Efficient copper-catalyzed amination of DNA-conjugated aryl iodides under mild aqueous conditions

Article abstract of DOI:10.1039/c8md00185e

Herein, we describe the development of copper-catalyzed cross-coupling of DNA-conjugated aryl iodides with aliphatic amines. This protocol leverages a novel ligand, 2-((2,6-dimethoxyphenyl)amino)-2-oxoacetic acid, to effect the transformation in aqueous D

Full text of DOI:10.1039/c8md00185e

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Efficient copper-catalyzed amination of DNA-conjugated aryl
iodides under mild aqueous conditions
Y. Ruffa and F. Berst*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract. Herein, we describe the development of a copper- oligonucleotides consists in performing nucleophilic aromatic
catalyzed cross-coupling of DNA-conjugated aryl iodides with substitution (NAS) using heteroaromatic systems (Scheme 1).
aliphatic amines. This protocol leverages a novel ligand, 2-((2,6- While successfully used in DEL synthesis15-19, it is limited in
dimethoxyphenyl)amino)-2-oxoacetic acid, to effect the practice to strongly-activated heteroaromatic systems such as
transformation in aqueous DMSO, under mild conditions, in air, triazine15, 16, 19 and pyrimidine8 chlorides, or nitro-substituted
making it an ideal candidate for the synthesis of DNA-encoded aromatic fluorides.20
libraries.
DNA-Encoded Libraries (DELs) consist in collections of
hundreds of millions to billions synthetic small molecules each
conjugated to a unique DNA sequence, or DNA tag1, 2. These
vast collections of synthetic compounds are screened in
mixtures by affinity selection processes, making them a
powerful tool for the discovery of ligands to biological
targets.1, 3-5 To build these libraries, synthetic small molecules
are constructed directly on DNA using split-and-mix
Scheme 1. Current and proposed N-arylation approaches for DELs synthesis.
A 46 equiv. R2-
combinatorial chemistry protocols often involving several
hundreds if not thousands of building blocks.1, 6 Therefore, DEL
synthesis rests on the development of methodologies for the
formation of covalent bonds under conditions compatible with
the solubility and stability of the nucleic acid tags,1, 7-10 tolerant
of a wide substrate scope and practical enough to facilitate
miniaturization and parallelization. Thus, “nitrogen-capping”
reactions such as acylation, urethanation, sulfonylation and
reductive amination have been applied to the synthesis of
NH2 (200mM DMA stock), 80°C, 6h. B CuI or Cu(OAc)2 (25mM), Ligand (50-200mM), Na
Ascorbate (50mM), base K3PO4 (500mM), R4-NH2 (500mM) DMSO/Water 1/1, 5/3 or 1/3, 40°C.
In order to extend the scope of this transformation to less-
activated aromatic cores, we and others21 chose to investigate
the copper catalyzed Ullmann N-arylation of amines with aryl
halides22-24 (Scheme 1). Indeed, while this manuscript was in
preparation, Lu et al. reported their efforts to optimize
palladium- and copper-based N-arylations of DNA-conjugated
aryl iodides with primary aliphatic and aromatic amines. While
a wide range of such amines were shown to be competent
under the reported conditions, cross-coupling reactions
involving secondary amines still appeared to pose a significant
challenge.21 Spurred by the large numbers of ligands reported
to enable such cross-couplings under mild reaction conditions
in polar solvents25-27 and, in some cases, in the presence of
air28 and water,29 we surmised that a systematic survey of
catalytic systems might unlock previously unreachable
portions of chemical space.
7
millions to trillions of DNA-encoded compounds1, among
which numerous potent protein ligands have been identified.5
The formation of N-aryl bonds is another nitrogen-
derivatization transformation commonly deployed in medicinal
chemistry for the generation of bioactive molecules.11, 12-14 It is
therefore not surprising that several DNA-encoded library
chemistry groups sought to identify amine arylation conditions
compatible with the generation of DNA-encoded libraries. One
approach to construct N-aryl bonds in the presence of
We started with investigating the model on-DNA coupling
reaction between DNA-conjugated aryl iodide 1a and a set of
amine substrates 2a-f mediated by ligands L1-1026, 28-34 under
reaction conditions compatible with DNA-encoded library
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synthesis.7, 8 Namely, we desired to manipulate building block results, we did not further investigate oligonucleotide damage
stock solutions in water-miscible organic co-solvents and in at this stage and proceeded with reaction optimization.
plate format (Figure 1A).
