Mild chemical and biological synthesis of donor-acceptor flanked reporter stilbenes: Demonstration of a physiological wittig olefination reaction

Article abstract of DOI:10.1002/ejoc.201201042

Unprecedented chemoselectivity is reported for the Wittig olefination reaction leading to the formation of reporter stilbenes under physiological conditions.

Full text of DOI:10.1002/ejoc.201201042

Job/Unit: O21042
/KAP1
Date: 25-09-12 16:26:22
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201042
Mild Chemical and Biological Synthesis of Donor–Acceptor Flanked Reporter
Stilbenes: Demonstration of a Physiological Wittig Olefination Reaction
David McLeod[a] and James McNulty*[a]
Keywords: Organocatalysis / Water chemistry / Wittig reactions / Bioorthogonal chemistry
Unprecedented chemoselectivity is reported for the Wittig olefination reaction leading to the formation of reporter stilbenes
under physiological conditions.
or tetrahydrofuran and strong non-aqueous bases such as
Introduction
butyllithium or lithium diisopropylamide. In addition, pro-
The development of a privileged set of reaction mani-
tecting groups are usually required on any exposed acidic
folds classified as “click” reactions[1] has advanced rapidly
hydrogen atoms (alcohol, phenol, amino, etc.). Nonetheless,
over the last decade in view of an expanding array of appli-
significant advantages may be envisioned were satifactory
cations in diverse fields including chemical biology,[2] mate-
conditions for such a process realized (Scheme 1). The cou-
pling of functionalized aldehyde 1 with functionalized
phosphonium salt 2 would produce donor–acceptor flanked
rials sciences, and hybrid bioconjugate areas.[3] The quintes-
sential click reaction evolved from the copper-catalyzed
small-molecule/small-molecule Huisgen azide/alkyne cyclo-
“reporter” stilbene 3, which could be detected by using
addition (CuAAC) yielding functionalized 1,2,3-tri-
standard analytical methods (NMR, UV, and/or fluores-
azoles.[1c] Although the CuAAC reaction is very successful
cence spectroscopy, mass spectrometry). In addition to fa-
in chemical and materials applications, requirements that
cilitating the conjugation of two functionalized units, such
the reaction occur under physiological conditions and not
a process would open a novel approach to labeling or fluo-
require toxic solvents, reagents, or metal catalysts (etc.) are
rescent tagging. The reporter unit is not appended as an
of concern in biological applications. Reagents that display
existing tag but constructed as a designed element intrinsic
orthogonal reactivity to the myriad of functionality present
to the conjugation process. Stilbene units form the core of
a range of valuable materials including pharmaceuticals,[7]
light-emitting diodes,[8] and dye-sensitized photovoltaic so-
lar cells.[9] Stilbene cores have been conjugated as structural
and reporter units on varied materials[10] including dendri-
mers,[11] as well as to biological constructs such as nucleic
acids[12] and proteins (including lysozomes[13] and antibody
binding[14]) and even to viral particles.[15] Development of
a mild olefination “click” process could thus prove of stra-
tegic value to the conjugation and detection of a wide range
of materials, bioconjugates, and other applications. We have
investigated aqueous Wittig olefination reactions over the
last few years under increasingly milder chemical conditions
showing that stabilized and semistabilized ylides can be ef-
ficiently generated and trapped to give a range of useful
alkenes, including stilbenes.[16] More recently, we demon-
strated the first organocatalytic aqueous Wittig olefination
reactions using weakly and non-basic amines including l-
proline, tosylamide, and diphenylamine.[16d] We proposed a
catalytic cycle for this process proceeding through an imin-
ium ion intermediate[16d] as a carbonyl surrogate.[17] To ex-
tend to even milder conditions, we decided to investigate
the critical issue of whether a Wittig olefination process is
compatible and achievable under physiological conditions.
