Diboronic Acid Anhydride-Catalyzed Direct Peptide Bond Formation Enabled by Hydroxy-Directed Dehydrative Condensation

Article abstract of DOI:10.1021/acs.orglett.0c03252

We report the catalytic direct peptide bond formations via dehydrative condensation of β-hydroxy-α-amino acids, affording the serine, threonine, or β-hydroxyvaline-derived peptides in high to excellent yields with high functional group tolerance, minimum epimerization, and excellent chemoselectivity. The key to the success of these atom-economical transformations is the use of diboronic acid anhydride catalyst for the hydroxy-directed reactions.

Full text of DOI:10.1021/acs.orglett.0c03252

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Letter
Diboronic Acid Anhydride-Catalyzed Direct Peptide Bond Formation
Enabled by Hydroxy-Directed Dehydrative Condensation
Masayoshi Koshizuka, Kazuishi Makino, and Naoyuki Shimada*
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ABSTRACT: We report the catalytic direct peptide bond formations via dehydrative condensation of β-hydroxy-α-amino acids,
affording the serine, threonine, or β-hydroxyvaline-derived peptides in high to excellent yields with high functional group tolerance,
minimum epimerization, and excellent chemoselectivity. The key to the success of these atom-economical transformations is the use
of diboronic acid anhydride catalyst for the hydroxy-directed reactions.
eptides are extremely valuable species as biomolecules and
carbamate-protected α-amino acid derivatives have been
reported, room exists for turnover number improvements.25c,27
The main reason for the observed low catalytic efficiencies may
be boronic acid inhibition resulting from the formation of inert
species by chelating of amino acids as bidentate substrates.29
Hall30 and Ishihara31 independently found that use of
alternative N-protecting groups of α-amino acids, like
phthaloyl,30 azido,30 and trifluoroacetyl31 groups, increased
catalytic efficiencies (Scheme 1a). Over the past three years,
breakthroughs in the development of organoboron catalysts
other than monoboronic acids have been reported, which
afford peptide bond formation using N-carbamate-protected
amino acids as substrates (Scheme 1a). In 2018, Sheppard32
demonstrated that a borate ester derived from trifluoroethanol
is a highly efficient catalyst for the dehydrative amidation of a
range of substrates, including N-carbamate-protected α-amino
acids32a,b and unprotected α-amino acids.32a Around the same
time, Shibasaki and Kumagai et al. reported the catalytic
dehydrative amidation of N-carbamate-protected function-
alized α-amino acids using catalyst 1,3-dioxa-5-aza-2,4,6-
1
functional materials,2
Pconstituents of pharmaceuticals,
and catalysts.3 Several methods4 for peptide bond formation
have been developed relying on carboxylic acid surrogates,
including acid halides,5 thioesters,6 acyl hydrazides,7 acyl
ureas,8 esters,9 selenoesters,10 amides,11 thioacids,12 keto
acids,13 acyl trifluoroborates,14 and nitro alkanes.15 Some
innovative approaches using isonitriles,16 azides,17 thioa-
mides,18 hydroxy amines,13 and alkoxyamines13 as amine
surrogates have also been reported. However, these strategies
often involve tedious substrate preparation procedures. Thus,
the dehydrative condensation of carboxylic acids and amines is
one of the most attractive methodologies for peptide bond
construction.19 Although dehydrative condensation using
stoichiometric amounts of condensation reagents20 has been
widely utilized in liquid-phase and solid-phase peptide
synthesis,21 its implementation results in low atom economy
and partial racemization. The catalytic version of direct
dehydrative peptide bond formation provides the means to
overcome such drawbacks.22
In 1996, Yamamoto23 reported a pioneering study of
catalytic dehydrative condensation of carboxylic acids with
amines using electron-deficient arylboronic acids. Subse-
quently, modified aromatic boronic acid catalysts were
developed by Ishihara,24 Whiting,25 Hall,26 and Blanchet.27,28
By contrast, successful examples of boronic acid-catalyzed
peptide bond formation are limited. Although some studies on
boronic acid-catalyzed peptide synthesis using common N-
Received: September 28, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03252
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
Scheme 1. Catalytic Peptide Bond Formations
Table 1. Optimization of Catalytic Dehydrative Peptide
a
Bond Formation
b
entry
catalyst
DBAA 1
DBAA 1
DBAA 1
DBAA 1
DBAA 1
DBAA 1
B(OCH2CF3)3
DATB
gem-DBA
DBAA 1
solvent
conc (M) yield (%) % ee
1
2
3
4
5
6
7
8
9
toluene
C6H5Cl
CPME
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0.10
0.10
0.10
0.10
0.05
0.20
0.05
0.05
0.05
0.05
0.05
72
31
11
89
95
81
trace
47
9
97
98
96
99
>99
98
nd
98
99
c
10
90
trace
>99
nd
d
11
DCE
a
The reactions were carried out in the presence of Cbz-Ser-OH (2a)
(0.10 mmol, 1.0 equiv), H-Gly-OtBu (3a) (0.10 mmol, 1.0 equiv),
b
and catalyst 1 (2.0 μmol, 2.0 mol %) at 90 °C (bath temp). Ee was
c
determined by chiral HPLC analysis. Performed with HCl salt of H-
Gly-OtBu (3a·HCl) (1.0 equiv) in the presence of 4 Å molecular
d
sieves (100 mg/0.10 mmol). In the absence of catalyst 1. CPME:
cyclopentyl methyl ether; DCE: 1,2-dichloroethane.
