Arylboronate Ester Protected Amino Acids as Orthogonal Building Blocks for Fmoc Solid-Phase Peptide Synthesis

Article abstract of DOI:10.1002/ejoc.201701064

Three new arylboronate ester protected amino acids and their on-resin deprotection methods have been developed. These useful building blocks were found to exhibit favorable chemical properties that are fully compatible with Fmoc strategy solid-phase peptide synthesis. Furthermore, the formation of over-oxidation side-product methionine was minimized by using N-methyl-N-phenylaniline N-oxide as the oxidizing reagent. Effective application of the three new amino acids for the synthesis of different types of peptidomimetics has been demonstrated by high-quality preparation of lipidated peptide MP-196 C-C₈, on-resin head-to-tail cyclization of desotamide B, and lactam bridging of hPTHrP-(11–19) through a facile and metal-free procedure by standard Fmoc solid-phase peptide synthesis.

Full text of DOI:10.1002/ejoc.201701064

A Journal of
Accepted Article
Title: Novel Aryl Boronate Ester Based Amino Acids as Orthogonal
Building Blocks for Fmoc Solid Phase Peptide Synthesis
Authors: Chao Liu, Yan Zou, Hui Song, Fang Yan, Yuanye Jiang, and
Honggang Hu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701064
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701064
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10.1002/ejoc.201701064
European Journal of Organic Chemistry
COMMUNICATION
Novel Aryl Boronate Ester Protected Amino Acids as Orthogonal
Building Blocks for Fmoc Solid-Phase Peptide Synthesis
Chao Liu,†a Yan Zou,†a Hui Song,c Yuan-Ye Jiang*b and Hong-Gang Hu*a
Dedication ((optional))
Abstract: Three novel aryl boronate ester protected amino acids
and their on-resin deprotection methods were developed. These
useful building blocks were found to exhibit favourable chemical
properties that are fully compatible with Fmoc strategy solid-phase
peptide synthesis. Furthermore, the side over-oxidation product of
methionine was minimized by using N-methyl-N-phenylaniline N-
oxide as oxidizing reagent. Effective applications of the three new
amino acids for synthesis of different types of peptidomimetics have
been demonstrated by high-quality preparation of lipidated peptide
MP-196 C-C8, on-resin head-to-tail cyclization of desotamide B and
lactam bridging of hPTHrP-(11-19) through a facile and metal-free
procedure by standard Fmoc solid-phase peptide synthesis.
requires the use of Pd (PPh3)4 which may cause palladium
contamination problem detrimental to the preparation of peptides
for pharmaceutical use. Furthermore, the use of inert
atmosphere and the time-consuming process hinder the
convenient operation demanded by SPPS.[4] Thus, the
development of innovative building blocks as more appropriate
alternatives still remains a necessity.
Introduction
With the development of peptide chemistry, cyclization or side
chain modification of peptides allows for the generation of many
interesting peptidomimetics with excellent pharmacological
properties. Due to their improved selectivity and stability, these
modified peptides have received tremendous attention for the
development of novel pharmaceuticals.[1]
Classical methods usually prepare these analogues in
solution phase after cleavage of the on-resin linear precursors.
Tedious operations and repeated purifications are inevitable for
this synthetic strategy and therefore, resulting in some cases a
considerable loss of products.[2] Thus, the total solid phase
synthesis (SPPS) method is considered as an attractive
alternative in which the final cyclization or modification step is
achieved while the peptide still remains anchored to the resin.
The latter strategy requires the introduction of orthogonally
protected amino acid building blocks which are compatible with
Figure 1. Structures of aryl boronate ester based building blocks.
