A tractable and efficient one-pot synthesis of 5′-azido-5′- deoxyribonucleosides

Article abstract of DOI:10.3390/molecules19022434

Synthetic routes to 5′-azidoribonucleosides are reported for adenosine, cytidine, guanosine, and uridine, resulting in a widely applicable one-pot methodology for the synthesis of these and related compounds. The target compounds are appropriate as precursors in a variety of purposive syntheses, as the synthetic and therapeutic relevance of azido- and amino-modified nucleosides is expansive. Furthermore, in the conversion of alcohols to azides, these methods offer a tractable alternative to the Mitsunobu and other more difficult reactions.

Full text of DOI:10.3390/molecules19022434

Molecules 2014, 19, 2434-2444; doi:10.3390/molecules19022434
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Tractable and Efficient One-Pot Synthesis of
5'-Azido-5'-deoxyribonucleosides
Theodore V. Peterson, Tobin U. B. Streamland and Ahmed M. Awad *
Chemistry Program, California State University Channel Islands, One University Drive, Camarillo,
CA 93012, USA; E-Mails: peterson.tv@gmail.com (T.V.P.); tobin.streamland@gmail.com (T.U.B.S.)
* Author to whom correspondence should be addressed; E-Mail: ahmed.awad@csuci.edu;
Tel.: +1-805-437-2794; Fax: +1-805-437-8895.
Received: 11 September 2013; in revised form: 11 February 2014 / Accepted: 12 February 2014 /
Published: 21 February 2014
Abstract: Synthetic routes to 5'-azidoribonucleosides are reported for adenosine, cytidine,
guanosine, and uridine, resulting in a widely applicable one-pot methodology for the
synthesis of these and related compounds. The target compounds are appropriate as
precursors in a variety of purposive syntheses, as the synthetic and therapeutic relevance of
azido- and amino-modified nucleosides is expansive. Furthermore, in the conversion of
alcohols to azides, these methods offer a tractable alternative to the Mitsunobu and other
more difficult reactions.
Keywords: modified nucleosides; 5'-azido nucleosides; Appel reaction; Mitsunobu
reaction; antisense oligonucleotides; ribonucleic guanidine (RNG)
1. Introduction
The synthesis and chemical modification of nucleosides is a major research topic in medicinal and
bioorganic chemistry. The vast utilization of nucleosides in most aspects of cellular function makes
them a tantalizing target for a variety of therapies with potentially wide ranging physiological and
pharmacological effects [1–4]. The molecular binding of nucleotide oligomers to highly specific
targets as well as more heterogeneous binding has been shown to rival the affinity exhibited by
antibodies both in vitro and in vivo [1,5–7]. This strong binding affinity and the generally low level of
immunogenicity observed with nucleotide therapeutics uniquely position them to move quickly from
the research bench to clinical applications [3,8]. The use of modified nucleosides as enzyme inhibitors,

