Triazine-Based Janus G-C Nucleobase as a Building Block for Self-Assembly, Peptide Nucleic Acids, and Smart Polymers

Article abstract of DOI:10.1021/acs.joc.0c02530

This communication reports on the utility of a triazine-based self-assembling system, reminiscent of a Janus G-C nucleobase, as a building block for developing (1) supramolecular polymers, (2) peptide nucleic acids (PNAs), and (3) smart polymers. The strategically positioned self-complementary triple H-bonding arrays DDA and AAD facilitate efficient self-assembly, leading to a linear supramolecular polymer.

Full text of DOI:10.1021/acs.joc.0c02530

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Article
Triazine-Based Janus G−C Nucleobase as a Building Block for Self-
Assembly, Peptide Nucleic Acids, and Smart Polymers
Chhuttan L. Meena, Dharmendra Singh, Bhavya Kizhakeetil, Manasa Prasad, Malini George,
Srinu Tothadi, and Gangadhar J. Sanjayan*
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ABSTRACT: This communication reports on the utility of a
triazine-based self-assembling system, reminiscent of a Janus G−C
nucleobase, as a building block for developing (1) supramolecular
polymers, (2) peptide nucleic acids (PNAs), and (3) smart
polymers. The strategically positioned self-complementary triple
H-bonding arrays DDA and AAD facilitate efficient self-assembly,
leading to a linear supramolecular polymer.
INTRODUCTION
■
Molecular self-assembly has ushered into prominence as a
powerful strategy to construct complex nanostructures with
innovative applications in diverse areas such as chemical
synthesis,1,2 polymer science,3 nanotechnology,4 smart materi-
als,5 and tissue engineering.6 De novo designed self-assembling
systems have been proven to be useful for developing
functional polymers, supramolecular hydrogels, and strong
adhesives7 with a range of attractive mechanical characteristics
suitable for medical applications and fabricating advanced
materials.8,9 By virtue of their structural similarity with
nucleobases,10 synthetic self-assembling systems have also
found application in developing novel peptide nucleic acids
(PNAs)a class of nucleic acid mimics made of a
pseudopeptide backbone with excellent recognition-specificity.11
Of particular interest is the use of self-assembling motifs
featuring multiple H-bonding arrays within the molecule as
bifacial nucleobases (also called as “Janus bases”) to target
double-stranded DNA or RNA by engaging both strands at
once.12 Inspired by the nucleic acid base pairing, chemists have
over the years developed a myriad of self-assembling molecules
with diverse H-bonding characteristics.13 GC hybrid molecules
that are capable of forming intriguing rosette structures14a,b
and linear supramolecular polymer networks14c,d have also
been reported. One of the extensively studied self-assembling
motifs that instantaneously forms supramolecular polymers is
the melamine-cyanuric/barbituric acid complementary dual
motif (MA-CA/BA) (Figure 1, top).15
Figure 1. Complementary assembly of barbituric/cyanuric acid-
melamine dual motif (top; reported15,16) and self-complementary self-
assembly driven supramolecular polymerization of triazine-based
Janus G−C nucleobase (bottom; this work).
Received: October 24, 2020
Published: February 1, 2021
Depending upon the substitution pattern on melamine, MA-
CA/BA assembly can give rise to three different types of
aggregates: the cyclic rosettes (finite), linear tapes (infinite),
and crinkled tapes (infinite).16 However, it should be
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emphasized that the multiple possibilities of self-assembly
pathways will be detrimental to applications particularly when
formation of a mixture of polymeric aggregates is not desired.17
Furthermore, the need to maintain an equimolar proportion of
the complementary self-assembling components for effecting
self-assembly further adds to the practical difficulties.18
Scheme 2. Synthesis of a Triazine-Based Janus G−C
a
Nucleobase Containing PNA Building Blocks
In this context, use of self-complementary self-assembling
motifs capable of instant supramolecular polymerization but
devoid of multiple assembly pathways could be of considerable
advantage for practical applications. Herein, we disclose the
self-assembling characteristics of a Janus G−C-base nucleic
acid motif, capable of efficient self-assembly leading
“exclusively” to a single set of linear supramolecular
polymerwithout any possibilities of multiple pathways of
self-assembly and thus avoiding the formation of a mixture of
supramolecular polymers (Figure 1, vide supra). Instantaneous
supramolecular polymerization (and thus negating the
prerequisite to mix individual complementary self-assembling
components) coupled with its exquisite nature of following a
single pathway of self-assembly (and thus avoiding a mixture of
supramolecular polymers) would stand out as prominent
advantages of this system which may usher its application
potential particularly in the delicate areas of material and
medical applications which demand structural homogeneity of
the materials.19 Owing to its structural resemblance to
nucleobases, we envisaged that the self-assembling motif 6
(Scheme 1, vide infra), a multifaceted nucleobase featuring
a
Reagents and conditions: (i) Cbz−OSu, CHCl3:water (1:1); (ii)
ethyl bromoacetate, ACN, K2CO3, 24 h, rt; (iii) DCM, TEA, benzyl
bromoacetate 2 h, rt; (iv) TFA:DCM (1:1), 40 min, 0 °C; (v) Fmoc−
OSu, TEA, DCM, 2 h; (vi) H2/Pd−C, MeOH, rt; (vii) HBTU,
HOBt, DIPEA, DMF, 12 h, rt.
Scheme 1. Synthesis of a Triazine-Based Janus G−C Base as
a
Potential Building Blocks for Self-Assembly
target double-stranded nucleic acids by engaging both strands
simultaneously.20b We also disclose the synthesis of several
value-added ready-to-be-used monomer building blocks for
polymer synthesis such as acrylamide, acrylic ester, allyl, and
norbornene imide (for ROMP-ring-opening metathesis poly-
merization)20c,d derivatives 16a−d, featuring the Janus G−C
nucleobase, which may find application in developing func-
tional polymers (Scheme 3).
Scheme 3. Synthesis of a Triazine-Based Janus G−C
Nucleobase Containing Smart Polymer Building Blocks
a
a
Reagents and conditions: (i) NaOH, (Boc)2O, water, acetone; (ii)
CDI, DCM, rt, 5 h; (iii) DIPEA, ACN, 50 °C, 4−5 h; (iv) CDI,
NaHCO3, ACN, 48 h, rt; (v) 50% TFA:DCM (1:1), 0 °C, 45 min.
Notes: #, 5c and 5d were first debenzylated using H2/Pd−C prior to
Boc deprotection to afford 6c and 6d; $, 5g was subjected to
deprotection using 95% TFA in DCM to simultaneously deblock both
pbf and BOC. Experimental details are in the Supporting Information.
both G and C faces within the molecule, would also find
application in developing novel peptide nucleic acids (PNAs)
with distinctive properties.20a In this regard, we synthesized
novel ready-to-be-used peptide nucleic acid (PNA) monomer
building blocks 13a,b and 14a,b, suitable for Fmoc-based
solid/solution-phase synthesis and Cbz-based solution-phase
synthesis (Scheme 2). It is noteworthy that PNAs carrying
multifaceted nucleobases have found innovative applications to
a
Reagents and Conditions: (i) DIPEA, ACN, 45−50 °C, 4 h; (ii)
CDI, NaHCO3, ACN, RT, 48 h; (iii) TFA, DCM (1:1), 30 min.
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obviously owing to extensive aggregation triggered by
supramolecular polymerization.
RESULTS AND DISCUSSION
■
We began the work with the synthesis of the triazine-based
Janus G−C base 6 as potential building blocks for self-
assembly (Scheme 1). Straightaway synthesis of unprotected 6
was thought to be practically imprudent primarily owing to the
perceived high degree of aggregation and solubility issues
which could be triggered by supramolecular polymerization
aided by two sets of self-complementary H-bonding arrays
within the molecule (see the crystal structure of 6d in Figure 2,
PNA monomer building blocks carrying unnatural nucleo-
bases have found application in developing PNAs for site-
specific interaction with DNAs and RNAs. PNA oligomers
have been shown to inhibit transcription (antigene) and
translation (antisense) of genes by tight binding to DNA or
mRNA.23,24 In this context, we have synthesized a novel class
of PNA building blocks 13 and 14 (Scheme 2, vide infra)
carrying the triazine-based Janus G−C nucleobase featuring
orthogonally protected backbones, which could find applica-
tion in developing PNAs useful for DNA/RNA interaction/
recognition studies.25
The PNA building blocks 13 and 14 carrying an Fmoc N-
terminus protecting group which are ready for PNA synthesis
on the solid phase were obtained following the synthetic routes
as given in Scheme 2 (vide infra). 5e (glycine-derived) and 5g
(arginine-derived) Boc-protected triazine benzyl esters were
first debenzylated to afford the free carboxylic acid 12, which
were independently coupled with Fmoc-protected benzyl (2-
aminoethyl)glycinate (Fmoc-aeg-OBn) 11 and Cbz-protected
ethyl (2-aminoethyl) glycinate (Cbz-aeg-OEt) 8 to obtain the
Fmoc analogue 13 and Cbz analogue 14, respectivelythus
furnishing the valuable triazine-based Janus G−C nucleobase-
containing PNA building blocks which are useful for Fmoc-
based solid-phase synthesis or Cbz-based solution-phase
synthesis of PNAs.
