In Silico Anticipation of Metabolic Pathways Extended to Organic Chemistry Reactions: A Case Study with Caffeine Alkaline Hydrolysis and The Origin of Camellimidazoles

Article abstract of DOI:10.1002/chem.202002196

Camellimidazoles A–C were recently reported as natural substances in Keemun black tea. Although a “biosynthetic” route to these intriguing imidazole dimers was proposed from caffeine by the authors in this seminal report, we envisioned that a artefactual scenario, consisting of alkaline hydrolysis of caffeine and spontaneous cascade reactions with a methylene donor such as formaldehyde or methylene chloride, could also have led to their formation. To capture the diversity of molecules obtained under these conditions (i.e. alkaline treatment of caffeine/formaldehyde), an in silico MetWork-based pipeline was implemented, highlighting the sought-after camellimidazoles B and C. A wealth of further compounds were also tagged, notably comprising the herein newly described and unnatural camellimidazoles D–F that were subsequently confirmed as anticipated in silico upon extensive spectroscopic analyses. Likewise, camellimidazoles B and C could also be obtained using methylene chloride as an alternative methylene donor which may also have occurred in the initial phytochemical pipeline that implied this solvent. The current investigation emphasizes the fitness of MetWork tagging to extend the logic of in silico anticipation of metabolic pathways to organic chemistry reactions.

Full text of DOI:10.1002/chem.202002196

Accepted Article
Accepted Article
Title: In silico anticipation of metabolic pathways extended to organic
chemistry reactions: a case study with caffeine alkaline hydrolysis
and the origin of camellimidazoles
Authors: Victor Turpin, Mehdi A. Beniddir, Grégory Genta-Jouve, Adam
Skiredj, Jean-François Gallard, Karine Leblanc, Pierre Le
Pogam, and Erwan Poupon
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002196
Link to VoR: https://doi.org/10.1002/chem.202002196
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1/2020

Chemistry - A European Journal
10.1002/chem.202002196
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In silico anticipation of metabolic pathways extended to organic
chemistry reactions: a case study with caffeine alkaline
hydrolysis and the origin of camellimidazoles
Victor Turpin, Mehdi A. Beniddir, Grégory Genta-Jouve, [b,c] Adam Skiredj,[a] Jean-François
[
a]
[a]
Gallard, Karine Leblanc, Pierre Le Pogam, *[a] and Erwan Poupon* [a]
[
d]
[a]
[a]
Victor Turpin, Dr. Mehdi A. Beniddir, Dr. Adam Skiredj, Karine Leblanc, Dr. Pierre Le Pogam, Prof. Dr. Erwan Poupon
Chimie des Substances Naturelles, BioCIS, Université Paris-Saclay, CNRS
92290 Châtenay-Malabry (France)
*
E-mail: erwan.poupon@universite-paris-saclay.fr; pierre.le-pogam-alluard@universite-paris-saclay.fr
[b]
[c]
[d]
Dr. Grégory Genta-Jouve
Laboratoire de Chimie-Toxicologie Analytique et Cellulaire (C-TAC), UMR CNRS 8038 CiTCoM, Université de Paris,
4, Avenue de l’Observatoire, 75006, Paris (France)
Dr. Grégory Genta-Jouve
Laboratoire Écologie, Évolution, Interactions des Systèmes Amazoniens (LEEISA), USR 3456, Université de Guyane, CNRS Guyane
275, route de Montabo, 97334 Cayenne (French Guiana)
J.-F. Gallard
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay
1, avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Supporting information for this article is given via a link at the end of the document.
