DNA-Based Asymmetric Inverse Electron-Demand Hetero-Diels–Alder

Article abstract of DOI:10.1002/chem.202000516

While artificial cyclases hold great promise in chemical synthesis, this work presents the first example of a DNA-catalyzed inverse electron-demand hetero-Diels–Alder (IEDHDA) between dihydrofuran and various α,β-unsaturated acyl imidazoles. The resulting

Full text of DOI:10.1002/chem.202000516

A Journal of
Accepted Article
Title: DNA-Based Asymmetric Inverse Electron-Demand Hetero-Diels-
Alder
Authors: Michael Smietana, Justine Mansot, Jimmy Lauberteaux,
Aurelien Lebrun, Marc Mauduit, Jean-Jacques Vasseur,
Renata Marcia de Figueiredo, Jean-Marc Campagne, and
Stellios Arseniyadis
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To be cited as: Chem. Eur. J. 10.1002/chem.202000516
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10.1002/chem.202000516
Chemistry - A European Journal
COMMUNICATION
DNA-Based Asymmetric Inverse Electron-Demand Hetero-
Diels-Alder**
Justine Mansot, Jimmy Lauberteaux, Aurélien Lebrun, Marc Mauduit, Jean-Jacques Vasseur,
Renata Marcia de Figueiredo, Stellios Arseniyadis,* Jean-Marc Campagne* and Michael Smietana*
Abstract: While artificial cyclases hold great promise in chemical
synthesis, we present here the first example of a DNA-catalyzed
inverse electron-demand hetero-Diels-Alder (IEDHDA) between
dihydrofuran and various ,-unsaturated acyl imidazoles. The
resulting fused bicyclic O,O-acetals containing three contiguous
stereogenic centers are obtained in high yields (up to 99%) and
excellent diastereo- (up to >99:1 dr) and enantioselectivities (up to
95% ee) using a low catalyst loading. Most importantly, these results
show that the concept of DNA-based asymmetric catalysis can be
expanded to new synthetic transformations offering an efficient,
sustainable, and highly selective tool for the construction of chiral
building blocks.
The field of bio-hybrid catalysis has evolved over the years to
become a particularly powerful tool for the construction of
carboncarbon
and
carbonheteroatom
bonds,
with
metalloenzymes playing a key role.[1] The double stranded helix
of DNA has however recently integrated the bio-hybrid catalyst
arsenal emerging as a valuable alternative. This new concept,
which was first introduced by Roelfes and Feringa in 2005,[2] is
based on a transfer of chirality of the DNA double helix to a pro-
chiral substrate and relies on a subtle association between an
achiral transition metal catalyst and the DNA through either a
covalent or a supramolecular interaction. Since the first example,
Figure 1. DNA-based asymmetric cycloadditions
which involved
a
Diels-Alder cycloaddition between an
key cycloaddition reactions including a [2+2] photocatalysed
cycloaddition[5] using a benzophenone-modified DNA as a
photosensitizer (Figure 1, B) and two cyclopropanation reactions
using either a Cu-dmbipy-DNA complex[6] or a heme-DNA
artificial enzyme[7] (Figure 1, C). Surprisingly, despite all these
efforts, there has been no example of an asymmetric DNA-
catalyzed hetero-Diels-Alder cycloaddition reported in the
literature so far. As a matter of fact, the number of natural or
artificial biocatalysts capable of promoting a hetero-Diels-Alder
cycloaddition are rather scarce.[8,9] We report here the results of
our endeavor which have led to the development of a highly
stereoselective DNA-catalyzed inverse electron-demand hetero-
Diels-Alder cycloaddition between ,-unsaturated acyl
imidazoles and dihydrofuran leading to the corresponding
bicyclic O,O-acetals in high yields and excellent enantio- and
diasteroselectivities (Figure 1, D).
