Multifunctional Building Blocks Compatible with Photoredox-Mediated Alkylation for DNA-Encoded Library Synthesis

Article abstract of DOI:10.1021/acs.orglett.9b04568

DNA-encoded library (DEL) technology has emerged as a novel interrogation modality for ligand discovery in the pharmaceutical industry. Given the increasing demand for a higher proportion of C(sp³)-hybridized centers in DEL platforms, a photore

Full text of DOI:10.1021/acs.orglett.9b04568

pubs.acs.org/OrgLett
Letter
Multifunctional Building Blocks Compatible with Photoredox-
Mediated Alkylation for DNA-Encoded Library Synthesis
Shorouk O. Badir,§ Jaehoon Sim,§ Katelyn Billings, Adam Csakai, Xuange Zhang, Weizhe Dong,
and Gary A. Molander*
Cite This: https://dx.doi.org/10.1021/acs.orglett.9b04568
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ABSTRACT: DNA-encoded library (DEL) technology has emerged as a
novel interrogation modality for ligand discovery in the pharmaceutical
industry. Given the increasing demand for a higher proportion of C(sp3)-
hybridized centers in DEL platforms, a photoredox-mediated cross-coupling
and defluorinative alkylation process is introduced using commercially
available alkyl bromides and structurally diverse α-silylamines. Notably, no
protecting group strategies for amines are necessary for the incorporation of a
variety of amino-acid-based organosilanes, providing crucial branching points
for further derivatization.
subsequently the chemical structures are decoded via PCR
he discovery of small organic ligands with high-affinity
Tbinding to proteins is a central theme of biomedical amplification and DNA sequencing.8 In this vein, DEL screens
research in both academic and industrial settings.1 Robust
provide a time- and cost-effective format for exploration of
uncharted chemical space.
chemical probes are key to validating the tractability and
translatability of a therapeutic target in drug discovery programs,
and they provide a critical starting point for the development of
new therapeutic chemical entities.2 Consequently, considerable
attention has been devoted to the development of novel
screening methods that diminish clinical attrition and to identify
chemical matter with superior specificity more rapidly.
A wide array of medicinal candidates has been identified from
DEL platforms.9 The inherent nature of the DNA barcode,
however, renders the implementation of such synthetic
transformations challenging. On-DNA reactions must be
compatible with water, must be performed at high dilutions,
must be high-yielding with the ability to identify any major
byproducts, should be user-friendly, and must avoid the use of
strong bases and harsh oxidizing or reducing agents.10 Recent
work by the Baran and Dawson groups11 to increase the
solubility of DNA tags in organic solvents utilizing cationic
resins has been demonstrated, but this protocol presents its own
obstacles when merged with photoredox-mediated alkylation
processes. Therefore, myriad structural gaps persist in DEL
paradigms, with an increasing need to incorporate functional
groups amenable to sequential derivatization.
In the search for novel therapeutic compound classes, a
strategy has evolved to cast a wide net to capture as many
potential hit compounds as possible across a broad range of
substructures. Owing to the need for individual synthesis and
screening of small molecules that make up a conventional high-
throughput screening library, campaigns of a few million
compounds against a complex biological target have proven to
be cost- and time-intensive, with an estimated price tag of $1000
per library member.1,3 In recent years, DNA-encoded library
(DEL) technology4 has emerged as an innovative platform to
enable the assembly and sampling of combinatorial libraries of
unprecedented magnitude (>106 to 1012 drug-like candidates).5
Originally conceived by Brenner and Lerner in 1992, DELs are
composed of small molecules covalently conjugated with a DNA
tag, which functions as a molecular identifier or barcode for each
subunit.6 By harnessing split-and-pool routines, an entire library
can be made in a few months by 1−2 chemists and, in a single
experiment, screened against immobilized biomolecular targets
(Figure 1).7 Once nonbinders are washed away, the desired
ligands are released under denaturing conditions, and
To ensure a versatile chemical foundation, careful selection of
building blocks (BBs) is instrumental in constructing libraries. A
comprehensive set of BBs encompassing structural motifs that
resemble bioactive molecules in combination with those bearing
an additional handle for diversification is ideal.12 Although
Received: December 20, 2019
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renders such anionic alkylation processes unusable in DEL
environments.21 By contrast, electrophilic reagents such as
aliphatic halides have greater abundance and offer excellent
structural complexity, with over 2 million building blocks
commercially available. Bypassing the need for stoichiometric
zinc or manganese reductants, we disclose a versatile cross-
coupling with excellent functional group tolerance on DNA.
