Isostearyl Mixed Anhydrides for the Preparation of N-Methylated Peptides Using C-Terminally Unprotected N-Methylamino Acids

Article abstract of DOI:10.1021/acs.orglett.0c02984

Sustainable and efficient manufacturing methods for N-methylated peptides remain underexplored despite growing interest in therapeutic N-methylated peptides within the pharmaceutical industry. A methodology for the coupling of C-terminally unprotected N-methylamino acids mediated by an isostearic acid halide (ISTAX) and silylating reagent has been developed. This approach allows for the coupling of a wide variety of amino acids and peptides in high yields under mild conditions without the need for a C-terminal deprotection step in the process of C-terminal elongation. These advantages make this a useful synthetic method for the production of peptide therapeutics and diagnostics containing N-methylamino acids.

Full text of DOI:10.1021/acs.orglett.0c02984

pubs.acs.org/OrgLett
Letter
Isostearyl Mixed Anhydrides for the Preparation of N‑Methylated
Peptides Using C‑Terminally Unprotected N‑Methylamino Acids
Haruaki Kurasaki,* Akihiro Nagaya, Yutaka Kobayashi, Ayumu Matsuda, Masatoshi Matsumoto,
Koki Morimoto, Tomonori Taguri, Hisayuki Takeuchi, Michiharu Handa, Douglas R. Cary,
Naoki Nishizawa,* and Keiichi Masuya*
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ABSTRACT: Sustainable and efficient manufacturing methods for N-methylated peptides remain underexplored despite growing
interest in therapeutic N-methylated peptides within the pharmaceutical industry. A methodology for the coupling of C-terminally
unprotected N-methylamino acids mediated by an isostearic acid halide (ISTAX) and silylating reagent has been developed. This
approach allows for the coupling of a wide variety of amino acids and peptides in high yields under mild conditions without the need
for a C-terminal deprotection step in the process of C-terminal elongation. These advantages make this a useful synthetic method for
the production of peptide therapeutics and diagnostics containing N-methylamino acids.
eptide therapeutics have been receiving increased
attention in drug discovery and development due to
the required labor and reducing overall yield. Further
complications can arise when selective deprotection is essential
to differentiate between the C-terminal ester and other
protective groups on the N-terminus or side chains of the
peptide. Therefore, a new coupling method employing a C-
terminally unprotected N-methylamino acid as the nucleophile,
without the need for an intermediate deprotection reaction,
could have great impact in overcoming the aforementioned
P
their high efficacy and target selectivity, combined with their
1
generally acceptable safety profiles. Since the advent of solid-
phase peptide synthesis techniques in the 1960s, various
improvements have been made in both solid- and liquid-phase
2
synthesis protocols. Despite these advancements, peptide
synthesis has not been able to move away from the
requirement of repetitive deprotection steps between coupling
reactions. These repetitive deprotection steps present
difficulties in the manufacturing of complex peptide drugs.
Accordingly, new synthetic methods are being actively pursued
to reduce manufacturing steps to decrease synthesis time and
6
drawbacks. While peptide synthesis using C-terminally
unprotected N-methylamino acids is an attractive synthetic
approach, such methods have not been thoroughly examined
7
to date (Scheme 1). Tantry and Babu have reported the use of
a mixed anhydride and TMSCl as silylating agent, but the
substrate scope was limited, with sarcosine (H-MeGly-OH)
the only N-methylamino acid examined, and the product
3
cost as well as minimize negative environmental impact.
During the process of discovery and development of peptide
therapeutics, the incorporation of N-methylamino acids is a
well-established approach to improve permeability and/or
7a
formed in moderate yield.