,-unsaturated 2-acyl pyridine and cyclopentadiene using a
9-aminoacridine-derived copper-binding diamine and salmon
testes DNA (st-DNA), the concept of DNA-based asymmetric
catalysis has been extended to various other synthetic
transformations[3] by a number of groups around the world
including ours.[4] In particular, many efforts have been devoted to
unveil new biomimetic DNA-based cycloaddition processes
inspired by the seminal [4+2] Diels-Alder cycloaddition[2,3a-g]
(Figure 1, A). This has resulted in the development of various
[*]
J. Mansot, A. Lebrun, Dr. J.-J. Vassur, Prof. Dr. M. Smietana
Institut des Biomolécules Max Mousseron,
CNRS, UMR 5247 Université de Montpellier, ENSCM
Place Eugène Bataillon 34095 Montpellier (France)
E-mail: michael.smietana@umontpellier.fr
The reaction between ,-unsaturated 2-acyl imidazole[10]
1a and dihydrofuran 2 in the presence of [Cu(dmbipy)(NO3)2]
and st-DNA was chosen as the benchmark reaction (Table 1).
A thorough optimization study (see SI for the complete study)
revealed that a 1:250 ratio between 1a and the heterodienophile
2, 3 mol% of the Cu(II) complex and a 1 mM bp concentration of
st-DNA in a MOPS buffer (pH 6.5) at 4 °C for 3 days afforded
the best results with the desired bicyclic cycloadduct 3a obtained
in 83% ee and a 94:6 endo/exo ratio. Control experiments
confirmed that the combination of the metallic cofactor
[Cu(dmbipy)(NO3)2] and DNA was necessary to achieve both
high conversions and high enantioselectivities. A higher
concentration of the biohybrid catalyst did not improve the result
J. Lauberteaux, Dr. R. Marcia de Figueiredo, Prof. Dr. J.-M.
Campagne
Institut Charles Gerhardt, Université de Montpellier, CNRS, ENSCM,
Avenue Emile Jeanbrau, 34296 Montpellier, France
E-mail: jean-marc.campagne@enscm.fr
M. Mauduit
Univ Rennes, Ecole Nationale Supérieure de Chimie de Rennes,
CNRS, ISCR UMR 6226, F-35000 Rennes (France)
Dr. S. Arseniyadis
Queen Mary University of London
School of Biological and Chemical Sciences
Mile End Road, London, E1 4NS (UK)
E-mail: s.arseniyadis@qmul.ac.uk
[**]
Supporting information and the ORCID identification numbers for the
authors of this article can be found under: https://doi.org
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10.1002/chem.202000516
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COMMUNICATION
Table 1. Systematic study.[a]
without affecting the stereoselectivity, with THF standing out as
the optimum co-solvent (94:6 endo/exo ratio, 83% ee)
(Scheme 1).
A systematic circular dichroism (CD) study
confirmed that the double helical structure of DNA was
maintained in the presence of all the aforementioned
co-solvents,[11] which is consistent with previous studies reported
in the literature.[12] Moreover, varying the nature of the copper(II)
complex by replacing 4,4’-dimethyl-2,2’-bipyridine (dmbpy),
which binds to st-DNA through groove binding, by phenantroline
(phen), which is a good DNA intercalator, or either 2,2’:6’,2”-
terpyridine (terpy) or dipyrido[3,2-a:2’,3’-c]phenazine (dppz),
which are known to bind to DNA through a mix of minor groove
binding and intercalation,[13] had a detrimental effect on both the
conversion and the selectivity. These results are in agreement
with the ones obtained for the Diels–Alder reaction; groove
binding interactions allow more flexibility of the complex while
maintaining the substrate in the second coordination sphere of
the DNA helix.[14]
With these results in hand, we next evaluated the substrate
scope by subjecting
a variety of ,-unsaturated 2-acyl
imidazoles (1b-o) to our optimized conditions; the results are
depicted in Scheme 1. As a general trend, the corresponding
bicyclic adducts 3b-o were obtained in moderate to high
conversions ranging from 35% to >99%, excellent
[a] Reactions conditions: 1a (1 mM), 2 (250 equiv), in a 20 mM MOPS buffer solution pH 6.5
for 3 d at 4 °C. Conversions, des and ees were determined by High Pressure Liquid
Chromatography (HPLC) analysis.