Figure 2. Structural and electronic effect on ligand efficiency: selected screening results.
Reaction conditions: A: 1a (1nmol), 2b-j (500mM), Cu(OAc)2 (25mM), ligand
sodium ascorbate (50mM), K3PO4 (500mM), DMSO (8ul), water (8ul), 40°C, 3h. B: 1b (1nmol),
2b-j (500mM), Cu(OAc)2 (25mM), ligand (50mM), sodium ascorbate (50mM), K3PO4
(500mM), DMSO (8ul), water (8ul), 40°C, 3h. The color and diameter of circles correlates with
the conversion to 3b-j ) or 4b-j ) determined by UPLC-TOF analysis.
L (50mM),
L
Figure 1. Initial screening of known ligands for the Copper-catalyzed coupling of
representative amines and model DNA-conjugated aryl iodide 1a Reaction conditions: A: 1a
(1nmol), 2a-f (500mM), CuI (25mM), ligand (50mM), K3PO4 (500mM), DMSO (8µl), water
(8µl), 40°C, 3h; B: 1a (1nmol), 2a-f (500mM), CuI (25mM), ligand (50mM), sodium ascorbate
.
(A
(B
L
L
Since library synthesis under inert atmosphere or using
degassed solvents can prove cumbersome in practice, we
repeated the experiment to investigate the effect of an
additional reducing agent introduced to circumvent the risk of
aerobic oxidation of the copper catalyst (Figure 1B). The
superior conversions of starting DNA-conjugate into product
and by-products observed in the presence of ascorbic acid
provided circumstantial evidence that copper oxidation was
indeed limiting the reactivity of the system. Gratifyingly, when
50 mM aqueous sodium ascorbate solution was added to the
reaction (2 eq. compared to CuI), significantly improved
conversions to the N-arylated products 3a-c could be
(50mM), K3PO4 (500mM), DMSO (8µl), water (8µl), 40°C, 3h. Reactions performed in air. Pie
chart areas represent conversion to 3a-f (%) as determined by UPLC-TOF.
Among the ligands reported for the N-arylation of aliphatic
amines, L733 (8-hydroxyquinoline 1-oxide) and L835 (DMPAO: 2-
(2,6-dimethylphenylamino)- 2-oxoacetic acid) showed
moderate to good conversion of 1a with amines 2a, 2b and 2c
to the respective products 3a36, 3b and 3c under aerobic
aqueous conditions at 40°C. Notably, L8 provided the cleanest
reaction profile and lowest proportion of side products 1di and
1oh while only limited amounts of DNA degradation could be
observed by LC-MS.37 Satisfied with these early, positive
2 | J. Name., 2012, 00, 1-3
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observed. Again, ligand L8 led consistently to higher yields of concentration of ligands to 200 mM did cause a noticeable
product than any of the other ligands tested L1-10
.
increase in the formation of N-arylated 2f (data not shown,
please see supporting information section VII). We therefore
sought to validate this observation in the reaction of DNA-
Ligand L8 was originally reported as particularly efficient for conjugated aryliodide 1a and 1b39 with our set of diverse test
the N-arylation of hindered secondary aliphatic amines.35 amines. Suspecting that the proportion of DMSO in water
Under our aqueous conditions, it performed better for the N- might also affect the yield and formation of side-products
arylation of hindered substrates 2d, N-methylbenzylamine 2e during the reaction, we introduced this additional parameter
and N-methylcyclohexylamine 2f (Figure 1B, entry 2d
2e L8 and 2f L8) than any of the other candidates. Encouraged
by this positive trend, we set out to investigate alternative
designs of L8
/
L8
,
in the experimental design (Figure 3).
/
/
.
The group of Ma demonstrated the utility of the two methyl
groups in L8 and the beneficial effect of introducing electron-
donating moieties on structurally-related oxalic diamide
ligands.38 Since the steric and electronic properties of the
ligand appeared critical to its efficiency in this study, we
synthesized 11 analogues of L8 and evaluated them for
competency in the amination of DNA-conjugates 1a and 1b
with a panel of diverse amines (Figure 2A and 2B). We elected
to use this particular pair of DNA-conjugates to rule out any
electronic effect that could be specific to 1a. For practical
reasons, we also replaced copper (I) iodide with copper (II)
acetate, as the latter is not sensitive to oxidation and yields
stable stock solutions in either DMSO or water. In
preliminary experiment, this change did not appear to cause
any detrimental effect (recapitulated in Figure 1 /combination
1a 2b L8 78% compared with Figure 2 /combination 1a 2b L8
a
B
/
/
A
/
/
75% conversion). The results of this screening experiment
showed a dramatic influence of the ligand structure on its
reactivity. As evidenced by the conversion observed for ligands
L8, L12, L13 and L14, the addition of electron-donating
moieties in para- did not provide noticeable advantages.
