N, N′-Di(acylamino)-2,5-diketopiperazines: Strategic Incorporation of Reciprocal n → π? Interactions in a Druglike Scaffold

Article abstract of DOI:10.1021/acs.orglett.8b02449

The incorporation of the recently discovered reciprocal n → π? interactions in 2,5-diketopiperazines (DKPs) is reported to design a novel N,N′-di(acylamino)-2,5-diketopiperazine (daa-DKP) scaffold. The design, synthesis, and structural features of daa-DKPs and the effect of reciprocal n → π? interactions in their structural rigidity is discussed.

Full text of DOI:10.1021/acs.orglett.8b02449

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
N,N′‑Di(acylamino)-2,5-diketopiperazines: Strategic Incorporation of
Reciprocal n → π* Interactions in a Druglike Scaffold
Abdur Rahim, Biswajit Sahariah, and Bani Kanta Sarma*
Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Uttar Pradesh 201314, India
S
* Supporting Information
ABSTRACT: The incorporation of the recently discovered reciprocal n → π*
interactions in 2,5-diketopiperazines (DKPs) is reported to design a novel
N,N′-di(acylamino)-2,5-diketopiperazine (daa-DKP) scaffold. The design,
synthesis, and structural features of daa-DKPs and the effect of reciprocal n
→ π* interactions in their structural rigidity is discussed.
n → π* interaction where the lone pair of electrons on a donor
atom is delocalized into the antibonding π orbital of an
acceptor group has attracted a lot of attention in recent years
due to its ability to affect the geometries of both small and
macromolecules.1 For example, carbonyl−carbonyl (CO···CO)
n → π* interaction is known to stabilize small molecules of
biological significance such as aspirin and N-acylhomoserine
lactones.2 (CO···CO) n → π* interactions also influence the
three-dimensional structures of polyesters, peptoids, and
peptides.3 The emergence of CO···CO n → π* interaction
as a stabilizing force in α-helices, polyproline II (PPII) helices
and collagen triple helices has created a lot of excitement in
this area and the scientific community now considers n → π*
interaction as an important noncovalent interaction that
warrants incorporation in the computational force fields.4 In
recent years, amide-aromatic n → π*Ar interactions have also
been effectively used to impart conformational rigidity in
peptoids by controlling the cis−trans equilibrium of their
tertiary amide bonds.3c,e,f,5 Despite their growing importance,
to the best of our knowledge, there has been no attempt to
systematically incorporate n → π* interactions to design and
stabilize any small molecule drug-like scaffold around which
combinatorial libraries could be made and screened for
identification of bioactive molecules. It is not clear if a scaffold
derived by incorporating a small fragment that is known to
participate in n → π* interaction would produce library
molecules having n → π* interaction retained in them. And if
so, would it be possible to tune the magnitude of the
noncovalent interaction to impose rigidity and get control over
the conformational stability of the molecules in the library?
Herein, we take 2,5-diketopiperazine (DKP), a privileged
scaffold, as our candidate of choice to investigate these
possibilities.
permeable, and proteolytically stable small molecules found in
many natural products and bioactive compounds. The small
and semirigid 2,5-DKP core is ideal for designing highly
diverse and stereochemistry controlled combinatorial libraries
of druglike small molecules that obey the Lipinski rules.7
Recently, GlaxoSmithKline compound epelsiban (GSK-
557,296-B), a 2,5-DKP-based orally bioavailable oxytocin
receptor antagonist, was approved by the FDA for treatment
of premature ejaculation in men.8 Many research groups have
also explored various DKP analogues such as peptoid-DKPs,9
aza-DKPs,10 diketomorpholines (DKMs),11 and aza-DKMs12
as potential sources of bioactive molecules.
Recently, we reported the presence of reciprocal CO···CO n
→ π* interactions in small molecules and proteins.13 For
example, the two carbonyl groups of N,N′-diacylhydrazines
(Figure 1A) orient in an arrangement favorable for reciprocal
CO···CO interactions.13 We envisaged that incorporation of
the N,N′-diacylhydrazine fragment into the 2,5-DKP scaffold
(Figure 1B) could retain the reciprocal CO···CO interaction.
This endeavor led to the design and synthesis of a novel N,N′-
di(acylamino)-2,5-diketopiperazine (daa-DKP) scaffold with
several different sites for diversification (Figure 1C). In this
paper, we describe their design, synthesis, and structural
features and evaluate the role of reciprocal n → π* interactions
on their structural rigidity.
