Synthesis and conformational characterization of diketopiperazines bearing a benzyl moiety

Article abstract of DOI:10.1246/cl.131001

Diketopiperazines bearing a benzyl moiety with different para-substituents were synthesized and analyzed by ¹HNMR spectroscopy. All of these diketopiperazines were found to adopt a folded conformation according to the upfield chemical shift of the cis-proton (cis to the benzyl moiety) due to a shielding effect in the ¹HNMR spectra. An intramolecular CH-π interaction appears to be an important factor for the folded conformation due to the effects of para-substituents on the benzyl group.

Full text of DOI:10.1246/cl.131001

CL-131001
Received: October 25, 2013 | Accepted: November 13, 2013 | Web Released: November 19, 2013
Synthesis and Conformational Characterization of Diketopiperazines Bearing a Benzyl Moiety
Michiyasu Nakao, Yuriko Toriuchi, Shintaro Fukayama, and Shigeki Sano*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505
(E-mail: ssano@tokushima-u.ac.jp)
CO2R2
Diketopiperazines bearing a benzyl moiety with different
para-substituents were synthesized and analyzed by 1H NMR
spectroscopy. All of these diketopiperazines were found to adopt
a folded conformation according to the upfield chemical shift of
the cis-proton (cis to the benzyl moiety) due to a shielding effect
in the 1H NMR spectra. An intramolecular CH-π interaction
appears to be an important factor for the folded conformation
due to the effects of para-substituents on the benzyl group.
HCl • H2N
R1
BOP reagent
(1.5 mol equiv)
i-Pr2NEt
H
H
(S)
Boc
N
CO2H
2, (S)-3
(1.1 mol equiv)
H
(3 mol equiv)
CH2Cl2
rt, 2-3 h
X
(S)-1a-1e
2: R1 = H, R2 = Et, (S)-3: R1 = R2 = Me
O
H
H
R1
CO2R2
H
(S)
Boc
N
Diketopiperazines (DKPs) have attracted attention due to
various biological activities1 such as antiviral,2 antifungal,3
antitumor,4 and antibacterial5 activities. With regard to con-
formation, several DKPs bearing a benzyl moiety have been
reported to adopt a folded conformation, in which the benzyl
moiety is folded over the DKP ring.6 Based on the folded
conformation of DKPs, we have previously reported that the
absolute configuration of a chiral α-substituted N-Cbz-serine was
N
H2O–MeOH (3 : 1)
MW (170 °C)
10 min
H
X
(S)-4a-4e: (R1 = H, R2 = Et) 87-98%
(S,S)-5a-5e: (R1 = R2 = Me) 65-97%
O
H
a: X = H
1
NH
R1
successfully determined by H NMR analyses of both diaster-
b: X = OMe
c: X = OBn
d: X = Cl
H
(S)
HN
eomeric DKPs derived from reactions with (R)- and (S)-
phenylalanine methyl ester hydrochlorides.7 In the present study
we synthesized DKPs bearing a benzyl moiety with different
para-substituents, and their conformational characterization
O
X
e: X = NO2
(S)-6a-6e: (R1 = H) 17-50%
(S,S)-7a-7e: (R1 = Me) 29-65%
1
was performed by an analysis of H NMR spectra. The upfield
chemical shifts of the cis-protons, which were on the same side
as the para-substituted benzyl moieties of the DKP ring, indicate
that DKPs bearing a benzyl moiety adopt a folded conformation.
Furthermore, the effects of substituents on the benzyl group of
the DKPs suggest that intramolecular CH-π interactions could
be an important factor in creating the folded conformation.
The synthetic route of DKPs bearing a benzyl moiety with
different para-substituents is outlined in Scheme 1. Condensa-
tion of para-substituted Boc-L-phenylalanine derivatives (S)-1a-
1e with glycine ethyl ester hydrochloride (2) and L-alanine
methyl ester hydrochloride [(S)-3] using benzotriazol-1-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate (BOP
reagent) as a coupling reagent in the presence of N,N-
diisopropylethylamine (i-Pr2NEt) afforded the dipeptides (S)-
4a-4e and (S,S)-5a-5e, respectively. Subsequently, microwave-
assisted removal of the Boc group followed by intramolecular
cyclization furnished the DKPs (S)-6a-6e and (S,S)-7a-7e.8,9
Catalytic hydrogenolysis of (S)-6c and (S,S)-7c under hydrogen
with Pd-C (10% Pd) provided the para-hydroxy derivatives (S)-
6f and (S,S)-7f. In contrast, para-amino derivatives (S)-6g and
(S,S)-7g were obtained by catalytic hydrogenolysis of (S)-6e and
(S,S)-7e with Pd(OH)2-C (20% Pd), respectively.
O
O
H
H
H2 / Pd-C
NH
R1
HN
NH
R1
(0.05 mol equiv)
H
H
HN
(S)
(S)
O
MeOH
O
OBn
OH
rt, 2.5-4.5 h
(S)-6c (R1 = H)
(S,S)-7c (R1 = Me)
(S)-6f (R1 = H) 92%
(S,S)-7f (R1 = Me) 79%
O
H
O
H
H2 / Pd(OH)2-C
(0.05 mol equiv)
NH
H
(S)
NH
H
(S)
R1
HN
R1
HN
O
MeOH
O
NO2
NH2
rt, 1.5 h
(S)-6e (R1 = H)
(S,S)-7e (R1 = Me)
(S)-6g (R1 = H) 89%
(S,S)-7g (R1 = Me) quant.
Scheme 1. Synthesis of DKPs (S)-6a-6g and (S,S)-7a-7g.
HD (trans to the benzyl moiety) were also observed at slightly
upfield regions compared to those of (S)-8. Upfield chemical
shifts of HA and HC could be attributed to the strong shielding
effect of the benzene ring of the benzyl moiety. These results
strongly suggest that DKPs (S)-6a-6g and (S,S)-7a-7g adopt a
folded conformation and that cis-protons HA and HC are close to
the benzene ring in solution, as shown in Figure 2. Lin and
Webb have already reported the folded conformation of (S)-6f
The 1H NMR (500 MHz, DMSO-d6) chemical shifts of
selected protons of DKPs (S)-6a-6g and (S,S)-7a-7g are shown
in Tables 1 and 2. We found that all the signals of cis-protons HA
and HC (cis to the benzyl moiety) appeared at much higher
magnetic fields than those of the corresponding protons of DKP
(S)-8 without a benzyl moiety (Figure 1). trans-Protons HB and
340 | Chem. Lett. 2014, 43, 340–342 | doi:10.1246/cl.131001
© 2014 The Chemical Society of Japan