In two further protocols, α-silylamines have been incorpo-
rated as surrogates of structural motifs embedded within natural
products.12,22 We have thus engaged several members of this
class of substrates in both Ni/photoredox dual cross-coupling
and defluorinative alkylation processes. Importantly, all of the
protocols developed are completed within minutes and do not require
an inert atmosphere, providing an exceedingly low barrier to
practical implementation.
A fundamental challenge facing cross-electrophile couplings is
selectivity.20 Because of the labile nature of both electrophilic
starting materials toward oxidative addition in the presence of a
nickel catalyst, careful design of reaction parameters must be
implemented to synchronize the nickel and photoredox catalytic
cycles (Figure 2A).13
Figure 1. Schematic presentation of DNA-encoded library technology.
monofunctional BBs suitable for existing DEL chemistries are
widely accessible, a recent survey estimates that the number of
available bifunctional BBs, serving as crucial linkers, encom-
passes only ∼3500 scaffolds.12 In light of these considerations,
we sought to expand the BBs amenable for photoredox-catalyzed
DEL synthesis to incorporate two complementary families of
radical precursors, namely, aliphatic bromides13 and α-silyl-
amines.14
In recent years, metallaphotoredox catalysis has emerged as a
valuable tool for providing unique and alternative C−C bond
disconnections, especially in the context of complex biomo-
lecular design.15 Because of the impact of C(sp3)-hybridized
centers on the enhancement of solubility and specificity in
druggable molecules, single-electron transfer (SET) processes
have found extensive use in the medicinal chemistry
community.16,17
Recently, our group and others have validated Ni/photoredox
dual catalysis in DNA-encoded synthesis using carboxylic acids
and 1,4-dihydropyridines (DHPs) as radical precursors.18,19
Although this advance presented a milestone in its own right, the
scope of these transformations was restricted to α-amino acids,
which generate stabilized α-heterosubstituted radicals.18,19 In
the case of DHPs, the cross-coupling was limited to benzylic,
secondary, or α-alkoxy structural motifs.18 The use of other
electrophiles was restricted to DNA-conjugated aryl iodides.19
To address these limitations, we sought to develop three
photoredox approaches to expand chemical space in the DEL
platform. In the first, a photoredox/nickel-mediated reductive
coupling on DNA was developed, employing primary and
secondary alkyl bromides as reaction partners using triethyl-
amine as a mild reductant. Such cross-electrophile couplings
furnish several advantages over traditional catalytic cycles.20 For
example, the need for preformed carbon nucleophiles, including
harsh organometallic reagents prepared from the corresponding
halides, severely limits functional group compatibility and
Figure 2. Plausible catalytic cycle, key optimization parameters, and
scope of this transformation.
To induce selectivity in substrates with inherently equal or
similar reactivities, excess amounts of one reagent over the other
can be leveraged.20,23 This strategy is particularly powerful in the
context of DEL chemistries, which are carried out on an
extremely small scale (∼25 nmol).18 To clarify this perspective
further, the use of 250 equiv of radical precursor equates to
only 6.25 μmol of starting material. Notably, the ease of
separation of homodimers from DNA-alkylated products further
highlights the potential of implementing cross-electrophile
couplings in DEL strategies.
B
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We initiated our studies using a DNA-tagged para-substituted
aryl bromide (1) and 4-bromotetrahydropyran as the model
substrates under 20% aqueous conditions (Figure 2). Given the
reductive nature of this transformation, a variety of photo-
catalysts were screened (Figure 2B). Although product
formation was observed in the case of the organic dye 1,2,3,5-
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN),24 the
iridium-based photoreductant [Ir(dtbbpy)(ppy)2]PF6 (E1/2
=
−0.96 V vs SCE) proved superior.25,26 Of particular note,
minimal product was generated using 10-phenylphenothiazine
(PTH). With a drastically higher reduction potential (E1/2
=
−2.1 V vs SCE) compared to that of Ir(ppy)3 (E1/2 = −1.7 V vs
SCE),27 this photoreductant presumably engages the aryl halide
on DNA in protodehalogenation via reductive fragmentation of
the corresponding C−X bond. After a variety of parameters was
assessed, a loading of 250 equiv of alkyl bromide, coupled with a
4:1 ratio of the NiBr2·bpy precomplex-to-photocatalyst, was
determined to afford the desired product in suitable yield. The
addition of magnesium chloride (MgCl2) was utilized to
enhance stabilization of the DNA backbone.28 Of note, the
reactions were complete in <45 min and did not require an inert
atmosphere.
We subsequently evaluated the scope of this reductive
coupling (Figure 2C). A wide range of primary and secondary
alkyl bromides served as competent substrates, including those
with bifunctional handles such as N-Boc-protected amine 3d,
unactivated alkene 3i, alkyl chlorides 3j and 3k, and nitrile 3o.