diastereoselectivities
(endo/exo up to >99:1)
and
high
enantioselectivities (ees up to 95%). Hence, the introduction of
electron-donating substituents at the para position of the
aromatic ring such as a methyl (3b, 89% ee, endo/exo>17:1), a
methoxy (3c, 90% ee, endo/exo>9:1) or a thiomethyl (3e, 90%
while reducing the DNA concentration to 0.5 mM affected mainly
the conversion. Interestingly, the addition of a co-solvent
(2% v/v) such as DMSO, DMF, THF, ACN, DCM, and dioxane
increased the substrate solubility as well as the conversion
Scheme 1. Reaction scope. [a] All reactions were carried out with st-DNA (1 mM bp concentration), 1a-o (1 mM), 2 (250 equiv), and [Cu(dmbipy)(NO3)2] (0.03 mM)
in a 20 mM MOPS buffer solution pH 6.5 with 2% THF as co-solvent for 3 d at 4 °C. [b] Conversions and ees were determined by High Pressure Liquid
Chromatography (HPLC) analysis.
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Table 2. Scale-up of the hetero Diels-Alder reaction and structural determination by NMR.
Coupling constants (Hz)
[]D
(c, solvent)
Isolated Yield
Compound
ee (%), dr
NOE effect
3J H7a-H3a
3J H4-H3a
(scale)
4J H7a-H4
+6,0°
79%
88%, 12:1
4.0
3.8
4.1
4.5
strong
(255 mg, 1.2 mmol)
(0.3, CH2Cl2)
+9.7°
(0.4, CH2Cl2)17
99%
73%, >99:1
6.4
4.4
strong
strong
(105 mg, 0.7 mmol)
+12.5°
88%
95%, 32:1
(96 mg, 0.5 mmol)
(0.6, CH2Cl2)
ee, endo/exo>99:1), did not alter the selectivity, however it is
worth pointing out the decrease in reactivity observed in the
case of the thioanisole derivative most probably due to the ability
of the sulfur atom to chelate copper ions.[15] The introduction of a
slightly electron-withdrawing substituent such as a fluorine
atom[16] (3f, 88% ee, endo/exo>12:1) was not detrimental
however more electron-deficient aromatic rings such as the
p-bromo- and the p-nitrobenzene derivatives led to very low
conversions (data not shown). -Heteroaromatic acyl imidazoles
(1g-i) were also found to be excellent substrates as showcased
by the high yields and remarkable diastereo- (endo/exo up to
>99:1) and enantioselectivities (ees ranging between 76% and
85%) obtained for the resulting bicyclic O,O-acetals 3g-i. Finally,
in contrast to the -aryl- and the -heteroaryl-substituted
substrates (1a-i), complete conversions were observed with
practically all the -alkyl-substituted derivatives (1j-n) tested.
Moreover, the endo/exo ratios appeared to decrease and the
ees increase as the size of the alkyl chain became more bulky.
The prevalence of the 2-acyl-methylimidazole motif in bio-hydrid
catalysis was further confirmed by the results obtained with the
analogous 2-acyl-isopropylimidazole precursor, which afforded
the corresponding cycloadduct 3o in 90% conversion albeit only
61% ee, or with the related ,-unsaturated 2-acylpyridine, the
1,3-diphenyl-2-propenone and the 2-methyl-1-(thiazol-2-yl)prop-
2-en-1-one, which failed to produce any product (data not
shown).
but none of them afforded the desired IEDDA product.