Table 1. 1H NMR (500 MHz, DMSO-d6) analysis of DKPs (S)-
6a-6g
X
X
O
HB
HC
HC
a: X = H
e: X = NO2
HC
O
NH
HA
HA
HB
O
H
H
H
b: X = OMe f: X = OH
c: X = OBn
d: X = Cl
HN
N
N
(S)
(S)
HD
(S)
H
(S)
g: X = NH2
N
N
O
H
H
H
X
O
O
(S)-6a-6g
(S,S)-7a-7g
(S)-6a-6g
Compounds
X
H
OMe
OBn
Cl
NO2
OH
NH2
b
¤ (HA)a
¤ (HB)a
(S)-6a
(S)-6b
(S)-6c
(S)-6d
(S)-6e
(S)-6f
(S)-6g
2.77
2.79
2.80
3.01
3.21
2.70
2.63
3.36b
3.36b
3.36b
3.46
3.52
3.32b
3.26
Figure 2. Folded conformation of DKPs (S)-6a-6g and (S,S)-
7a-7g.
0.63
3.47
3.53
H
1.43
Me
O
O
H
H
0.26
1.70
Me
H
Me
Me
0.60
0.13
0.76
NH
NH
H
(S)
(S)
H
(S)
H
HN
HN
H
(S)
0.65
aChemical shifts (ppm). After D2O exchange.
O
O
Table 2. 1H NMR (500 MHz, DMSO-d6) analysis of DKPs
(S,S)-9
(S,S)-10
(S,S)-7a-7g
Figure 3. 1H NMR (500 MHz, DMSO-d6) analysis of DKPs
(S,S)-9 and (S,S)-10.
O
HD
HC
a: X = H
e: X = NO2
NH
HC
HC
(S)
H
b: X = OMe f: X = OH
HN
(S)
In general, a charge-transfer interaction is considered to be
an important factor in the CH-π interaction.10 As shown in
Table 1, the chemical shifts of HA are influenced by the effects
of para-substituents on the benzyl group of DKPs (S)-6a-6g. In
other words, the π electron density of a benzene ring of the
benzyl moiety seems to correlate with the existence of a charge-
transfer interaction (π to σ*C-H) in these DKPs. Therefore, the
folded conformation of DKPs (S)-6a-6g could be attributed to
the intramolecular CH-π interaction.
c: X = OBn
d: X = Cl
g: X = NH2
O
X
(S,S)-7a-7g
Compounds
X
¤ (HC)a
¤ (HD)a
(S,S)-7a
(S,S)-7b
(S,S)-7c
(S,S)-7d
(S,S)-7e
(S,S)-7f
(S,S)-7g
H
0.48
0.54
0.48
0.59
0.69
0.54
0.58
3.62
3.63
3.61
3.67
3.73
3.61
3.61
OMe
OBn
Cl
NO2
OH
NH2
The chemical shifts of HC of DKPs (S,S)-7d and (S,S)-7e,
which bear electron-withdrawing para-substituents -Cl and
-NO2 similar to those of (S)-6d and (S)-6e, were observed at
lower magnetic field than that of (S,S)-7a. However, the
chemical shifts of HC of DKPs (S,S)-7b, -7c, -7f, and -7g with
electron-donating para-substituents were also observed at lower
magnetic field than that of (S,S)-7a. Thus, some kind of steric
effect of the cis-methyl group (cis to the benzyl moiety) of (S,S)-
7b, -7c, -7f, and -7g might be involved.
aChemical shifts (ppm).
3.71
O
HB
3.74
HA
NH
3.84
(S)
HD
HC
HC HC
HN
DKPs (S,S)-9 and (S,S)-1011 have cis-isopropyl and cis-
isobutyl groups instead of the cis-methyl group of (S,S)-7a, and
presumably adopt a folded conformation in solution. The
O
1.26
(S)-8
1
definitive feature of H NMR spectra of these cis-substituents
