Epoc group: Transformable protecting group with gold(iii)-catalyzed fluorene formation

Article abstract of DOI:10.1039/d1sc03125b

This study presents the novel concept of a transformable protecting group, which changes its properties through structural transformation. Based on this concept, we developed a 2-(2-ethynylphenyl)-2-(5-methylfuran-2-yl)-ethoxycarbonyl (Epoc) group. The Epoc group was transformed into an Fmoc-like structure with gold(iii)-catalyzed fluorene formation and was removable under Fmoc-like mild basic conditions post-transformation even though it was originally stable under strongly basic conditions. As an application for organic synthesis, the Epoc group provides the novel orthogonality of gold(iii)-labile protecting groups in solid-phase peptide synthesis. In addition, the high turnover number of fluorene formation in aqueous media is suggestive of the applicability of the Epoc group to biological systems. This journal is

Full text of DOI:10.1039/d1sc03125b

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Epoc group: transformable protecting group with
gold(III)-catalyzed fluorene formation†
Cite this: DOI: 10.1039/d1sc03125b
a
abc
Tsung-Che Changa and Katsunori Tanaka
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Tomoya Yamamoto,
This study presents the novel concept of a transformable protecting group, which changes its properties
through structural transformation. Based on this concept, we developed a 2-(2-ethynylphenyl)-2-(5-
methylfuran-2-yl)-ethoxycarbonyl (Epoc) group. The Epoc group was transformed into an Fmoc-like
structure with gold(III)-catalyzed fluorene formation and was removable under Fmoc-like mild basic
conditions post-transformation even though it was originally stable under strongly basic conditions. As
an application for organic synthesis, the Epoc group provides the novel orthogonality of gold(III)-labile
protecting groups in solid-phase peptide synthesis. In addition, the high turnover number of fluorene
formation in aqueous media is suggestive of the applicability of the Epoc group to biological systems.
Received 9th June 2021
Accepted 8th July 2021
DOI: 10.1039/d1sc03125b
rsc.li/chemical-science
substitution of diarylmethane for uorene in the Fmoc group
increases stability. Based on this, we proposed the novel
Introduction
The mild deprotection of the Fmoc protecting group is advan-
tageous to avoid side reactions and to obtain free functional
groups efficiently.1 Thus, the Fmoc group has been applied to
the synthesis of a wide variety of compounds including natural
products, glycans, and peptides.2–5 This lability is also appli-
cable to the controlled release of drugs in vivo; the modication
of peptide drugs with an Fmoc structure prolongs their lifetime
in circulation.6,7 In addition, some Fmoc-protected amino acids,
peptides, and sugars have been used for low-molecular-weight
gelators and applied as biomaterials.8–13 These compounds
form brils with the p–p or CH–p stacking of uorene rings,
which results in the formation of hydrogels.
Although this base lability is useful, the Fmoc group is not
tolerant to reactions using strong basic reagents. A protecting
group that achieves both Fmoc-like mild deprotection and high
stability would solve this problem. However, it is difficult to
develop such a protecting group because the stability of the
protecting group is generally inseparable from its harsh
deprotection conditions.
The base lability of the Fmoc group originates from the
aromaticity of uorenes, which stabilizes its anion and accel-
erates Ec1b elimination. The pKa value of uorene is 10 less
than that of diphenylmethane (Fig. 1a).14,15 Thus, the
aBiofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for Pioneering
Research, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan. E-mail: kotzenori@
riken.jp
bDepartment of Chemical Science and Engineering, School of Materials and Chemical
Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8552, Japan
cBiofunctional Chemistry Laboratory, Alexander Butlerov Institute of Chemistry, Kazan
Federal University, 18 Kremlyovskaya Street, 420008, Kazan, Russian Federation
† Electronic supplementary information (ESI) available: Experimental procedure,
compound data, NMR spectra. See DOI: 10.1039/d1sc03125b
Fig. 1 (a) The difference in pKa between diphenylmethane and fluo-
rene. (b) Our strategy for the development of a transformable pro-
tecting group. (c) The novel protecting group developed in this work.