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diagnostic reporters, and as anticancer or antiviral drugs is well documented in the literature [3,4,9–11],
illustrating the extensive utility of these molecules. As the discovery of pharmacological targets
increases the demand for synthetic analogs of nucleic acid monomers and oligomers, efficient
reactions with wide-ranging biological applicability will be emphasized.
The azide functional group is among the most useful in organic synthesis, owing to its superlative
reactivity. A great body of work has been done on azidonucleotides in particular, and although their
bioactivity has been found to be negligible in many instances, they remain an important intermediate in
a variety of purposive syntheses [12]. Nucleosides substituted with azide moieties are uniquely suited
to combinable applications in click chemistry [13–17] and bio-conjugation (e.g., Staudinger
ligation [18–21]) due to their reactivity and stability under physiological conditions. Furthermore, in
conjugation reactions, azides confer a measure of kinetic control that overcomes the inability to control
carbonyl chemistry with the efficiency nature exhibits [22]. In addition to these combinatorial
applications and their fundamental use in the synthesis of heterocyclic compounds, azides are perhaps
the most convenient source of naturally and pharmacologically pervasive amines [23–25].
Most contemporary alcohol to azide syntheses rely on two-step protocols proceeding through a
halogenated intermediate, Mitsunobu-type displacement reactions, or other tenuous methodologies
employing toxic, complex and/or expensive reagents [26–28]. However, the Appel reaction remains a
simple reliable way to convert alcohols into to alkyl halides, and further substitution of this product by
an azide salt produces azides in suitable yields. It has previously been reported that these two
reactions can be combined affording azides from primary and secondary alcohols in one convenient
synthesis [28,29]. Because Staudinger reduction of the resulting azide to a primary amine is a
pervasive synthetic fate of azides, further reports have surfaced of a one-pot synthesis of amines
directly from both primary and secondary alcohols, utilizing an Appel-Staudinger combinational
approach [30]. The utility of a direct alcohol to amine conversion has spurned other approaches with
equivalent goals [31,32]. However except for a few examples [28,29,33–35], research focusing on
nucleic acids has largely ignored these routes to azides and amines, with syntheses proceeding through
a Mitsunobu-type reaction seeming to be the preferred route. In reports utilizing azide addition as
described by Hata, Yamamoto, and Sekine [36], application of the method resulted in low or
unreported yields of modified nucleosides, with application to guanosine conspicuously absent. In
contrast, we report in the present study a highly efficient one-pot synthetic approach to produce both
purine and pyrimidine 5'-azido ribonucleosides. Our one-pot synthetic route relies on readily available
compounds and mild reaction conditions, allowing synthesis of azide-substituted nucleosides in
suitable yields for follow-on syntheses without the reliance on Mitsunobu and its previously
mentioned issues.
2. Results and Discussion
Protected ribonucleosides utilized as starting material were synthesized in two steps, except for
uridine. Adenosine, cytidine and guanosine first require protection of the exo-cyclic amine moieties
found in their respective nitrogenous bases prior to selective substitution of the 5'-hydroxyl group.
Subsequent protection of the 2' and 3' hydroxyl groups of each nucleoside to produce starting material
compounds 1–4 (Figure 1) was performed in anhydrous acetone with 2,2-dimethoxypropane in the

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presence of an acid catalyst. The reaction mixture was refluxed until complete disappearance of the
starting material, as monitored by TLC. While analogs of adenosine, guanosine and cytidine required
significant times at reflux temperature, the yield of 4 was higher when reacted at room temperature.
Nearly pure products of 2 and 3 were obtained after a bicarbonate wash and evaporation of the reaction
mixture, however in the case of 1 and 4, flash column chromatography was required for final purification.
Figure 1. Ribonucleosides analogs used for the one-pot synthesis of 5'-azido nucleosides.
1
2
3
4
Initially we were interested in the direct synthesis of 5'-amino substituted nucleosides via a one-pot
combined Appel-Staudinger mechanism, but modeling our approach on work done with other
alcohols [30,32] did not produce the desired nucleoside product in easily recoverable yields.
Elemental analysis by ESI mass spectrometry indicated that our initial approach produced a 5'-chloro
nucleoside, the expected Appel product (Scheme 1).
Scheme 1. Appel reaction product: 5'-chloro-2',3'-O-isopropylideneguanosine.
Heating the protected nucleosides with CBr4 as a halide source in the presence of triphenylphosphine
and an excess of NaN3 favored the formation of 5'-azidonucleosides in high yields (Scheme 2).
Staudinger reduction of azides requires excess triphenylphosphine to form the iminophosphorane
intermediate (Scheme 3), which is then hydrolyzed to form the corresponding amino derivative.
However, using excess PPh3 did not produce the 5'-aminonucleoside. As noted by Hata et al. and
observed in our syntheses, excess PPh3 or alkyl halide concentration results in a mixture of products
and a more difficult extraction [29]. Reducing the molar contribution of PPh3 in this one-pot synthesis
ensures that: (i) after creation of the initial Appel product and subsequent substitution by azide, no
PPh3 remains to form the said intermediate; and (ii) product recovery is significantly improved due to a