Hydrogen-bonding plays a vital role in the designing of
smart polymers and functional materials. Monomers contain-
ing self-assembling motifs offer the opportunity of developing
materials featuring controlled self-assembly.7a,26 In this context,
we have synthesized a class of novel polymer building blocks
16 containing the Janus G−C nucleobase unit in a protected
form (Scheme 3, vide infra). It is noteworthy that the Boc
protecting group in the building blocks 16 would serve as a
deterrent to effectively prevent self-assembly which would
cause solubility issues during “covalent polymerization”. Once
deprotected after covalent polymerization, the Janus G−C
nucleobase being self-complementary can trigger 3 + 3 type H-
bonded “supramolecular polymerization”, which could sub-
stantially influence the overall property of the polymers. The
polymer building blocks 16 were synthesized by a synthetic
route depicted in Scheme 3. The novel imidazole carbonyl-
coupled reactive intermediate 3 upon reaction with various
amines afforded amidino urea 15, which could be easily
cyclized by reacting with CDI, yielding 16 from which the free
amino triazine 17 can be obtained quickly by Boc deprotection
with TFA−DCM.
Figure 2. Single-crystal X-ray structures of triazine-based Janus G−C
nucleobases 6d and 17b showing supramolecular self-assembly. H-
bonding is highlighted in dashes (red color), above which H-bond
distances (N−H···N, N···H−N, and N−H···O) are displayed in Å.
This figure was made using Mercury software. Note: Crystal structure
of 17d given in the Supporting Information (p S90).
vide infra). Such a consideration was further reinforced owing
to the apparent difficulties in working with insoluble value-
added building blocks for application purposes. Therefore, we
designed a strategy to first obtain the Janus G−C nucleobase 6
in a carbamate-protected form devoid of solubility issuesby
masking the H-bonding codes, as in 5, which can be readily
converted to the free Janus G−C nucleobase 6, as and when
required (Scheme 1).
The BOC-protected Janus G−C nucleobase 5 having diverse
N-substituents could be efficiently synthesized in four steps by
starting from guanidine 1, as outlined in Scheme 1. After
several attempts, we found that the imidazolecarbonyl-coupled
3 could serve as a valuable reactive intermediate which could
readily react with amines under mild conditions to form
amidino urea 4, which was amenable to cyclization to afford 5.
Thus, as per this plan, N-Boc-guanidine 2, readily obtainable
from guanidine by mono Boc protection,21a was carefully
reacted with carbonyldiimidazole (CDI) to afford the reactive
intermediate 3, which was sufficiently stable to be isolated and
could be preserved under ambient conditions. The novel
intermediate 3 upon reaction with various primary amines
furnished amidino urea 4, which could be easily cyclized by
reacting with CDI, yielding 5. Boc deprotection of 5 finally
furnished the Janus G−C nucleobase 6, with characteristic
poor solubility in common organic solvents as anticipated
In order to provide insights into the structural details of self-
assembly of the Janus G−C nucleobase, we made extensive
attempts for their crystallization, even though many of them
had poor solubility in common organic solvents.
However, after tenacious efforts, three molecules could be
crystallized: 6d (Scheme 1) and the polymer monomer
building blocks 17b and 17d (Scheme 3). Whereas 6d could
be crystallized from hot aqueous methanol containing traces of
HCl, 17b and 17d could be crystallized from DMSO (Figure 2,
vide supra; crystal structure of 17d given in the Supporting
Information, p S90). Analysis of their single-crystal X-ray
structure revealed the anticipated 3 + 3 repeating H-bonding.
Each molecule is held from both sides by two sets of DDA−
AAD-type triple hydrogen-bonding arraysreminiscent of the
guanine−cytosine GC-type triple H-bonding pattern seen in
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Compound 2. The synthesis of compound 2 was as per an earlier
reported procedure.21a Guanidinium chloride monohydrate (23 g, 1
equiv, 240 mmol) was dissolved in water (48 mL), and NaOH was
added (19.2 g, 2 equiv, 481 mmol). This was stirred at 0 °C for 15
min, followed by addition of a solution of di-tert-butyl dicarbonate
(13.1 g, 0.25 equiv, 60 mmol) in acetone (200 mL) and stirring at
room temperature for an additional 10 h. The solvent was removed
under a vacuum, and the resultant residue was dissolved in water (30
mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer
was washed with brine solution, dried (Na2SO4), filtered, and
concentrated in vacuo to dryness. The resultant residue was suspended
in cold diethyl ether, and solid was filtered under a vacuum to afford
compound 2 as a white powder. Yield 7.70 g (80%); Rf = 0.2 (silica
gel TLC, 10% methanol in DCM); 1H NMR (400 MHz, DMSO-d6) δ
6.78 (bs, 4 H), 1.34 (s, 9 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
163.9, 163.2, 76.0, 28.7, 28.7, 28.7; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C6H14N3O2 160.1081; Found 160.1079; [M + Na]+
Calcd for C6H13N3O2Na 182.0900; Found 182.0898.
nucleic acids. It is noteworthy that the H-bonding parameters
of 6d and 17b are comparable to those of native G−C base
pairs.27 Owing to self-complementarity, the DDA−AAD-type
triple hydrogen-bonding leads to supramolecular polymer
formation, as expected. A notable feature of this supra-
molecular assembly is that, unlike the CA−MA motif which
often leads to the formation of mixtures of cyclic rosette/
crinkled tape/linear self-assembled structures, our Janus G−C
nucleobase leads to the formation of a single set of
supramolecular polymer owing to the orthogonal positioning
of the DDA−AAD H-bonding arrays within the molecule
increasing the hope for its application in sensitive areas
wherein material homogeneity is warranted.
CONCLUSION
■
In conclusion, we have developed a novel class of bifacial triple
hydrogen-bonding G−C motif 6, inspired by DNA base
pairing. These triazine-based Janus G−C nucleobases could
serve as potential building blocks for multiple application
purposes vis-a-vis: molecular self-assembly, nucleic acid
interactions, and smart polymers. The Janus G−C base,
endowed with self-complementary H-bonding codes reminis-
cent of guanine (G) and cytosine (C) nucleic acid bases, is
capable of undergoing efficient self-assembly leading to
supramolecular polymers, as is unequivocally evident from
crystal structure studies. This work also describes the
development of novel ready-to-use PNA monomers 13 and
14 featuring multifacial recognition sites within the molecule.
The orthogonally protected PNA building blocks carrying the
triazine-based Janus G−C nucleobase could find application in
developing PNAs useful for DNA/RNA recognition studies.
We have also developed a novel class of polymer building
blocks 16 carrying multifacial H-bonding sites with potential
utility in the development of smart/self-healing/functional
polymers. Structural investigations unambiguously showed
their G−C-like H-bonding base pairing and eventual supra-
molecular self-assembly owing to self-complementarity of the
molecule. We are currently exploring their utility in diverse
domains of areas of applications, as envisaged above, and will
report the results in due course.
Compound 3. N-Boc-guanidine 2 (14 g, 87.1 equiv, 95 mmol, 1
equiv) was suspended in dichloromethane (50 mL), and 1,1-
carbonyldiimidazole (CDI) was added (15.69 g, 1.1 equiv, 96.94
mmol). The solution was stirred at room temperature for 5 h. The
resultant solution was washed with water (3 × 30 mL), dried
(Na2SO4), and concentrated under a vacuum to afford 3 as a
crystalline white solid, which was carried forward for the next step.
Yield 20 g (90%); Rf = 0.3 tailing (silica gel TLC, 60% ethyl acetate in
1
pet. ether); mp 155−160 °C; H NMR (400 MHz, CDCl3) δ 11.08
(bs, 1 H), 9.27 (bs, 1 H), 8.89 (bs, 1 H), 8.54 (s, 1 H), 7.54 (s, 1 H),
6.98 (s, 1 H), 1.55 (s, 9 H); 13C{1H} NMR (100 MHz, CDCl3) δ
160.8, 157.9, 153.8, 137.8, 128.8, 117.0, 83.6, 28.1, 28.1, 28.1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C10H16N5O3 254.1248; Found
254.1243.
Compound 4a. The compound 3 (1 equiv, 2.00 g, 7.9 mmol) was
dissolved in acetonitrile (50 mL), and benzyl amine was added (1.2
equiv, 1.01 g, 9.52 mmol). This mixture was stirred at 50 °C in an oil
bath for 4 h. The reaction mixture was cooled at room temperature
and concentrated under vacuo. The resultant residue was dissolved in
ethyl acetate (100 mL) and subsequently washed with diluted KHSO4
solution (2 × 30 mL) and brine solution (30 mL) and dried
(Na2SO4). The organic layer was concentrated under a vacuum to
afford 4a as a white solid. Yield 2.01 g (87%); mp 90−100 °C; Rf =
1
0.5 (silica gel TLC, 70% ethyl acetate in pet. ether); H NMR (400
MHz, CDCl3) δ 8.85 (bs, 3 H), 7.68 (bs, 1 H), 7.36−7.22 (m, 5 H),
4.37−4.35 (d, J = 5.34 Hz, 2 H), 1.48 (s, 9 H); 13C{1H} NMR (100
MHz, CDCl3) δ 155.2, 154.2, 137.2, 128.8, 128.8, 128.8, 127.7, 127.6,
127.6, 86.0, 44.0, 27.9, 27.9, 27.9; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C14H21N4O3 293.1608; Found 293.1601; [M + Na]+ Calcd
for C14H20N4O3Na 315.1428; Found 315.1419.
