, see supporting information).
Figure 2. Basic-to-acidic flash switching and subsequent flash dilution for
obtaining various NCAs including those with acid-labile functional groups.
Figure 1. Working hypothesis for the rapid and mild formation of NCAs based
on “basic-to-acidic flash switching.”
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10.1002/anie.201803549
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The substrate scope of our originally developed micro-flow
NCA formation was investigated, as shown in Figure 3. We
categorized the amino acids into 5 groups: 1) lipophilic amino
acids; 2) N-alkylated amino acids; 3) less lipophilic amino acids;
4) amino acids with nucleophilic side chains; and, 5) acid-labile
amino acids.
Sodium salts of phenylalanine 1a, O-benzyl-serine 1b, O-
benzyl-threonine 1c, and S-benzyl-cysteine 1d were categorized
in the first group and employed as substrates (Figure 3, group 1).
As a result, pure forms of NCAs 2a-2d were obtained in high to
excellent yields. In the case of 2b, recrystallization was performed
to increase the purity.
Sodium salts of sarcosine (1e) and proline 1f were
categorized in the second group and employed as substrates
(Figure 3, group 2). Pure sarcosine NCA 2e and proline NCA 2f
were obtained in high yields after simple phase separations and
recrystallization of obtained reaction mixtures. When using
conventional batch conditions, the reaction between proline and
phosgene affords only an acyclic intermediate due to the ring
strain of proline. Therefore, a further addition of base is required
to accelerate a second nucleophilic addition, but the additional
base generates an undesired proline dimer.[20] On the other hand,
our originally developed conditions afforded the desired NCA 2f
in a single step without generating the undesired dimer.
Sodium salts of glycine (1g), alanine 1h, valine 1i, leucine 1j,
isoleucine 1k, and methionine 1l were categorized in the third
group and employed as substrates (Figure 3, group 3). Less
lipophilic amino acids have insufficient solubility against organic
solvents and usually require an extended amount of reaction time
21]
when conventional batch conditions are used.[7,
The long
reaction time causes an undesired reaction of NCAs. On the other
hand, our developed conditions afforded pure NCAs 2g-2l in good
to high yields after simple phase separations and recrystallization
of obtained reaction mixtures. In the case of 2h, 2k and 2l, phase
separation was sufficient to obtain pure products. It should be
noted that leucine NCA 2j is industrially synthesized for producing
polyleucine that is the catalyst for Julià-Colonna asymmetric
epoxidation. Large-scale synthesis of 2j under conventional acidic
conditions requires long time, which causes an undesired ring
opening of NCA.[22] The use of an acid scavenger is a proven
solution for these problems,[6a] but this approach leads to the
generation of stoichiometric amounts of lipophilic by-product that
Figure 3. Basic-to-acidic flash switching and subsequent flash dilution for obtaining various NCAs including those with acid-labile
functional groups.
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complicates the recrystallization of 2j. On the other hand, most
by-products are easily removed by simple aqueous washing using
the conditions we developed. Moreover, this reaction was readily
scaled-up by simply extending the pumping time, and pure 2j was
obtained in an excellent yield (91% yield, 3.8 grams).
and several important non-proteinogenic amino acids. The basic-
to-acidic flash switching enabled both an acceleration of the
desired NCA formation and the avoidance of an undesired ring
opening of NCAs. The flash dilution avoided the undesired
decomposition of acid-labile functional groups. This technology
could be useful for other reactions affording labile intermediates
and/or products. In addition, our developed process uses simple
phase separations and recrystallizations to yield pure NCAs. It
should be noted that flash mixing in a micro-flow reactor enabled
rapid pH control of this biphasic reaction. Comparable batch
conditions did not afford reproducible results. Although NCAs are
important materials, strict control of temperature for storage and
transportation is required due to their instability that limits their
utility. Because micro-flow synthesis is readily scalable and
space-saving, the developed approach should pave the way for
on-demand, on-site synthesis of NCAs with expanded utility.
