Organocatalytic and Scalable Syntheses of Unsymmetrical 1,2,4,5-Tetrazines by Thiol-Containing Promotors

Article abstract of DOI:10.1002/anie.201812550

Despite the growing application of tetrazine bioorthogonal chemistry, it is still challenging to access tetrazines conveniently from easily available materials. Described here is the de novo formation of tetrazine from nitriles and hydrazine hydrate using a broad array of thiol-containing catalysts, including peptides. Using this facile methodology, the syntheses of 14 unsymmetric tetrazines, containing a range of reactive functional groups, on the gram scale were achieved with satisfactory yields. Using tetrazine methylphosphonate as a building block, a highly efficient Horner–Wadsworth–Emmons reaction was developed for further derivatization under mild reaction conditions. Tetrazine probes with diverse functions can be scalably produced in yields of 87–93 %. This methodology may facilitate the widespread application of tetrazine bioorthogonal chemistry.

Full text of DOI:10.1002/anie.201812550

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Accepted Article
Title: Organocatalytic and Scalable Syntheses of Unsymmetrical
1,2,4,5-Tetrazines by Thiol-containing Promotors
Authors: Wuyu Mao, Wei Shi, Jie Li, Dunyan Su, Xiaomeng Wang,
Lyuye Zhang, Lili Pan, Xiaoai Wu, and Haoxing Wu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812550
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10.1002/anie.201812550
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COMMUNICATION
Organocatalytic and Scalable Syntheses of Unsymmetrical
1,2,4,5-Tetrazines by Thiol-containing Promotors
Wuyu Mao+, Wei Shi+, Jie Li, Dunyan Su, Xiaomeng Wang, Lyuye Zhang, Lili Pan, Xiaoai Wu, Haoxing
Wu*
Dedicated to the 100th Anniversary of West China School of Pharmacy, Sichuan University
Abstract: Despite the growing application of tetrazine bioorthogonal
chemistry, it is still challenging to access tetrazines conveniently from
easily available materials. Here we describe de novo formation of
tetrazine from nitriles and hydrazine hydrate using a broad array of
thiol-containing catalysts, including peptides. Using this facile
methodology, we describe 14 syntheses of unsymmetric tetrazines
containing a range of reactive functional groups on the gram scale
with satisfactory yield. Using tetrazine methylphosphonate as a
building block, we develop a highly efficient Horner-Wadsworth-
Emmons reaction for further derivatization under mild conditions.
Tetrazine probes with diverse functions can be scalably produced in
yields of 87–93%. This methodology may facilitate the widespread
application of tetrazine bioorthogonal chemistry.
co-workers demonstrated that dichloromethane can be used
instead of regular formamidine as a starting material in the
synthesis of monosubstituted tetrazines.[11b] However, this
reaction requires prolonged microwave irradiation, limiting its
usefulness, especially for scale-up. Sequentially, several groups
have bypassed these issues by using metal-catalyzed cross-
coupling reactions to generate functionalized tetrazines.[6c, 6e, 12]
Nevertheless, mild, scalable syntheses are still needed in order to
endow tetrazine with new functions and develop downstream
applications. Inspired by the interaction of nitriles with the
biological media, here we report an organocatalytic approach to
prepare unsymmetrical tetrazines. Our approach is mild and
economical, and it is compatible with water. It can be carried out
in most chemistry or biochemistry laboratories because it does
not require dangerous reagents, harsh conditions or sophisticated
equipment. In the presence of simple thiol as catalyst,
commercially available nitriles bearing multiple functional groups,
including free acid, azide, phosphonate, or hydroxy, can be
activated smoothly. Tetrazines can be formed from nitriles and
hydrazine hydrate at room temperature with satisfactory yields on
Tetrazine, a centuried molecule, has been used for many years
for coordination chemistry, total synthesis and design of materials
with high energy density.[1] With the emergence of bioorthogonal
chemistry early this century,[2] tetrazine has become extremely
attractive to chemical biologists and biomedical researchers.[3] In
living systems, tetrazine can serve as a magic bullet for delivering
imaging probes or drugs in targeted manner,[4] as an unnatural
amino acid for site-specific protein labeling,[5] as fluorescence
storage,[6] as a key for decaging proteins[7] or as a precursor of
biomaterials.[8]
a
gram-scale.