in living cells further restricts the set of amenable reaction
parameters.[4] The CuAAC reaction is most often employed
in materials and bioconjugation applications, and issues of
copper metal and azide toxicity[4b,4c] have encouraged the
development of copper-free Huisgen cycloadditions using
strained alkynes.[5] A few alternate reaction manifolds have
been developed including Staudinger ligation,[4c] amine or
hydrazine carbonyl additions,[4c,4e] Michael addition,[4d] and
Diels–Alder cycloaddition reactions.[4f] The development of
innovative alternatives to metal and azide-free click mani-
folds applicable for the synthesis of functionalized materials
and bioconjugates is an active area of investigation.[4a]
On initial consideration, the Wittig olefination reaction
does not appear to be a suitable candidate as a potential
physiological reaction manifold. The classical reaction[6] re-
quires the use of dry organic solvents such as diethyl ether
[a] Department of Chemistry and Chemical Biology, McMaster
University
1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada
E-mail: jmcnult@mcmaster.ca
Homepage: http://www.chemistry.mcmaster.ca/mcnulty/index.
html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201042.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. McLeod, J. McNulty
SHORT COMMUNICATION
In this article we report the chemical synthesis of donor–
acceptor flanked reporter stilbenes under extremely mild
chemical conditions by employing l-proline organocatalysis
(water, 37 °C, pH = 8.0). Most significantly, we also report
the unprecedented synthesis of reporter stilbenes under
completely natural physiological conditions in living plants
conducted hydroponically and in soil through separate feed-
ing of the Wittig reaction partners.
Scheme 2. Synthesis of aldehyde 1a and phosphonium salt 2a. Rea-
gents and conditions: (i) morpholine, AlCl3, 1,2-DCE, r.t., 88%;
(ii) (COCl)2, DMSO, Et3N, DCM, –78 °C, 84%; (iii) Ac2O, Et3N,
DCM, r.t. gave 8 (99%); (iv) LiHMDS, MeI, THF, r.t. gave 9
(95%); (v) NBS, BPO, PhH, reflux, 3 h, (80%); (vi) PPh3, PhMe,
reflux, 6 h, (96%).
The Wittig olefination reaction of 1a and 2a was first
Scheme 1. Organocatalytic and bioorthogonal Wittig process. Syn-
thesis of donor–acceptor flanked reporter stilbene 3 under mild
chemical conditions and under physiological conditions.
investigated under
a range of chemical conditions
(Scheme 3, A). The reaction was observed to proceed slowly
in water at 37 °C in the presence of sodium hydrogen car-
bonate and a catalytic quantity of l-proline as the sole or-
ganic catalyst. This reaction was complete in 24 h, and do-
nor–acceptor stilbene 3a was isolated in 84% yield as a 1:1
(E)/(Z) mixture. The olefination reaction could also be
completed more rapidly in water by using the relatively
stronger base potassium carbonate at 70 °C. Under these
Results and Discussion
We designed and prepared amide-containing dual-func- conditions, the reaction was complete within 3 h, yielding
tionalized test substrates 1a and 2a as reaction partners stilbene 3a in 76% isolated yield as a 65:35 (E)/(Z) mixture,
(Scheme 2). Wittig olefination was expected to yield donor– selectivity in accord with the literature data.[16d] Full spec-
acceptor flanked reporter stilbene 3a. Amides were chosen troscopic characterization of the (E) and (Z) isomers was
to connect the functional groups on both the aldehyde and accomplished, and the NMR spectroscopic data of the ole-
phosphonium salt reaction partners, suggesting immediate finic protons of each isomer are clearly resolved. The mass
locations for alternative variations on this process on what spectrum (EI-TOF) gave the molecular ion at m/z = 364
is effectively a reporter amino acid derivative. The phos- (87%) and readily identifiable fragments at m/z = 277
phonium salt reactivity is intrinsically orthogonal, and we (100%) and m/z = 236/237 (48/86%). The compounds could
elected to make this the “donor” substituent and settled on be readily detected at low concentrations by using LC and
4-N-methylacetanilide 2a.[18] Aldehydes are known partners LC–MS and also by UV and fluorescence spectroscopy.