showing higher catalytic activity of 1 (entry 5 vs entries 7−
9).39 In this catalytic system, commercially available HCl salts
of amino esters could be used as substrates: the HCl salt of H-
Gly-OtBu (3a·HCl), in the presence of 4 Å molecular sieves,
afforded a product yield (90%) comparable with that of free
amine 3 (entry 5 vs entry 10). This protocol is experimentally
advantageous as it does not require advance free amine. No
peptide bond formation occurred without 1 (entry 11). These
results indicate the suitability of 1 as the catalyst for the
dehydrative coupling of β-hydroxy-α-amino acid.39
With the optimal conditions in hand, we explored the
substrate scope of the catalytic dipeptide synthesis (Scheme 2).
Besides Cbz, Boc and Fmoc could be used as serine N-
protecting groups, affording Boc-Ser-Gly-OBn (4b) and Fmoc-
Ser-Gly-OEt (4c) in 88 and 81% yield, respectively. We then
evaluated the reactivities of a range of α-amino esters. All
reactions involving H-Ala-OtBu (3d), H-Leu-OMe (3e), H-Ile-
OMe (3f), and H-Val-OMe (3g) possessing an alkyl side-chain
at the α-position proceeded smoothly within 24 h with
dipeptides 4d−4j obtained in high to excellent yields (74−
>99%). Notably, all dipeptide bonds were formed without
substantial epimerization (dr 98/2−>99/1). In the case of 4i,
catalyst loading could be reduced to 0.5 mol %, and the turn
over number recorded 142 (71% yield). The present protocol
could be performed in 1.0 mmol scale, affording 4j in 88%
yield without epimerization. Bulky tert-leucine derivative H-
Tle-OMe (3h) could also be used as an α-amino ester
substrate, affording Boc-Ser-Tle-OMe (4k) in excellent yield
(97%) in the presence of 5.0 mol % of 1. In the case of α,α-
disubstituted amino ester-derived dipeptide 4l, the coupling
reaction progressed at elevated temperature in toluene with
high racemization at the carbonyl α-position. By contrast, use
of sarcosine derivative H-Sar-OBn (3j) as secondary amine
substrate afforded dipeptide Boc-Ser-Sar-OBn (4m) in
moderate yield and minimal racemization. Subsequently, we
triborinate (DATB).33 The exceptional power of this catalysis
was demonstrated by application to the syntheses of an
oligopeptide and various dipeptides.34 Most recently, Take-
moto35 designed a gem-diboronic acid (gem-DBA) catalyst for
dehydrative peptide synthesis based on a revised mechanism of
boronic acid-catalyzed amidation via a dimeric anhydride
intermediate with a B−O−B skeleton described by Whiting
and Sheppard.36
We recently disclosed that diboronic acid anhydride
(DBAA) with a preorganized B−O−B motif is an effective
catalyst for the hydroxy-directed dehydrative amidation
carboxylic acids.37,38 Herein, we report the DBAA-catalyzed
dehydrative peptide bond formations of α-amino acids having
a free hydroxy group on the β-position (Scheme 1b). This
hydroxy-directed reaction using low catalyst loading enabled
the direct formation of serine- or threonine-derived dipeptides
with high functional group tolerance, minimum epimerization,
and excellent chemoselectivity.
Initially, we explored the dehydrative coupling of an
equimolar mixture of Cbz-Ser-OH (2a) and H-Gly-OtBu
(3a) in the presence of 2.0 mol % of DBAA 1 in toluene
(Table 1). The reaction proceeded at 90 °C within 4 h without
the need for dehydration protocols, affording the desired
dipeptide Cbz-Ser-Gly-OtBu (4a) in 72% yield with minimum
racemization at the α-position of the carbonyl group (entry 1).