Compound 4b. The synthetic method of 4a was adopted to
synthesize 4b; white solid. Yield 1.81 g (84%); mp 100−110 °C; Rf =
0.5 tailing (silica gel TLC, 80% ethyl acetate in pet. ether); 1H NMR
(400 MHz, CDCl3) δ 10.08 (bs, 3 H), 7.55−6.90 (bs, 1 H), 3.05 (s, 2
H), 1.53 (s, 9 H), 0.94 (s, 9 H); 13C{1H} NMR (100 MHz, CDCl3) δ
159.4, 155.0, 154.0, 86.0, 51.4, 32.1, 27.8, 27.8, 27.8, 27.3, 27.2, 27.2;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H25N4O3 273.1921;
Found 273.1914; [M + Na]+ Calcd for C12H24N4O3Na 295.1741;
Found 295.1733.
Compound 4c. tert-Butyl (2-(benzyloxy) ethyl) carbamate (5 g, 1
equiv, 19.89 mmol), which was synthesized as per an earlier reported
procedure,21b was dissolved in 50% solution of TFA in DCM (50 mL)
and stirred at 0 °C for 45 min. The solvent was evaporated under a
vacuum and coevaporated with toluene (2 × 20 mL) to take off the
residual TFA from the reaction mixture to afford TFA salt as a
semisolid. The resultant TFA salt (1 equiv, 5.2 g, 1 equiv, 19.60
mmol) was dissolved in acetonitrile (40 mL), and compound 3 (1.1
equiv, 5.43 g, 21.56 mmol) and DIPEA (3 equiv, 10.22 mL, 58.81
mmol) were added. This mixture was stirred at 50 °C for 4 h. The
resultant reaction mixture was cooled at room temperature and
concentrated under a vacuum. The residue was dissolved in ethyl
acetate (100 mL) and subsequently washed with dilute KHSO4
EXPERIMENTAL SECTION
■
General Information. All reagents were purchased at the highest
commercial quality and used without further purification, unless
otherwise stated. All reactions were carried out with laboratory grade
solvent, and the purity of intermediates and final compounds was
checked on precoated silica gel G254 TLC plates (Merck).
Visualization of spot on TLC was achieved by the use of UV light
(254 nm) ninhydrin. The oil bath was used as a heating source for
reactions. All synthesized compounds were purified via silica gel
column chromatography by using 100−200 and 230−400 mesh silica
gel. Melting points were recorded by MEL-TEMP; melting points are
uncorrected; and 1H, 13C {1H}, and DEPT-135 spectra were recorded
on Bruker AV-400 and AV-500 MHz instruments, using CDCl3/
DMSO-d6 as solvents and TMS as internal standard. H NMR and
1
13C{1H} NMR chemical shifts are expressed in parts per million
(ppm, δ scale) and were referenced to NMR solvent CDCl3 δ 7.26, 77
ppm and DMSO-d6 δ 2.5, 39.8 ppm, respectively. The following
abbreviations were used to describe peak patterns when appropriate;
bs = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, and
m = multiplet. High resolution mass spectra (HRMS) were recorded
on an Agilent LC/MSD TOF mass spectrometer by electrospray
ionization time off light reflection (ESI-TOF) experiments. Single-
crystal data were collected using a Bruker SMART APEX II single-
crystal X-ray CCD.
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solution and brine solution, dried (Na2SO4), and concentrated under
a vacuum for dryness to obtain crude 4c as a white solid, which was
purified by column chromatography using 10−90% ethyl acetate in
pet. ether. The resultant white solid was triturated using cold 50%
diethyl ether in pet. ether (10 mL) to afford 4c as a pale semisolid.
Yield 5.8 g (88%); Rf = 0.5 (silica gel TLC, 70% ethyl acetate in pet.
ether); 1H NMR (400 MHz, CDCl3) δ 9.39 (bs, 1 H), 8.17 (bs, 1 H),
7.33−7.28 (m, 5 H), 6.33 (bs, 1 H), 4.51 (s, 2 H), 3.55−3.52 (m, 2
H), 3.41−3.37 (m, 2 H), 1.47 (s, 9 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 158.4, 157.8, 138.0, 128.5, 128.5, 128.5, 127.9, 127.8, 127.8,
82.2, 73.2, 69.3, 39.9, 28.2. 28.2, 28.2; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C16H25N4O4 337.1870; Found 337.1867.
Compound 4d. The synthetic method of 4a was adopted to
synthesize 4d. The benzyl (2-aminoethyl) carbamate was synthesized
as per an earlier reported procedure.22a The resulting residue was
directly purified by column chromatography using 100−200 mesh size
and mobile 0−10% MeOH in dichloromethane. The solvent was
removed under a vacuum, and the residue was triturated with diethyl
ether to afford 4d as an off-white solid. Yield 2.56 g (85%); mp 80−90
°C; Rf = 0.3 (silica gel, TLC, 10% methanol in DCM); 1H NMR (400
MHz, CDCl3) δ 8.00 (bs, 2 H), 7.32−7.28 (m, 5 H), 7.11 (bs, 1 H),
6.64 (bs, 1 H), 5.57 (bs, 1 H), 5.06 (bs, 2 H), 3.30 (m., 4 H), 1.47
(m, 9 H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.3, 158.8, 156.8,
156.8, 136.6, 128.6, 128.6, 128.1, 128.1, 128.1, 83.7, 66.8, 41.2, 40.0,
28.1, 28.1, 28.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H26N5O5 380.1928; Found 380.1924; [M + Na]+ Calcd for
C17H25N5O5Na 402.1748; Found 402.1737.
synthesized by a previously reported method21d) by using 50% TFA
in DCM (30 mL) stirred at ice-bath temperature for 45 min. The
solvent was removed under a vacuum, and the remaining TFA was
stripped off by coevaporating with toluene (2 × 20 mL) to afford TFA
salt as a semisolid that was carried forward for the next step. The
resultant TFA salt (5 g, 1 equiv, 7.92 mmol) was dissolved in
acetonitrile (40 mL), and compound 3 (2.69 g, 1.1 equiv, 8.72 mmol)
and DIPEA (4.13 mL, 3 equiv, 23.78 mmol) were added; the mixture
was stirred at 50 °C for 4−5 h. The resultant solution was cooled at
room temperature and concentrated under a vacuum. The residue was
diluted with ethyl acetate (150 mL) and subsequently washed with
dilute KHSO4 solution and brine solution and then dried (Na2SO4).
The solvent was evaporated under reduced pressure to afford 4g as a
white solid. Yield 5.43 g (80%); mp 90−100 °C; Rf = 0.3 (silica gel
1
TLC, 80% ethyl acetate in pet. ether); H NMR (400 MHz, DMSO-
d6) δ 9.01 (bs, 1 H), 8.31 (bs, 1 H), 8.13 (bs, 1 H), 7.36−7.33 (m, J =
5.4 Hz, 5 H), 6.74 (bs, 1 H), 6.45 (bs, 2 H), 5.10 (bs, 2 H), 4.23−
4.21 (d, J = 5.3 Hz, 1 H), 3.05−304 (dd, J = 6.1, 10.2 Hz, 2 H), 2.92−
2.69 (s, 2 H), 2.47 (s, 3 H), 2.42 (s, 3 H), 1.99 (s, 4 H), 1.97−1.90
(m, 2 H), 1.68 (bs, 1 H), 1.45 (s, 9 H), 1.39−1.38 (m, 8 H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 174.3, 171.3, 171.3, 157.2, 157.2,
155.8, 137.0, 135.5, 134.6, 131.2, 128.2, 128.2, 127.9, 127.7, 127.7,
124.1, 116.0, 86.1, 66.0, 52.4, 42.2, 31.3, 28.8, 28.0, 28.0, 28.0, 27.5,
27.5, 18.7, 17.4, 13.4, 12.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C33H48N7O8S 702.3280; Found 702.3274; [M + Na]+ Calcd for
C33H47N7O8SNa 724.3099; Found 724.3082.