The Epoc group is removed with a unique two-step procedure:
gold(III)-catalyzed fluorene formation and base-induced Ec1b
elimination.
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concept of a transformable protecting group, which changes its
properties through structural transformation (Fig. 1b). For
example, if the protecting group with diarylmethane is trans-
formable into an Fmoc-like structure, its lability will be changed
by the transformation, and this protecting group will achieve
both high stability (before the transformation) and Fmoc-like
lability (aer the transformation). This system can also be
applied to biological systems. Recently, metal catalysts have
been used for prodrug activation and uorescence labeling in
biological systems.16–20 If these catalysts perform the trans-
formation in vivo, this could create potential new application of
the Fmoc group in biological systems such as triggering drug
release and hydrogelations.
For the uorene formation of this design, we focused on the
gold(III)-catalyzed21,22 phenol synthesis reported by Hashmi
et al.23–27 They have reported that the furan-yne system tethered
with an aromatic linker is transformed into 4-OH-uorenol with
gold(III) catalysts within 10 minutes.28 Thus, we envisioned that
the protecting group containing this sub-structure could meet
our criteria for the design of a transformable protecting group.
In this study, we developed a novel protecting group con-
taining the precursor structure of uorene, 2-(2-ethynylphenyl)-
2-(5-methylfuran-2-yl)-ethoxycarbonyl (Epoc) (Fig. 1c), which is
the rst example of a transformable protecting group. The Epoc
group is stable under strongly basic conditions. On the other
hand, a catalytic amount of gold(III) salt transforms the Epoc
Scheme 1 Synthesis of reagents for introducing Epoc group.
was prepared by the reaction of EpOH 6 with di(N-succinimidyl)
carbonate, which can be used to introduce the Epoc group to
amines.
Introduction and deprotection conditions for protecting
group
Before investigating the applicability of the Epoc group for
protecting groups, we sought suitable conditions for gold-
catalyzed uorene formation. The Epoc-protected aniline 8
(Table 1) was obtained in the reaction with EpOH 6 and phenyl
isocyanate and used as the substrate for screening reaction
conditions. A catalytic amount of commercially available
group
into
a
(4-hydroxy-3-methyl-9H-uoren-9-yl)-
methoxycarbonyl (Hmoc) group, and shows Fmoc-like lability.
The gold(III)-labile protecting group has not been reported to the
best of our knowledge, and thus this group provided the novel
orthogonality of the protecting group strategy. The Epoc group
was successfully applied for the synthesis of branched peptides
on resins. In addition, the uorene formation proceeded even
in aqueous media, which is suggestive of the application of the
Epoc group for controlling the function of the Fmoc group in
vivo.
Table 1 Condition screening for fluorene formation
Results and discussions
Synthesis of reagents for Epoc protecting groups
To develop the Epoc protecting group explained above, we rst
established the synthetic route of the reagent for introducing
the Epoc group to various functional groups (Scheme 1). The
TIPS-ethynyl group was introduced to 2-bromo-1-iodobenzene 1
with Sonogashira coupling, followed by lithiation and nucleo-
philic attack of 5-methyl-2-furfural to obtain alcohol 2. Ketone 3
was obtained via the oxidation of alcohol 2 with 2-iodoxybenzoic
acid and the subsequent Wittig reaction gave enol ether 4. Aer
hydrolysis of enol ether 4 under acidic conditions to obtain the
aldehyde, this aldehyde was subsequently reduced with sodium
borohydride to yield alcohol 5 as a racemic mixture. The TIPS
group of alcohol 5 was removed with tetrabutylammonium
uoride to obtain EpOH 6.
