Synthesis of C6-Substituted Purine Nucleoside Analogues via Late-Stage Photoredox/Nickel Dual Catalytic Cross-Coupling

Article abstract of DOI:10.1021/acsmedchemlett.0c00673

Nucleoside analogues have been and continue to be extremely important compounds in drug discovery. Despite the significant effort dedicated to their synthesis, medicinal chemistry campaigns around these structures are often hampered by synthetic challenges. We describe a strategy for the functionalization of purine nucleosides via photoredox and nickel-catalyzed sp2-sp3 cross-coupling. The conditions described herein allow for coupling of unprotected nucleosides with readily available alkyl bromides, providing opportunities for their application to parallel medicinal chemistry.

Full text of DOI:10.1021/acsmedchemlett.0c00673

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Technology Note
Synthesis of C6-Substituted Purine Nucleoside Analogues via Late-
Stage Photoredox/Nickel Dual Catalytic Cross-Coupling
James J. Perkins,‡ Valerie W. Shurtleff,‡ Alayna M. Johnson, and Abdellatif El Marrouni*
Cite This: ACS Med. Chem. Lett. 2021, 12, 662−666
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ABSTRACT: Nucleoside analogues have been and continue to be extremely important compounds in drug discovery. Despite the
significant effort dedicated to their synthesis, medicinal chemistry campaigns around these structures are often hampered by
synthetic challenges. We describe a strategy for the functionalization of purine nucleosides via photoredox and nickel-catalyzed sp2−
sp3 cross-coupling. The conditions described herein allow for coupling of unprotected nucleosides with readily available alkyl
bromides, providing opportunities for their application to parallel medicinal chemistry.
KEYWORDS: Purine nucleosides, photoredox, cross-electrophile, late-stage diversification
s the basic building blocks of nucleic acids, nucleosides
Aare of fundamental importance to biological systems and
are recognized as privileged structures in the search for new
drugs. Purine nucleoside analogues represent an important
subset of this class and have found applications in multiple
therapeutic areas including infectious diseases, oncology, and
immunology1 (e.g., aciclovir,2 fludarabine,3 and cladribine,4
respectively; see Figure 1A). Recently, interest in nucleoside
and nucleotide therapeutics has been reinvigorated by the
urgent need for treatments to combat SARS-CoV-2, against
which several of these compounds have shown promising
antiviral activity.5 This fact underscores the importance of
efficient methods to rapidly synthesize new nucleoside drug
candidates to aid the scientific community not only in battling
the current pandemic but also in preparing for the emergence
of new viral diseases in the future. Despite decades of drug
discovery research dedicated to the study of these important
compounds, medicinal chemistry efforts toward such structures
are often hampered by synthetic challenges. Indeed, lengthy
syntheses and the limited number of strategies for incorpo-
ration of novel functionality on either the sugar backbone or
Figure 1. (A) Purine nucleoside/nucleotide analogues as pharma-
the nucleobase can impede the exploration of structure−
activity relationships (SAR) and limit the scope of compounds
that can be prepared for testing.6
ceuticals. (B) Installation of alkyl substituents via multistep syn-
thesis.13 (C) This work: cross-coupling for direct installation of alkyl
groups.
New synthetic methods that allow for the direct installation
of diverse functionality on nucleoside derivatives should
decrease design−make−test cycle time and expand the scope
of chemical space available to medicinal chemists. With this
logic in mind, we focused our attention on the functionaliza-
tion of the purine nucleobase. One of the transformations used
most often for this purpose is nucleophilic aromatic
Received: December 21, 2020
Accepted: February 24, 2021
Published: March 8, 2021
https://dx.doi.org/10.1021/acsmedchemlett.0c00673
© 2021 American Chemical Society
ACS Med. Chem. Lett. 2021, 12, 662−666
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Technology Note
substitution, which can be effective for installation of
heteroatom substituents but is not broadly useful for the
formation of C−C bonds.7,8 Advances in sp2−sp2 cross-
coupling have facilitated the installation of aryl/heteroaryl
groups,9,10 but the installation of alkyl functionality remains
challenging. Common strategies rely on the use of reactive
nucleophiles that may limit functional group compatibility and
reaction scope11,12 or require multiple-step sequences to
convert alkene functionality installed via sp2−sp2 cross-
coupling into an alkyl group13 (Figure 1B). More recently,
radical-based approaches have been applied to the function-
alization of purine nucleosides via the Minisci reaction.14 In
these examples, carboxylic acids serve as radical precursors for
C−H alkylation, with regioselectivity governed by the
electronics and substitution pattern of the heterocycle
substrate.