Compound 5a. Compound 4a (2g, 5.27 mmol, 1 equiv) was
dissolved in acetonitrile (25 mL), NaHCO3 (0.886 g, 10.5 mmol, 1.5
equiv) and CDI (1.28 g, 7.91 mmol, 1.2 equiv) were added, and the
mixture was stirred at room temperature for 48 h. The resultant
precipitate was filtered under a vacuum, and solid precipitate was
suspended in ethyl acetate (100 mL) and carefully acidified with
dilute KHSO4 solution. The organic layer was washed with brine
solution, dried (Na2SO4), and concentrated under a vacuum to
dryness. The resulting white solid was washed with diethyl ether to
afford 5a as a white solid. Yield 1.53 g (70%); mp >400 °C; Rf = 0.5
(silica gel TLC, 10% methanol in DCM); 1H NMR (400 MHz,
CDCl3) δ 11.24 (bs, 1 H), 10.29 (bs, 1 H), 7.48−7.46 (d, J = 6.10 Hz,
2 H), 7.30−7.28 (s, 3 H), 5.05 (s, 2 H), 1.49 (s, 9 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 154.4, 154.1, 152.8, 149.0, 136.1, 129.1, 128.4,
128.4, 128.4, 127.9, 85.5, 44.7, 27.8, 27.8, 27.8; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C15H19N4O4 319.1401; Found 319.1393;
[M + Na]+ Calcd for C15H18N4O4Na 341.1220; Found 341.1212.
Compound 5b. The synthetic method of 5a was adopted to
synthesize 5b; white solid. Yield 1.45 g (66%); mp >400 °C; Rf = 0.5
(silica gel TLC, 10% methanol in DCM); 1H NMR (400 MHz,
CDCl3) δ 11.15 (bs, 1 H), 9.82 (bs, 1 H), 3.78 (s, 2 H), 1.51 (s, 9 H),
0.94 (s, 9 H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.3, 153.6,
152.8, 149.8, 85.5, 51.3, 34.0, 28.4, 28.4, 28.4, 28.0, 28.0, 28.0; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H23N4O4 299.1714; Found
299.1712; [M + Na]+ Calcd for C13H22N4O4Na 321.1533; Found
321.1531.
Compound 4e. Compound 3 (2.00 g, 1 equiv, 7.9 mmol) was
dissolved in acetonitrile (30 mL), and Gly−OBn−PTSA (1.2 equiv,
1.07 g, 9.48 mmol, which was synthesized by a previously reported
procedure21c) and DIPEA (2.74 mL, 2 equiv 15.81 mmol) were
added and then stirred at 50 °C in oil bath for 4 h. The reaction
mixture was cooled at room temperature, diluted with ethyl acetate
(70 mL), and subsequently washed with dilute KHSO4 solution, brine
solution and dried (Na2SO4). The resultant organic layer was
concentrated under a vacuum to dryness and solid residue triturated
with diethyl ether to afford 4e as a white solid. Yield 2.23 g (80%);
mp 110−115 °C; Rf = 0.4 (silica gel TLC, 80% ethyl acetate in pet.
ether); 1H NMR (400 MHz, DMSO-d6) δ 10.83 (bs, 1 H), 9.37 (bs, 2
H), 8.65 (bs, 1 H), 7.35−7.32 (m, 5 H), 5.12 (s, 2 H), 3.96−3.94 (d,
J = 6.1 Hz, 2 H), 1.44 (s, 9 H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 169.8, 154.8, 154.5, 152.6, 136.3, 129.0, 128.7, 128.7, 128.5,
126.0, 84.3, 66.7, 41.9, 28.1, 28.1, 28.1; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C16H23N4O5 351.1663; Found 351.1653; [M + Na]+
Calcd for C16H22N4O5Na 373.1482; Found 373.1470.
Compound 4f. Benzyl N6-((benzyloxy)carbonyl)-L-lysinate TFA
salt (2.1 g, 1 equiv, 4.33 mmol, which was synthesized by a previously
reported method21d) was dissolved in acetonitrile (50 mL), in round-
bottom flask, the compound 3 (1.20 g, 1.1 equiv, 4.76 mmol) and
DIPEA (2.26 mL, 3 equiv, 13.00 mmol) were added; the mixture was
stirred at 50 °C for 4−5 h. The resultant solution was cooled at room
temperature and concentrated under a vacuum. The residue was
diluted with ethyl acetate (100 mL) and subsequently washed with
dilute KHSO4 solution, brine solution and dried (Na2SO4). The
solvent was evaporated under reduced pressure to afford 4f as a white
solid. Yield 2.3 g (87%); mp 80−90 °C; Rf = 0.4 (silica gel TLC, 80%
Compound 5c. The synthetic method of 5a was adopted to
synthesize 5c; white solid. Yield 1.63 g (75%); mp >250 °C; Rf = 0.6
(silica gel TLC, 10% methanol in DCM); 1H NMR (400 MHz,
CDCl3) δ 11.08 (bs, 1 H), 9.91 (bs, 1 H), 7.31−7.30 (m, 5 H), 4.51
(s, 2 H), 4.13−4.11 (m, 2 H), 3.72−3.69 (t, J = 5.7 Hz, 2 H), 1.49 (s,
9 H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.2, 153.0, 153.0,
149.4, 138.1, 128.5, 128.5, 127.8, 127.7, 127.7, 85.5, 72.8, 66.5, 40.7,
27.9, 27.9, 27.9; HRMS (ESI-TOF) m/z: [M + H]+ C17H23N4O5
363.1663; Found 363.1656; [M + Na]+ Calcd for C17H22N4O5Na
385.1482; Found 385.1475.
1
ethyl acetate in pet. ether); H NMR (500 MHz, DMSO-d6) δ 9.86
(bs, 1 H), 8.23 (bs, 2 H), 7.72 (bs, 1 H), 7.36−7.32 (m, 10 H), 6.90
(t, J = 5.5 Hz, 1 H), 5.14−5.12 (m, 2 H), 5.00 (s, 2 H), 4.18−4.16 (d,
J = 5.3 Hz, 1 H), 3.35 (s, 1 H), 2.96−2.95 (q, J = 6.6 Hz, 2 H), 1.68−
1.65 (d, J = 8.0 Hz, 2 H), 1.43−1.38 (m, 11 H), 1.31−1.28 (m, 2 H);
13C{1H} NMR (125 MHz, DMSO-d6) δ 172.7, 158.1, 156.5, 137.7,
136.4, 128.9, 128.8, 128.5, 128.3, 128.3, 128.2, 128.2, 127.8, 127.8,
127.6, 127.8, 79.1, 66.4, 65.6, 59.7, 53.1, 31.0, 29.4, 28.4, 28.4, 28.4,
23.0, 14.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H38N5O7
556.2771; Found 556.2766. Note: δ 4.10, 2.07, and 1.27 residual
peaks of ethyl acetate.
Compound 5d. The synthetic method of 5a was adopted to
synthesize 5d as a white solid. Yield 1.62 g (76%); mp >350 °C; Rf =
1
0.4 (silica gel TLC, 80% ethyl acetate in pet. ether); H NMR (400
MHz, CDCl3) δ 11.04 (bs, 1 H), 9.15 (bs, 1 H), 7.34−7.30 (m, 5 H),
5.30 (bs, 1 H), 5.15−5.07 (s, 2 H), 4.08−4.06 (m, 2 H), 3.50- 3.49
(m, 2 H), 1.53 (s, 9 H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.7,
155.2, 153.8, 152.6, 151.7, 149.2, 136.6, 128.5, 128.5, 128.1, 128.1,
128.1, 86.0, 66.7, 41.2, 39.9, 27.9, 27.9, 27.9; HRMS (ESI-TOF) m/z:
Compound 4g. The BOC group deprotection of Benzyl N2-(tert-
butoxycarbonyl)-Nω((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-
5-yl)sulfonyl)-L-argininate (5.00 g, 1 equiv, 8.11 mmol, which was
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[M + H]+ Calcd for C18H24N5O6 406.1721; Found 406.1716. Note:
1H NMR δ 1.53 residual CH2Cl2, δ 1.56 residual water.
(m, 2 H), 3.44−3.41 (t, J = 6.5 Hz, 2 H); 13C{1H} NMR (400 MHz,
DMSO-d6) δ 160.9, 155.7, 152.6, 58.2, 42.9; HRMS (ESI-TOF) m/z:
+
[M + H]+ Calcd for C5H9N4O3 173.0669; Found 173.0669. Note:
Compound 5e. The synthetic method of 5a was adopted to
synthesize 5e as a white solid. Yield 1.30 g (60%); mp 280−290 °C;
Poor solubility in hot DMSO-d6.
1
Compound 6d. The synthetic method of 6a was adopted to
synthesize 6d as a white solid; overall yield 0.044 g (70%); mp >250
Rf = 0.4 (silica gel TLC, 70% ethyl acetate in pet. ether); H NMR
(400 MHz, DMSO-d6) δ 11.41 (bs, 2 H), 7.37 (m, J = 3.0 Hz, 5 H),
5.18 (s, 2 H), 4.55 (s, 2 H), 1.49 (s, 9 H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 168.1, 156.8, 154.5, 153.7, 136.0, 128.9, 128.7, 128.5,
128.4, 128.3, 126.0, 84.0, 66.9, 42.4, 28.1, 28.1, 28.1; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C17H21N4O6 377.1456; Found
377.1452; [M + Na]+ Calcd for C17H20N4O6Na 399.1275; Found
399.1271. Note: Residual peak of ethyl acetate at δ 1.27, 2.07, and
4.26. Note: Feebly UV active but ninhydrin active with green color on
long heating.