Because of the mild base utilized, free alcohols 3l−n, stemming
from a primary alkyl bromide, were effectively coupled in
acceptable yields. The scope of this method was further
extended to cyclic systems, including oxetane 3c, azetidine 3d,
and pyran 3g.
To establish robust reactivity, we surveyed these DNA
substrates with one primary and one secondary alkyl bromide
(Figure 2D). Aryl bromides and iodides bearing electron-
withdrawing and electron-donating groups were cross-coupled
effectively. Activated heteroaryl systems (3ab, 3ac, 3ad) reacted
in moderate yields because of their delicate nature under
reducing photoredox conditions. This limitation, however,
complements existing SET-mediated cross-coupling procedures
operating under an oxidative fragmentation paradigm.18,19 By
contrast, electron-neutral aryl bromides or those bearing
electron-donating substituents, not viable under previous
reports,18,19 furnished the desired alkylated products in
moderate yields in this cross-electrophile coupling. A variety
of other structural motifs were accommodated, including aryl
fluoride 3ae, styrene 3af, N-Boc-protected amines (3oj and
3ok), aldehyde 3al, and free primary amines (3om and 3on).
Remarkably, aryl halide 3ao, containing a morpholine residue,
did not suffer diminished reactivity, despite its structural
resemblance to the triethylamine used as a stoichiometric
reducing agent in this reaction.
Figure 3. Cross-coupling and radical/polar defluorinative amino-
methylation.
Imatinib and Donepezil.14,30 Strategies based on DOS attest to
their success in the discovery of new therapeutic treatments,31
especially in DNA-encoded library synthesis as described
recently by Schreiber et al.32
We envisioned that single-electron oxidation of electron-rich
alkyl(trimethyl)silanes 4 under photoredox conditions would
give rise to silyl radical cations.14,33 This species would undergo
facile desilylation to yield the desired α-aminomethyl radical,
which could then be intercepted by the nickel catalytic cycle to
furnish the coupled product. We anticipated that nucleophili-
cally assisted desilylation could occur when using water as a
(co)solvent. This added benefit could be further leveraged as the
free amine handle allows systematic branching sequences in
DEL platforms. Driven by low oxidation potentials in protic
solvents,33 we demonstrate for the first time that unprotected
aminomethylsilanes are efficiently oxidized by [Ir{dFCF3ppy}-
(bpy)]PF6. Notably, diverse alkyl(trimethyl)silanes can be
accessed in a single step from the corresponding commercially
available amines and chlorotrimethylsilane. Importantly, the
reactions require less than 15 min to proceed to completion and are
carried out in the absence of an inert atmosphere.
The bifunctional nature and commercial availability of amino
acids make them highly valued building blocks for library
synthesis, and we successfully carried out the aminomethylation
with a variety of electron-deficient and electron-rich halides with
an organosilane stemming from proline to produce synthetically
useful levels of product. An aryl iodide bearing an N-Boc-
protected amine (5p) served as a competent substrate.
Additionally, aryl iodides bearing a free amine 5n and tertiary
amine 5o both reacted with ease. We have also successfully
demonstrated the cross-coupling with non-amino-acid-derived
organosilanes (5b and 5c).
Having explored the utility of alkyl bromides as electrophilic
cross-coupling partners on DNA, we then investigated α-
silylamines as radical precursors.14 An ambitious goal of
unbiased DNA-encoded libraries aimed at multiple biological
targets is to encompass a large collection of diverse scaffolds.28
Inspired by the concept of diversity-oriented synthesis (DOS),
first championed by Schreiber in 2000,29 we pursued the
aminomethylation of (hetero)aryl bromides to yield skeletal
diversity prevalent in natural products (Figure 3). Indeed, the
aminomethyl subunit serves as a pivotal linker in bioactive
molecules as well as leading pharmaceutical drugs such as
Given the metabolic stability of gem-difluoroalkenes as
carbonyl mimics,34 we subjected α-silylamines to radical/polar
C
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crossover defluorinative alkylation processes (Figure 3D).18,35
We propose that a single-electron oxidation of the α-silylamine
radical precursor by the photoexcited state of the photocatalyst
furnishes a nucleophilic primary radical. This species then
undergoes addition to the trifluoromethyl alkene to generate an
α-CF3 radical, which is further reduced to the carbanion by the
photocatalyst. Subsequent fluoride elimination occurs to yield
7.18,35
After extensive reaction optimization, we assessed the scope
of this transformation (Figure 3E). A wide array of amino-acid-
based organosilanes proved competent, including leucine 7e,
phenylalanine 7f, proline 7h, methionine 7i, and tryptophan 7k.