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reduction in the amount of phosphonium oxide by-product formed. Applying this reduced-reagent one-
pot technique to the protected starting material generated from adenosine, guanosine, cytidine, and
uridine afforded 5'-azido-5'-deoxyribonucleosides in high yields for application as intermediates and
precursors in a variety of nucleoside syntheses.
Scheme 2. General synthesis of 5'-azido ribonucleosides.
Reagents and conditions: Protected nucleosides in anhydrous DMF, PPh3, CBr4, NaN3, heat at 90 °C.
Scheme 3. Reduction of azides to amines by Staudinger reaction.
PPh3
N
N
PPh3
N
Ph
Ph
Ph
Base
Base
Base
N
N
N
N N N
P
O
O
O
OH OH
OH OH
OH OH
- N2
Base
Base
Base
H2N
Ph3P
N
Ph3P
N
O
O
O
H2O
OH OH
OH OH
OH OH
Our interest in 5'-azido- and 5'-aminonucleoside analogs stems primarily from their application as
precursors in the synthesis of positively charged guanidine-linked ribooligonucleotides (RNG in
Figure 2a) and P3'→N5' phosphoramidate ribonucleotides (Figure 2b). We have previously
reported synthetic routes to 3' and 5'-terminal monomers of cytidine and uridine required for these
applications [37,38]. Notably, synthesis of the 3'-terminal monomer utilized the Mitsunobu reaction to
facilitate the eventual amination of the 5' moiety. However, adaptation of this method in related
syntheses for guanosine proved largely ineffective. Of the four most common nucleobases found in
RNA, guanine has been acknowledged to increase experimental problems. In our experience, this

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character is further exasperated in Mitsunobu-type reactions, in which there is substantial potential for
reaction interference. To avoid this in the present study, we decided to explore alternatives and
abandon the Mitsunobu approach for all nucleosides included here.
Figure 2. (a) Ribonucleic guanidine (RNG); (b) P3'→N5' phophoramidate RNA.
Base
HN
O
NH OH
H2N
Base
HN
O
OH OH
(a)
(b)
One pot reactions were instead prepared from 1–4 in the minimum amount of anhydrous DMF and
then allowed to react with PPh3, CBr4, and NaN3 added in order, allowing the previous reactant to
completely dissolve before proceeding to the next. The reaction mixtures were stirred for 10 min at
room temperature then stirred overnight at 90 °C. The products were purified by column chromatography
to afford 5'-azidonucleotides 5–8 in excellent yields (81%–90%). Protection of the 2' and 3' hydroxyl
groups seems to be vindicated as our one-pot yields exceeded those reported by Hata et al. [29] for two
of the three bases our syntheses shared (Table 1).
Table 1. 5'-Azidonucleoside synthesis from base-protected nucleosides of A, G, C and U:
comparison of synthetic approaches.
Overall yield
(One-pot Yield)
74.0% (86%)
68.0% (81%)
77.3% (85%)
79.2% (90%)
Hata et al. yields
Nucleoside
Synthetic Path
(One step rxn.)
N6-Benzoyladenosine
N2-Isobutyrylguanosine
N4-Benzoylcytidine
Uridine
1→5
2→6
3→7
4→8
56%
N/A
45%
92%
Although guanidinium linkages are of primary focus within our lab, further modification may
reveal synthetic nucleoside analogues with the ability to treat or aid immune system response, whether
through anti-viral or therapeutic methods. Nucleosides were of primary focus only several decades
ago, and with advances in methodology and technology, therapeutic nucleosides will again move into
the spotlight as agents of vast clinical potential.