Table 1. Reaction Conditions for Cross-Electrophile
Coupling
a
b
reaction conditions
as above
yield of 3
53%
47%
38%
4%
4CzlPN as photocatalyst
(TMS)3SiH as reductant
LiOH as base
2,6-lutidine as base
DME as solvent
MeCN as solvent
no nickel catalyst
22%
13%
8%
As an alternative, we envisioned sp2−sp3 cross-coupling of
halogenated nucleosides, which would enable direct and
regiospecific installation of saturated functionality in a single
step. By incorporating alkyl substituents, this transformation
would provide access to novel products with increased sp3
character, which has been correlated with higher success rates
from drug discovery through approval.15 Within this context,
we felt that cross-electrophile coupling would be a particularly
attractive strategy, as it would offer the advantage of drawing
from a large pool of commercially building blocks such as alkyl
bromides, resulting in increased structural diversity of the
newly accessible products. Methods for cross-coupling of aryl
halides and alkyl halides have been published using nickel,16
palladium,17 and cobalt18 catalysts in conjunction with
reducing metals such as zinc or manganese. In addition,
photoredox catalysis and electrochemistry have recently been
combined with nickel catalysis to enable aryl−alkyl cross-
electrophile couplings in the absence of stoichiometric metal
reductants.19,20
With our specific goals in mind, we chose to apply nickel/
photoredox dual catalysis to the direct cross-coupling of 6-
chloropurine with alkyl bromides (Figure 1C). Because of the
mildness of the reaction conditions generally employed in
visible light-mediated dual catalytic cross-couplings, we
expected that this method would be suitable for coupling at
a late stage and should thereby circumvent the need for
challenging multistep syntheses to be carried out in parallel.
We began our investigations by exploring reaction
conditions for sp2−sp3 coupling of nucleoside 1 with alkyl
bromide 2 to provide the alkylated derivative 3. We took our
initial inspiration from the conditions described in the original
report of photoredox and nickel-catalyzed cross-electrophile
coupling from Zhang et al.19a As a light source, we chose an
integrated photoreactor developed to improve ease of use as
well as consistency of illumination.21,22 After modifying a
number of parameters, we were delighted to find conditions
under which the fully unprotected nucleoside 1 could serve as
a suitable substrate for cross-coupling (Table 1). This result
was particularly consequential in light of our goal of designing
a strategy amenable to late-stage diversification. Because
protection of the nucleoside is not required, we envision that
coupling could be carried out as the very last step of a synthesis
using readily available alkyl bromides. As such, a single batch of
the desired nucleoside core could be prepared and then
broadly diversified in a single step without the need for
deprotection of the resulting product library, which might
comprise dozens or even hundreds of compounds.
3%
a
Standard conditions: 0.07 mmol 1, 2 equiv of 2, 2 mol %
photocatalyst, 10 mol % Ni catalyst, 1 equiv of silanol, 3 equiv of
b
1
base, 0.10 M. Determined by HNMR using mesitylene as internal
standard.