Furthermore,
the
resulting
tetrazine
methylphosphonate is
a
key building block for further
derivatizations, and a mild Horner-Wadsworth-Emmons (HWE)
reaction is developed to efficiently construct a linkage between
tetrazine and other molecules of biomedical interest. This route
should remove major obstacles to tetrazine synthesis, facilitating
further development of bioorthogonal solutions to chemical,
biological and medical challenges.
Although it is one of the most attractive bioorthogonal tools,[9]
1,2,4,5-tetrazines are not easy to synthesize. In the classical two-
step tetrazine synthesis, the first step of condensation of
hydrazine with nitriles tolerates a narrower range of substrates
10]
than the subsequent oxidation of 1,2-dihydrotetrazine.[1a,
In
recent years, several groups have tried to broaden the range of
functional tetrazines that can be produced.[11] In 2012, the Devaraj
group pioneered a metal-catalyzed approach to unsymmetrical
tetrazine, producing a series of alkyl tetrazines for the first time.[11a]
Widespread use of this reaction is some hindered by the fact that
it employs hazardous anhydrous hydrazine, which is not
commercially available in several countries. In a recent approach
based on an ethanol solution of hydrazine hydrate, Audebert and
[a]
Dr. W. Mao[+], W. Shi[+], J. Li, D. Su, X. Wang, L. Zhang, Prof. H.
Wu
Scheme 1. Proposed organocatalytic role for tetrazine synthesis.
Huaxi MR Research Center, Department of Radiology, West China
Hospital and West China School of Medicine, Sichuan University
Chengdu 610041 (China)
E-mail: haoxingwu@scu.edu.cn
We began designing our strategy by searching for an appropriate
catalyst to activate sluggish aliphatic nitriles. An ideal
methodology to overcome the present limitations should be able
to perform with a wide range of commercially available materials,
it should be compatible with water and most functional groups,
and it should be easy to scale up. Recently, the Rao, Chin and Lin
L. Pan, Dr. X. Wu Department of Nuclear Medicine, West China
Hospital, Sichuan University, Chengdu, 610041 (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/anie.201812550
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COMMUNICATION
groups achieved the bioorthogonal ligation of electron-deficient
cyano groups, typically cyanobenzothiazole, with an aminothiol or
cysteine tag.[13] We also noted that nitrile moieties in some
pharmaceuticals can interact reversibly with the thiol group in the
active site of target proteins or enzymes.[14] Inspired by these
discoveries in biological milieux, we hypothesized that thiols could
reversibly activate weakly electrophilic aliphatic and aromatic
our approach by preparing 1 on multigram-scale in consistent
yield (entry 8).
nitriles at room temperature, generating
a more reactive
thioimidate ester intermediate in situ. Hydrazine nucleophilically
attacks this intermediate, regenerating the thiol so that it can drive
another catalytic cycle of activation in tetrazine synthesis
(Scheme 1). And this catalytic process would be compatible with
a wide range of functional groups in aqueous solution.
To determine whether our approach was feasible, we treated N-
(tert-Butoxycarbonyl)-2-aminoacetonitrile (2 mmol) with an
ethanol solution of hydrazine hydrate (16 mmol) in the presence
of L-cysteine (0.2 mmol) as catalyst. To our delight, the reaction
occurred efficiently at room temperature, affording symmetric 3,6-
(di-N-Boc-aminomethyl)-tetrazine 1 in 69% yield, which is twice
as high as the yield of a previous method (entry 1, Table 1).[11a]
Table 1. Optimization of the reaction conditions.