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3. Experimental
General Procedures
1H-NMR spectra were recorded on a 500 MHz Varian instrument, using CDCl3 or DMSO-d6 as
solvents. Chemical shifts were reported in δ ppm and coupling constants (J) are given in Hz. Thin-
layer chromatography (TLC) was carried out on Silica Gel 60 F-254 pre-coated plates (Selecto
Scientific, Suwanee, GA, USA and EMD Millipore, Merck KGaA, Darmstadt, Germany) and
visualization of the products was performed under UV light. Silica gel used for flash column
chromatography was Scientific Silica Gel (particle size 32–63, Selecto Scientific and/or particle size
38–63, Whatman International, Maidstone, Kent, UK). ESI mass spectra were recorded on QSTAR
Pulsar Quadrupole/time-of-flight mass spectrometer with Turbo Ion Spray Ionization Source (Applied
Biosystems, Foster City, CA, USA). All reactions were performed using anhydrous solvents under N2
atmosphere. All flash column chromatography performed used 3:1 ethyl acetate to hexanes for
product isolation.
N6-Benzoyl-2',3'-O-isopropylideneadenosine (1). To a stirred solution of N6-benzoyladenosine (5.60 g,
15 mmol) in anhydrous acetone (100 mL) was added 2,2-dimethoxypropane (16.6 mL, 135 mmol) and
p-toluenesulfonic acid monohydrate (0.15 g, 0.75 mmol). The reaction mixture was refluxed for 18 h,
then filtered to remove any unreacted starting material. The filtrate was concentrated under vacuum
and the residue was dissolved in EtOAc, washed with 5% NaHCO3, brine, and dried over sodium
sulfate anhydrous. The solvent was removed under reduced pressure and the solid product was washed
with diethyl ether to remove any residual 2,2-dimethoxypropane then filtered. The product was further
purified by silica gel column chromatography (3:1 EtOAc to hexanes) to afford pure compound 1 (5.31 g,
86%). HRMS (ESI) m/z calcd. for C20H21N5O5 (M+Na)+ 434.1440, found 434.1441. NMR (DMSO-d6):
11.38 br s, 1H (NH); 8.91 s, 1H (H-8); 8.81 s, 1H (H-2); 8.18-7.67 m, 5H (H-Bz); 6.40 d, 1H, J = 11.8
(H-1'); 5.56 q, 1H, J = 8.3 (H-2'); 5.28 br s, 1H (OH-5'); 5.13 t, 1H, J = 5.9 (H-3'); 4.18 q, 1H, J = 6.3
(H-4'); 3.69–3.67 m, 2H (H-5'); 1.63 s, 3H (CH3); 1.25 s, 3H (CH3).
N2-Isobutyryl-2',3'-O-isopropylideneguanosine (2). To a stirred solution of N2-isobutyrylguanosine
(5.30 g, 15 mmol) in anhydrous acetone (100 mL) was added 2,2-dimethoxypropane (16.6 mL, 135 mmol)
and p-toluenesulfonic acid monohydrate (0.15 g, 0.75 mmol). The reaction mixture was refluxed for 18 h.
The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc, washed
with 5% NaHCO3, brine, and dried over sodium sulfate anhydrous. The solvent was removed under
vacuum, and the residue was stirred for five minutes in ether then filtered to afford pure compound 2
1
(4.96 g, 84%). H-NMR (DMSO-d6): 12.10 s, 1H (NH); 11.54 s, 1H (NH); 7.83 s, 1H (H-8); 5.84 d,
1H, J = 2.8, (H-1'); 5.11 m, 1H (H-2'); 5.04 m, 1H (H-3'); 4.44 q, 1H, J = 3.9 (H-4'); 3.99–3.78 m, 2H,
(H-5'); 2.78-2.76 m, 1H (CH); 1.62 s, 3H (CH3); 1.37 s, 3H (CH3); 1.28 d, 6H, J = 6.8 (C(CH3)2).
N4-Benzoyl-2',3'-O-isopropylidenecytidine (3). To a stirred suspension of N4-benzoylcytidine (5.20 g,
15 mmol) in anhydrous acetone (100 mL), p-toluenesulfonic acid monohydrate (0.15 g, 0.75 mmol)
and 2-2-dimethyoxypropane (13.85 mL, 112.5 mmol) were added and the reaction mixture was
refluxed overnight under N2 atmosphere. To remove the unreacted starting material, the mixture was