To this end, we aimed to develop a more versatile amide
coupling methodology using C-terminally unprotected N-
methylamino acids that provides peptides in fewer steps and
4
proteolytic stability. However, during synthesis, the formation
of the amide bond between an N-methylamino acid and the
adjacent activated carboxylic acid of an N-terminally protected
amino acid can often result in lower yields than their non-N-
methylated counterparts due to the low reactivity of the N-
Received: September 7, 2020
5
methylamine moiety. In the context of C-terminal elongation
of peptide chains, selective deprotection of the protected C-
terminus that is to be reacted with the adjacent amino acid N-
terminus necessitates iterative deprotection steps, increasing
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c02984
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Scheme 1. General Strategy for This Method
Table 1. Screening Activating Reagents with 1a and 2a
reaction with
activated 1a
and silylated
b
2a
activating
reagents
scale
activation time
a
time
(h)
temp
yield
(%)
entry
(mmol)
of 1a (h)
(°C)
high yields. Here, we describe a practical synthetic method-
ology for the production of N-methylated peptides employing
the reaction of a mixed acid anhydride formed by isostearic
acid halide (ISTAX) activation with the putative silylated N-
methylamino acids generated in situ (Scheme 1). As coupling
via mixed anhydrides represents a cost-effective method that
has historically been used for large-scale peptide manufactur-
c
1
2
3
4
5
IBCF
PivCl
ISTACl
ISTABr
ISTABr
0.4
0.4
0.4
0.4
0.4
4
1
5
24
0.5
0.5
0.5
2
12
24
24
4
0
30
30
30
60
60
4
75
92
98
d
e
g
e
g
e
g
97
f
e
g
6
ISTABr
4
94
a
b
8
Reaction time for 1a and activating reagents. Time and temperature
c
ing, we expected that it would be amenable to use with N-
after addition of silylated 2a to activated 1a. Calculated based on
methylamino acids. In addition, the utilization of isostearyl
mixed anhydrides for amino acid coupling has not been
reported to date. Furthermore, we expected that the generation
of O-trimethylsilylated N-methylamino acids in situ, such as
those demonstrated in these studies, would prevent over-
reaction, such as double incorporation of the nucleophilic N-
d
ELSD area percentage of crude product. Determined by quantitative
H NMR using internal standard. Since ISTAX were insoluble in
MeCN, a toluene solution of the ISTAX was added to a MeCN
solution of 1a (final volume ratio of toluene/MeCN was 1:4).
Concentration of combined final reaction mixture was 0.5 M.
Isolated yield without column chromatography.
1
e
f
g
6b
methylated amino acid and increase the solubility of the
9
10
resulting intermediates to yield improved results.
Our initial studies focused on sterically hindered Fmoc-Val-
OH (1a) to compare the performance of various potential
activating reagents. For the nucleophilic N-methylamino acid
coupling partner, N-methylphenylalanine (H-MePhe-OH, 2a)
was selected after confirming that loss of enantiopurity of H-
MePhe-OH is not observed under the silylating conditions
at 30 °C afforded the target dipeptide 3a with sufficient
regioselectivity and no detectable epimerization (confirmed by
comparison with authentic Fmoc-D-Val-L-MePhe-OH) in 92%
isolated yield without column chromatography (entry 3). As
for the workup process, after quenching the reaction with 1 M
aq KHSO , the byproduct ISTAOH was easily removed by
4
1
1
employed using N,O-bis(trimethylsilyl)acetamide (BSA).
Usage of the common coupling reagent isobutyl chloroformate
washing with heptane as well as a small amount of 2a acylated
with excess ISTACl. A wide variety of solvents, including
toluene, THF, DMA, and NMP, gave comparable results to
MeCN, and generally, the amide bond formation was
completed in less than 24 h at room temperature (data not
shown). Overall, MeCN was somewhat preferable due to the
8
b
(
IBCF, Table 1, entry 1) showed poor conversion due to
insufficient regioselectivity in the subsequent reaction of the
12
resulting mixed anhydride. On the other hand, pivaloyl
8
c
chloride (PivCl, entry 2) gave moderate conversion, but the
corresponding pivaloylated derivative of 2a and residual
PivOH were formed as byproducts and could not be
completely removed through any convenient workup process
in our hands. These results indicated that the main challenge of
the mixed anhydride method may be to maintain good
conversion including regiochemical control and byproduct
removal, which we sought to overcome by employing a new
13
fast reaction rate and minimized anhydride formation of 1a.
To further improve yield, we decided to identify minor
impurities observed under these conditions. The main impurity
observed was thought to be derived from anhydride formation
of 1a, generated from unreacted 1a and activated 1a. In order
to minimize this impurity, the more reactive isostearic acid
bromide (ISTABr) was tested to reduce the activation time.
Reaction with ISTABr and 1a smoothly completed at 0 °C
within 30 min, and as expected, generation of the anhydride
impurity was suppressed below the LC detection limit (entry
5a
activating reagent with appropriate steric bulk that could also
12
be readily removed by extraction with nonpolar solvents.