Aryl boronic acids or aryl boronate esters are widely used
in organic chemistry, but their applications were majorly focused
on synthetic intermediates and fluorescence probes.[5]
Intriguingly, p-dihydroxyborylbenzyloxycarbonyl (Dobz) group
was employed as an effective N-α-protecting group in the
synthesis of small peptides (up to a pentamer) through solution
phase coupling by Roberts in 1975.[6] In 2014, pDobz-Cys(Trt)-
OH (pDobz, p-dihydroxyborylbenzyl- oxycarbonyl pinacol ester)
was employed in the total synthesis of modified histones. After
cleavage from the solid support, the corresponding Dobz group
was successfully removed by a rapid aryl boronate oxidation
reaction mediated by H2O2.[7] This less time-consuming and
metal-free deprotection process may render pDobz or pDobb
(dihydroxyborylbenzyl pinacol ester) a superior capping group
for development of orthogonal amino acid building blocks such
as Fmoc-Lys(pDobz)-OH (1), Fmoc-Asp-OpDobb (2) and Fmoc-
Asp(pDobb)-OH (3) (Figure 1). Furthermore, the acid-stable
chemical property[7] makes these building blocks orthogonal to
various acid-liable protecting groups frequently employed in
SPPS such as p-methoxybenzyloxycarbonyl (Moz)[8], p-
nitrobenzyloxycarbonyl (pNZ)/p-nitrobenzyl (pNB)[9] and 4-
methyltriphenyl (Mtt)[10], etc. Nevertheless, the aqueous-phase
based deprotection condition and the lack of oxidation selectivity
of H2O2 (especially for methionine) restrict their applications in
SPPS.[11] Therefore, to develop pDobz/pDobb based amino
acids building blocks suitable for SPPS, the critical issue is to
establish a general on-resin deprotection method at the very
beginning.
tert-butyloxycarbonyl
(Boc),
tert-butyl
(tBu),
2,2,4,6,7-
pentamethyl-dihydrobenzo-furane-5-sulfonyl (Pbf) and trityl (Trt)
groups in Fmoc SPPS. To date, the most frequently used
building blocks are Fmoc-Lys(Alloc)-OH (Alloc, allyloxycarbonyl),
Fmoc-Asp(OAllyl)-OH and Fmoc-Asp-OAllyl. They have so far
been widely adopted during cyclic, branched, and chimeric
peptides synthesis and successfully applied in protein
modifications.[3] However, on-resin removal of Alloc/Allyl groups
[a]
[b]
Department of Organic Chemistry, College of Pharmacy, Second
Military Medical University, Shanghai 200433, China
E-mail: hhu66@smmu.edu.cn
School of Chemistry and Chemical Engineering, Qufu Normal
University, Qufu 273165, China
Email: qfnu_yuanyejiang@163.com
[c]
College of Pharmacy, Weifang Medical University, Weifang,
Shandong, 261053, China
[†]
These authors contributed equally to this work
Supporting information for this article is given via a link at the end
of the document. ((Please delete this text if not appropriate))
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10.1002/ejoc.201701064
European Journal of Organic Chemistry
COMMUNICATION
Table 1. The theoretical calculation results.
Entry
N-oxide
N1
∆G‡ (kcal/mol)
1
2
3
26.7
24.6
20.2
N2
N3
Recently, we are interested in
transformation from aryl boric acid to phenol mediated by
trimethylamine N-oxide (N1, TMAO) through metal-free
a
mild and rapid
Scheme 1. Synthesis route of small molecules. Reagents and conditions:
a) MCPBA, DCM, rt, 1 h, 79.8% for N2 and 73.7% for N3; b) i) BTC, THF,
rt, 12 h; ii) NaN3, 1,4-dioxane/water, rt, 2 h; iii) Benzylamine, Et3N, DMF,
rt, 12 h, 81.4% in 3 steps; c) 2-phenylacetic acid, DCC, DMAP,DCM, rt,
4 h, 79.3%; d) i) BTC, THF, rt, 12 h; ii) NaN3, 1,4-dioxane/water, rt, 2 h;
iii) Fmoc-Lys-OH, Et3N, DMF, rt, 12 h, 71.8% in 3 steps; e) Fmoc-
Asp(OtBu)-OH, DCC, DMAP, DCM, rt, 4 h, 85.9%; f) Fmoc-Asp-OtBu,
DCC, DMAP, DCM, rt, 4 h, 83.4%; g) TFA/DCM (3:1, v/v), rt, 2 h, 95.0%
for 2 and 95.3% for 3;
a
condition reported by Köster and Morita in 1967[12]. This reaction
was accelerated by turning to N,N,N-dialkylaryl N-oxides
reported by Falck in 2012[13]. The N-oxide together with sorts of
phenylboronic acids or aryl boronate pinacol esters gave the
corresponding phenols with high chemical yields. Subsequently,
this reaction was well studied by Bertozzi and co-workers, which
was applied as a novel bond-cleaving bioorthogonal reaction
inside mammalian cells. They found that the reaction between
N,N,N-dialkylaryl N-oxide and bis(pinacolato)-diboron (B2pin2)
showcased a second-order rate constant as high as 2.3 × 103 M-
limiting step for the oxidation reaction by Bertozzi and co-
workers.[14] Therefore, the free energy barriers of this step
referring to separate reactants were calculated at the level of
theory of M06/6-11+G(d,p)//M06/6-31G(d) in solution-phase with
SMD solvation model (solvent=water) (see the Supporting
Information).The calculation results showed that two phenyl-
substituted N-oxide (N3) is superior to the ones bearing one (N2)
or no phenyl group (N1).
