Highly efficient enantioselective synthesis of 1,3-disubstituted 2,5-diketopiperazine derivatives via microwave irradiation

Article abstract of DOI:10.1080/00397911.2019.1671983

Chiral 2,5-diketopiperazine (2,5-DKP) derivatives have a broad range of biological activities in the medicinal field. The synthetic protocols of 1,3-disubstituted 2,5-DKPs via base-catalyzed cyclization of chloroacetamide have been reported. However, there are several drawbacks, such as an overly long reaction time, low to moderate yield, and racemization of the products. The sequence modified herein of 1,3-disubstituted 2,5-DKPs involves microwave-assisted cyclization. It increases yields and reduces reaction time. Furthermore, employing N-PMB protection prevents racemization, which frequently occurs in the base-catalyzed cyclization reaction. Consequently, the rapid synthetic method of enantiomerically pure 1,3-disubstituted 2,5-DKPs via microwave reaction was established successfully.

Full text of DOI:10.1080/00397911.2019.1671983

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Highly efficient enantioselective synthesis of 1,3-
disubstituted 2,5-diketopiperazine derivatives via
microwave irradiation
Si Yeon Han & Young-Dae Gong
To cite this article: Si Yeon Han & Young-Dae Gong (2019): Highly efficient enantioselective
synthesis of 1,3-disubstituted 2,5-diketopiperazine derivatives via microwave irradiation, Synthetic
Communications, DOI: 10.1080/00397911.2019.1671983
To link to this article: https://doi.org/10.1080/00397911.2019.1671983
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https://doi.org/10.1080/00397911.2019.1671983
Highly efficient enantioselective synthesis of
1,3-disubstituted 2,5-diketopiperazine derivatives via
microwave irradiation
Si Yeon Han and Young-Dae Gong
Center for Innovative Drug Library Research, Department of Chemistry, College of Science, Dongguk
University, Seoul, Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 5 June 2019
Chiral 2,5-diketopiperazine (2,5-DKP) derivatives have a broad range
of biological activities in the medicinal field. The synthetic protocols
of 1,3-disubstituted 2,5-DKPs via base-catalyzed cyclization of chlor-
oacetamide have been reported. However, there are several draw-
backs, such as an overly long reaction time, low to moderate yield,
and racemization of the products. The sequence modified herein of
1,3-disubstituted 2,5-DKPs involves microwave-assisted cyclization. It
increases yields and reduces reaction time. Furthermore, employing
N-PMB protection prevents racemization, which frequently occurs in
the base-catalyzed cyclization reaction. Consequently, the rapid syn-
thetic method of enantiomerically pure 1,3-disubstituted 2,5-DKPs
via microwave reaction was established successfully.
KEYWORDS
Chiral; 1,3-disubstituted
2,5-diketopiperazine (DKP);
DKP cyclization; enantiomer;
microwave;
p-methoxybenzyl (PMB)
protection
GRAPHICAL ABSTRACT
The key step of the synthetic method
Introduction
The compounds containing heterocyclic scaffolds have shown considerable biological
activities in the field of medicinal chemistry.[1] There is a plurality of nitrogen-based
heterocycles as marketed drugs. The 2,5-diketopiperazines (2,5-DKPs) are six-membered
N-heterocyclic compounds and are the smallest cyclic peptide bearing two amide
bonds.[2] A wide range of pharmacological activities of 2,5-DKPs has been demon-
strated; these include antiviral, antifungal, antibacterial, and antitumor activities.[3]
CONTACT Young-Dae Gong
ydgong@dongguk.edu
Center for Innovative Drug Library Research, Department of
Chemistry, College of Science, Dongguk University, Seoul 04620, Republic of Korea.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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S. HAN AND Y.-D. GONG
Figure 1. Biologically active 2,5-DKP derivatives.
There are numerous drugs and biologically active molecules that contain a 2,5-DKP
moiety; these include (a) the oxytocin antagonists, retosiban and epelsiban,[4]
(b) cytotoxic agents inhibiting tubulin polymerization, such as phenylahistin and
plinabulin,[5] (c) tadalafil as a PDE5 inhibitor[6] and (d) brevianamide F as
prenyltranferase.[7]
Additionally, 2,5-DKP derivatives have also shown potential as (e) secondary structures of
protein mimickers.[8] Design of peptidomimetic drugs is a substantial concept in pharma-
ceutical research, because of their high potencies, selectivities, and fewer side effects.[9]
Therefore, many medicinal chemists have enormous interest in constrained peptide chain-
like structures. The 2,5-DKP-based b-turm mimickers have a modified cyclic dipeptide resi-
due.[10] Among them, bicyclic scaffolds containing a 2,5-DKP skeleton are privileged b-turn
mimickers resulting from the scaffold rigidity of 2,5-DKP backbones (Fig. 1).[11]
Most of the 2,5-DKP pharmaceuticals embody more than one chiral carbon, so the
optical purities of a-substituted 2,5-DKP derivatives in total synthesis are crucial.
Moreover, homochiral a-substituted 2,5-DKPs are significant precursors to obtain 2-
substituted piperazines, which are prominent subunits in pharmacologically potent mol-
ecules by straightforward reduction.[12] And the chirality of drugs is a critical issue in
the medicinal field.[13] such as (S)-(-)-propranolol acts as a potent b-blocker,[14] (S)-
(-)-carvedilol,[15] (S)-(-)- thalidomide.[16] So, developing synthetic methods for chiral
pure a-substituted 2,5-DKPs is extremely important.
Various synthetic approaches toward 1,3-disubstituted 2,5-DKPs have been reported,
such as base-catalyzed cyclization of chloroacetamide,[17] Ugi multicomponent reaction
(MCR)[18], and condensation or dimerization of amino acids.[19] Among these methods,
the prevalent 1,3-disubstituted 2,5-DKPs synthesis with chloroacetamide is a one-pot reac-
tion using relatively cheap reagents. It is a well-known synthetic sequence involving amina-
tion and intramolecular cyclization. Also, it is easy to introduce diverse substituents at the
N-position of 2,5-DKPs via reaction with a variety of amines. However, doing do requires
a long reaction time and generates the product with only a moderate yield.
Microwave-assisted organic synthesis (MAOS) is renowned for accelerating reaction
rates and reducing side reactions and time.[20] Therefore, we expected to synthesize 1,3-