Remarkably, nitrogen protecting groups were not necessary in
this alkylation platform, providing an additional branching point
to be utilized for further building block incorporation.
AUTHOR INFORMATION
Corresponding Author
■
Gary A. Molander − University of Pennsylvania,
Philadelphia, Pennsylvania; orcid.org/0000-0002-
9114-5584; Email: gmolandr@sas.upenn.edu
Other Authors
Shorouk O. Badir − University of Pennsylvania,
Philadelphia, Pennsylvania
Jaehoon Sim − University of Pennsylvania, Philadelphia,
Pennsylvania
Katelyn Billings − GlaxoSmithKline, Cambridge,
Massachusetts; orcid.org/0000-0002-7483-8928
Adam Csakai − GlaxoSmithKline, Cambridge,
Massachusetts
Numerous other silylamines, derived from commercially
available aminomethylsilane and the corresponding ketones/
aldehydes via reductive amination, displayed adequate reactivity
with a variety of substrates, including aniline 7a, glycoside 7l,
oxetane 7m, pyridine 7o, and amide 7p. Notably, we subjected
aminomethyltrimethylsilane to the reaction conditions and
obtained the primary amine 7q without any loss in reactivity. We
foresee that the structural diversity created in these photoredox-
mediated processes will be instrumental in providing unique and
alternative bond disconnections in DEL libraries.
Xuange Zhang − University of Pennsylvania, Philadelphia,
Pennsylvania
Weizhe Dong − University of Pennsylvania, Philadelphia,
Pennsylvania
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04568
Author Contributions
§S.O.B. and J.S. contributed equally to this work.
Notes
Finally, maintaining the integrity of the DNA tag during
library synthesis is vital to the success of encoded library
technology as a drug discovery platform because the DNA
barcode is the only record available to decode the synthetic steps
used to construct the putative binder following selection. We
verified the integrity of the DNA tag when subjected to the
photoredox conditions developed herein (see Supporting
Information for details). We observed no significant differences
in the ability of our samples treated with standard conditions to
undergo ligation, PCR amplification, quantification, or sequenc-
ing when compared to a no-blue-light-exposed control sample.
These results, consistent with historical findings,18 suggest that
the reported transformations are amenable for DEL synthesis
without compromising the integrity of the DNA.
In summary, taking advantage of diverse and commercially
available alkyl bromides, a selective cross-electrophile coupling
on DNA has been devised. A variety of unactivated primary and
secondary radical precursors are employed with high functional
group tolerance. Of further advantage, photoredox-mediated
radical/polar crossover reactions using structurally diverse α-
silylamines were employed to generate novel gem-difluoroalkene
scaffolds without the need for nitrogen protecting groups.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
NIGMS (R35 GM 131680 to G.M.) We thank Dr. Charles W.
Ross, III (UPenn) for his assistance in obtaining LCMS and
HRMS data. We thank Dr. Svetlana Belyanskaya (GSK) and
Divya Parikh (GSK) for their assistance obtaining qPCR and
sequencing data. We thank Johnson Matthey for the donation of
iridium(III) chloride and Kessil for donation of lamps.
REFERENCES
■
(1) Neri, D.; Lerner, R. A. DNA-Encoded Chemical Libraries: A
Selection System Based on Endowing Organic Compounds with
Amplifiable Information. Annu. Rev. Biochem. 2018, 87, 479−502.
(2) Garbaccio, R. M.; Parmee, E. R. The Impact of Chemical Probes in
Drug Discovery: A Pharmaceutical Industry Perspective. Cell Chem.
Biol. 2016, 23, 10−17.
(3) For selected examples, see: (a) Erlanson, D. A.; Fesik, S. W.;
Hubbard, R. E.; Jahnke, W.; Jhoti, H. Twenty years on: the impact of
fragments on drug discovery. Nat. Rev. Drug Discovery 2016, 15, 605−
619. (b) Folmer, R. H. A. Integrating biophysics with HTS-driven drug
discovery projects. Drug Discovery Today 2016, 21, 491−498. (c) Halai,
R.; Cooper, M. A. Using label-free screening technology to improve
efficiency in drug discovery. Expert Opin. Drug Discovery 2012, 7, 123−
131. (d) Nielsen, T. E.; Schreiber, S. L. Diversity-oriented synthesis -
Towards the optimal screening collection: A synthesis strategy. Angew.
Chem., Int. Ed. 2008, 47, 48−56.