1
°C; H NMR (400 MHz, DMSO-d6) δ 11.49 (bs, 1 H), 7.76 (bs, 2
H), 7.42 (bs, 2 H), 3.88−3.85 (d, 2 H), 2.95 (d, J = 6.5 Hz, 2 H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 162.8, 162.7, 157.1, 69.1,
+
55.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C5H10N5O2
172.0829; Found 172.0829. Note: Poor solubility in DMSO-d6, δ 3.39
(bs, residual water).
Compound 6e. The synthetic method of 6a was adopted to
synthesize 6e as a white solid. Yield 0.060 g (80%); mp >250 °C; 1H
NMR (400 MHz, DMSO-d6) δ 7.33 (m, 5 H), 7.19 (bs, 2 H), 5.12 (s,
2 H), 4.44 (s, 2 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.8,
156.8, 156.8, 153.2, 136.2, 129.0, 128.7, 128.7, 128.4, 128.4, 66.7,
Compound 5f. The synthetic method of 5a was adopted to
synthesize 5f; white solid. Yield 0.095 g (45%); mp 80−90 °C; Rf =
1
0.5 (silica gel TLC, 45% ethyl acetate in pet. ether); H NMR (400
+
42.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H13N4O4
MHz, DMSO-d6) δ 11.22 (bs, 1 H), 7.36−7.30 (m, 11 H), 5.24 (t, J =
5.5 Hz, 1 H), 5.23−5.10 (m, 3 H), 5.07−4.99 (m, 2 H), 2.97−2.95
(m, 2 H), 2.08 (dd, J = 5.9, 8.9 Hz, 1 H), 1.91 (m, 1 H), 1.47 (s, 9 H),
1.41−1.23 (m, 3 H), 1.26 (d, J = 6.9 Hz, 2 H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 172.5, 172.3, 169.5, 156.6, 154.6, 153.7, 137.7,
136.3, 128.9, 128.9, 128.8, 128.8, 128.4, 128.4, 128.4, 128.2, 128.2,
128.0, 84.0, 66.7, 65.6, 54.0, 29.5, 28.1, 28.0, 28.0, 28.0, 23.2, 14.5;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H36N5O8 582.2558;
Found 582.2547. Note: Feebly UV active but ninhydrin active with
green color on long heating.
277.0931; Found 277.0926; [M + Na]+ Calcd for C12H12N4O4Na
299.0751; Found 299.0744.
Compound 6f. The synthetic method of 6a was adopted to
synthesize 6f as a white solid. Yield 0.063 g (78%); mp 270−280 °C;
1H NMR (400 MHz, DMSO-d6) δ 7.37−7.30 (m, 10 H), 7.23 (bs,
2H), 5.19−5.15 (dd, J = 5.0, 9.5 Hz, 1 H), 5.13−5.05 (m, 2 H), 4.99
(s, 2 H), 2.98 (q, J = 6.6 Hz, 2 H), 2.04−1.96 (m, 2 H), 1.42−1.37
(m, 2 H), 1.23−1.18 (dd, J = 6.5, 14.9 Hz, 2 H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 170.1, 159.7, 156.8, 156.6, 153.3, 137.8, 136.6,
128.9, 128.9, 128.4, 128.4, 128.2, 128.2, 128.0, 128.0, 128.0, 28.0,
66.5, 65.6, 53.4, 29.6, 28.5, 23.4, 18.3; HRMS (ESI-TOF) m/z: [M +
Compound 5g. The synthetic method of 5a was adopted to
synthesize 5g; white solid. Yield 1 g (49%); mp 220−230 °C; Rf = 0.4
(silica gel TLC, 10% methanol in DCM); 1H NMR (400 MHz,
CDCl3) δ 11.29 (bs, 1 H), 7.89 (bs, 1 H), 7.29−7.24 (m, 5 H), 6.28−
6.19 (bs, 3 H), 5.29−5.25(m, 1 H), 5.12−5.09 (m, 3 H), 5.01 (d, J =
2.3 Hz, 1 H), 3.49−3.47 (m, 1 H), 3.18−3.16 (m, 1 H), 2.92 (s, 3 H),
2.53 (s, 3 H), 2.47 (s, 3 H), 2.16 (bs, 1 H), 2.06 (s, 3 H), 1.46−1.45
(d, J = 5.3 Hz, 15 H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.1,
158.7, 156.3, 152.8, 152.8, 148.6, 138.4, 135.4, 133.1, 132.3, 128.6,
128.4, 128.4, 128.2, 128.2, 124.4, 117.5, 86.4, 67.4, 65.9, 54.3, 43.3,
40.7, 28.7, 28.7, 27.9, 27.9, 27.9, 25.7, 25.6, 19.3, 18.0, 15.4, 12.6;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C34H46N7O9S
728.3072; Found 728.3071. Note: Feebly UV active but ninhydrin
active with green color on long heating.
Compound 6a. Compound 5a was (100 mg, 1 equiv 0.331 mmol)
dissolved in 50% TFA in DCM (5 mL) and stirred at ice temperature
for 45 min. The reaction mixture was concentrated in vacuo and
coevaporated with dichloromethane (2 × 10 mL). The resulting
residue was diluted with diethyl ether (5 mL), and the solid was
filtered under a vacuum to afford 6a as a white solid. Yield 0.062 g
(90%); mp >400 °C; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C10H11N4O2+ 219.0877; Found 219.0876. Note: No solubility even in
hot DMSO-d6.
+
H]+ Calcd for C24H28N5O6 482.2034; Found 482.2036.
Compound 6g. Deprotection of 5g using 95% TFA−DCM
afforded 6g as an insoluble material. Owing to poor solubility, it
could not be satisfactorily characterized. Overall yield 0.032 g (62%);
mp 175−185 °C; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
+
C16H22N7O4 376.1728; Found 376.1724.
Compound 12a. Compound 5e (1 g, 2.66 mmol, 1 equiv) was
dissolved in methanol (5 mL), and Pd/C was added (20 mol %); the
mixture was stirred at room temperature under a H2 atmosphere for 5
h. The resultant reaction mixture was passed through a thin Celite
pad, and the filtrate was concentrated under vacuo to afford 12a as a
white solid. Yield 0.690 g (90%); mp >250 °C; 1H NMR (400 MHz,
DMSO-d6) δ 11.70 (m, 3 H), 4.37 (s, 2 H), 1.48 (s, 9 H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 169.5, 169.5, 154.4, 154.4, 153.8,
83.9, 42.3, 28.1, 28.1, 28.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C10H15N4O6 287.0986; Found 287.0981. Note: Residual ethyl
acetate peak at δ 1.07.
Compound 12b. The synthetic method of 12a (1 g, 1.37 mmol, 1
equiv) was adopted to synthesize 12b as a white solid. Yield 0.760 g
1
(86%); mp 220−230 °C; H NMR (400 MHz, DMSO-d6) δ 12.48
(bs, 1 H), 11.32 (bs, 2 H), 6.70 (bs, 1 H), 6.37 (bs, 1 H), 5.02 (bs, 1
H), 3.36 (m, 3 H), 3.01 (d, J = 5.3 Hz, 2 H), 2.96 (s, 2 H), 2.47 (s, 3
H), 2.42 (s, 3 H), 2.00 (m, 4 H), 1.48 (s, 9H), 1.41 (s, 6 H), 1.35 (d,
J = 10.7 Hz, 2 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 166.6,
161.8, 158.0, 156.6, 137.8, 134.6, 131.9, 124.9, 116.8, 113.1, 102.0,
86.8, 65.5, 65.5, 60.3, 43.0, 28.8, 28.8, 28.2, 28.2, 25.8, 25.8, 25.8,
18.1, 15.7, 14.6, 12.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C27H40N7O9S 638.2603; Found 638.2604.
Compound 6b. The synthetic method of 6a was adopted to
synthesize 6b as a white solid. Yield 0.061 g (92%); mp >400 °C; the
product was poorly soluble in any solvent; HRMS (ESI-TOF) m/z:
+
[M + H]+ Calcd for C8H15N4O2 199.1190; Found 199.1189; [M +
Na]+ Calcd for C8H14N4O2 221.1009; Found 221.1007. Note: No
solubility in DMSO-d6.
Compound 6c. The compound 5c (1 g, 1 equiv, 2.47 mmol) was
dissolved in methanol (5 mL) followed by addition of Pd/C (20 mol
%) and stirred at room temperature for 4 h under a hydrogen (H2)
atmosphere. The reaction mixture was passed through a Celite pad
(thin pad), and the pad was washed repetitively by MeOH (4 × 20
mL). The resultant filtrate was concentrated under a vacuum to afford
benzyl free intermediate (0.6 g, 80%) as a white solid. Further, the
resultant solid (0.1 g, 1 equiv) was dissolved in 50% solution of TFA
in DCM and stirred at ice temperature for 45 min. The solvent was
removed under a vacuum and coevaporated with DCM (2 × 5 mL).