Our studies revealed DMF as the optimal solvent and
sodium carbonate as the base of choice. For convenience and
consistency of the ligand-to-metal-ratio, we employed the
preligated complex [Ni(dtbbpy)(H2O)4]Cl2 reported by
Molander and co-workers as our source of nickel.23 In
addition, while we expected that a large excess of the alkyl
halide might provide improved yields, we chose to limit the
loading of this coupling partner to 2 equiv in anticipation of
cases where the reagent might be custom-synthesized and quite
precious. Using the ubiquitous photocatalyst Ir[dF(CF3)-
ppy]2(dtbbpy)PF6 and tris(trimethylsilyl)silane, a promising
38% NMR yield of the desired product was observed. During
the course of the reaction, deleterious debromination side
products resulting from the reduction of 2 were often
observed. Replacing tris(trimethylsilyl)silane with the increas-
ingly common reagent tris(trimethylsilyl)silanol24 suppressed
this unproductive pathway and increased the observed assay
yield to 53%. We were also pleased to find that the organic
photocatalyst 4CzIPN provided comparable yields to the
optimal iridium catalyst. However, subsequent time studies
indicated that the rate of reaction using 4CzIPN was
significantly lower, and we therefore chose to proceed with
Ir[dF(CF3)ppy]2(dtbbpy)PF6 for further investigation.
During the course of our studies, we recognized the
potential for this reaction to proceed through a homolytic
aromatic substitution mechanism instead of the dual-catalytic
cross-coupling pathway originally proposed by MacMillan and
co-workers,19a given that direct radical substitution reactions
are known for related heterocyclic substrates.25 The dual-
catalytic mechanism would require nickel to undergo oxidative
addition and reductive elimination steps in order to effect the
desired coupling. By contrast, homolytic aromatic substitution
would proceed through direct addition of an alkyl radical to
the aryl chloride, followed by single-electron reduction and
elimination steps to provide the desired product. No nickel
catalyst would be required for the latter reaction pathway to
proceed. In order to test whether a direct-addition mechanism
might be operative, we performed a reaction under the newly
defined standard reaction conditions, but omitted the nickel
663
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ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Technology Note
a b
,
Table 2. Alkyl Bromide Scope in Cross-Electrophile Coupling of Chloropurines
a
Standard conditions: 0.17 mmol 1, 2 equiv of alkyl bromide, 2 mol % lr[dF(CF3)ppy]2(dtbbpy)PF6, 10 mol % [Ni(dtbbpy)(H2O)4]CI2, 1 equiv
b
c
of (TMS)3SiOH, 3 equiv of Na2CO3, DMF (0.10 M). Isolated yields. For alkyl bromides with the potential to form new diastereomers after
coupling, one major diastereomer was isolated, sometimes containing a small amount of the minor diastereomer.
catalyst. Under these conditions, trace amounts of product
were observed (3% NMR yield), suggesting that a direct
homolytic aromatic substitution mechanism is unlikely to
contribute significantly to the overall reaction pathway.
Having determined useful reaction conditions, we began to
explore the scope of nucleoside functionalization with respect
to the alkyl coupling partner (Table 2). Upon isolation, we
were pleased to find that the model substrate 2 coupled as
expected based on our screening experiments, providing 59%
yield of the desired product 3. Encouraged by this result, we
tested a number of other secondary alkyl bromides. Simple
cycloalkanes furnished nucleosides functionalized with rings of
various sizes (4, 5, and 8, 37−54% yield). Products 5 and 8
have demonstrated substrate activity with E. coli purine
nucleoside phosphorylase, suggesting the potential utility of
additional analogues.11 The coupling of additional function-
alized cyclic bromides provided good to excellent yields under
the standard reaction conditions (6, 7, and 9, 53−96% yield).
We were especially pleased with the 53% yield achieved for 9
resulting from the coupling of 3-bromocyclobutanol, which not
only incorporates a strained ring but also another free alcohol.
In addition, we found that the sterically encumbered 2-
bromoadamantane could be employed to incorporate an
adamantyl group in a moderate but useful 30% yield (10),
providing straightforward access to a motif that is known to be
valuable in drug design.26
bromides were well-tolerated and allow for the incorporation
of polarity in varying positions (3, 6, 9, 11, 13, and 15−17).