ASSOCIATED CONTENT
■
sı
* Supporting Information
(4) Dickson, P.; Kodadek, T. Chemical composition of DNA-encoded
libraries, past present and future. Org. Biomol. Chem. 2019, 17, 4676−
4688.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04568.
(5) For selected examples, see: (a) Clark, M. A.; Acharya, R. A.; Arico-
Muendel, C. C.; Belyanskaya, S. L.; Benjamin, D. R.; Carlson, N. R.;
Centrella, P. A.; Chiu, C. H.; Creaser, S. P.; Cuozzo, J. W.; Davie, C. P.;
Ding, Y.; Franklin, G. J.; Franzen, K. D.; Gefter, M. L.; Hale, S. P.;
Hansen, N. J. V.; Israel, D. I.; Jiang, J. W.; Kavarana, M. J.; Kelley, M. S.;
Kollmann, C. S.; Li, F.; Lind, K.; Mataruse, S.; Medeiros, P. F.; Messer,
Detailed experimental procedures (including workflow
and qPCR/sequencing of representative examples),
preparation of on-DNA substrates and α-silylmethyl-
amines, characterization data, NMR spectra for new
compounds, and UPLC/MS of on-DNA reactions (PDF)
D
https://dx.doi.org/10.1021/acs.orglett.9b04568
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Organic Letters
pubs.acs.org/OrgLett
Letter
J. A.; Myers, P.; O’Keefe, H.; Oliff, M. C.; Rise, C. E.; Satz, A. L.;
Skinner, S. R.; Svendsen, J. L.; Tang, L. J.; van Vloten, K.; Wagner, R.
W.; Yao, G.; Zhao, B. G.; Morgan, B. A. Design, synthesis and selection
of DNA-encoded small-molecule libraries. Nat. Chem. Biol. 2009, 5,
647−654. (b) Litovchick, A.; Dumelin, C. E.; Habeshian, S.; Gikunju,
D.; Guie, M. A.; Centrella, P.; Zhang, Y.; Sigel, E. A.; Cuozzo, J. W.;
Keefe, A. D.; Clark, M. A. Encoded Library Synthesis Using Chemical
Ligation and the Discovery of sEH Inhibitors from a 334-Million
Member Library. Sci. Rep. 2015, 5, 10916. (c) Harris, P. A.; King, B. W.;
Bandyopadhyay, D.; Berger, S. B.; Campobasso, N.; Capriotti, C. A.;
Cox, J. A.; Dare, L.; Dong, X. Y.; Finger, J. N.; Grady, L. C.; Hoffman, S.
J.; Jeong, J. U.; Kang, J.; Kasparcova, V.; Lakdawala, A. S.; Lehr, R.;
McNulty, D. E.; Nagilla, R.; Ouellette, M. T.; Pao, C. S.; Rendina, A. R.;
Schaeffer, M. C.; Summerfield, J. D.; Swift, B. A.; Totoritis, R. D.; Ward,
P.; Zhang, A. M.; Zhang, D. H.; Marquis, R. W.; Bertin, J.; Gough, P. J.
DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-
ones as Highly Potent and Monoselective Receptor Interacting Protein
1 Kinase Inhibitors. J. Med. Chem. 2016, 59, 2163−2178. (d) Mullard,
A. DNA Tags Help the Hunt for Drugs. Nature 2016, 530, 367−369.
(6) Brenner, S.; Lerner, R. A. Encoded combinatorial chemistry. Proc.
Natl. Acad. Sci. U. S. A. 1992, 89, 5381−5383.
W.; Pani, B.; Wang, Q. T.; Zhao, S.; Wall, A. L.; Strachan, R. T.; Staus,
D. P.; Wingler, L. M.; Sun, L. D.; Sinnaeve, J.; Choi, M. J.; Cho, T.; Xu,
T. T.; Hansen, G. M.; Burnett, M. B.; Lamerdin, J. E.; Bassoni, D. L.;
Gavino, B. J.; Husemoen, G.; Olsen, E. K.; Franch, T.; Costanzi, S.;
Chen, X.; Lefkowitz, R. J. Allosteric ″beta-blocker″ isolated from a
DNA-encoded small molecule library. Proc. Natl. Acad. Sci. U. S. A.
2017, 114, 1708−1713.
(10) (a) Malone, M. L.; Paegel, B. M. What is a ″DNA-Compatible″
Reaction? ACS Comb. Sci. 2016, 18, 182−187. (b) Satz, A. L.; Cai, J. P.;
Chen, Y.; Goodnow, R.; Gruber, F.; Kowalczyk, A.; Petersen, A.;
Naderi-Oboodi, G.; Orzechowski, L.; Strebel, Q. DNA Compatible
Multistep Synthesis and Applications to DNA Encoded Libraries.