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filtered through Celite, which was then washed with acetone and methylene chloride. The filtrate was
concentrated under vacuum and the residue was dissolved in EtOAc, washed with 5% NaHCO3, brine,
and dried over sodium sulfate anhydrous. The solvent was removed under reduced pressure, and the
residue was stirred for five minutes in ether then filtered to afford pure compound 3 (5.29 g, 91%).
1H- NMR (DMSO-d6): 11.22 br s, 1H (NH); 8.29 d, 1H, J = 7.8 (H-6); 8.00-7.51 m, 5H (BzH); 7.32 d,
1H, J = 7.2 (H-5); 5.85 d, 1H, J = 2.0 (H-1'); 5.12 t, 1H, J = 5.4 (OH-5'); 4.90 dd, 1H, J = 4.0, 1.9
(H-2'); 4.76 q, 1H, J = 3.4 (H-3'); 4.21 q, 1H, J = 3.5 (H-4'); 3.64-3.55 m, 2H (H-5'); 1.48 s, 3H (CH3);
1.28 s, 3H (CH3).
2',3'-O-Isopropylideneuridine (4). To a stirred solution of uridine (3.65 g, 15 mmol) in anhydrous
acetone (100 mL) was added 2,2-dimethoxypropane (10.05 mL, 82 mmol) and p-toluenesulfonic acid
monohydrate (0.15 g, 0.75 mmol). The reaction mixture was stirred overnight at room temperature.
The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc, washed
with 5% NaHCO3, brine, and dried over sodium sulfate anhydrous. The solvent was removed under
vacuum, and the crude was purified by silica gel column chromatography (3:1 ratio of EtOAc to
1
hexanes) to afford compound 4 (3.75 g, 88%). H-NMR (DMSO-d6): 11.36 s 1H, (NH); 7.78 d, 1H,
J = 8.3 (H-6); 5.81 d, 1H, J = 2.5 (H-1'); 5.62 d, 1H, J = 7.9 (H-5); 5.08 t, 1H, J = 5.4 (OH-5'); 4.88 q,
1H, J = 2.4 (H-2'); 4.73 q, 1H, J = 3.9 (H-3'); 4.06 q, 1H, J = 4.4 (H-4'); 3.57–3.52 m, 2H (H-5'); 1.46
s, 3H (CH3); 1.27 s, 3H (CH3).
5'-Azido-N6-benzoyl-2',3'-O-isopropylidene-5'-deoxyadenosine (5). To a stirred solution of compound 1
(4.00 g, 10 mmol) in anhydrous DMF (30 mL) was added PPh3 (3.95 g, 15 mmol) and CBr4 (6.00 g,
18 mmol). The mixture was stirred under N2 at room temperature for 5 min, then excess NaN3 (2.95 g,
45 mmol) was added. The reaction mixture was heated under N2 at 90 °C for 24 h. The reaction was
quenched by addition of H2O (10 mL). After stirring for 5 min, the mixture was diluted with EtOAc
(20 mL), washed with 5% NaHCO3, brine, and the organic layer was collected and dried over sodium
sulfate anhydrous. The solvent was removed under reduced pressure and the crude product was
purified by silica gel column chromatography (3:1 ratio of EtOAc to hexanes) to afford white solid of
compound 5 (3.75 g, 86%). HRMS (ESI) m/z calcd. for C20H20N8O4 (M+Na)+ 459.1505, found
1
459.1490. H-NMR (CDCl3): 10.75 br s, 1H (NH); 8.99 s, 1H (H-8); 8.84 s, 1H (H-2); 8.16–7.26 m,
5H (H-Bz); 6.29 d, 1H, J = 11.8 (H-1'); 5.46 m, 1H (H-2'); 5.07 m, 1H (H-3'); 4.41 br s, 1H (OH-5');
4.13 q, 1H, J = 6.9 (H-4'); 3.60 m, 2H (H-5'); 1.60 s, 3H (CH3); 1.25 s, 3H (CH3).
5'-Azido-N2-isobutyryl-2',3'-O-isopropylidene-5'-deoxyguanosine (6). To a stirred solution of
compound 2 (3.95g, 10 mmol) in anhydrous DMF (30 mL) was added PPh3 (3.95 g, 15 mmol) and
CBr4 (6.00 g, 18 mmol). The mixture was stirred under N2 at room temperature for 5 min, then excess
NaN3 (2.95 g, 45 mmol) was added. The reaction mixture was heated under N2 at 90 °C for 24 h. The
reaction was quenched by addition of H2O (10 mL). After stirring for 5 min, the mixture was diluted
with EtOAc (20 mL), washed with 5% NaHCO3, brine, and the organic layer was collected and dried
over sodium sulfate anhydrous. The solvent was removed under reduced pressure and the crude
product was purified by silica gel column chromatography (3:1 ratio of EtOAc to hexanes) to afford a
pale yellow solid of compound 6 (3.39 g, 81%). HRMS (ESI) m/z calcd. for C17H22N8O5 (M+Na)+