Although no product yield improvements were observed using
C6H5Cl or cyclopentyl methyl ether as solvents (entries 2, 3),
use of 1,2-dichloroethane afforded 4a in 89% yield (entry 4). A
survey of solvent concentrations indicated 0.05 M to be
optimal for product yield and racemization, increasing
dipeptide 4a yield to 95% without loss of optical purity
(entry 5 vs entries 4, 6). To compare the catalytic efficiency,
we examined the reaction using some organoboron catalysts,
B
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a
Scheme 2. Substrate Scope for Diboronic Acid Anhydride-Catalyzed Serine-Derived Peptide Bond Formation
a
The reactions were carried out in the presence of serine derivative 2 (0.10 mmol, 1.0 equiv), amino ester 3 (0.10 mmol, 1.0 equiv), and catalyst 1
(2.0 μmol, 2.0 mol %) in 1,2-dichloroethane (DCE, 0.05 M) under reflux (bath temp, 90 °C). Ee and dr were determined by chiral HPLC analysis.
b
c
d
e
f
Performed with 5.0 mol % of 1. Performed with 0.5 mol % of 1. Performed in 1.0 mmol scale. Performed with 10 mol % of 1. Performed in
g
toluene (0.05 M) under reflux (bath temp, 110 °C). Performed with HCl salt of amino ester 3 (1.0 equiv) in the presence of 4 Å molecular sieves
(100 mg/0.10 mmol). Performed at 80 °C (bath temp).
h
explored the use of functionalized α-amino esters incorporating
heteroatoms as substrates. Reaction of H-Tyr(tBu)-OMe (3k),
whereby a hydroxy group is protected by a tert-butyl group,
gave dipeptides 4n−4p in high yields (79−88%). Moreover,
unprotected H-Tyr-OMe (3l) afforded dipeptide Boc-Ser-Tyr-
OMe (4q) in high yield. Evidence thus indicates that an
unprotected phenolic hydroxy group does not suppress the
present catalysis. Aspartic acid derivative H-Asp(tBu)-OtBu
(3m) gave dipeptide 4r in 97% yield. 1 was also effective for
the dipeptide coupling between serine and asparagine to
produce dipeptide Boc-Ser-Asn-OtBu (4s) with a primary
amide functional group. We then examined the tolerance of the
present protocol for N-functional groups: not only was N-H
free indole tolerated, but so were acid-labile N-tert-
butoxycarbonyl-protected amine, N-2,2,4,6,7-pentamethyl-
dihydrobenzofuran-5-surfonyl-protected guanidine, and N-
trytyl-protected imidazole. H-Trp-OMe (3o), H-Lys(Boc)-
OMe (3p), H-Arg(Pbf)-OMe (3q), and H-His(Trt)-OMe
(3r) afforded dipeptides 4t−4w in acceptable yields (64−
99%). Significantly, stereochemical integrity was almost
completely preserved in most cases (dr 96/4−>99/1). The
reaction between 2b and H-Met-OMe (3s) proceeded
smoothly within 8 h, affording dipeptide Boc-Ser-Met-OMe
(4x) in 81% yield. This result indicates the tolerance of our
DBAA-based catalysis for the Lewis-basic sulfide group. The S-
functionalized α-amino ester H-Cys(Bn)-OMe (3t) produced
Boc-Ser-Cys(Bn)-OMe (4y) in high yield in 1,2-dichloro-
ethane, although the reaction temperature had to be lowered to
80 °C to avoid a noticeable drop in stereochemical integrity.
The wide functional group tolerance of the catalysis was thus
demonstrated.
To expand the scope of this DBAA-catalyzed peptide bond
formation, we investigated threonine derivatives bearing β-
hydroxy-α-amino acid motifs similar to serine. As detailed in
Scheme 3, Boc-Thr-OH (5a), Fmoc-Thr-OH (5b), and Cbz-
Thr-OH (5c) afforded dipeptides 6a−6f in high to excellent
yields (72−98%). No major negative impact was associated
with the steric hindrance of the additional β-methyl substituent
group. Notably, high functional tolerance and no detectable
epimerization were observed in all cases.
To confirm the importance of the β-hydroxy group in the
substrate-directed reaction, we conducted some additional
experiments (Scheme 4).40 First, we performed a catalytic
dipeptide synthesis using β-hydroxyvaline derivative 7 as a
challenging β,β-disubstituted substrate (Scheme 4a). In the
presence of 5.0 mol % of 1, the corresponding dipeptide 8 was
C
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Scheme 3. Diboronic Acid Anhydride-Catalyzed Threonine-
Derived Peptide Bond Formation
Scheme 4. Diboronic Acid Anhydride-Catalyzed
Dehydrative Peptide Bond Formation
a
a
a
The reactions were carried out in the presence of threonine
derivative 5 (0.10 mmol, 1.0 equiv), amino ester 3 (0.10 mmol, 1.0
equiv), and catalyst 1 (2.0 μmol, 2.0 mol %) in 1,2-dichloroethane
(DCE, 0.05 M) under reflux (bath temp, 90 °C). Diastereomers were
not detected by 13C NMR analysis.
obtained in 68% yield without any racemization, indicating the
steric tolerance of this coupling reaction.