To synthesize daa-DKPs (Scheme 1), first, acylhydrazides
were reacted with 2-bromoester (1) to generate compounds
2a−d. Compounds 2a−d were then reacted with bromoacetyl
bromide in the presence of 2,6-di-tert-butylpyridine to form
compounds 3a−d, which were then treated with 2 equiv of
acylhydrazides at 80 °C to produce daa-DKPs (5a−j) probably
We focused on 2,5-DKP as it offers numerous advantages as
Received: August 1, 2018
a drug scaffold.6 2,5-DKPs are conformationally rigid, cell
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Crystal packing diagrams of daa-DKPs. (A) Layered packing
in 5a and (B) tape structure of 5n.
Figure 1. Incorporation reciprocal CO···CO interactions in DKPs.
Chemical structures of (A) N,N′-diacylhydrazine, (B) 2,5-DKP, and
(C) daa-DKP showing various possible positions of diversification.
Broken arrows represent n → π* interactions.
position favored intermolecular hydrogen bonding through the
ring carbonyl oxygens (5c, 5d, 5f, and 5h) (Figure 3A,B and
Figure S1). Therefore, by tuning the electronic environment
around the side-chain amide groups, we could control the
hydrogen bonding patterns in the daa-DKPs (Table S4).
a
Scheme 1. Synthetic Route for daa-DKPs (5a−n)
a
Compounds 5o,p were used for computational analysis but not
synthesized.
via compounds 4a−j that we were not isolatable under the
reaction conditions used. To incorporate chiral centers into the
DKP ring (compounds 5k−m; R3 = CH3), 2a was reacted with
S-2-methylbromopropionic acid in the presence of diisopro-
pylcarbodiimide (DIC) at 37 °C to form 3e, which was then
treated with the corresponding acylhydrazides to produce 5k−
m. To synthesize 5n, a daa-DKP having two chiral centers in
the ring (R1 = R3 = CH3), chiral 2-chloropropionic ester was
used in the first step (see the Supporting Information for
details). We observed that 2,6-di-tert-butylpyridine, a non-
nucleophilic base, worked best in step 2 in which bromide
displacement by base and intramolecular cyclization of 3 to
form oxadiazinone could lead to side reactions. Further, to
avoid oxadiazinone formation from 3, we carried out step 3 in
the absence of any external base. Note that the most common
strategy14 of heating chloroacetamides in the presence of base
to make 2,5-DKPs failed with chloro- and bromoacylated
acylhydrazides due to their hydrolysis and intramolecular
cyclization under these conditions.
We were able to grow single crystals of compounds 5a−f,
5h, 5m, and 5n and determine their solid-state structures. We
found the daa-DKPs to pack either in tape (with two
neighbors) or layer (with four neighbors) structures through
intermolecular N−H···CO hydrogen bonding (Figure
2A,B). The presence of an electron-donating group at the 4-
position of the side-chain aromatic ring favored intermolecular
hydrogen bonding through the side-chain carbonyl oxygen (5b
and 5e), whereas electron-withdrawing groups at the same
Figure 3. (A) Twisted arrangements of the carbonyl groups in 5e. (B)
NBO overlap diagram showing ring oxygen to side-chain π*CO
donation and (C) side-chain oxygen to ring π*CO donation in 5e.
Only the 4-OMe-Ph side is shown.
We observed twisted arrangement between the ring and
side-chain carbonyl groups of daa-DKPs (C−N−N−C ∼
80°), orientations expected for molecules having reciprocal
CO···CO interactions.13 X-ray crystallographic O···C distances
(dr−s and ds−r) shorter than 3.22 Å (the sum of van der Waals
radii between C and O)15 and O···CO angles (θr−s and θs−r
)
of 85
10° indicate the presence of reciprocal CO···CO
interactions in them (Table 1).13 Natural Bond Orbital
(NBO)16 analysis of crystal geometries of the daa-DKPs also
indicated the presence of reciprocal n → π* interactions in
them (Table 1). We observed stronger reciprocal n → π*
interactions when the side-chain aromatic ring contained an
electron-donating or -withdrawing group at the 4-position. For
example, in 5c, the presence of an electron-withdrawing group
(NO2) increased the acceptor ability of the side-chain carbonyl
π* orbital and n → π* interaction from the ring carbonyl
oxygen lone pairs to the side-chain carbonyl π* orbital (Er−s
=
0.35 kcal·mol−1) (Table 1). Interestingly, an increase in
donation from ring carbonyl to side-chain carbonyl increased