NaAuCl4$2H2O
(mol%)
Entry
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
1,4-Dioxane
1,4-Dioxane
THF
Acetone
DMF
CH3CN
DMSO
10
1
10
1
10
10
10
10
10
>99
>99
94
15
0
0
0
0
0
a
EpOH 6 can be used for the introduction of the 2-(2-
ethynylphenyl)-2-(5-methylfuranyl)-ethyl (Ep) protecting group
to carboxylic acid, which is transformed to a structure similar to
the uorenylmethyl (Fm) group by gold catalysis. EpocOSu 7
Yields determined by HPLC. The reactions were performed with 300
nmol of compound 8 in 200 mL of solvents (1.5 mM), at room
temperature for 1 hour. The reactions were run in triplicate and the
average yields were shown.
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gold(III) salt, NaAuCl4$2H2O, transformed the Epoc group into as the mixtures of diastereomers because the reagents for
the Hmoc group. This reaction proceeded the most efficiently in introducing the Epoc groups were obtained as racemic mixtures
CH2Cl2, where 1 mol% of gold(III) catalyst smoothly trans- using the current technique.
formed the Epoc group into the Hmoc group. Thus, we decided
The uorene formation of the Epoc and Ep group in
to use this solvent as the standard deprotection condition. substrates 11, 13, 15 proceeded smoothly (within 10 minutes)
Although the reaction proceeded in 1,4-dioxane, a larger with 1 mol% of gold(III) catalyst in CH2Cl2 (Scheme 2b). The
amount of gold catalyst is needed for its completion. On the transformed protecting groups were easily removed with the
other hand, in other polar solvents such as THF, acetone, DMF, subsequent addition of piperidine in a one-pot procedure aer
CH3CN, and DMSO, this reaction did not proceed at all.
the completion of the uorene formation. Although the yield for
Next, we tested the reaction conditions for introducing the the deprotection of substrate 15 was relatively low (75%)
Epoc group (Scheme 2a). The introduction of the Epoc group compared to substrate 11 and 13, the uorene formation was
into the amino group in compound 10 was successful with complete within 10 minutes. Production of a small amount of
EpocOSu 7, which is a general condition for introducing byproducts and loss of the product 14 during its purication
carbamate protecting groups into amino groups. Carboxylic decreased the overall yield. These results indicate that the Epoc
acids can also be protected with the Ep group. The Ep group was and Ep groups are removed under mild conditions in almost the
introduced to the carboxylic acid of compound 12 by esteri- same manner as the Fmoc group.
cation with EpOH 6. This is similar to the uorenylmethyl (Fm)
group, which is used for the protecting group of carboxylic acid.
For the protection of alcohols with the Epoc group, the in situ
Orthogonality of Epoc group
formation of Epoc chloride with EpOH 6 and triphosgene and To demonstrate the stability and the mild removal conditions of
the subsequent addition of substrate 14 gave the best yield. The the Epoc group, we tested the orthogonality of the Epoc group
Epoc- and Ep- protected amino acids and sugars were obtained against other commonly used protecting groups. When
compound 16, which is protected with both the Epoc and the
Fmoc groups, was treated with piperidine, the Fmoc group was
chemoselectively removed (Scheme 3a). This indicates that the
Epoc group is tolerant to the conditions of Fmoc deprotection,
and thus can be applied to the orthogonal protecting group for
Fmoc solid-phase peptide synthesis (SPPS) and automated
glycan assembly. The selective deprotection experiments for
compound 18, possessing the Epoc, Boc, and ester groups,
indicate that the Epoc group is also tolerant to acidic conditions
for the Boc deprotection, and the conditions of the Epoc
deprotection do not affect either the Boc or the ester groups
(Scheme 3b). As expected, in the hydrolysis of methyl ester in
compound 18 under strongly basic conditions, the Epoc group
was stable and compound 20 was selectively obtained, where
the Fmoc group is known to be labile. This indicates that the
Epoc group achieves the criteria of our initial design for
a transformable protecting group: high stability against bases
and Fmoc-like lability post-transformation. Thus, the Epoc
group will be useful for the protection of the amino group of
compounds that are planned to undergo reactions under
strongly basic conditions and require mild conditions for
removal at the end of the synthetic route, where the Fmoc group
is not applicable.