Bioconjugate Chem. 2015, 26, 1623−1632.
(11) Flood, D. T.; Asai, S.; Zhang, X. J.; Wang, J.; Yoon, L.; Adams, Z.
C.; Dillingham, B. C.; Sanchez, B. B.; Vantourout, J. C.; Flanagan, M. E.;
Piotrowski, D. W.; Richardson, P.; Green, S. A.; Shenvi, R. A.; Chen, J.
S.; Baran, P. S.; Dawson, P. E. Expanding Reactivity in DNA-Encoded
Library Synthesis via Reversible Binding of DNA to an Inert Quaternary
Ammonium Support. J. Am. Chem. Soc. 2019, 141, 9998−10006.
(12) Zhao, G. X.; Huang, Y. R.; Zhou, Y.; Li, Y. Z.; Li, X. Y. Future
challenges with DNA-encoded chemical libraries in the drug discovery
domain. Expert Opin. Drug Discovery 2019, 14, 735−753.
(7) Ottl, J.; Leder, L.; Schaefer, J. V.; Dumelin, C. E. Encoded Library
Technologies as Integrated Lead Finding Platforms for Drug Discovery.
Molecules 2019, 24, 1629.
(13) Duan, Z. L.; Li, W.; Lei, A. W. Nickel-Catalyzed Reductive Cross-
Coupling of Aryl Bromides with Alkyl Bromides: Et3N as the Terminal
Reductant. Org. Lett. 2016, 18, 4012−4015.
(8) For selected examples, see: (a) Buller, F.; Mannocci, L.;
Scheuermann, J.; Neri, D. Drug Discovery with DNA-Encoded
Chemical Libraries. Bioconjugate Chem. 2010, 21, 1571−1580.
(b) Kleiner, R. E.; Dumelin, C. E.; Liu, D. R. Small-molecule discovery
from DNA-encoded chemical libraries. Chem. Soc. Rev. 2011, 40, 5707−
5717. (c) Ding, Y.; Franklin, G. J.; DeLorey, J. L.; Centrella, P. A.;
Mataruse, S.; Clark, M. A.; Skinner, S. R.; Belyanskaya, S. Design and
Synthesis of Biaryl DNA-Encoded Libraries. ACS Comb. Sci. 2016, 18,
625−629.
(14) Remeur, C.; Kelly, C. B.; Patel, N. R.; Molander, G. A.
Aminomethylation of Aryl Halides Using alpha-Silylamines Enabled by
Ni/Photoredox Dual Catalysis. ACS Catal. 2017, 7, 6065−6069.
(15) (a) Tellis, J. C.; Primer, D. N.; Molander, G. A. Single-electron
transmetalation in organoboron cross-coupling by photoredox/nickel
dual catalysis. Science 2014, 345, 433−436. (b) Milligan, J. A.; Phelan, J.
P.; Badir, S. O.; Molander, G. A. Alkyl Carbon-Carbon Bond Formation
by Nickel/Photoredox Cross-Coupling. Angew. Chem., Int. Ed. 2019,
58, 6152−6163. (c) Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans,
R. W.; MacMillan, D. W. C. The merger of transition metal and
photocatalysis. Nat. Rev. Chem. 2017, 1, No. 0052.
(9) For selected examples, see: (a) Maianti, J. P.; McFedries, A.; Foda,
Z. H.; Kleiner, R. E.; Du, X. Q.; Leissring, M. A.; Tang, W. J.; Charron,
M. J.; Seeliger, M. A.; Saghatelian, A.; Liu, D. R. Anti-diabetic activity of
insulin-degrading enzyme inhibitors mediated by multiple hormones.
Nature 2014, 511, 94−98. (b) Ding, Y.; O’Keefe, H.; DeLorey, J. L.;
Israel, D. I.; Messer, J. A.; Chiu, C. H.; Skinner, S. R.; Matico, R. E.;
Murray-Thompson, M. F.; Li, F.; Clark, M. A.; Cuozzo, J. W.; Arico-
Muendel, C.; Morgan, B. A. Discovery of Potent and Selective
Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology
(ELT). ACS Med. Chem. Lett. 2015, 6, 888−893. (c) Samain, F.;
Ekblad, T.; Mikutis, G.; Zhong, N.; Zimmermann, M.; Nauer, A.; Bajic,
D.; Decurtins, W.; Scheuermann, J.; Brown, P. J.; Hall, J.; Graslund, S.;
Schuler, H.; Neri, D.; Franzini, R. M. Tankyrase 1 Inhibitors with Drug-
like Properties Identified by Screening a DNA-Encoded Chemical
Library. J. Med. Chem. 2015, 58, 5143−5149. (d) Li, Y. Z.; De Luca, R.;
Cazzamalli, S.; Pretto, F.; Bajic, D.; Scheuermann, J.; Neri, D. Versatile
protein recognition by the encoded display of multiple chemical
elements on a constant macrocyclic scaffold. Nat. Chem. 2018, 10,
441−448. (e) Cuozzo, J. W.; Centrella, P. A.; Gikunju, D.; Habeshian,
S.; Hupp, C. D.; Keefe, A. D.; Sigel, E. A.; Soutter, H. H.; Thomson, H.