The resultant residue was diluted with diethyl ether (10 mL) and the
resultant solid was washed by filtration under a vacuum to afford 6c as
Compound 13a. Compound 12a (0.3 g, 1.05 mmol, 1 equiv) was
dissolved in dry DMF (5 mL), and HBTU (0.597 g, 1.57 mmol, 1.5
equiv), HOBt (212 mg, 1.57 mmol, 1.5 equiv), DIPEA (0.364 mL,
2.09 mmol, 2 equiv) were added; the mixture was stirred at 0 °C.
After stirring for 10 min at 0 °C, compound 11 (541 mg, 1.2 equiv,
1.26 mmol, which was synthesized by an earlier reported
procedure24a) was added and the reaction mixture was stirred at
room temperature for an additional 12 h. The resultant solution was
diluted with ice cold water, and the solid precipitate was filtered under
a vacuum. The solid residue was dissolved in ethyl acetate and
subsequently washed with KHSO4 solution, NaHCO3 solution, and
brine solution, dried (Na2SO4), and concentrated under vacuo to get a
white solid product which was purified by chromatography on silica.
1
a white solid; overall yield 0.051 g (80%); mp >250 °C; H NMR
(400 MHz, DMSO-d6) δ 7.49 (bs, 1 H), 4.84 (bs, 3 H), 3.71−3.68
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The mobile phase was 50−100% EtOAc in pet. ether to afford 13a as
Compound 15a. tert-Butyl (2-(allyloxy) ethyl) carbamate (5 g, 1
equiv, 24.87 mmol, synthesized as per an earlier reported
procedure21b) was dissolved in 50% TFA in DCM and allowed to
stir at 0 °C for 45 min. The resultant solution was stripped off and
coevaporated using toluene (2 × 20 mL) to obtain the TFA salt. The
resultant TFA salt (5 g, 1 equiv, 23.25 mmol) was dissolved in
acetonitrile (50 mL), and compound 3 (6.44 g, 1.1 equiv, 25.58
mmol) was added. Then, DIPEA (8 mL, 2 equiv, 46.511 mmol) was
added and the mixture was stirred at 50 °C in an oil bath for 5 h. The
resulting reaction mixture was cooled at room temperature and
concentrated under a vacuum, and the acquired residue was dissolved
in ethyl acetate (150 mL) and subsequently washed with KHSO4
solution and brine solution and dried (Na2SO4). The organic layer
was concentrated under a vacuum to afford 15a as a pale semisolid.
Yield 5.05 g (76%); Rf = 0.4 (silica gel TLC, 60% ethyl acetate in pet.
ether); 1H NMR (400 MHz, CDCl3) δ 929 (bs, 1 H), 8.08 (m, 1 H),
6.45 (m, 1 H), 5.87−5.80 (m, 1 H), 5.23−5.12 (m, 2 H), 3.95−3.94
(d, J = 5.3 Hz, 2 H), 3.49−3.48 (d, J = 5.3 Hz, 2 H), 3.46−3.33 (m, 2
H), 1.43 (s, 9 H), 1.08, bs, 1 H); 13C{1H} NMR (100 MHz, CDCl3)
δ 158.0, 134.5, 117.4, 82.1, 73.4, 72.2, 70.6, 69.3, 39.9, 28.2, 28.2,
1
a white solid. Yield 0.70 g (95%); mp 180−190 °C; H NMR (500
MHz, DMSO-d6) δ 11.37 (bs, 1 H), 11.07 (bs, 1 H), 7.90 (d, J = 7.4
Hz, 2 H), 7.88 (d, J = 7.4 Hz, 2 H), 7.41−7.33 (m, 10 H), 5.22−5.13
(s, 2 H), 4.69 (s, 1 H), 4.55 (s, 1 H), 4.33 (bs, 1 H), 4.28 (d, J = 6.9
Hz, 1 H), 4.23 (dd, J = 6.8, 18.8 Hz, 2 H), 4.21−4.13 (s, 1 H), 3.50−
3.49 (t, J = 6.3 Hz, 2 H), 3.36−3.24 (d, J = 5.9 Hz, 2 H), 1.49 (s, 9
H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 169.9, 169.4, 167.3,
167.2, 157.3, 156.8, 154.3, 144.4, 141.2, 136.2, 136.1, 129.4, 128.9,
128.5, 128.3, 128.1, 127.5, 125.6, 125.6, 125.6, 125.6, 120.6, 120.6,
83.9, 67.8, 67.0, 66.4, 66.0, 47.3, 47.3, 47.2, 40.6, 31.8, 28.1, 28.1,
28.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C36H39N6O9
699.2779; Found 699.2776; [M + Na]+ Calcd for C36H38N6O9Na
721.2598; Found 721.2592.
Compound 13b. The synthetic method of 13a was adopted to
synthesize 13b as a white solid. Yield 0.387 g (78%); mp 210−220
°C; 1H NMR (400 MHz, DMSO-d6) δ 11.26 (bs, 1 H), 7.87−7.85 (d,
J = 7.1 Hz, 2 H), 7.68−7.66 (d, J = 6.6 Hz, 2 H), 7.40−7.28 (m, 10
H), 7.16 (bs, 1 H), 6.72 (bs, 1 H), 6.33 (bs, 2 H), 5.22−5.17 (m, 1
H), 5.14−5.01 (m, 1 H), 4.87−4.84 (d, J = 12.1 Hz, 1 H), 4.28−4.16
(m, 4 H), 4.12−4.14 (m, 1 H), 4.10−3.91 (m, 2 H), 3.42 (d, J = 7.6
Hz, 1 H), 3.14 (bs, 3 H), 3.02 (m, 2 H), 2.94 (s, 3 H), 2.47 (s, 3 H),
2.41 (s, 2 H), 1.99 (m, 4 H), 1.44 (s, 6 H), 1.39 (m, 9 H), 1.34 (m, 2
H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 170.0, 157.9, 156.5,
144.4, 141.2, 137.7, 135.6, 131.9, 128.9, 128.9, 128.5, 128.5, 128.5,
128.3, 128.3, 128.3, 128.1, 128.1, 128.1, 127.5, 127.5, 125.6, 124.8,
120.5, 116.7, 86.7, 67.1, 67.1, 65.8, 60.2, 52.4, 48.9, 47.1, 42.9, 38.1,
30.6, 29.4, 28.8, 28.8, 28.1, 28.1, 28.1, 28.1, 26.4, 21.5, 21.2, 19.4,
18.0, 17.6, 14.7, 14.5, 14.4, 12.7; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C53H64N9O12S 1050.4390; Found 1050.4382.
28.2; HRMS (ESI-TOF) m/z: [M
+
H]+ Calcd for
C12H23N4O4287.1714; Found 287.1710; [M + Na]+ Calcd for
C12H22N4O4Na 309.1533; Found 309.1526.
Compound 15b. 2-((tert-Butoxycarbonyl) amino) ethyl acrylate
(10 g, 1 equiv, 46.46 mmol, synthesized as per an earlier reported
procedure24c) was dissolved in 50% TFA in DCM (40 mL) and
stirred at 0 °C for 60 min, monitored by TLC. The resultant solution
was stripped off and coevaporated using toluene (2 × 20 mL) at 30
°C (to avoid undesired polymerization) to obtain TFA salt which was
carried forward for the next step without purification. The resultant
TFA salt (10 g, 1 equiv, 43.66 mmol) was dissolved in acetonitrile (80
mL), and compound 3 (12.15 g, 1.1 equiv, 4.80 mmol) was added.
Then, DIPEA (14.96 mL, 2 equiv, 8.73 mmol) was added and the
mixture was stirred at 50 °C in an oil bath for 5 h. The solution was
cooled at room temperature and concentrated under a vacuum. The
resultant residue was diluted with ethyl acetate (200 mL) and
subsequently washed with dilute KHSO4 solution and brine solution
and dried (Na2SO4). The solvent was removed under a vacuum to
afford 15b as a pale semisolid. Yield 9.90 g (75%); Rf = 0.5 (silica gel
TLC, 60% ethyl acetate in pet. ether); 1H NMR (500 MHz, CDCl3) δ
9.23 (bs, 1 H), 8.39 (bs, 2 H), 6.39−6.36 (d, J = 17.5 Hz, 1 H), 6.11
(bs, 2 H), 6.07 (m, 1 H), 5.81−5.79 (d, J = 10.7 Hz, 1 H), 4.21 (bs, 2
H), 3.47 (bs, 2 H), 1.44 (d, J = 1.5 Hz, 9 H); 13C{1H} NMR (125
MHz,CDCl3) δ 166.0, 158.1, 131.2, 128.0, 82.2, 63.5, 60.3, 49.4, 38.8,
28.1, 28.1, 28.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C12H21N4O5 301.1506; Found 301.1510.