Abstract: Camellimidazoles A–C were recently reported as new
natural substances in Keemun black tea. Although a “biosynthetic”
route to these intriguing imidazole dimers was proposed from
caffeine by the authors in this seminal report, we envisioned that
a artefactual scenario, consisting of alkaline hydrolysis of caffeine
and spontaneous cascade reactions with a methylene donor such
as formaldehyde or methylene chloride, could also have led to
their formation. To capture the diversity of molecules obtained
under these conditions (i. e. alkaline treatment of
caffeine/formaldehyde), an in silico MetWork-based pipeline was
implemented, highlighting the sought-after camellimidazoles B
and C. A wealth of further compounds were also tagged, notably
comprising the herein newly described and unnatural
camellimidazoles D−F that were subsequently confirmed as
anticipated in silico upon extensive spectroscopic analyses.
Likewise, camellimidazoles B and C could also be obtained using
methylene chloride as an alternative methylene donor which may
also have occurred in the initial phytochemical pipeline that
implied this solvent. The current investigation emphasizes the
fitness of MetWork-tagging to extend the logic of in silico
anticipation of metabolic pathways to organic chemistry reactions.
mind the specific conditions used by Wang et al. to isolate
these compounds (vide infra), rather than being the end
products of the new catabolic pathway of caffeine, as
proposed by the authors in the seminal report of
camellimidazoles. Accordingly, two different purely chemical
scenarios (involving formaldehyde or methylene chloride as a
methylene donor) might have led to camellimidazoles in the
specific work reported by Wang et al.
At first, a retro(bio)synthetic analysis of camellimidazoles
reveals, indeed, the need for four building blocks, i.e.:
-
imidazoles 5 (aka caffeidine) and 6 that may both arise from
hydrolytic decarboxylation of caffeine (1);
methylamine that may be provided through hydrolysis of
imidazoles 5 and 6;
and a bridging methylene source such as formaldehyde or
-
-
methylene chloride, the origin of which will be discussed in the
following.
Isohypsic cascades of Mannich-type reactions and
involving cross condensations of 5 and 6 may then easily
explain the formation of camellimidazoles A-C (Figure 1).
Caffeine (1) content of tea leaves is notably stable all
along fermentation process (i.e. “green” to “black” tea)[1,2] in
opposition to polyphenols which are allowed to oxidize under
controlled humidity and temperatures (theaflavin and
thearubigin formation for example).[3,4] In that context,
camellimidazoles A−C (2–4) were recently reported as new,
seemingly natural, methylene-bridged dimeric imidazoles
from Keemun black tea.[5] These structures, along with some
trimethylallantoine derivatives later described by the same
research group,[6] were proposed to be generated through an
alternative caffeine catabolic pathway. Even though a detailed
Taking into account the basic conditions of some
extraction steps of the seminal paper, a mere chemical
reactivity can rather be envisaged to afford the newly reported
natural substances, especially when having in mind the huge
quantity of starting material (200 kg). This chemical reactivity-
driven scenario would rely on repeatedly described purine
alkaline hydrolysis reactions.[7–9] Quite strikingly, the putative
biosynthetic scheme proposed by the authors relies on a
surprisingly similar way as it proceeds via a caffeidine (5)
intermediate which was formerly chemically obtained from
caffeine (1) upon alkaline hydrolysis.
“
biosynthetic” pathway was proposed by the authors, a few
simple chemical reactions from caffeine can be deemed to
afford camellimidazoles, hinting their plausible unnatural
origin.[5] The present work aimed at assessing whether
camellimidazoles could be obtained from caffeine, having in
1
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COMMUNICATION
O
Me
H
2
O
hydrolytic degradation conditions that were deemed suitable
for camellimidazoles formation (i.e. in the presence of
formaldehyde in protic medium). Reaction crude mixtures can,
in this particular situation, be seen as “artificial metabolomes”
that are of very limited complexity by comparison to natural
organism extracts, so that they may advantageously enter a
prioritization rational workflow. For this purpose, untargeted
mass spectrometric data of the crude reaction batches were
generated by LC-HRMS/MS prior to being organized as a
molecular network (MN).[10] The resulting MN was then further
labelled by in silico-generated molecular structures obtained
with MetWork.[ From an applied standpoint, these putative
structures were obtained based on foreseen chemical
reactions that were first implemented into MetWork server and
their MS/MS spectra were further predicted by CFM-ID
(Competitive Fragmentation Modeling for Metabolite
Identification) .[ As a last step, a similarity comparison
between theoretical and experimental MS/MS spectra is
performed to annotate the MN (Figure 2).