A.; Zhang, Y.; Clark, M. A. Discovery of a Potent BTK Inhibitor with a
Novel Binding Mode by Using Parallel Selections with a DNA-Encoded
Chemical Library (vol 18). ChemBioChem 2017, 18, 2441−2441.
(f) Brown, D. G.; Brown, G. A.; Centrella, P.; Certel, K.; Cooke, R. M.;
Cuozzo, J. W.; Dekker, N.; Dumelin, C. E.; Ferguson, A.; Fiez-Vandal,
C.; Geschwindner, S.; Guie, M. A.; Habeshian, S.; Keefe, A. D.;
Schlenker, O.; Sigel, E. A.; Snijder, A.; Soutter, H. T.; Sundstrom, L.;
Troast, D. M.; Wiggin, G.; Zhang, J.; Zhang, Y.; Clark, M. A. Agonists
and Antagonists of Protease-Activated Receptor 2 Discovered within a
DNA-Encoded Chemical Library Using Mutational Stabilization of the
Target. SLAS Discovery 2018, 23, 429−436. (g) Petersen, L. K.;
Blakskjaer, P.; Chaikuad, A.; Christensen, A. B.; Dietvorst, J.;
Holmkvist, J.; Knapp, S.; Korinek, M.; Larsen, L. K.; Pedersen, A. E.;
Rohm, S.; Slok, F. A.; Hansen, N. J. V. Novel p38 alpha MAP kinase
inhibitors identified from yoctoReactor DNA-encoded small molecule
library. MedChemComm 2016, 7, 1332−1339. (h) Ahn, S.; Kahsai, A.
(16) Brown, D. G.; Bostrom, J. Analysis of Past and Present Synthetic
Methodologies on Medicinal Chemistry: Where Have All the New
Reactions Gone? J. Med. Chem. 2016, 59, 4443−4458.
(17) Schneider, N.; Lowe, D. M.; Sayle, R. A.; Tarselli, M. A.;
Landrum, G. A. Big Data from Pharmaceutical Patents: A Computa-
tional Analysis of Medicinal Chemists’ Bread and Butter. J. Med. Chem.
2016, 59, 4385−4402.
(18) Phelan, J. P.; Lang, S. B.; Sim, J.; Berritt, S.; Peat, A. J.; Billings, K.;
Fan, L. J.; Molander, G. A. Open-Air Alkylation Reactions in
Photoredox-Catalyzed DNA-Encoded Library Synthesis. J. Am. Chem.
Soc. 2019, 141, 3723−3732.
(19) Kolmel, D. K.; Meng, J.; Tsai, M. H.; Que, J. M.; Loach, R. P.;
Knauber, T.; Wan, J. Q.; Flanagan, M. E. On-DNA Decarboxylative
Arylation: Merging Photoredox with Nickel Catalysis in Water. ACS
Comb. Sci. 2019, 21, 588−597.
(20) Everson, D. A.; Weix, D. J. Cross-Electrophile Coupling:
Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79, 4793−
4798.
(21) Mal, D.; Jana, A. K.; Mitra, P.; Ghosh, K. Benzannulation for the
Regiodefined Synthesis of 2-Alkyl/Aryl-1-naphthols: Total Synthesis of
Arnottin I. J. Org. Chem. 2011, 76, 3392−3398.
(22) Gerry, C. J.; Wawer, M. J.; Clemons, P. A.; Schreiber, S. L. DNA
Barcoding a Complete Matrix of Stereoisomeric Small Molecules. J. Am.
Chem. Soc. 2019, 141, 10225−10235.
(23) Qian, Q.; Zang, Z. H.; Wang, S. L.; Chen, Y.; Lin, K. H.; Gong, H.
G. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides (vol 24,
pg 619, 2013). Synlett 2013, 24, 1164−1164.
(24) Cartier, A.; Levernier, E.; Corce, V.; Fukuyama, T.; Dhimane, A.