Sodium salts of N--Trt-histidine 1m and N--nitro-arginine 1n
were categorized in the fourth group and employed as substrates
(Figure 3, group 4). Nucleophilic side chains in 1m and 1n tend to
cause an undesired ring opening of NCAs. NCA 2m is an
important monomer for polyhistidine that is used as a pH stimuli
polymer with a suitable pKa value (ca. 6.5) for targetting cancer
cells.[23] Due to insufficient solubility, a diluted solution of 1m was
used for NCA formation at 40 °C (for details, see supporting
information). The desired pure 2m was obtained in a high yield
after simple phase separations of the obtained reaction mixture.
The NCA formation of 1n containing nucleophilic guanidine side
chain afforded the desired NCA 2n, although the yield was low
probably due to undesired intramolecular nucleophilic attack to
NCA from the guanidine side chain.[24]
Acknowledgements
Sodium salts of O-TBS-serine 1o, O-t-Bu-tyrosine 1p, O-t-Bu-
aspartate 1q, O-t-Bu-glutamate 1r, N-Trt-asparagine 1s, N-Trt-
glutamine 1t, N-Boc-lysine 1u, N-Boc-tryptophan 1v, allylglycine
1w, propargylglycine 1x, and acetonide-protected 3,4-
dihydroxyphenylalanine (DOPA) 1y were categorized in the fifth
group and employed as substrates (Figure 3, group 5). Acid-labile
amino acids could not be employed as substrates in a
conventional acidic synthesis of NCA. On the other hand, our
developed conditions afforded the desired NCA 2o-2y containing
acid-labile silyl, tert-butyl, trityl, Boc, allyl, propargyl, and
acetonide groups in high to excellent yields. It should be noted
that our developed conditions afforded the desired NCA 2w and
2x in high yields. These NCAs contain terminal alkene or alkyne
that are highly useful because various functional groups can be
introduced to polypetides that are derived from these NCAs via
thiol-ene or Huisgen reactions.[3d] Although conventional NCA
synthesis requires the use of an acid scavenger to avoid
undesired acidic reactions from alkenes or alkynes,[25] our
conditions afforded the NCAs after simple phase separation
without the use of the scavenger. Dimethyl acetal formation is one
of the most general protection for catechol, and it can be removed
under mild conditions. However, this frequently used protection is
unavailable in conventional NCA synthesis. On the other hand,
our developed conditions afforded pure DOPA NCA 2y containing
acetonide-protected catechol in a high yield (80%) after simple
phase separations and recrystallization of the obtained reaction
mixture. These results clearly showed the usefulness of our
developed basic-to-acidic flash switching and subsequent flash
dilution for a rapid and mild synthesis of acid-labile NCAs.
In order to confirm the optical purity of the synthesized NCAs,
those derived from the racemizable amino acids, 2b, 2d, 2h, 2m,
2n, and 2q, were reacted with an excess amount of L-
phenylalanine tert-butyl ester. HPLC analysis of obtained amides
indicated that no racemization of the NCAs had occurred (for
details, see supporting information).
This work was partially supported by a Grant-in-Aid for Young
Scientists (B), Scientific Research on Innovative Areas 2707
Middle molecular strategy (no. 15H05849) from Japan Society for
the Promotion of Science, and The Naito Foundation Natural
Science Scholarship.
Keywords: amino acids • anhydrides • continuous flow •
peptides • acylation
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In summary, we demonstrated a rapid (0.1 s) and mild (20 °C)
synthesis of NCAs including those containing acid-labile
functional groups that cannot be readily synthesized using the
conventional Fuchs-Farthing batch method. Our originally
developed process using basic-to-acidic flash switching and
subsequent flash dilution technology allowed us to synthesize
various 25 NCAs derived from all the proteinogenic amino acids
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COMMUNICATION
Rapid (0.1 s) and mild (20 °C)
synthesis of NCAs using “basic-to-
acidic flash switching” and subsequent
“flash dilution” was demonstrated. The
developed process enabled synthesis
of acid-labile NCAs that was
impossible using conventional batch
conditions. The developed process
requires simple phase separations and
recrystallization to yield pure NCAs.
Our micro-flow approach could pave
the way for on-demand, on-site NCA
synthesis.
Yuma Otake, Prof. Dr. Hiroyuki
Nakamura, Dr. Shinichiro Fuse*
Page No. – Page No.
Rapid and Mild Synthesis of Amino
Acid N-Carboxy Anhydrides Using
Basic-to-Acidic Flash Switching in a
Micro-flow Reactor
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