Figure 1. 1H NMR (500 MHz, DMSO-d6) analysis of DKP
(S)-8.
is the shielding effect of the benzene ring of the benzyl moiety,
analogous to the DKPs (S)-6a-6g and (S,S)-7a-7g (Figure 3).
In conclusion, we have synthesized DKPs bearing a benzyl
moiety with different para-substituents and have demonstrated
that these DKPs adopt a folded conformation by virtue of the
characteristic chemical shifts of the cis-substituents (cis to the
benzyl moiety) in 1H NMR spectroscopy. The probable origin of
the folded conformation was inferred to be CH-π interactions
from observations based on the electronic effects of para-
substituents on the benzyl group.
bearing a para-hydroxy group in the solid state by X-ray
crystallographic analysis.6d
1
In the H NMR spectra of (S)-6a-6g, the chemical shifts of
HA seem to depend on the nature of the para-substituents of the
benzyl groups. In DKPs (S)-6f and (S)-6g, which bear the
electron-donating para-substituents -OH and -NH2, the chemi-
cal shifts of HA were observed at higher magnetic field than that
of (S)-6a. In contrast, the chemical shifts of HA of DKPs (S)-6d
and (S)-6e, which bear electron-withdrawing para-substituents
-Cl and -NO2, were observed at lower magnetic field than that
of (S)-6a.
This work was supported in part by a Grant for the
Regional Innovation Cluster Program (Global Type) promoted
by MEXT.
Chem. Lett. 2014, 43, 340–342 | doi:10.1246/cl.131001
© 2014 The Chemical Society of Japan | 341

References and Notes
for 10 min utilizing a Biotage Initiatorμ microwave synthe-
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residue was washed with MeOH (3 mL) to afford DKP (S)-
6b (35.2 mg, 34% yield) as a white solid. Colorless powder
1
2
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3
4
(DMF-H2O); mp >240 °C (decompose); ½ꢀꢀD +43.7 (c
1
0.06, DMSO); H NMR (500 MHz, DMSO-d6): ¤ 2.79 (d,
1H, J = 17.3 Hz), 2.81 (dd, 1H, J = 4.9, 13.6 Hz), 3.03 (dd,
1H, J = 4.3, 13.6 Hz), 3.36 (dd, 1H, J = 0.3, 17.4 Hz after
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11 DKPs (S,S)-9 and (S,S)-10 were synthesized following a
similar procedures as that described for the synthesis of
DKPs (S)-6a-6g and (S,S)-7a-7g.
9
A typical procedure was as follows. A suspension of
dipeptide (S)-4b (170.1 mg, 0.447 mmol) in a mixed solvent
of H2O (3 mL) with MeOH (1 mL) was irradiated at 170 °C
342 | Chem. Lett. 2014, 43, 340–342 | doi:10.1246/cl.131001
© 2014 The Chemical Society of Japan