L.; Ollivier, C.; Ryu, I.; Fensterbank, L. Carbonylation of Alkyl Radicals
Derived from Organosilicates through Visible-Light Photoredox
Catalysis. Angew. Chem., Int. Ed. 2019, 58, 1789−1793.
(25) Duret, G.; Quinlan, R.; Bisseret, P.; Blanchard, N. Boron
chemistry in a new light. Chem. Sci. 2015, 6, 5366−5382.
E
https://dx.doi.org/10.1021/acs.orglett.9b04568
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(26) Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy for
the Visible-Light-Mediated Generation of Alkyl Radicals. Angew. Chem.,
Int. Ed. 2017, 56, 12336−12339.
(27) Discekici, E. H.; Treat, N. J.; Poelma, S. O.; Mattson, K. M.;
Hudson, Z. M.; Luo, Y. D.; Hawker, C. J.; de Alaniz, J. R. A highly
reducing metal-free photoredox catalyst: design and application in
radical dehalogenations. Chem. Commun. 2015, 51, 11705−11708.
(28) Lu, X. J.; Fan, L. J.; Phelps, C. B.; Davie, C. P.; Donahue, C. P.
Ruthenium Promoted On-DNA Ring-Closing Metathesis and Cross-
Metathesis. Bioconjugate Chem. 2017, 28, 1625−1629.
(29) Schreiber, S. L. Target-oriented and diversity-oriented organic
synthesis in drug discovery. Science 2000, 287, 1964−1969.
(30) Bolea, I.; Juarez-Jimenez, J.; de los Rios, C.; Chioua, M.;
Pouplana, R.; Luque, F. J.; Unzeta, M.; Marco-Contelles, J.; Samadi, A.
Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil
and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methyl-
prop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/
Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s
Disease. J. Med. Chem. 2011, 54, 8251−8270.
(31) Kato, N.; Comer, E.; Sakata-Kato, T.; Sharma, A.; Sharma, M.;
Maetani, M.; Bastien, J.; Brancucci, N. M.; Bittker, J. A.; Corey, V.;
Clarke, D.; Derbyshire, E. R.; Dornan, G. L.; Duffy, S.; Eckley, S.; Itoe,
M. A.; Koolen, K. M. J.; Lewis, T. A.; Lui, P. S.; Lukens, A. K.; Lund, E.;
March, S.; Meibalan, E.; Meier, B. C.; McPhail, J. A.; Mitasev, B.; Moss,
E. L.; Sayes, M.; Van Gessel, Y.; Wawer, M. J.; Yoshinaga, T.; Zeeman,
A. M.; Avery, V. M.; Bhatia, S. N.; Burke, J. E.; Catteruccia, F.; Clardy, J.
C.; Clemons, P. A.; Dechering, K. J.; Duvall, J. R.; Foley, M. A.;
Gusovsky, F.; Kocken, C. H. M.; Marti, M.; Morningstar, M. L.; Munoz,
B.; Neafsey, D. E.; Sharma, A.; Winzeler, E. A.; Wirth, D. F.; Scherer, C.
A.; Schreiber, S. L. Diversity-oriented synthesis yields novel multistage
antimalarial inhibitors. Nature 2016, 538, 344−349.
(32) Gerry, C. J.; Wawer, M. J.; Clemons, P. A.; Schreiber, S. L. DNA
Barcoding a Complete Matrix of Stereoisomeric Small Molecules. J. Am.
Chem. Soc. 2019, 141, 10225−10235.
(33) Cao, Z. Y.; Ghosh, T.; Melchiorre, P. Enantioselective radical
conjugate additions driven by a photoactive intramolecular iminium-
ion-based EDA complex. Nat. Commun. 2018, 9, 3274.
(34) Magueur, G.; Crousse, B.; Ourevitch, M.; Bonnet-Delpon, D.;
Begue, J. P. Fluoro-artemisinins: When a gem-difluoroethylene replaces
a carbonyl group. J. Fluorine Chem. 2006, 127, 637−642.
(35) (a) Xiao, T. B.; Li, L. Y.; Zhou, L. Synthesis of Functionalized
gem-Difluoroalkenes via a Photocatalytic Decarboxylative/Defluor-
inative Reaction. J. Org. Chem. 2016, 81, 7908−7916. (b) Lang, S. B.;
Wiles, R. J.; Kelly, C. B.; Molander, G. A. Photoredox Generation of
Carbon-Centered Radicals Enables the Construction of 1,1-Difluor-
oalkene Carbonyl Mimics. Angew. Chem., Int. Ed. 2017, 56, 15073−
15077.
F
https://dx.doi.org/10.1021/acs.orglett.9b04568
Org. Lett. XXXX, XXX, XXX−XXX