Replacing one of the methyl groups in L8 with methoxy (L8
→
L11) led to an increase in conversion across the panel of
tested amines, while increasing the steric bulk around the
oxalic amide L8 L18 did not provide any noticeable
advantage. Ligands lacking two ortho-substituents (L17 L19
(
→
)
,
Figure 3: Optimization of the concentration of L15 and cosolvent proportion in a plate format.
Reaction conditions: A 1a (1nmol), 2b-j(500mM), Cu(OAc)2(25mM), ligand L15 (50-200mM),
Sodium Ascorbate (50mM), K3PO4 (500mM), DMSO/Water(1/3-3/1 16ul), 40°C, 3h. The color
and diameter of circles correlates with the yield of 3b-j determined by UPLC-TOF analysis. B 1a
(1nmol), 2b-j(500mM), Cu(OAc)2(25mM), ligand L15 (50-200mM), Sodium Ascorbate (50mM),
K3PO4 (500mM), DMSO/Water(1/3-3/1 16ul), 40°C, 3h. The color and diameter of circles
correlates with the yield of 5a determined by UPLC-TOF analysis.
and L21) were generally found to be inferior to L8 despite
attempts to vary the electron density on the aromatic ring.
Finally, di-ortho- substitution appeared mandatory to get
efficient ligands: replacing both methyl groups on L8 by two
methoxy groups led to the strikingly more efficient ligand L15
and this finding was recapitulated by the matched pair
L12
improvement in product yield could be observed for secondary
amine 2f when L15 was used instead of L8 (Figure 2 L8 2f
6%; L15 2f: 39%).
→
L20
.
Notably, using 1b as substrate,
a
6-fold
This experiment confirmed that increasing the concentration
of ligand had a beneficial effect on the conversion for reactions
A
:
- :
-
with hindered substrates 2f and 2j (Figure
3 and SI VI1). In
While excellent conversions were already observed for L15 in
most cases, the yields were still low to moderate for the most
hindered substrates N-methylcyclohexylamine 2f and 2,4-
dimethylpiperidine 2j. We therefore went through another
round of reaction condition optimization, studying the effect
of the concentration of ligand L15, base, sodium ascorbate and
amine on the yield of the N-arylation of 2f with 1b. While
varying the concentrations of amine, base and ascorbic acid
had marginal effects on conversion, increasing the
addition, increasing the ligand concentration and DMSO
proportion worked synergistically to improve the yield of the
reaction with a maximal 56% yield of 3f obtained with a
200mM concentration of L15 in DMSO/water : 5/3. However,
these observations could not be broadly generalized as the
proportion of DMSO had
a deleterious effect on the
conversions observed for primary amines 2b and 2d (Figure
3A). Indeed, altering the DMSO/water ratio from 1/3 to 3/1
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caused a 56% reduction in the yield of N-arylation between 1a
1
. In a manner analogous to that described by the group of
and 2-methoxybenzylamine 2b (Figure 3A line 2b).
Paegel,40 model reactions were conducted in the presence of a
We hypothesize that the amine and DMSO compete for small amount of amplifiable DNA. Gratifyingly, quantification
coordination of the copper catalyst and as a consequence, an by qPCR after work-up and comparison with a reference
inhibitory effect of this co-solvent is observed for higher ratios. sample indicated that 65% of the amplifiable DNA remained
Indeed, using 1a as substrate in particular, increasing the after submission to conditions 1. This amount is in line with
proportion of DMSO led to the appearance of side-products those observed for reactions we have already deployed in the
resulting from unwanted N-arylation of the ligand, with up to synthesis of large discovery libraries40 (a full experimental
42% of the starting material 1a being converted into 5a when account is provided in the supporting information, SI IX).
combined with 2-methoxybenzylamine (Figure 3
B
and SI VI2).