in bioorthogonal reactions[4a,4b] and have also been used in The LC–MS (Phenomenex Luna C18, H2O, 0.1% formic
the “aldehyde tag” process for site-specific protein encoding acid/CH3CN gradient elution, see Supporting Information
and covalent labeling.[2b] To limit possible oxidoreductase for full details) showed clear resolution of two distinct near-
reactions and to increase the electrophilicity of the alde- baseline resolved peaks for the (E) and (Z) stereoisomers
hyde, we opted to functionalize the aldehyde with an ortho- (tR = 13.5 and 14.1 min), each displaying a similar fragmen-
electron-withdrawing group and thus settled on morpholin- tation pattern. LC–MS–MS analysis of 3a demonstrated
amide derivative 1a. Nucleophilic opening of phthalide 5 clearly that the fragmentation at m/z = 277.9 led to second-
with morpholine in the presence of a stoichiometric amount ary fragmentation at m/z = 235.8, thus providing a defin-
of AlCl3 gave 6, which was subjected to Swern oxidation itive fingerprint for the identification of the stilbenes. In a
to provide a short entry to aldehyde 1a. Acylation of 4- similar fashion (Scheme 3), 4-cyanobenzaldehyde (1b) was
methylaniline proceeded smoothly and subsequent N-meth- treated with phosphonium salt 2b to yield stilbene 3b, which
ylation using LiHMDS and iodomethane followed by benz- was likewise characterized. Fluorescence measurements on
ylic bromination yielded desired substituted benzyl bromide 3a by using excitations at both 219 and 301 nm produced
10. Quaternization with triphenylphosphane yielded phos- broad emission just outside the visible region at 395 nm.
phonium salt 2a. An alternative synthetic route to salt 2a
was also developed (see the Supporting Information) from requires the presence of a catalytic quantity of a primary
4-aminobenzyl alcohol. or secondary amine. Endogenous amines and nitrogen het-
The aqueous organocatalytic Wittig olefination reaction
2
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Donor–Acceptor Flanked Reporter Stilbenes
Scheme 3. Wittig olefination of aldehyde 1a and phosphonium salt 2a under mild chemical conditions. Conditions A: 37 °C, l-pro 24 h,
NaHCO3, 84% 3a, 80% 3b. In a bioorthogonal process, conditions B: Calystegia sepium, 25 °C; or P. sativum 25 °C.
erocycles are ubiquitous in living organisms, occurring as formation of the reporter stilbenes in labeled plants grown
both primary and secondary metabolites (for examples, see in soil and those grown hydroponically. Two peaks were ob-
Figure 1).[19] We now focused on testing the feasibility of served with identical retention times in comparison to the
conducting a Wittig olefination reaction under purely phys- synthetic controls. Detection of the fragment at m/z = 278
iological conditions in living tissue. We initially chose the and the secondary fragmentation of each isomer was iden-
plant Calystegia sepium (Convolvulaceae) as a vehicle for tical to the stilbene standards. Similarly, separate feeding
several reasons. The plant is a well-known member of the of 1b and 2b to hydroponically grown C. sepium (see the
Convolvulaceaea (bindweed or morning glory) family Supporting Information) resulted in formation of analyti-
known to produce a small assemblage of nortropane sec- cally detectable quantities of stilbene 3b.
ondary amine alkaloid natural products known as the calys-
tegines (Figure 1).[19a] Seeds of the plant are commonly
available, are easily and rapidly germinated in water, and
can be cultivated in soil or hydroponically under labora-
tory-controlled conditions. Root and tissue cultures of the
plant can also be prepared.[19b,19c] We investigated the ger-
mination of seedlings of C. sepium grown under hydroponic
conditions, to minimize interference from soil-borne micro-
organisms, in a custom-built growth chamber. Soaking in
water allowed seedling germination to occur usually within Adalia 2-punctata.[19d]
Figure 1. Examples of naturally occurring secondary amines in
plants and animals. Calystegine A3 a common ornithine-derived
nortropane secondary amine metabolite from Calystegia sepi-
um.[19a] Adaline, a fatty-acid-derived amine from the ladybird
2–3 d. Plants were grown to a height of 3–4 cm under three
Microscopic analysis of root, stem, and leaf sections of
conditions: in soil, in pure water, and in a dilute aqueous
NPK blend [total nitrogen 10%, available phosphoric acid
(P2O5) 52%, soluble potash (K2O) 10%, micronutrients
1%]. Upon germination, the plant materials were irradiated
with a sunlamp for 6 h/d at a constant temperature of
25Ϯ2 °C. Seedlings were then injected separately with
aqueous solutions of aldehyde 1a and phosphonium salt 2a
(Scheme 3, B). Each solution was 2 mm in water; 100 μL of
each was added twice a day. The growth of the plants was
visually unaffected by treatment with compounds 1a and
2a, and relative to non-labeled controls, no evidence of her-
bicidal activity was observed. Non-labeled control and lab-
eled plants were harvested after 8 d, and the organic solu-
bles were extracted into methanol. LC–MS analysis of the
control plant extracts (non-labeled) and control media, con-
sisting of compounds 1a and 2a in pure water and com-
pounds 1a and 2a in the NPK solution, showed conclu-
sively that no olefination reaction occurs. Individual plants
treated with 1a and 2a grown in soil (above-ground leaves/
stems) and under hydroponic conditions were carefully re-
moved and washed thoroughly with water. The methanol
C. sepium after feeding with compounds 1a and 2a were
taken at 20ϫ magnification with a Leica DMI 6000B de-
convolution microscope (excitation 377 nm, emission
447 nm). In addition to general background fluorescence,
these images showed an accumulation of stilbene 3a on the
plant cell surface and/or intercellular media of the stem
(Figure 2).