Entry
Catalyst
Yield [%][a]
1
2
3
4
5
6
7
8
L-Cysteine
1,3-Propanedithiol
2-Aminoethanethiol
3-Mercaptopropionic Acid
Thioglycolic acid
69
49
46
Scheme 2. Substrate scope. Reaction isolated yields are given based on R1CN.
Reactions were conducted with 4 equiv R2CN to R1CN, except as otherwise
noted. [a] 8 equiv R2CN, [b] 20 equiv R2CN, [c] 0.2 equiv catalyst, [d] 0.4 equiv
catalyst, [e] 1 equiv catalyst, [f] 40 °C .
77
70
N-Acetyl-L-Cysteine
Glutathione
71
66
With optimized reaction conditions in hand, we next investigated
the scope of our approach to prepare unsymmetric tetrazines. By
tuning the molar ratio of two nitriles and slightly increasing catalyst
loading, we smoothly synthesized 14 unsymmetric tetrazines in
good yield (Scheme 2). All these tetrazines bear at least one
functional group and show broad application prospects. For
example, unsymmetric tetrazines with aryl and small alkyl
substituents at positions 3 and 6, respectively, usually offer a
balance of bioorthogonal reactivity and stability, and are quite
efficient in “click to release” reactions.[15] Our mild organocatalytic
approach afforded aromatic tetrazines 2–7 bearing small alkyl
carboxylic acid, hydroxy or amino handles in yields of 34–67%.
Even higher yields of 63–71% were obtained of tetrazines 8–10
bearing different functional groups at positions 3 and 6. This is
likely due to the greater solubility of nitrile materials. Similarly high
yields of 69–75% were obtained for tetrazines 11-13 containing
proline or phenylalanine derivatives for site-specific protein
labeling. Remarkably, we prepared an unnatural amino acid
tetrazine probe 14 in 49% yield; the probe bears a PEG-azide
handle for orthogonal Staudinger ligation or click reaction.[9a, 9b] To
our knowledge, this tetrazine provides the first example of de novo
synthesis with the potential for multiplexed bioorthogonal analysis.
3-Mercaptopropionic Acid
75[b]
All reactions in table 1 were conducted on the 1-mmol scale with 16 equivalents
of N2H4H2O in an EtOH solution overnight, except as otherwise noted. [a]
Isolated yields are reported after silica flash chromatography. [b] Gram scale.
We then surveyed a variety of commercial thiols to determine the
best catalyst for tetrazine synthesis. All thiols were able to
promote tetrazine synthesis, giving moderate to high yields (Table
1). Interestingly, thiols containing adjacent nucleophile
substituents gave relatively modest yields (entries 2 and 3). We
hypothesized that the thioimidate may undergo a side reaction of
intramolecular nucleophilic attack instead of being attacked by
hydrazine. In contrast, 3-mercaptopropionic acid (entry 4),
thioglycolic acid (entry 5), and N-acetyl-L-cysteine (entry 6)
exhibited satisfactory catalytic efficiency, generating tetrazine 1 in
up to 77% isolated yield. Impressively, a catalytic amount of the
thiol-containing bioactive peptide glutathione also promoted
tetrazine formation in good yield (entry 7). After brief screening of
solvents (see Supporting Information), we found conditions to
work best with 3-mercaptopropionic acid, which is also the least
expensive in China (<15 USD for 100 gram) and ethanol as
solvent. Notably, we successfully demonstrated the scalability of
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COMMUNICATION
Table 2. Optimization of the tetrazine-HWE reaction
a
Entry
Base
Solvent
T [C]
Time [h]
Yield [%][ ]
1
2
3
4
5
6
NaH
t-BuOK
DBU, LiCl
TEA, LiCl
LiHFI
THF
THF
-20
-20
0
1.5
1.5
4
58
60
MeCN
THF
31
RT
0
4
<20
81
THF
0.5
3
LiHFI
THF
-20
98
All reactions in table 2 were conducted with 0.1 mmol of benzaldehyde and 1.1
equiv 15. [a] Isolated yield.