the donation from side-chain carbonyl to ring carbonyl and
vice versa. We also observed weak π → π* interactions
B
DOI: 10.1021/acs.orglett.8b02449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Table 1. X-ray Crystallographic Parameters and NBO Energies Showing Reciprocal CO···CO Interactions
Er−s(n→π*) (kcal·
Es−r(n→π*) (kcal·
ET (kcal·
compd
dr−s (Å)
3.211
3.174
3.171
3.211
3.074, 3.233
3.193, 3.266
3.450, 3.249
3.336, 3.226
3.122
θr−s (deg)
Θr−s (deg)
ds−r (Å)
3.209
3.209
3.206
3.143
3.025, 3.221
3.208, 3.257
3.418, 3.241
3.322, 3.232
3.073
θs−r (deg)
Θs−r (deg)
mol−1
)
mol−1
)
mol−1
)
5a
5b
5c
5d
5e
5f
5h
5m
5n
87.2
91.5
90.6
87.5
82.9, 87.4
86.8, 88.8
96.1, 92.9
91.7, 89.6
88.0
−1.46
−0.13
0.92
3.18
1.79, −1.36
−1.21, −1.40
2.85, 1.73
−0.53, 0.98
1.27
87.2
90.3
88.7
90.7
85.3, 88.1
85.8, 89.0
97.6, 93.2
92.4, 89.4
0.41
1.23
−0.64
2.31
2.10, 1.28
0.04, 0
1.26, 1.83
1.94, 2.89
1.37
0.14
0.26
0.35
0.20
0.26, 0.10
0.08, NP
NP, 0.11
NP, 0.11
0.38
0.14
0.08
0.12
0.21
0.19, NP
0.07, NP
NP, NP
NP, NP
0.46
0.40
0.54
0.61
0.59
0.60
0.15
0.22
0.11
1.14
90.5
a
b
The calculations were done at the MP2/6-311+G(2d,p) level of theory. Key: dr−s, distance between ring carbonyl O to side-chain carbonyl C in
angstroms (Å); ds−r, distance between side-chain carbonyl O to ring carbonyl C in angstroms (Å); θr−s, angle from ring carbonyl O to side-chain
CO bond in degrees (deg); θs−r, angle from side-chain carbonyl O to ring CO bond in degrees (deg); Er−s(n→π*) = n → π* second-order
perturbation energy for donation from ring carbonyl O lone pair to side-chain carbonyl π* orbital (π*CO); Es−‑r(n→π*) = n → π* second-order
perturbation energy for donation from side-chain carbonyl O lone pair to ring carbonyl π* orbital (π*CO); Θr−s, pyramidality of side-chain
carbonyl C in degrees (deg); Θs−r, pyramidality of ring carbonyl C in degrees (deg); ET = [Er−s(n→π*) + Es−r(n→π*) + Er−s(π→π*) + Es−r(π→π*)]. The
stabilization energies of π → π* interaction are taken from Table S6. NP = not present at 0.05 kca·mol−1 threshold.
between the carbonyl pairs of the daa-DKPs (Table S6).
Among the daa-DKPs studied here, the strongest reciprocal
interactions were observed in 5n having two chiral centers
within the DKP ring. This observation opens the possibility of
modulating n → π* interactions by varying the substituents
within the DKP ring. We did not find a strong correlation
between pyramidality (Θ) of the acceptor carbonyl carbons
and the nonbonded O···C distances. However, a positive
pyramidalization of the acceptor carbon toward the donor
oxygen was observed when the O···C distances were
significantly shorter than 3.22 Å (Table 1, Figure S2).
It should be noted that incorporation of a motif having
reciprocal n → π* interaction may not always lead to
molecules with the interactions intact as evidenced from the
crystal geometries of 2a, 3a, 3c, and 3f, where no reciprocal
interactions were observed (Figure S4−S7). For diacylhy-
drazines that show reciprocal interactions,13 the N−N−CO
torsion angles should be ∼0°. In daa-DKPs, the ring amide
group is locked in the cis-conformation with respect to the N−
N bond (N−N−CO ∼ 0°), whereas the side-chain amide
group is locked in the trans-conformation with respect to the
NH group (H−N−CO ∼ 180°) due to steric reasons, which
orients the carbonyl groups for a favorable reciprocal
interaction.
We hypothesized that the magnitude of reciprocal
interactions could play a role in determining the conforma-
tional preference of the DKP ring. However, we observed that
the symmetric daa-DKPs crystallized in centrosymmetric space
groups with chair or planar DKP ring conformation while the
asymmetric ones crystallized in the boat form independent of
the strength of reciprocal interactions (Table S4). As the
reciprocal interactions are weak, packing forces could possibly
overcome them to crystallize the molecules in the more
symmetrical forms. Theoretical calculations in the gas phase
for isolated daa-DKP molecules show that the reciprocal
interactions are stronger in boat form. The gas phase
calculations also suggest that the boat forms (C2) of the
DKP rings are more stable than the chair or planar forms (Ci)
for all the daa-DKP molecules (Table 2, Table S5).