S-1.[14] Taking these explorations into account, we speculate N-
1
oxide may solve the deprotection issue of pDobz/pDobb group
on solid phase for the following reasons. 1) This reaction was
found to explicit a quite higher reaction rate in DCM, the most
frequently used solvent in SPPS, than in water. 2) Some
oxidation-sensitive substrates (sulfide and aldehydes) were
intact under this condition, which may solve the methionine over-
oxidation problem as aforementioned.[13] 3) This reaction could
carry on at ambient temperature, without base and in the
presence of oxygen and water, offering a simple and convenient
operation required by SPPS.
To confirm this result, we obtained N2 and N3 from N,N-
dimethylaniline and N-methyl-N-phenylaniline via the oxidation
of 3-chloroperbenzoic acid (MCPBA) respectively (Scheme 1A).
Then, phenyl boronic acid pinacol ester (4) were subjected to
2.0 equivalent of NMO (N-Methyl morpholine-N-oxide), N1, N2
and N3 in DCM (0.2 M). It was found that the introduction of
aromatic groups into N-oxide has expectedly accelerated the
oxidation rate. Hence, we finally selected the N3 as the oxidizing
agent. Although the oxidation of the substrate was observed, the
reaction was unable to be completely realized even after 90
minutes treatment. Considering the facile removing of excess
reactants during SPPS reactions, we choose to adjust the
equivalent of N3 to accelerate this conversion. It was
demonstrated that 5.0 equivalents of N3 could convert more
than 97.0% substrates in 15 minutes which was an acceptable
reaction time for SPPS (Figure 2A, Table S1, see the
Supporting Information). Meanwhile, the stability of Fmoc-Met-
OH was investigated under this condition. As results, more than
96.0% of methionine remained intact after treatment with 5.0
equivalents of N3 in 15 minutes. Besides, there was only less
than 10.0% oxidation by-products generating even after 90
minutes exposure (Table S2, see the Supporting Information).
Hence, 5.0 equivalents of N3 for 15 minutes oxidation was
selected as the suitable condition.
Results and Discussion
At the beginning of our study, theoretical calculations were
employed to compare several economical and easy-to-prepare
N-oxide candidates (Table 1). The concerted N-O bond
cleavage and O-C bond formation was proposed to be the rate-
Figure 2. A) The conversion rates of
4 (0.2 mmol, DCM, rt) with 2.0 eq
or 5.0 eq N-oxides. B) The degradation rates of Fmoc-His(Boc)-OH,
Fmoc-Lys(Boc)-OH, Fmoc-Trp(Boc)-OH (0.2 mmol, rt) with 5.0%
TFA/DCM containing 20.0% m-cresol.
In a previous report, the pDobz group was deprotected
from amine in a basic condition (pH= 9.5) after oxidation through
quinomethide form as an intermediate in the aqueous phase.[6]
However, we noticed that the carbobenzoxy form could also be
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10.1002/ejoc.201701064
European Journal of Organic Chemistry
COMMUNICATION
NaN3 in 1,4-dioxane/water which was better than
carbonochloridate form for storage and use because of its
chemical stability and solid-state property. The reaction of
pDobz-N3 with Fmoc-Lys-OH in the presence of Et3N provided
Fmoc-Lys(pDobz)-OH (1) with a yield of 71.8%. We chose the
cationic antimicrobial peptides MP-196 C-C8, a side chain
lipidated MP-196 derivative, as our first target.[17] It contains
multiple repeated arginine and tryptophan sequences and is
currently considered to be one of the typical antimicrobial
peptides. Among all the lipidated MP-196 derivatives, those with
lipid chains of eight carbon atoms turned out to be the most
promising candidate for antibacterials development.[18] Building
block 1 was successfully incorporated into linear peptide on
resin (7) through SPPS. Then, it was subjected to the general
deprotection condition (5 equivalent of N3 in DCM for 15
minutes, then 5% TFA/ DCM solution containing 20.0% m-cresol
for 15 minutes) to achieve the linear peptide with a free amino
group at Lys side chain (8). Coupling with n-octanoic acid using
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflu
orophosphate (HATU), 1-hydroxy-7-azabenzotriazole (HOAt)
and N,N-Diisopropylethylamine (DIEA) in DMF for 2 hours and
the following global deprotection and cleavage by trifluoroacetic
acid (TFA), triisopropylsilane (TIPs), 1,2-Ethanedithiol (EDT) and
water (95:2:2:1, v/v/v/v) successfully provided the crude MP-196
C-C8 in a purity of 85.2% and a yield of 47.3% after purification
by RP-HPLC (Figure 3).