As well as the acid-labile and base-labile protecting groups,
the Epoc group is orthogonal to the Pd-labile Alloc protecting
group29 and the hydrazine-labile Dde protecting group (Scheme
3c),30 which are commonly used as the orthogonal protecting
groups for amines. When PhSiH3 was used as a nucleophilic
scavenger, the Alloc deprotection of compound 21 was unsuc-
cessful because of the undesired reduction of alkyne in the Epoc
group. On the other hand, the use of dimedone instead
improved this problem. The Alloc group was chemoselectively
removed with a palladium catalyst and compound 170 was ob-
tained. The treatment of an excess amount of hydrazine to
Scheme 2 (a) Introduction and (b) removal of the Epoc and Ep groups. compound 23 gave compound 25, where the Dde group was
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Fig. 2 Transformation and removal of the Epoc group on resin. HPLC
charts of the cleaved peptide are shown. HPLC methods: Table S2.
27 was then treated with piperidine to remove the Hmoc group.
Aer the coupling with Fmoc-Gly-OH and cleavage, Fmoc-Gly-
Val-Phe-OH 29 was successfully obtained. This indicates that
the deprotection of the Epoc group proceeds properly even on
resins and the Epoc group works as a protecting group for solid-
phase synthesis.
As a negative control, we treated a 20% piperidine/DMF
solution and the coupling reagents with the same resin 26
without the transformation from the Epoc to the Hmoc group.
The Epoc group did not react with piperidine or the coupling
reagents without transformation into the Hmoc group, and
Epoc-Val-Phe-OH 28 was selectively obtained aer cleavage. In
this experiment, the peptides other than Epoc-Val-Phe-OH 28,
such as the Fmoc-Gly-Val-Phe-OH 29 and other peptides derived
from side reactions on the Epoc group were not obtained based
on the HPLC chart (Fig. S5†). Therefore, the Epoc group is
tolerant of the conditions for Fmoc removal and coupling on
resins, and applicable to the orthogonal protecting group for
the on-resin synthesis of peptides.
The use of the Epoc group for SPPS enabled the elongation of
the branched peptides in two different directions with different
amino acid sequences. In the rst example, Epoc-Lys(Fmoc)-OH
was incorporated into the elongation of the linear peptide with
7 amino acids on resin 30, whose N-terminus was protected
with the Boc group (Scheme 4a). Although the Epoc group in the
middle part of peptides on the resin was less reactive compared
to the case of N-Epoc-valylphenylalanine, the transformation
into the Hmoc group proceeded with a longer reaction time (5
hours total). Aer the removal of the Hmoc group with piperi-
dine to obtain the resin-bound peptide 31, several amino acids
were coupled from Na at lysine. Aer the cleavage from resin
and HPLC purication, the branched peptide 32 was obtained
in a 34% yield. Fmoc-Lys(Epoc)-OH was applied in the second
example, and peptides with 10 amino acids on resin 33 were
synthesized (Scheme 4b). The transformation and removal of
the Epoc group proceeded well also in this peptide. Aer the
Scheme
3 Orthogonality of the Epoc group. (a) Fmoc-selective
deprotection. (b) Orthogonality of the Epoc group to acid- and base-
labile protecting groups. (c) Orthogonality of Epoc group to Pd- and
hydrazine-labile protecting groups.
selectively removed. Thus, the Epoc group was also stable under
the conditions required for Dde removal. The Epoc group was
selectively removed from compounds 21 and 23 to obtain
compounds 22 and 24 respectively, indicating that the removal
of the Epoc group requires relatively mild conditions to keep
other protecting groups unaffected. These results indicate the
orthogonality of the Epoc group against the Alloc and Dde
groups. The Alloc and Dde groups have been used for the solid-
phase synthesis of cyclic and branched peptides. Thus, the
addition of the Epoc group to a series of these orthogonal
protecting groups enables the synthesis of more complex cyclic
and branched peptides on resins.