H
2
O
Me
N
N
1
hydrolyses, decarboxylations
O
N
N
Me
O
CO
2
H
2
O
CO
2
Me
Me
caffeine (1)
Me
N
2
condensations
× 2
Me
N
NH
N
H
H
2
O
N
N
MeNH
2
2 HCHO
O
N
HN
Me
Me
caffeidine (5)
× 2
imidazole (6)
HCHO
HCHO
Me
O
imidazole (6)
NH
O
Me
HN
Me
Me
Me Me
O
N
N
N
N
N
HN
H
O
Me
N
Me
N
HN Me
O
Me
Me
N
Me
N
N
N
N
N
N
N
Me Me
N
Me
Me
N
N
N
11]
Me
N
O
Me
camellimidazole C (4)
camellimidazole B (3)
camellimidazole A (2)
HN
Me
Figure 1. The (bio)chemical logic of camellimidazoles formation.
12]
The current investigation aims at assessing the
chemical diversity generated under accelerated caffeine
2
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COMMUNICATION
Keemun black tea
Me
HN
1
O
Proposed chemical route to camellimidazoles
Me
Me
Me
Me
N
N
N
O
Me
Me
N
Retrobiosynthesis
H2N
O
N
Me
O
N
N
N
O
camellimidazole C (4)
Me
N
N
HN
O
N
Me
Me
NH
H
H
Me
Me Me
O
N
N
caffeine (1)
N
N
HN
H
O
Me
N
camellimidazole B (3)
Me
N
Me
N
HN Me
N
N
Me
Me
N
N
Me Me
O
camellimidazole A (2)
Me
N
N
amide hydrolysis
urea hydrolysis
2
Mix and MetWork-labelled MN
alcohol dehydration
.
..
In silico metabolization
A
B
MS/MS spectra
prediction
Data acquisition
MS/MS spectra
comparison
C
Untargeted profiling
MN tagging
GNPS
Data organization
MetWork annotations
Sought-after compounds
MS/MS networking
New anticipated camellimidazoles
H
Me
N
N
N
O
Me
Me
Me
Me
Me
Me
N
N
N
H
NH
Me
N
Me
N
N
N
N
O
Me
N
Me
O
N
N
O
N
N
Me
Me
N
O
N
Me
HN Me
Me
camellimidazole D (7
)
N
N
N
N
N
Me
HN
N
Me Me
Me
O
Me
N
Me
N
O
N
N
camellimidazole C (4)
Me
N
Me
HN
O
camellimidazole B (3)
N
Me
Me
camellimidazole E (8)
camellimidazole F (9
)
Figure 2. Overview of the analytical workflow developed in this study along with the structures of the obtained compounds.
The Wang et al. “biosynthetic” hypothesis was mimicked
at the bench. Caffeine (1) was reacted under basic conditions
NaOH) and hydrolysis was accelerated by heating (80 °C).
metabolome consistency concept,[14] MetWork was
developed to anticipate new natural products from untargeted
tandem mass spectrometric analyses organized as molecular
networks.[10] For this purpose, MetWork web server features
(i) a collaborative library of (bio)chemical transformations and
(ii) a CFM-ID based MS/MS spectra prediction module. From
a spectral library match annotation in the molecular network,
in silico metabolization algorithms generate putative
structures prior to predicting the associated MS/MS spectra.