Bromides bearing fluorinated alkyl substituents were also
readily coupled and can be useful for modulating lipophilicity,
building new interactions, and/or blocking metabolism (7, 12,
and 14).27 In addition, compounds incorporating free or
masked reactivity provide opportunities for further function-
alization through handles including amines, alcohols, carbox-
ylic acids, and phosphonates (3, 9, 11, 16, and 17).
In conclusion, we have demonstrated a strategy for the
synthesis of C6-alkylated purine analogues via photoredox and
nickel-catalyzed sp2−sp3 cross-electrophile coupling. The
application of this dual catalytic method allows for the direct
coupling of chloropurine with a wide range of readily available
primary and secondary alkyl bromides. Importantly, under the
optimized reaction conditions, unprotected nucleosides can be
functionalized efficiently, such that diversification can be
carried out at the final stage of synthesis if desired. Given
this fact and the large starting material pool offered by alkyl
bromides as coupling partners, we expect that this strategy will
facilitate SAR exploration in drug discovery and should find
particular utility in parallel medicinal chemistry efforts.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00673.
Primary alkyl halides were generally very good substrates for
alkylation of chloropurine 1 (12−16, 50−90% yield). Within
this class, we were delighted to find that even the potentially
sensitive bromomethyl acetate was a competent substrate,
yielding acetoxymethyl nucleoside 17 in 37% yield. In contrast
to their primary and secondary counterparts, tertiary alkyl
bromides provided messy reactions and only traces of the
desired products. Nonetheless, these conditions provide
straightforward access to a diverse array of products bearing
a range of functionality. Oxygen- and nitrogen-containing alkyl
General procedures for cross-coupling, 1H and 13C
NMR spectra, and other characterization data for all
compounds prepared (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Abdellatif El Marrouni − Merck & Co., Inc., West Point,
Pennsylvania 19486, United States; orcid.org/0000-
664
https://dx.doi.org/10.1021/acsmedchemlett.0c00673
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ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Technology Note
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M.; Zhou, B.; Yen, Y.; Grifantini, M. Synthesis and biological activity
of novel N6-substituted and 2,N6-disubstituted adenine ribo- and 3′-
C-methyl-ribonucleosides as antitumor agents. Eur. J. Med. Chem.
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Safarjalani, O. N.; Naguib, F. N.M.; el Kouni, M. H. Synthesis,
biological evaluation and molecular modeling studies of N6-
benzyladenosine analogues as potential anti-toxoplasma agents.
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Org. Biomol. Chem. 2011, 9, 2065. (b) Qu, G.-R.; Mao, Z.-J.; Niu, H.-
Y.; Wang, D.-C.; Xia, C.; Guo, H.-M. Straightforward and Highly
Efficient Catalyst-Free One-Step Synthesis of 2-(Purin-6-yl)-
acetoacetic Acid Ethyl Esters, (Purin-6-yl)acetates, and 6-Methyl-
purines through SNAr-Based Reactions of 6-Halopurines with Ethyl
Acetoacetate. Org. Lett. 2009, 11, 1745.
0001-5408-0374; Email: abdellatif.el.marrouni@
merck.com
Authors
James J. Perkins − Merck & Co., Inc., West Point,
Pennsylvania 19486, United States
Valerie W. Shurtleff − Merck & Co., Inc., West Point,
Pennsylvania 19486, United States
Alayna M. Johnson − Merck & Co., Inc., West Point,
Pennsylvania 19486, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00673
Author Contributions
‡J.J.P. and V.W.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors would like to thank Michael D. VanHeyst for
helpful discussions during the course of our investigations. We
would also like to acknowledge Anthony Soares for his
assistance in obtaining HRMS data for all compounds. In
addition, we would like to thank Antonella Converso and Min
Lu for reviewing this manuscript.
ABBREVIATIONS
■
DMF, N,N-dimethylformamide; DME, 1,2-dimethoxyethane;
LED, light-emitting diode; 4CzIPN, 2,4,5,6-tetra(9H-carbazol-
9-yl)isophthalonitrile
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