Compound 14a. Compound 12a (0.3 g, 1.05 mmol, 1 equiv) was
dissolved in DMF (5 mL), and HBTU (0.597 g, 1.57 mmol, 1.5
equiv), HOBt (212 mg, 1.57 mmol, 1.5 equiv), DIPEA (0.364 mL,
2.09 mmol, 2 equiv) were added; the mixture was stirred for 5 min at
0 °C. Ethyl (2-(((benzyloxy) carbonyl) amino) ethyl) glycinate 8
(Cbz-aeg-OEt) (0.352 g, 1.26 mmol, 1.2 equiv, synthesized as per an
earlier procedure)24b was added, and the reaction mixture was stirred
at room temperature for an additional 16 h. The resultant solution
was diluted with ice cold water, and solid precipitate was filtered
under a vacuum. The solid residue was dissolved in ethyl acetate,
subsequently washed with dilute KHSO4 solution, NaHCO3 solution,
and brine solution, dried (Na2SO4), and concentrated under vacuo to
get a white solid crude product which was purified by column
chromatography silica gel (230−400). The mobile phase was EtOAc
(50−90%) in pet. ether to afford 14a as a white solid. Yield 0.449 g
1
(79%); mp 150−160 °C; H NMR (500 MHz, DMSO-d6) δ 11.39
Compound 15c. tert-Butyl (2-acrylamidoethyl) carbamate (4.28 g,
1 equiv, 20.00 mmol, synthesized as per an earlier reported
procedure24c) was deprotected by using 50% solution of TFA in
DCM (40 mL) at ice temperature for 45 min. The resultant solution
was stripped off and coevaporated at 30 °C (to avoid undesired
polymerization) using toluene (2 × 20 mL) to obtain the TFA salt
(4.52 g, 1 equiv, 19.84 mmol) as a semisolid, which was dissolved in
acetonitrile. Compound 3 (5 g, 1 equiv, 19.84 mmol) and DIPEA (3
equiv, 10.34 mL, 59.52 mmol) were added, and the solution was
stirred at 50 °C in oil bath for 5 h. The resultant solution was cooled
at room temperature and filtered through a cotton pad, and the filtrate
was diluted with ethyl acetate (100 mL) and subsequently washed
with dilute KHSO4 solution and brine solution and dried (Na2SO4).
The solvent was removed under a vacuum to afford 15c as a white
solid. Yield 4.3 g (80%); mp 95−105 °C; Rf = 0.3 (silica gel TLC,
80% ethyl acetate in pet. ether); 1H NMR (400 MHz, CDCl3) δ 8.22
(bs, 3 H), 7.03 (bs, 2 H), 6.58 (bs, 3 H), 6.24−6.06 (m, 2 H), 5.59−
5.56 (d, J = 10.7 Hz, 1 H), 3.43−3.34 (m, 4 H), 1.44 (s, 9 H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 166.5, 157.8, 131.0,
126.4, 82.3, 60.5, 40.7, 39.5, 28.2, 28.2, 28.2; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C12H22N5O4 300.1666; Found 300.1662. [Note:
δ 1.26, δ 2.05, and δ 4.12 are residual peaks of ethyl acetate.]
Compound 15d. The synthetic method of 4a was adopted to
synthesize 15d. The mono-endo-amine was synthesized via an earlier
(bs, 1 H), 11.11 (bs, 1 H), 7.37−7.22 (m, 5 H), 7.31 (bs, 1 H), 5.03−
5.01 (m, 2 H), 4.66 (s, 2 H), 4.51 (m, 1 H), 4.06 (m, 2 H), 4.04 (s, 2
H), 3.50−3.48 (d, J = 6.6 Hz, 2 H), 3.25 (bs, 2 H), 1.49 (s, 9 H), 1.17
(m, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 169.1, 167.0,
162.1, 157.1, 154.2, 152.9, 136.8, 128.6, 128.4, 128.2, 128.2, 86.0,
67.1, 66.8, 62.4, 61.8, 50.7, 49.3, 49.0, 42.2, 39.5, 28.1, 28.1, 28.1,
14.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H33N6O9
549.2304; Found 549.2294.
Compound 14b. The synthetic method of 14a was adopted to
synthesize 14b as a white solid. Yield 0.307 g (72%); mp 150−160
1
°C. H NMR (400 MHz, DMSO-d6) δ 11.47 (bs, 1 H), 11.05 (bs, 1
H), 7.35−7.32 (m, 5 H), 7.19−7.01 (m, 1 H), 6.67 (bs, 1 H), 6.36
(bs, 1 H), 5.16 (m, 1 H), 5.00−4.97 (m, 2 H), 4.08 (m, 4 H), 3.43−
3.40 (dd, J = 5.7, 12.7 Hz, 2 H), 3.15−3.08 (m, 3 H), 3.02−2.96 (m,
5 H), 2.46 (s, 3 H), 2.41 (s, 3 H), 2.00−1.99 (m, 4 H), 1.47−1.46 (m,
10 H), 1.40 (s, 7 H), 1.23−1.14 (m, 3 H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 169.9, 168.9, 157.9, 156.6, 156.5, 137.7, 137.7, 134.6,
131.9, 128.8, 128.8, 128.3, 128.1, 128.1, 124.8, 116.7, 86.8, 84.0, 65.8,
65.7, 65.7, 61.4, 60.9, 60.2, 52.5, 47.7, 42.9, 38.8, 32.3, 31.4, 28.7,
28.7, 28.0, 28.0, 28.0, 25.9, 19.0, 18.0, 14.4, 14.2, 12.7; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C41H58N9O12 900.3920; Found
900.3925; [M + Na]+ Calcd for C41H58N9O12Na 922.3740; Found
922.3735.
3192
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The Journal of Organic Chemistry
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Article
reported procedure.25a Yield 3.4 g (79%); Rf = 0.4 (silica gel TLC,
60% ethyl acetate in pet. ether); 1H NMR (400 MHz, CDCl3) δ 9.28
(m, 1 H), 8.23 (m, 2 H), 6.06 (s, 2 H), 5.26 (bs, 1 H), 3.49−3.46 (m,
2 H), 3.32 (bs, 2 H), 3.28 (q, J = 6.1 Hz, 2 H), 3.26−3.21 (bs, 2 H),
1.69−1.66 (m, 1 H), 1.50−1.48 (d, J = 9.2 Hz, 1 H), 1.43 (s, 9 H);
13C{1H} NMR (100 MHz, CDCl3) δ 177.9, 177.9, 161.8, 157.7,
134.5, 134.5, 134.5, 82.1, 60.4, 53.5, 52.2, 45.8, 44.9, 37.9, 37.7, 28.1,
28.1, 28.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H26N5O5
392.1928; Found 392.1919.
156.1, 156.1, 135.0, 116.2, 70.5, 69.2, 66.1, 39.9; HRMS (ESI-TOF)
+
m/z: [M + H]+ Calcd for C8H13N4O3 213.0982; Found 213.0982.
Compound 17b. The synthetic method of 17a was adopted to
synthesize 17b as a white solid. Yield 0.054 g (78%); mp >300 °C; 1H
NMR (400 MHz, DMSO-d6) δ 7.14 (bs, 1 H), 6.30−6.26 (dd, J = 1.6,
17.3 Hz, 1 H), 6.14−6.07 (dd, J = 10.4, 17.3 Hz, 1 H), 5.94−5.91
(dd, J = 1.5, 10.4 Hz, 1 H), 4.27−4.24 (t, J = 5.4 Hz, 2 H), 3.97−3.94
(t, J = 5.5 Hz, 2 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.8,
156.5, 153.3, 150.2, 132.1, 128.7, 61.7, 40.6. HRMS (ESI-TOF) m/z:
+
[M + H]+ Calcd for C8H11N4O4 227.0775; Found 227.0775.
Compound 16a. The synthetic method of 5a was adopted to
synthesize 16a as a white solid. Yield 1.2 g (55%); mp 130−135 °C;
Compound 17c. The synthetic method of 17a was adopted to
synthesize 17c as a white solid. Yield 0.061 g (88%); mp >300 °C;
note: poor solubility in DMSO-d6; HRMS (ESI-TOF) m/z: [M + H]+
1
Rf = 0.45 (silica gel TLC, 60% ethyl acetate in pet. ether); H NMR
(400 MHz, CDCl3) δ 9.95 (bs, 2 H), 5.83−5.79 (tdd, J = 5.6, 11.0,
16.7 Hz, 1 H), 5.23−5.11 (m, 2 H), 4.09−4.06 (t, J = 5.7 Hz, 2 H),
3.96−3.94 (d, J = 6.1 Hz, 2 H), 3.64−3.61 (t, J = 5.7 Hz, 2 H), 1.48
(s, 9 H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.3, 153.0, 151.4,
149.4, 134.5, 117.3, 85.5, 71.7, 66.3, 40.7, 27.9, 27.9, 27.9; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H21N4O5 313.1506; Found
313.1496; [M + Na]+ Calcd for C13H20N4O5Na 335.1326; Found
335.1315.