We demonstrated that our approach tolerates a wide range of
substrates, so we wanted to ask whether it could work beyond the
relatively limited range of commercially available nitriles. We
envisioned that we could use this mild organocatalytic
methodology to develop a simple tetrazine as a robust building
block for further derivatizations. First, we synthesized tetrazine
methylphosphonate 15, an HWE reaction precursor, with 45%
isolated yield on the gram scale (Scheme 2). Rapid screening of
reaction conditions (Table 2) identified lithium 1,1,1,3,3,3-
hexafluoroisopropoxide (LiHFI) as the ideal weak base for the
HWE reaction: it afforded product 16 in nearly quantitative yield.
Using the optimal reaction conditions, we examined substrate
scope of the tetrazine-HWE reaction. We focused our
investigation on alkyl derivatizations that were challenging by
other cross-coupling strategies.[6c-e] As shown in Scheme 3,
starting from 15 and the corresponding aldehydes, we prepared a
panel of tetrazine derivatives 17-25 in excellent yields of 87-94%.
These molecules included a series of novel probes in which
tetrazine was decorated with azide, alkynyl, amino acid
analogues, cleavable multiplexed probe or glucopyranose
moieties via a double bond linkage. We were pleased to find that
we could reproducibly conduct the tetrazine-HWE reaction on the
gram scale (22, Scheme 3). The robustness of the mild HWE
reaction meant that we could obtain di-tetrazine product 25 in 87%
yield; this molecule can be used as a crosslink precursor for
biomaterial formation. We also tested the ability of our HWE
reaction to create coupling with complex aromatic aldehyde. As
the test reaction, we synthesized a highly fluorogenic BODIPY-
tetrazine probe 26, previously prepared in modest yield.[6c] To our
delight, our mild coupling approach significantly increased the
yield of 26 to 95%. This tetrazine-HWE reaction may be useful for
designing fluorogenic bioorthogonal probe in future.
Scheme 3. Substrate scope. Reactions were conducted on scales of 0.05-0.13
mmol (see Supporting Information). Equivalents of 15, reaction time and
isolated yield are shown under each product. [a] 1.2 equivalents of 15, 3 h.
In conclusion, we have discovered an organocatalytic approach
for unsymmetric tetrazine synthesis. Tetrazines can be facilely
prepared on the gram scale from accessible materials in the
presence of thiol-containing organic catalysts such as 3-
mercaptopropionic acid or glutathione. We easily endowed
tetrazine with a variety of functions in good yield, including
tetrazine methylphosphonate as a novel building block for further
HWE derivatization. Our approach eliminates the need for
hydrazine anhydride and harsh reaction conditions, and it
substantially improves scale-up possibilities. By greatly
increasing the accessibility of tetrazines, our approach may lead
to new bioorthogonal tools for biomedical, organometallic and
materials research and applications.
Acknowledgements
We acknowledge financial support from National Natural Science
Foundation of China (Grant No. 21602146). We would like to
thank the Analytical & Testing Center of Sichuan University for
NMR Tests.
Keywords: bioorthogonal chemistry • tetrazines • scalable •
organocatalysts
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Thiols such as glutathione can be
served as novel catalysts for the
tetrazine formation. This simple, mild,
scalable approach is inspired by the
interaction of nitriles with proteins, has
broad substrate tolerance and allows
access to unsymmetric tetrazines
including robust building block for
further derivatizations. This
methodology could enable most
chemical laboratories to prepare
tetrazine bioorthogonal probes and
other reagents to address challenges
in biomedicine, organometallic
Wuyu Mao+, Wei Shi+, Jie Li, Dunyan
Su, Xiaomeng Wang, Lyuye Zhang, Lili
Pan, Xiaoai Wu, Haoxing Wu*
Page No. – Page No.
Organocatalytic and Scalable
Syntheses of Unsymmetrical 1,2,4,5-
Tetrazines by Thiol-containing
Promotors
Tetrazine formation
Mild conditions
Inexpensive catalyst
Broad substrate scope
Synthetic building block
Gram scale
chemistry and materials research.
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