Lastly, a similarity comparison between the MS/MS spectra is
performed to annotate the node. Based on aforementioned
literature reports on purines and imidazoles reactivity, the
foreseen chemical reactions were uploaded into MetWork
(
Mild acidic conditions were then imposed to favor the key
decarboxylating steps presumably leading to imidazoles 5
and 6 (Figure 1). Finally, formaldehyde was added in the
mixture which was allowed to slowly react at room
temperature for a dozen days. To get a wide insight into the
generated species, the crude batch was profiled by HPLC-
HRMS/MS to be later organized as a molecular network.[10,13]
The later was further labelled by in silico generated
compounds obtained through MetWork pipeline as described
in the following section. As an implementation of the
3
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web server: amide hydrolysis, urea hydrolysis, alcohol
methylamine, and formaldehyde. This analytical pipeline
instantly tagged the seminal camellimidazoles B and C (3 and
4) along with most intermediates proposed to intercede in
dehydration,
amine
hydroxymethylation,
enamine
hydroxymethylation,
carbamic acid decarboxylation,
imidazole decarboxylation, iminium amination, hemiaminal
dehydration, aza-Michael addition and Michael addition with
enamine (Figure 3A) and are made available to users. This
reaction panel was applied in silico on caffeine (1),
camellimidazole
unprecedented structures such as methylene-bridged
imidazole derivatives (Figure 3B).
formations
and
some
putative
4
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Figure 3. A: Putative chemical scenario to camellimidazoles with detailed mechanisms. B: MetWork-tagged cluster of the organic crude batch highlighting inferred
intermediates to the camellimidazole series and some anticipated new structures, highlighting prioritized ions for isolation and NMR structure elucidation.
Camellimidazoles B and C, and caffeidine (3 and 4)
were instantly tagged upon MetWork data processing, with
this latter being already proposed as a “biosynthetic” pillar en
route to the former. Mass spectrometric-streamlined isolation
of these compounds validated their tentative identities through
the thorough analysis of the complete set of NMR spectra.[
5]
5
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Under our conditions, camellimidazole A (2) seems not to
have been obtained, the methylene bridge formation in this
latter may require a series of slower reactions (enamine
versus nitrogen nucleophilic attack to anchor the second
imidazole unit). Besides having pinpointed these expected
structures, MetWork facilitated the annotation of a further
dozen ions. Some of these putative structures were prioritized
for isolation based on i) the degree of scaffold originality ii) the
possibility to be isolated for subsequent NMR structure
temperature for 3 days. Untargeted LC-MS² analysis of the
crude batch and subsequent MN revealed the occurrence of
the camellimidazole derivatives reported from our former
reactive conditions (Figure S6, Supporting Information),
strengthening the possibility of an artefactual origin.
Besides unveiling in a straightforward manner the likely
occurrence of formerly reported camellimidazoles and its
postulated “biosynthetic” intermediates, the MetWork pipeline
also shed light on some unprecedented appendages. Mass
spectrometric approaches offer interesting perspectives
owing to their high sensitivity. As such, tandem mass
spectrometry-based dereplicative strategies lie at the forefront
of modern natural product discovery research and proved
their ability to provide a sharp glance into the chemical space
encompassed by an analyzed sample to further pinpoint and
streamline new products from various natural sources.[20] As
of 2020, the field of organic synthesis does not yet benefit
from such advanced mass spectrometric platforms and the
degree of structural information conveyed by these
techniques remains most often limited to a poorly informative
molecular formula. To overcome this bottleneck, the CFM-ID
predicted mass spectrometric fragmentation of in silico
derivatized reactants is herein demonstrated as a valuable
strategy to straightforwardly pinpoint tentative structures from
the crude batch without the need for any standard nor even
any former literature report. The specific example of
camellimidazoles might be ideally fitted to retrieve the full
extent of advantages offered by the MetWork pipeline since it
involves (i) a set of limited and simple organic molecules and
(ii) a reduced number of possible chemical processes to afford
a diversity of more complex compounds through iterative
metabolization steps. This workflow is highly dependent on
the predictive value of CFM-ID which, due to its machine-
learning functioning, has uneven performances across
structural series. As such, structures close to those comprised
in the training set of CFM-ID have higher chances of having
their tandem mass spectrum correctly predicted than
structures having no such close derivative. In the present case,
we were delighted to observe that the predicted MS² spectra
of our various camellimidazoles were of good quality
notwithstanding their original structures. The rather unique
scaffold of camellimidazoles could indeed be correctly
predicted with cosine values ranging from 0.3 to 0.6 which are
very good scores when dereplicating against in silico MS²
spectra. Accordingly, MetWork workflow can be deemed of
peculiar interest where chemical diversity stems from such
« minimalistic » conditions, e.g. bio-inspired cascade
elucidation.