Application to solid-phase peptide synthesis
We tested whether the transformation from Epoc to Hmoc and
its subsequent deprotection proceeded on resins using N-Epoc-
valylphenylalanine bound to Trt(2-Cl) resin 26 (Fig. 2). The
transformation from the Epoc to the Hmoc group proceeded
smoothly even on resins with the treatment of 10 mol% of
NaAuCl4$2H2O for 10 minutes. The resulting peptide on resin
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Scheme 4 Application of the Epoc group as an orthogonal protecting group for branched peptide synthesis.
elongation from N3 at the lysine, peptides were cleaved and the
branched peptide 35 was obtained at 26% yield aer HPLC
purication. In these syntheses, we conrmed that acid-labile
protecting groups such as Trt, tBu, Boc, and Pbf, which are
commonly used as permanent protecting groups in SPPS, were
not affected by treatment with NaAuCl4$2H2O. These experi-
ments demonstrate that the Epoc group is tolerant to multiple
cycles of Fmoc deprotection and couplings. In addition, the
transformation into the Hmoc group and its removal were
shown to proceed even in the sterically hindered middle parts of
peptides. Thus, the Epoc group is applicable for the synthesis of
complex branched or cyclic peptides on resins. Similar to the
Fmoc group, the absorbance of the Hmoc-piperidine adduct
cleaved from resins is detectable using UV spectroscopy, which
helps monitor the completion of the deprotections. At this
point, the Epoc protecting group is more useful than other
orthogonal protecting groups previously applied for the solid-
phase synthesis of peptides and glycans.
Transformation of the Epoc group under aqueous conditions
To demonstrate the applicability of the Epoc group to biological
systems, we performed the uorene formation of the Epoc
group under aqueous conditions (Table 2). The uorene
formation of compound 8 proceeded in PBS buffer at 37 ꢀC for
24 hours and gave 50% yield with 1 mol% of NaAuCl4$2H2O.
The reaction itself proceeded even with a very small amount of
gold(III) catalyst (0.1 mol%) with a turnover number of approx-
imately 340.
These results indicate that the uorene formation of the
Epoc group proceeds under conditions similar to biological
settings, where a small concentration of gold catalysts exists in
an aqueous solution. Although the gold catalysts, the substrate
structure, pH of the solvent etc. have to be further optimized
before its applications to biological systems, we were able to
demonstrate that the transformation of the Epoc group could be
applied to trigger drug release and hydrogelations.
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Table 2 Fluorene formation under aqueous conditions
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was nancially supported by the AMED Grant
JP15KM0908001, research grants from the Astellas Foundation,
Mizutani Foundation and JSPS KAKENHI Grant Number,
JP21H02065 (to K. T.) as well as additional support from
a RIKEN Incentive Research Project grant (to T. Y.). This work
was also funded by the subsidy allocated to Kazan Federal
University for the state assignment in the sphere of scientic
activities (0671-2020-0063), with the support of the Kazan
Federal University Strategic Academic Leadership Program.
NaAuCl4$2H2O
(mol%)
Entry
Yielda (%)
1
2
0.1
1
34
50
a
Yields were determined by HPLC. The reactions were performed with
300 nmol of compound 8 in 100 mL of PBS buffer/1,4-dioxane ¼ 9/1 (3.0
mM), at 37 ꢀC for 24 hours. The reactions were run in triplicate and the
average yields were shown.
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In this study, we designed the novel concept of a transformable
protecting group, which includes the transformation of the
protecting group, changing its properties. To the best of our
knowledge, a protecting group with this type of unique two-step
deprotection procedure has not previously been developed.
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