On the basis of these initial results and hypotheses, we
selected ISTAX as a sterically demanding acid halide, which
can be easily prepared from the commercially available
corresponding carboxylic acid (ISTAOH), while also anticipat-
ing that ISTAOH byproduct should be removable by
extraction of the reaction mixture with nonpolar solvents.
Moreover, unlike the use of chloroformate reagents, ISTAX
14
4). To further reduce total reaction time, the reaction was
conducted with activated 1a and 2a at 60 °C, resulting in not
only shorter reaction time with the same yield, but it is also
noteworthy that no epimerization was detected (entry 5).
Moreover, conducting the reaction on larger scale and higher
concentration gave 94% yield and satisfactory purity (96 area%
HPLC), even without purification by column chromatography
(Table 1, entry 6). With these favorable results in hand, we
assessed the thermal stability of ISTACl and ISTABr by
differential scanning calorimetry and confirmed that these
does not generate CO , thus eliminating the safety hazards of
2
reactor pressurization and CO off-gassing in drummed waste
2
streams. As expected, isostearic acid chloride (ISTACl) reacted
with 1a at 0 °C for 24 h followed by coupling with silylated 2a
B
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reagents are more stable than chloroformate reagents, and thus
suitable for large-scale synthesis.
with various side-chain protecting groups (3g−3j) could be
isolated in good yield by using the corresponding H-
MeCys(Trt)-OH (2g), H-MeAsn(Trt)-OH (2h), H-MeLys-
(Boc)-OH (2i), and H-MeArg(Pbf)-OH (2j). Notably, all
dipeptides could be isolated in high yield and satisfactory
purity without column chromatography.
Next, we tested the scope of various electrophile substrates
reacted with H-MePhe-OH (2a). N-Boc- and N-Cbz-protected
valines (1b and 1c) both afforded the corresponding
compounds 3k and 3l in good yields (Figure 2. Acyclic and
15
With these new activating reagents and reaction conditions
in hand, a survey of the scope of various N-methylamino acids
amenable for use as the nucleophile was conducted. We first
tested H-MeGly-OH (2b) to compare the reactivity of ISTABr
7
to a previous report using IBCF. The reaction produced the
corresponding dipeptide 3b in excellent yield (Figure 1. The
Figure 2. Exploration of substrate scope with H-MePhe-OH (2a).
a
Isolated yields shown. THF was used as solvent for silylation.
b
c
Coupling reaction was conducted at 60 °C. Activation by ISTABr
Figure 1. Exploration of substrate scope with Fmoc-Val-OH (1a).
a
d
Isolated yields shown. H-MePhe-OH hydrochloric acid salt was used.
was conducted at −30 °C. Coupling reactions were carried out at 0
b
d
c
e
BSA (4.5 equiv) was used. THF was used as solvent for silylation.
°C. Crude material was purified by reversed-phase column
e
chromatography.
The reaction was carried out at 60 °C. NMP was used as solvent for
silylation.
cyclic aliphatic amino acids, such as Fmoc-MeVal-OH (1d)
and Fmoc-Pro-OH (1e), were also converted into the
corresponding dipeptides 3m and 3n in good yields. The use
hydrochloride salt of H-MePhe-OH (2a) was tested and was
also directly usable under these conditions without any
neutralization needed when the hydrochloride salt was treated
with 4.5 equiv of BSA. Turning our attention to the substrate
scope of the nucleophile, β-branched N-methylamino acids
t
of sterically hindered substrates such as Fmoc-Thr( Bu)-OH
(1f) and Fmoc-Trp(Boc)-OH (1g) was also tolerated under
these reaction conditions to afford dipeptides 3o and 3p in
90% and 78% yields, respectively. An unnatural phenylalanine
derivative, such as 3q with a nucleophilic nitrogen atom in the
phenyl ring, could also be prepared using ISTABr in high yield.
Notably, functionalized amino acids such as Fmoc-Cys(Trt)-
t
such as H-MeThr( Bu)-OH (2c) and the relatively sterically
hindered H-MeTrp(Boc)-OH (2d) were also well tolerated to
afford 3c and 3d in 86% and 94% yields, respectively. As
expected, the unprotected hydroxyl groups in H-MeSer-OH
OH (1i) and Fmoc-Arg(Boc) -OH (1j), which are prone to
2
(
2e) and H-MeThr-OH (2f) were compatible with this
epimerization, also afforded the desired products 3r and 3s
without significant epimerization. Most dipeptides except for
3s could be isolated in good yield and satisfactory purity
without column chromatography.
method and the side chain unprotected peptides 3e and 3f
were obtained in quantitative yields using a slight excess of
BSA. Moreover, other functionalized N-methylamino acids
C
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Letter
To confirm the viability of this approach for peptide
synthesis, we applied these conditions to the synthesis of
tripeptides containing N-methylamino acids (Figure 3). Using
ASSOCIATED CONTENT
Supporting Information
■
*
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02984.