Compound 16b. A mixture of 15b (2.5 g, 8.33 mmol, 1 equiv),
NaHCO3 (1.0 g, 12.5 mmol, 1.5 equiv), and CDI (1.62 g, 10 mmol,
1.2 equiv) in 30 mL acetonitrile was stirred at room temperature for
48 h. The resultant reaction mixture was filtered under a vacuum, and
solid residue was suspended in ethyl acetate (100 mL) and acidified
with dilute KHSO4 solution. The organic layer was washed with brine
solution, dried (Na2SO4), filtered, and concentrated under a vacuum
at 30 °C (to avoid undesired polymerization), and the resulting
semisolid was purified by column chromatography using ethyl acetate
0−80% in petroleum ether. The solvent was removed under a vacuum
at 30 °C to get viscous oil which was kept in a refrigerator overnight
to afford 16b as a white solid. Yield 0.840 g (30%); mp 95−105 °C; Rf
= 0.6 (silica gel TLC, 60% ethyl acetate in pet. ether); 1H NMR (400
MHz, CDCl3) δ 11.14 (bs, 1 H), 9.84 (bs, 1 H), 6.40−6.35 (m, 1 H),
6.02 (m, 1 H), 5.83−5.80 (m, 1 H), 4.38−4.37 (m, 2 H), 4.21−4.18
(m, 2 H), 1.50 (s, 9 H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.0,
154.5, 154.2, 152.8, 149.0, 131.4, 128.1, 85.8, 61.3, 40.5, 27.9, 27.9,
27.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H19N4O6
327.1299; Found 327.1295; [M + Na]+ Calcd for C13H18N4O6Na
349.1119; Found 349.1115.
+
Calcd for C8H12N5O3 226.0935; Found 226.0932.
Compound 17d. The synthetic method of 17a was adopted to
synthesize 17d as a white solid. Yield 0.064 g (84%); mp >250 °C; 1H
NMR (400 MHz, DMSO-d6) δ 7.07 (bs, 3 H), 5.97−5.96 (s, 2 H),
3.71−3.69 (m, 2 H), 3.42−3.39 (d, J = 10.7 Hz, 2 H), 3.19−316 (d, J
= 13.0 Hz, 4 H), 1.49 (s, 2 H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 177.2, 177.2, 175.5, 167.2, 155.8, 152.8, 152.8, 134.2, 134.2, 51.7,
45.2, 44.0, 38.8, 35.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
+
C14H16N5O4 318.1197; Found 318.1194.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02530.
Associated analytical data of all newly synthesized
compounds and copies of 1H, 13C, DEPT-135, and
HRMS spectra for compounds 2, 3, 4a−g, 5a−g, 6a−g,
12a,b, 13a,b, 14a,b, 15a−d, 16a−d, and 17a−d (PDF)
Accession Codes
CCDC 2011989−2011991 and 2051830 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Compound 16c. The synthetic method of 16b was adopted to
synthesize 16c as a white solid. Yield 2.25 g (82%); mp >250 °C; Rf =
1
0.3 (silica gel TLC, 10% methanol in DCM); H NMR (400 MHz,
DMSO-d6) δ 8.18−8.17 (s, 1 H), 6.14−6.01 (m, 2 H), 5.58−5.55
(dd, J = 3.1, 9.9 Hz, 1 H), 3.82−3.79 (bs, 3 H), 3.38−3.33 (d, J = 6.1
Hz, 2 H), 1.48 (s, 9 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
165.4, 165.4, 154.0, 154.0, 132.2, 132.6, 125.6, 83.3, 40.9, 36.5, 28.1,
28.1, 28.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H20N5O5
326.1459; Found 326.1452; [M + Na]+ Calcd for C13H19N5O5Na
348.1284; Found 348.1271.
AUTHOR INFORMATION
■
Corresponding Author
Gangadhar J. Sanjayan − Organic Chemistry Division,
Council of Scientific and Industrial Research National
Chemical Laboratory (CSIR-NCL), Pune 411008, India;
orcid.org/0000-0001-7764-7329; Email: gj.sanjayan@
ncl.res.in
Compound 16d. The synthetic method of 16b was adopted to
synthesize 16d as a white solid. Yield 2.1 g (78%); mp >250 °C; Rf =
1
0.45 (silica gel TLC, 10% MeOH in DCM); H NMR (400 MHz,
Authors
CDCl3) δ 11.02 (bs, 1 H), 9.31 (bs, 1 H), 6.04−6.03 (m, 2 H), 4.00−
3.98 (m, 2 H), 3.66−6.65 (td, J = 2.3, 4.6 Hz, 2 H), 3.31−3.24 (d, J =
19.1 Hz, 4 H), 1.69−1.67 (m, 1 H), 1.51 (m, 1 H), 1.47 (m, 9 H);
13C{1H} NMR (100 MHz, CDCl3) δ 178.2, 178.2, 154.9, 153.8,
152.7, 149.2, 134.5, 134.5, 85.8, 52.4, 46.0, 46.0, 44.7, 44.7, 40.3, 36.1,
27.9, 27.9, 27.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H24N5O6 418.1721; Found 418.1716; [M + Na]+ Calcd for
C19H23N5O6Na 440.1541; Found 440.1536.
Chhuttan L. Meena − Organic Chemistry Division, Council of
Scientific and Industrial Research National Chemical
Laboratory (CSIR-NCL), Pune 411008, India
Dharmendra Singh − Organic Chemistry Division, Council of
Scientific and Industrial Research National Chemical
Laboratory (CSIR-NCL), Pune 411008, India
Bhavya Kizhakeetil − Organic Chemistry Division, Council of
Scientific and Industrial Research National Chemical
Laboratory (CSIR-NCL), Pune 411008, India
Manasa Prasad − Organic Chemistry Division, Council of
Scientific and Industrial Research National Chemical
Laboratory (CSIR-NCL), Pune 411008, India
Malini George − Organic Chemistry Division, Council of
Scientific and Industrial Research National Chemical
Laboratory (CSIR-NCL), Pune 411008, India
Compound 17a. A solution of 16a (0.1 g) in 50% TFA in DCM
was stirred for 45 min at ice temperature. The reaction mixture was
concentrated in vacuo; the resulting residue was dissolved in diethyl
ether, and the solid was filtered in a vacuum to afford 17a as a white
1
solid. Yield 0.055 g (80%); mp >250; H NMR (500 MHz, DMSO-
d6) δ 11.08 (bs, 1 H), 7.68 (bs, 1 H), 6.43 (bs, 1 H), 5.86−6.83 (tdd,
J = 5.3, 10.4, 17.2 Hz, 1 H), 5.22−5.20 (m, 1 H), 5.10 (m, 2 H),
3.93−3.92 (td, J = 1.5, 5.3 Hz, 2 H), 3.84−3.82 (t, J = 6.5 Hz, 2 H),
3.50 (t, J = 6.3 Hz, 2 H); 13C{1H} NMR (125 MHz, DMSO-d6) δ
3193
https://dx.doi.org/10.1021/acs.joc.0c02530
J. Org. Chem. 2021, 86, 3186−3195

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Nucleic Acid Aldehydes. J. Am. Chem. Soc. 2008, 130 (14), 4646−
4659.
Srinu Tothadi − Organic Chemistry Division, Council of
Scientific and Industrial Research National Chemical
Laboratory (CSIR-NCL), Pune 411008, India;
orcid.org/0000-0001-6840-6937
(12) Self-assembling motifs featuring multiple H-bonding arrays
within the molecule (also called “Janus bases”) have been used to
target double-stranded DNA or RNA by engaging both strands at
once. See: (a) Branda, N.; Kurz, G.; Lehn, J.-M. Janus Wedges: A
New Approach Towards Nucleobase-Pair Recognition. Chem.
Commun. 1996, 2443. (b) Chen, F. H.; Meena; McLaughlin, L. W.
A. Janus Wedge DNA triplex with A-W1-T and G-W2-C Base triplets.
J. Am. Chem. Soc. 2008, 130, 13190−13091. (c) Miao, S.; Liang, Y.;
Marathe, I.; Mao, J.; DeSantis, C.; Bong, D. Duplex Stem
Replacement with bPNA+ Triplex Hybrid Stems Enables Reporting
on Tertiary Interactions of Internal RNA Domains. J. Am. Chem. Soc.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02530
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.L.M. thanks the University Grant Commission (UGC), New
Delhi, Government of India, for the award of a Postdoc
fellowship (Award No. F./31-1/2017/PDFSS-2017-18-RAJ-
14211). The grant to G.J.S. (CSIR SSB-000726, seed grant) is
also gratefully acknowledged.
2019, 141 (23), 9365−9372. (d) Drozdz, W.; Walczak, A.; Bessin, Y.;
̇ ̇
Gervais, V.; Cao, X.-Y.; Lehn, L.-M.; Sébastien, U.; Stefankiewicz, A.
R. Multivalent Metallosupramolecular Assemblies as Effective DNA
Binding. Agents. Chem. - Eur. J. 2018, 24 (42), 10802−10811.
(13) (a) Kheria, S.; Rayavarapu, S.; Kotmale, A. S.; Gonnade, R. G.;
Sanjayan, G. J. Triazine-Based Highly Stable AADD-Type Self-
Complementary Quadruple Hydrogen-Bonded Systems Devoid of
Prototropy. Chem. - Eur. J. 2017, 23, 783−787. (b) Prabhakaran, P.;
Puranik, V. G.; Sanjayan, G. J. Pre-organizing Linear (Self-
Complementary) Quadruple Hydrogen-Bonding Arrays Using Inter-
molecular Hydrogen Bonding as the Sole Force. J. Org. Chem. 2005,
70 (24), 10067−10072.
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