Nevertheless, based on symmetry and energetics, we can
make a priori prediction that the centrosymmetric daa-DKPs
would crystallize in the chair or planar conformation of the
DKP ring whereas noncentrosymmetric ones would crystallize
Table 2. Zero-Point Energy Corrected Electronic Energy
Δ(E + ZPE) of daa-DKPs Calculated Using B3LYP, M06-
2X, and MP2 Methods and 6-31G(d) and 6-311+G(2d,p)
a
Basis Sets
Δ(E + ZPE) (kcal·mol−1
)
compd
PG
B3LYP
M06-2X
MP2
b
b
5a
Ci
C2
Ci
C2
Ci
C2
Ci
C2
Ci
C2
0.0 (0.0 )
0.34 (0.82)
0.0 (0.0)
0.39 (0.59 )
0.0 (0.0)
0.67 (0.75)
0.0 (0.0)
0.52 (0.82)
0.0 (0.0)
0.85 (0.90)
0.0 (0.0)
ND (0.95)
ND (0.0)
ND (0.97)
ND (0.0)
ND (0.99)
ND (0.0)
0.66 (1.07)
0.0 (0.0)
0.68 (0.45)
b
b
b
5b
5c
5o
5p
0.0 (0.0 )
1.84 (1.92)
b
b
0.0 (0.0 )
0.58 (0.25)
b
0.0 (0.0)
0.39 (0.01)
b
0.0 (0.0)
0.89 (1.20)
0.0 (0.0)
0.32 (0.29)
a
Key: PG, point group; ND, not determined, as the calculations could
not be completed. Values in parentheses are obtained using 6-31G(d)
b
basis set. Optimized with C1 point group as the Ci point group
resulted in an imaginary frequency.
in the more stable boat form. Accordingly, we observed chair
conformation of DKP ring in 5a−d and 5n and boat
conformation in 5e, 5h, and 5m (Table S4). Only in 5f, the
DKP ring conformation was found to be different from our
prediction.
Finally, reciprocal interactions, the repulsion between the
nitrogen lone pairs, repulsion between the ring and side-chain
carbonyl lone pairs, and other delocalization effects17 [nN →
σ*C−N and nN → σ*N−H interactions; Table S14] should
restrict free rotation around the N−N bonds in daa-DKPs. The
high barrier (>20 kcal·mol−1) of rotation around the N−N
bond in 5a and 5p supports this assumption (Figure S3). As
can be seen from Figure S3, the substituent on the side-chain
amide group does not have significant effect on the barrier to
N−N bond rotation, which will need further investigation. Due
to the high N−N bond rotation, the side-chain and the ring
carbonyl groups of daa-DKPs are found to be locked in an
orientation favorable for reciprocal interactions (C−N−N−C
∼
80°). Further, the side-chain amide bond (H−N−CO)
geometry is expected to be locked in the trans-conformation
due to steric reasons, which is also supported by their crystal
C
DOI: 10.1021/acs.orglett.8b02449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In conclusion, we have shown that reciprocal n → π*
interactions could be strategically incorporated in a drug-like
scaffold by conveniently synthesizing the daa-DKPs having
reciprocal n → π* interactions. To the best of our knowledge,
this is the first study where strategic incorporation of n → π*
interaction has been carried out to design a druglike scaffold.
The daa-DKP scaffold is ideal for combinatorial synthesis as it
can be diversified and its stereochemistry can be controlled at
multiple positions. Our experimental and theoretical data
suggest that the daa-DKP molecules are rigid, a property which
may be useful for binding to biological targets. Further, the
hydrogen bond donor and acceptor units in the side-chain
amide groups in daa-DKPs should provide additional sites for
engagement with biological targets such as proteins and DNA.
Finally, as these are low molecular weight compounds that
follow Lipinski rules, they are potential candidates to be
included in orally bioavailable drug discovery campaigns.
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ASSOCIATED CONTENT
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Accession Codes
CCDC 1844723−1844734 and 1844767 contains the
supplementary 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
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: banikanta.sarma@snu.edu.in.
ORCID
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J.-F.; Radford, S.; Pflimlin, E.; Riche, S.; Doman, P.; Hibert, M.;
Ganesan, A. ACS Comb. Sci. 2012, 14, 323−334.
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Abdur Rahim: 0000-0003-4236-6089
Biswajit Sahariah: 0000-0001-6649-892X
Bani Kanta Sarma: 0000-0003-0830-6007
Notes
The authors declare no competing financial interest.
(13) Rahim, A.; Saha, P.; Jha, K. K.; Sukumar, N.; Sarma, B. K. Nat.
Commun. 2017, 8, 78.
ACKNOWLEDGMENTS
■
This project was funded by Shiv Nadar University (SNU) and
an Early Career Research Grant (ECR/2015/000337) from
the Science and Engineering Research Board (SERB),
Department of Science and Technology (DST), Government
of India. We acknowledge the MAGUS supercomputing facility
at SNU.
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