Molecules 2014, 19
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441.1611, found 441.1591. 1H-NMR (CDCl3): 12.02 s, 1H (NH); 7.83 s, 1H (H-8); 5.99 d, 1H, J = 2.9
(H-1'); 5.15 q, 1H, J = 2.9 (H-2'); 4.94 q, 1H, J = 3.9 (H-3'); 4.35 q, 1H, J = 4.4 (H-4'); 3.65–3.51 m,
2H, (H-5'); 2.62-2.58 m, 1H (CH); 1.62 s, 3H (CH3); 1.39 s, 3H (CH3); 1.29 d, 6H, J = 6.8 (C(CH3)2).
5'-Azido-N4-benzoyl-2',3'-O-isopropylidene-5'-deoxycytidine (7). To a stirred solution of compound 3
(3.90g, 10 mmol) in anhydrous DMF (30 mL) was added PPh3 (3.15 g, 12 mmol) and CBr4 (6.00 g,
18 mmol). The mixture was stirred under N2 at room temperature for 5 min, then excess NaN3 (2.95 g,
45 mmol) was added. The reaction mixture was heated under N2 at 90 °C for 24 h. The reaction was
quenched by addition of H2O (10 mL). After stirring for 5 min, the mixture was diluted with EtOAc
(20 mL), washed with 5% NaHCO3, brine, and the organic layer was collected and dried over sodium
sulfate anhydrous. The solvent was removed under reduced pressure and the crude product was
purified by silica gel column chromatography (3:1 ratio of EtOAc to hexanes) to afford compound 7
(3.51 g, 85%). HRMS (ESI) m/z calcd. for C19H20N6O5 (M+Na)+ 435.1393, found 435.1375. 1H-NMR
(CDCl3): 7.91 d, 1H, J = 7.3 (H-6); 7.63-7.51 m, 5H (BzH); 7.32 d, 1H, J = 7.2 (H-5); 5.70 d, 1H,
J = 1.6 (H-1'); 4.91 dd, 1H, J = 4.4, 3.9 (H-2'); 4.34 m, 1H (H-3'); 4.14 q, 1H, J = 6.8 (H-4'); 3.77–3.63 m,
2H (H-5'); 1.58 s, 3H (CH3); 1.36 s, 3H (CH3).
5'-Azido-2',3'-O-isopropylidene-5'-deoxyuridine (8). To a stirred solution of compound 4 (2.85 g, 10 mmol)
in anhydrous DMF (30 mL) was added PPh3 (3.15 g, 12 mmol) and CBr4 (6.00 g, 18 mmol). The
mixture was stirred under N2 at room temperature for 5 min, then excess NaN3 (2.95 g, 45 mmol) was
added. The reaction mixture was heated under N2 at 90 °C for 24 h. The reaction was quenched by
addition of H2O (10 mL). After stirring for 5 min, the mixture was diluted with EtOAc (20 mL),
washed with 5% NaHCO3, brine, and the organic layer was collected and dried over sodium sulfate
anhydrous. The solvent was removed under reduced pressure and the crude product was purified by
silica gel column chromatography (3:1 ratio of EtOAc to hexanes) to afford a white solid of compound 8
(2.78 g, 90%). HRMS (ESI) m/z calcd. for C12H15N5O5 (M+Na)+ 332.0971, found 332.0972. 1H-NMR
(CDCl3): 9.30 s 1H, (NH); 7.30 d, 1H, J = 7.9 (H-6); 5.91 d, 1H (H-1'); 5.78 d, 1H, J = 7.8 (H-5); 5.00
d, 1H, J = 6.4 (H-2'); 4.82 t, 1H, J = 3.9 (H-3'); 4.24 q, 1H, J = 4.9 (H-4'); 4.13–3.62 m, 2H (H-5');
1.56 s, 3H (CH3); 1.35 s, 3H (CH3).
4. Conclusions
We have confirmed the synthesis of 5'-azido-5'-deoxyribonucleosides of the bases adenine, guanine,
cytosine, and uracil by means of 1H-NMR and high resolution mass spectrometry. Owing to the unique
chemical characteristics of the azide functional group, these molecules have the potential to be used in
applications even more diverse than their contemporary use. In particular, these molecules are
available for solid-phase synthesis of ribonucleic acids with guanadium linkages.
Acknowledgments
Funding was provided by the Chemistry Program at CSU Channel Islands. Special thanks to James
Pavlovich at University of California Santa Barbara and Scott Duffer at CSU Channel Islands for
assistance in obtaining spectral data.

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Author Contributions
Theodore V. Peterson assisted in the preparation of starting material and target compounds,
prepared the manuscript, and performed necessary revisions during review. Tobin U.B. Streamland
performed synthesis and final purification of target compounds. Ahmed M. Awad provided the initial
experimental design and invaluable scientific advice and synthetic insight. All authors helped in
characterization of synthesized molecules and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of all compounds are available from the authors.
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