To investigate the applicability of building block 2, we
synthesized Desotamide B, a 6-residue head-to-tail cyclopeptide
with growth inhibitory activity against Gram-positive bacteria.[19]
In the previous studies, these kinds of cyclopeptide containing
Asp and/or Asn residue were synthesized via on-resin head-to-
tail cyclization strategy with Allyl based building blocks.[20] Herein,
we first prepared 2 as follows (Scheme 1C). The esterification
reaction between Fmoc-Asp(OtBu)-OH and (4-(4,4,5,5-tetra-
Figure 3. A) Synthesis route of MP-196 C-C8, Reagents and conditions:
a) i) 5.0 eq N3, DCM, rt, 15 min; ii) TFA/m-cresol/DCM (5:20:75, v/v/v), rt,
15 min; b) i) HATU, HOAt, DIPEA, DMF, rt, 15 min; ii) Octanoic
acid/DMF, rt, 2 h; iii) TFA/TIPs/EDT/Water (95:2:2:1, v/v/v/v), rt, 2 h, 47.3%
yield. B) HPLC profile of the crude MP-196 C-C8
C-C8.
. C) HR-MS of MP-196
cleaved through acidic medium with different rates based on the
substituted groups.[6][15] Therefore, we were interested in the
method of acidic removing of Moz group, which was very close
to the pDobz/pDobb group after oxidation.[8] It was pointed out
that Moz group could be removed in high yield with 5.0% TFA
for 30 minutes, accompanied by 20.0% degradation of Boc,
which could be accelerated by 20.0% m-cresol addition.[16] To
investigate this condition, we built pDobz protected benzylamine
and pDobb protected 2-phenylacetic acid (5 and 6 Scheme 1B).
After treatment with 5 equivalents of N3 for 15 minutes, they
were subjected to different acidic conditions (1.0-5.0% TFA with
or without 20.0% m-cresol) and monitored at 15, 30 and 60
minutes by HPLC. We found that both of the intermediates
completely convert to benzylamine and phenylacetic acid in 15
minutes in the presence of 5% TFA/DCM solution containing
20.0% m-cresol (Table S3 and S4, see the Supporting
Information). Subsequently, protecting groups frequently used
during Fmoc SPPS such as Boc, tBu, Pbf and Trt were tested
under this condition. Trace degradation (< 5.0%) was only
observed for the Boc protecting group (Figure 2B, Table S5,
see the Supporting Information).
Having the deprotection condition available, our next plan
was to explore the application of 1 in side chain modified peptide
total synthesis. First of all, 1 was synthesized as follows
(Scheme 1B). The commercially available (4-(4,4,5,5-
Figure 4. A) Synthesis route of Desotamide B, Reagents and conditions:a) i)
5.0 eq N3 in DCM, rt, 15 min; ii) 20.0% piperidine/DMF, rt, 10 min; iii) TFA/m-
cresol/DCM (5:20:75, v/v/v), rt, 15 min; b) i) PyAOP, HOAt, NMM, NMP, rt, 12
h; ii) TFA/TIPs/EDT/Water (95:2:2:1, v/v/v/v), rt, 2 h, 43.8% yield. B) HPLC
profile of the crude Desotamide B. C) HR-MS of Desotamide B.
tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)
converted to carbonchloridate form through triphosgene (BTC) in
THF. Then, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzyl carbon-azidate (pDobz-N3) was obtained after addition of
methanol
was
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10.1002/ejoc.201701064
European Journal of Organic Chemistry
COMMUNICATION
biogenic cyclization via lactam formation between side chains of
Lys and Asp used to be realized through Fmoc/tBu strategy with
Allyl/Alloc based building blocks.[22] First of all, Fmoc-
Asp(pDobb)-OH (3) was obtained through the similar method
from 12 (Scheme 1C). Fully protected linear peptide could be
easily obtained by coupling Fmoc-Lys(pDobz)-OH (1) and 3 into
the peptide backbone (13) via SPPS. The following
simultaneous deprotection of pDobz/pDobb provided the on-
resin
cyclization
precursor
(14).