With these results in hand, we proceeded with investigating
the scope of conditions 1 and on a combinatorial matrix of 8
DNA-conjugated aryl iodides with 12 different amines (Figure
). This experiment confirmed that conditions 1 led to useful
2
4
yields for the majority of substrate combinations as long as the
halogen atom found itself in an unhindered environment. For
benzene derivatives, electronic effects on the aromatic ring
seemed to have negligible influence on the conversions
observed, as most amines gave good to excellent conversions
(41%-100%) with substrates 1b, 1f, 1g and 1h. Interestingly,
the 3-iodopyrrole derived substrate 1i could only be combined
with cyclic secondary amines 2o and 2i, giving 49% and 58%
conversion respectively, while reactions with simpler amines
failed to yield useful amounts of coupling product (Figure 4A).
The N-arylation reaction appeared, however, to be very
sensitive to steric hindrance. Indeed, little to no conversion
was observed with substrates 1c, 1d and 1e having
substituents ortho- to the reactive halogen (figure 4
contrast, it was satisfying to observe that unfavourable
combinations like 1d 2b or 1e 2b were still formed in
moderate yield (30 and 25% respectively) under conditions 2
when these products were only formed as traces under
conditions 1 (Figure 4 ). Interestingly, higher yields were also
obtained under conditions 2 for the reactions involving
iodopyridine 1h as substrate (Figure 4 ). Taken together, these
A). In
/
/
,
B
B
results highlighted the nuances of reactivity imparted by both
coupling partners: a thorough vetting of building blocks prior
to library synthesis will be necessary to ensure useful yields of
final library products.41
Conditions 2 appeared to be most
beneficial to very specific substrate combinations, which may
warrant their deployment in the synthesis of focused DNA-
encoded libraries. In contrast, conditions 1 appeared to more-
generally lead to higher product yields, making them our
natural choice for the synthesis of larger discovery libraries.
Figure 4: Scope determination of the N-arylation of susbtrates 1b-1i with amines 2b-2q. A
Reaction conditions 1: 1b-i (1nmol), 2b-q(500mM), Cu(OAc)2(25mM), ligand L15 (200mM),
Sodium Ascorbate (50mM), K3PO4 (500mM), DMSO/Water(1/3 16ul), 40°C, 3h. B Reaction
conditions 2: 1b-i (1nmol), 2b-q(500mM), Cu(OAc)2(25mM), ligand L15 (200mM), Sodium
Ascorbate (50mM), K3PO4 (500mM), DMSO/Water(5/3 16ul), 40°C, 3h.
Therefore, while our initial studies were conducted with an
equal proportion of DMSO and water in the reaction medium,
we found that lowering the proportion of DMSO to
DMSO/Water: 1/3 (Conditions 1) led to a more efficient
system for the majority of unhindered primary and secondary
amines while, at the same concentration of ligand L15, more
hindered substrates like 2f or 2j did benefit from increasing
the proportion of co-solvent to a ratio DMSO/Water : 5/3
Conclusions
In conclusion, we have developed a novel ligand and a set of
reaction conditions to facilitate the copper-catalyzed cross-
coupling of DNA-conjugated aryliodides with a variety of
aliphatic amines, most notably relatively hindered secondary
amines. Importantly, the catalytic system operates at low
temperature, in air, using an organic co-solvent compatible
with the generation and storage of a large number of amine
building block stock solutions. These features render our
reaction conditions highly amenable to the synthesis of DNA-
(Conditions 2). All other parameters being kept equal, the
perspective of using two different solvent proportions during
library synthesis was deemed only a minor annoyance. At this
stage of our optimization campaign, we decided to conduct a
more thorough analysis of DNA damage caused by conditions
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encoded libraries based on the formation of Csp2-N bonds and
15.
M. A. Clark, R. A. Acharya, C. C. Arico-Muendel, S. L.
complement the existing NAS and N-arylation protocols.21
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Conflicts of interest
The authors declare no competing interest.
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Acknowledgements
The research leading to these results was supported by the
NIBR Postdoctoral Program (Y.Ruff). We thank Dr. Christoph
Gaul for his help during the preparation of this manuscript. We
are also grateful to Mr. Xavier Pellé and Ms. Sandrine
Liverneaux for fruitful discussions and their help with the
purification of small molecule-oligonucleotide conjugates.
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The structure of 3a, 3h and 4h was further confirmed by
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the supplementary information section IV
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Representative screening results for the substrate 1b can
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As a rule of thumb, we estimate that a 40% product yield
is sufficient to ensure adequate representation of each
members of the library, provided that the presence of
unknown by-products is limited.
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8MD00185E
A practical and efficient protocol for the amination of DNA-conjugated aryl iodide using a novel ligand was
developed.

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