Next, a dehydrative condensation between serine derivative
2b and aspartic acid derivative H-Asp-OBn (3u) having a free
carboxyl group was performed (Scheme 4b). To facilitate
purification, the free carboxylic functional groups were
converted to methyl esters by treating the crude product
with excess trimethylsilyl diazomethane. After two-step
sequences, the expected dipeptide 4z was obtained in 69%
yield (60% isolated yield) alongside the methyl ester 9 (19%
yield), resulting from the esterification of unreacted aspartic
acid moiety. Analysis of stereochemical integrity of 4z revealed
no epimerization at the carbonyl α-position, indicating the
high chemoselectivity for β-hydroxycarboxylic acid over simple
carboxylic acid of the DBAA-catalyzed dehydrative coupling.
This tendency was confirmed by the results of the competition
experiment involving β-hydroxy-α-amino acid and simple α-
amino acid (Scheme 4c). The reaction of 1.0 equiv each of
Cbz-Ser-OH (2a) and Cbz-Val-OH (10) with H-Gly-OtBu
(3a) afforded dipeptide Cbz-Ser-Gly-OtBu (4a) as sole
product in 88% yield (99% ee). Valine-derived dipeptide 11
was not observed, confirming the extremely high chemo-
selectivity for β-hydroxycarboxylic acid.
a
Determined by 1H NMR analysis of the crude product mixture using
1,1,2,2-tetrachloroethane as internal standard.
applicable to a selective peptide coupling using a N-terminal
peptide fragment having a β-hydroxy-α-amino acid residue at
its C-terminus.
We then focused on tripeptide synthesis. Although a higher
catalyst loading of 10 mol % was required, the tripeptide Boc-
Ser-Leu-Val-OEt (13) was obtained in 54% yield via coupling
of 2b with dipeptide H-Leu-Val-OEt (12) as amine substrate
(Scheme 4d). Moreover, dipeptide Fmoc-Leu-Ser-OH (14)
comprising an amide linkage on the nitrogen atom of serine
was utilized to afford the tripeptide Fmoc-Leu-Ser-Val-OEt
(15) in 67% yield (Scheme 4e). Notably, 15 was obtained
without any loss of stereochemical integrity at the α-position of
serine’s carbonyl, despite epimerization often becoming a
problem in dehydrative condensation of peptides.20 These
results suggest that our DBAA-based catalysis might be
In summary, we demonstrated that DBAA is an effective
catalyst for the hydroxy-directed amidation of β-hydroxy-α-
amino acids with a wide range of α-amino esters. This catalysis
shows high functional group tolerance in peptide bond
formations using serine, threonine, and hydroxyvaline deriva-
tives as α-amino acid substrates, producing di- and tripeptides
in high to excellent yields and minimum epimerization. The
present protocol affords excellent chemoselectivity for α-amino
acids having the β-hydroxycarboxylic acid unit. Further
applications of DBAA-based catalysis are underway in our
laboratories.
D
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776−779. (b) Agouridas, V.; El Mahdi, O.; Diemer, V.; Cargoet, M.;
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AUTHOR INFORMATION
Corresponding Author
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6855.
■
Naoyuki Shimada − Laboratory of Organic Chemistry for Drug
Development and Medical Research Laboratories, Department
of Pharmaceutical Sciences, Kitasato University, Tokyo 108-
8641, Japan; orcid.org/0000-0002-0143-7867;
Email: shimadan@pharm.kitasato-u.ac.jp
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Synthesis. J. Am. Chem. Soc. 2019, 141, 12288−12295.
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General, Mild, and Metal-Free Synthesis of Phenyl Selenoesters from
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Authors
Masayoshi Koshizuka − Laboratory of Organic Chemistry for
Drug Development and Medical Research Laboratories,
Department of Pharmaceutical Sciences, Kitasato University,
Tokyo 108-8641, Japan
Kazuishi Makino − Laboratory of Organic Chemistry for Drug
Development and Medical Research Laboratories, Department
of Pharmaceutical Sciences, Kitasato University, Tokyo 108-
8641, Japan; orcid.org/0000-0001-8518-6593
(11) Hollanders, K.; Renders, E.; Gadais, C.; Masullo, D.; Van
Raemdonck, L.; Wybon, C. C. D.; Martin, C.; Herrebout, W. A.;
Maes, B. U. W.; Ballet, S. Zn-Catalyzed Nicotinate-Directed
Transamidations in Peptide Synthesis. ACS Catal. 2020, 10, 4280−
4289.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03252
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was partially supported by JSPS KAKENHI
Grant 19K07000 (N.S.) for Scientific Research (C). We thank
Dr. K. Nagai and Ms. N. Sato at Kitasato University for
instrumental analyses.
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F
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Letter
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(39) See the Supporting Information for details.
(40) For the investigations of the reaction mechanism, see the
Supporting Information.
G
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