Treatment
with
PyAOP/HOAt/NMM on solid support and the following cleavage
and global deprotection provided the hPTHrP-(11-19) with a high
purity of 79.3% and a yield of 38.1% after purification by RP-
HPLC (Figure 5).
Conclusions
In summary, it is the first time to describe the employment of
aryl boronate ester protected amino acids as building blocks for
facile and efficient preparation of various peptidomimetics. We
successfully solved their deprotection issue on solid support and
the methionine over-oxidation problem reported in the previous
study was minimized by using theoretical calculation optimized
N3 as oxidizing reagent. These novel building blocks were found
to exhibit favourable chemical properties that are fully
compatible with the Fmoc strategy SPPS and orthogonal to Boc,
tBu, pbf and Trt groups as demonstrated by high-quality
synthesis of MP-196 C-C8, Desotamide B and hPTHrP-(11-19).
They may provide superior alternatives in the synthesis of
peptidomimetics for pharmaceutical use because of their less-
time-consuming and metal-free handling properties. More
importantly, owing to their acid-stable chemical properties, these
building blocks are orthogonal to various acid-liable protecting
groups such as Moz, pNZ/pNB and Mtt which can be employed
to prepare more complex peptidomimetics and proteins. Further
applications of these building blocks are being explored in our
team.
Figure 5. A) Synthesis route of hPTHrP-(11-19), Reagents and
conditions: A) i) 5.0 eq N3 in DCM, rt, 15 min; ii) TFA/m-cresol/DCM
(5:20:75, v/v/v), rt, 15 min; b) i) PyAOP, HOAt, NMM, NMP, rt, 12 h, ii)
TFA/TIPs/EDT/ Water (95:2:2:1, v/v/v/v), rt, 2 h, 38.1% yield. B) HPLC
profile of the crude hPTHrP-(11-19).C) HR-MS of hPTHrP-(11-19).
methyl-1,3,2-dioxaborolan-2-yl)phenyl) methanol promoted by
dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine
(DMAP) afforded Fmoc-Asp(OtBu)-OpDobb (9) in 85.9% yield.
Then, Fmoc-Asp-OpDobb (2) was obtained after deprotection of
tBu group by TFA/DCM (3:1, v/v) with a yield of 95.0%. After
introduction of 2 into the linear peptide (10) via SPPS, pDobb
was deprotected on-resin successfully with the general
deprotection condition. Then, the Fmoc group was deprotected
with 20.0% piperidine/DMF, followed by the on-resin cyclization
in the presence of (7-azabenzotriazol-1-yloxy) tripyrrolidino
phosphonium hexafluoro phosphate (PyAOP), HOAt and 4-
methyl- morpholine (NMM) for 12 hours. However, after
cleavage from the resin by TFA/TIPs/EDT/water (95:2:2:1,
v/v/v/v), we were unable to obtain the desired product. However,
considering the trace cleavage linear peptide (11) was correct
(Figure S2, see the Supporting Information), we suspected that
the free C-terminal might be interfered by piperidine during the
Fmoc deprotection step by some means and could be rectified in
acidic conditions. To support this notion, we reversed the
treatment order of TFA/m-cresol/DCM and piperidine/DMF.
Gratifying, crude Desotamide B was successfully obtained in
81.6% purity and a yield of 43.8% after purification by RP-HPLC
(Figure 4).
Experimental Section
Supporting Information (see footnote on the first page of this article):
Experimental procedures, characterization data, and 1H and 13C NMR
spectra of the products.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21402235, No. 21602121) PLA Youth Medical
Science and Technology Youth Development Program
(No.16QNP086), and Instrumental Analysis Center of our
university for NMR spectroscopic and mass spectrometric
analyses.
Keywords: Aryl boronate ester • Orthogonal building blocks •
Finally, building block 3 was employed to synthesize a
lactam-bridge mimetic cyclopeptide, hPTHrP-(11-19) ([Ac-Lys-
Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-NH2]), a fragment of the potent
parathyroid hormone receptor 1 (PTHR1) antagonist containing
an extended and stabilized α-helical conformation.[21] Its non-
Peptide synthesis
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10.1002/ejoc.201701064
European Journal of Organic Chemistry
COMMUNICATION
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701064
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Chao Liu,†a Yan Zou,†a Hui Song,c Yuan-
Ye Jiang*b and Hong-Gang Hua*
Page No. – Page No.
Novel
aryl
boronate
acids
ester
as
protected
amino
orthogonal building blocks for
Fmoc
solid
phase
peptide
synthesis
This article is protected by copyright. All rights reserved.