Considering that these reactions are assumed to proceed
through a concerted, but asynchronous transition state, we
associate this lack of reactivity with the lower nucleophilicity of
these heterodienophiles.[17]
1
The endo selectivity was confirmed by H NMR analysis of
compounds 3a, 3j and 3l, all obtained in high yields at reaction
scales ranging from 0.5 to 1.2 mmol, which also demonstrates
the robustness of the method (Table 2). Hence, all three
compounds adopt a bicyclic cis junction characterized by a low
coupling constant between H7a and H3a (3J H7a-H3a  4.0 Hz) and
a
W coupling between H5 and H3a (4J H5-H3a  1.2 Hz).
In addition, the relatively low coupling constant between H4 and
H3a indicates that these two protons are facing each other.
Finally, a NOESY experiment established a correlation between
H4 and H7a consistent with an endo-selective cycloaddition.
As for the absolute configuration, the latter was ascertained by
comparing the specific optical rotation value of the endo product
3j (3aR, 4R, 7aS), which was obtained in quasi-quantitative yield
on a 105 mg scale, with the one reported in the literature,[18]
while all other products were assigned by analogy. Compound 3l
was also engaged in a hydrogenation reaction to further support
our assignment (Table 2). The reduction of the enol double bond
proceeded smoothly and preserved the integrity of the
O,O-acetal affording compound 4 as a single diastereoisomer in
quantitative yield and with no erosion of the selectivity.[19]
The nature of the heterodienophile was also evaluated using
a selection of electron-rich alkenes, including 3,4-dihydro-2H-
pyran, ethyl vinyl ether, 2-vinyloxirane or para-methoxystyrene,
In conclusion, we present here the first example of an
asymmetric DNA-catalyzed inverse electron-demand hetero-
Diels-Alder reaction. The reaction allows the formation of fused
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[4]
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bicyclic O,O-acetals in high yields (up to 99%) and excellent
diastereo- and enantioselectivities (up to >99:1 dr, up to 95% ee).
The method was applied to a variety of ,-unsaturated 2-acyl-
imidazoles and could be easily scaled up. Most importantly, this
reaction, which has no equivalent in the metalloenzyme arsenal
obtained through directed evolution, emphasizes furthermore the
versatility of DNA-based asymmetric catalysis and its efficacy in
mimicking nature’s hetero-Diels-Alderases in water. Ultimately,
we hope this will trigger new developments in the field and
inspire the development of other cycloaddition reactions.
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The authors declare no competing financial interest.
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This research was supported by the Agence Nationale de la
Recherche (D-CYSIV project; ANR-2015-CE29-0021-01).
Keywords: Inverse electron-demand hetero-Diels-Alder • DNA •
biohybrid catalysis • Copper • [4+2] cycloaddition
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COMMUNICATION
COMMUNICATION
Justine Mansot, Jimmy Lauberteaux,
Aurélien Lebrun, Marc Mauduit,
Jean-Jacques Vasseur, Renata Marcia
de Figueiredo, Stellios Arseniyadis,*
Jean-Marc Campagne* and Michael
Smietana*
1st DNA-based asymmetric hetero-Diels-Alder cycloaddition
O
R = Ar, HetAr & Alk
endo/exo up to >99:1
up to 95% ee
O
O
O
H
N
+
N
R
R
N
N
Mild conditions
High yielding
Highly stereoselective
Scalable
Page No. – Page No.
DNA-Based Asymmetric Inverse
Not just a [4+2] cycloaddition! DNA can also catalyse inverse electron-demand
hetero-Diels-Alder (IEDHDA) cycloadditions between dihydrofuran and
,-unsaturated acyl imidazoles. The resulting fused bicyclic O,O-acetals
containing three contiguous stereogenic centers can be obtained in high yields
(up to 99%) and excellent stereoselectivities (up to >99:1 dr and up to 95% ee)
using a low catalyst loading.
Electron-Demand Hetero-Diels-Alder
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