Figure 2. Deconvolution micrographs of labeled (left) and unla-
beled (right) stems of C. sepium showing localization of the re-
porter stilbene on the cell wall and/or intercellular media.
Lastly, because C. sepium accumulates toxic secondary
extract of each was analyzed by using the LC–MS–MS amines (see Figure 1) in addition to endogenous amino ac-
method described. The analysis demonstrated conclusive ids, it was of interest to investigate a possible physiological
Eur. J. Org. Chem. 0000, 0–0
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D. McLeod, J. McNulty
SHORT COMMUNICATION
13C NMR spectra, LC–MS (MS) spectra, UV/Vis spectra, and fluo-
rescence spectra.
olefination in a more benign plant. The reaction of 1a and
2a was investigated in the pea plant Pisum sativum, an in-
nocuous vehicle known for primary amino acid production
and nitrogen-free secondary products.[20] Seeds of P. sati-
vum are readily available, and the plant is rapidly germi-
nated in soil or under hydroponic conditions. Separate in-
jection of compounds 1a and 2a into rapidly growing seed-
lings of P. sativum and harvesting of the plant tissue after
8 d followed by LC–MS analysis (see above) allowed un-
equivocal identification of stilbene 3a in stem and leaf tis-
sue.
Acknowledgments
We thank Natural Sciences and Engineering Research Council
(NSERC) of Canada and Cytec Canada for financial support of
this work. We thank Jarkko Ylanko and Dr. David Andrews for
deconvolution microscopic analysis and Dr. Kirk Green for LC–
MS analysis.
The synthesis of precursors 1a and 2a (Scheme 2) is rapid
and its modular nature should enable application to analo-
gous reaction partners to connect functional units of inter-
est and to customize the properties of the chromophore.
The initial process connects an amine (here morpholine) to
a carboxylic acid (here acetate) through amide bonds by an
in situ and in vivo constructed reporter stilbene linkage.
The technology to construct such a molecularly defined
chromophore/fluorophore directly, while conjugating two
differentially functionalized entities, provides a new ap-
proach that is envisaged to be widely useful in installing
such a “reporter” in these systems, including in living tis-
sues. Stilbene 3a was chosen as a proof-of-principle for the
physiological olefination process and not designed as a tis-
sue-specific target. It is not yet known if the olefination
reaction occurs within the plant cell or if it is promoted by
endogenous amines in the extracellular media. Nonetheless,
it has now been demonstrated that Wittig-type olefination
reactions are compatible under mild physiological condi-
tions. The mild conditions, simplicity, and efficiency of the
chemical process (Scheme 3, conditions A) validate the
click-stilbene paradigm, whereas the applicability to physio-
logical conditions (Scheme 3, conditions B) opens ole-
fination chemistry to new and exciting applications.
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Donor–Acceptor Flanked Reporter Stilbenes
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Received: August 2, 2012
Published Online: ᭿
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5

Job/Unit: O21042
/KAP1
Date: 25-09-12 16:26:22
Pages: 6
D. McLeod, J. McNulty
SHORT COMMUNICATION
Chemoselective Olefination
Unprecedented chemoselectivity is re-
ported for the Wittig olefination reaction
leading to the formation of reporter stilb-
enes under physiological conditions.
D. McLeod, J. McNulty* .................. 1–6
Mild Chemical and Biological Synthesis of
Donor–Acceptor Flanked Reporter Stil-
benes: Demonstration of a Physiological
Wittig Olefination Reaction
Keywords: Organocatalysis / Water chemis-
try
/ Wittig reactions / Bioorthogonal
chemistry
6
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