Three
methylene-containing,
unnatural
compounds were indeed isolated and characterized, they
were subsequently named camellimidazoles D–F (7–9). The
structure elucidation of these new compounds is detailed in
the Supporting Information and further validate the Computer
Assisted Natural Products Anticipation (CANPA) approach
proposed last year.[15,16] MS/MS spectra related to the different
isolated camellimidazoles were uploaded to the GNPS
spectral libraries, with their individual identifiers being
provided in the supporting material.
As mentioned before, camellimidazoles were isolated in
minute amounts from tea (8 to 12 mg from 200 kg of tea)
following a convoluted phytochemical workflow which could
have triggered chemical transformations of caffeine towards
camellimidazoles through a succession of basic steps and
exposure to methylene chloride.[5] Efforts were made by the
first authors to address this query, but the analytical evidence
to support the claimed genuineness of camellimidazoles A−C
as natural products (viz. UPLC-HR-ESI-MS of fresh leaves
and processed materials) are poorly convincing (level of
confidence 4/5 according to Schymanski et al. i.e. “insufficient
evidence to propose possible structure”[17]). To benefit from a
higher degree of analytical confidence, the extraction process
having led to the dubious characterization of camellimidazoles
A−C in this seminal report were repeated by us from two
different Keemun black tea samples for subsequent HPLC-
HRMS2 chemical profiling. The obtained tandem-mass
spectrometric data were later organized as MNs and
annotated against (i) the experimental MS/MS spectra of all
isolated camellimidazole derivatives and (ii) the CFM-ID
predicted fragmentation patterns of all intermediates formerly
shown to step in camellimidazole synthesis. The lack of any
annotation as camellimidazoles in the obtained MNs further
supported the alkaline hydrolysis scenario as the (sole)
plausible route to reach the camellimidazole series (Figures
S2-S5, Supporting Information).
A
last point to mitigate was the nature of the
mechanisms having led to camellimidazole frameworks in the
specific phytochemical workflow followed by Wang and coll.,
that did not use formaldehyde nor methylamine. The in situ
generation of methylamine can be related to the alkaline
hydrolysis of caffeine,[7] as reasonably assumed by the
authors. The claimed endogenous content of HCHO in
Camellia sinensis is, conversely questionable, especially
when taking into account black tea manufacturing process.
This led us to infer that methylene chloride should have
served as the real methylene donor instead.[18,19] With this in
mind, liquid-liquid extraction conditions were mimicked by
stirring caffeine (1) in a biphasic system constituted of a basic
aqueous phase (NaOH, 2 eq.) and dichloromethane at room
reactions[ or prebiotic chemistry-related area.
21]
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Acknowledgements
We thank the French “Agence Nationale pour la
Recherche" (grant ANR-19-CE07-0002-01) for funding this
study. Laurent Evanno is thanked as the Ph. D. director of
Victor Turpin.
6
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Entry for the Table of Contents
Surmising an artefactual nature for camellimidazoles recently isolated from black tea, their synthesis was undertaken from caffeine. A
molecular-networking based workflow revealed the occurrence of the targeted compounds and anticipated some unprecedented
derivatives, benefitting from a virtual metabolization platform. The value of in silico prediction in organic synthesis is here emphasized
as a way to answer critical biosynthetic issues.
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