Detailed experimental procedures for all compounds and
all spectral data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Keiichi Masuya − PeptiDream, Inc., Kawasaki, Kanagawa 210-
0
821, Japan; Email: k-masuya@peptidream.com
Naoki Nishizawa − Chemical Research Laboratories, Nissan
Chemical Corporation, Funabashi, Chiba 274-8507, Japan;
orcid.org/0000-0002-5530-2511; Email: nishizawan@
nissanchem.co.jp
Haruaki Kurasaki − PeptiDream, Inc., Kawasaki, Kanagawa
2
10-0821, Japan; orcid.org/0000-0003-4276-0545;
Email: h-kurasaki@peptidream.com
Authors
Akihiro Nagaya − Chemical Research Laboratories, Nissan
Chemical Corporation, Funabashi, Chiba 274-8507, Japan
Yutaka Kobayashi − PeptiDream, Inc., Kawasaki, Kanagawa
2
10-0821, Japan
Ayumu Matsuda − PeptiDream, Inc., Kawasaki, Kanagawa
2
10-0821, Japan
Figure 3. Peptide couplings with ISTABr. Isolated yields shown.
Masatoshi Matsumoto − PeptiDream, Inc., Kawasaki,
Kanagawa 210-0821, Japan
Koki Morimoto − PeptiDream, Inc., Kawasaki, Kanagawa 210-
0
821, Japan
silylated H-MeVal-Phe-OH (2k) as the nucleophile, the
reaction of 1k activated with ISTABr afforded the tripeptide
Tomonori Taguri − PeptiDream, Inc., Kawasaki, Kanagawa
2
10-0821, Japan
4
in good yield. It is well established that dipeptides as
Hisayuki Takeuchi − Chemical Research Laboratories, Nissan
Chemical Corporation, Funabashi, Chiba 274-8507, Japan
Michiharu Handa − Chemical Research Laboratories, Nissan
Chemical Corporation, Funabashi, Chiba 274-8507, Japan
Douglas R. Cary − PeptiDream, Inc., Kawasaki, Kanagawa
electrophiles are more prone to epimerization than N-
16
carbamate-protected monomers. Therefore, we attempted
the activation of a dipeptide to be coupled with an N-
methylated amino acid as the nucleophile. The activation of
Fmoc-Phe-Ala-OH (3t) with ISTABr proceeded at −30 °C,
and the following reaction with silylated H-MePhe-OH (2a)
was conducted at low temperature to prevent epimerization,
affording tripeptide 5 in acceptable yield with an undetectable
level of epimerization. With good results for both silylation and
activation by ISTABr of dipeptides observed, reactions
between the dipeptides was performed as a test of applying
this method to the convergent synthesis of longer peptides. We
were pleased to obtain tetrapeptide 6 in 55% yield from the
reaction of dipeptides 3t and 2k without epimerization under
the reaction. These results suggested the promising utility of
this methodology in the synthesis of peptide compounds.
In summary, we have developed an efficient and general
peptide synthetic methodology through the coupling of readily
accessible mixed anhydrides of N-protected amino acids and
peptides, using ISTAX as a new activation reagent, to in situ
silylated C-terminally unprotected N-methylamino acids. We
believe this represents the first systematic study demonstrating
the practical synthesis of a variety of N-methylated peptides
using C-terminally unprotected N-methylamino acids. We are
confident that this new method will accelerate the further
development of peptide therapeutics. Further studies on the
utility of this new method for the development of constrained
peptide therapeutics and diagnostics are underway and will be
reported in due course.
2
10-0821, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02984
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Takeru Ehara (PeptiDream, Inc.) for insightful
discussions, Nasir K. Bashiruddin (PeptiDream, Inc.) for
carefully proofreading the manuscript, and Tadamichi
Nagashima (PeptiDream, Inc.) and Koji Yoshida (PeptiDream,
Inc.) for experimental assistance.
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(11) Loss of enantiopurity under the silylating condition was not
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Information for chiral analysis data.
E
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