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3
Scheme 1. Rapid microwave-assisted strategy for synthesizing 1,3-disubstituted 2,5-DKPs. Reaction
conditions: (a) Et3N, CH2Cl2, r.t., 2 h. see Ref. [17]; (b) R2-NH2, Et3N, n-BuOH, 180 ꢀC, 30 min, microwave
irradiation.
disubstituted 2,5-DKPs efficiently via a microwave reaction.[21] Herein, we report a
facile enantiospecific synthesis of 1,3-disubstituted 2,5-DKPs.
Results and discussion
The synthetic method represents sequentially the formation of chloroacetamide and 1,3-
disubstituted 2,5-DKP cyclization. The overall route is shown in Scheme 1.
The synthetic conditions for base-catalyzed cyclization of chloroacetamide were
reported.[22] Among these above, in Ref. [22a], the reaction between benzylamine and
chloroacetamide 2 (R1 ¼ Me, iBu, Bn) with Et3N by refluxing in MeOH for 20 h deliv-
ered the product in 89%, 78%, and 80%, respectively. It gave good yields but took long
time to terminate the reactions.
After preparing N-a-chloro acetyl amino methyl ester, we tried to optimize the reac-
tion condition for the nimble synthesis of a 1,3-disubstituted 2,5-DKP moiety. Methyl
2-(2-chloroacetamido)-3-phenylpropanoate 2c and 2,4-dimethoxybenzylamine were
chosen as model substrates. The results of the optimization of 3l are described in
Table 1.
First, the reaction was conducted under thermal dynamic conditions. The combina-
tions of the organic base Et3N and polar protic solvents, such as MeOH and n-BuOH
(Table 1, entries 2–3), gave better yields (75% and 71%, respectively) than did the com-
bination of NaH and MeOH (40%) (Table 1, entry 1). As reported, the thermal heating
conditions squandered a lot of time (16–24 h). Thus, we used microwave (MW) to cut
back the reaction time.
For a reaction using the inorganic base K2CO3 in distilled water with MW, the
desired product was obtained in a low yield (21%, Table 2, entry 4). Next, we used
Et3N as a base, which delivered the product in a good yield by thermal heating. The
MW-assisted cyclization with Et3N in distilled water (D.W.) and in n-BuOH gave the
desired products in 66% (Table 2, entry 5) and 81% (Table 2, entry 6) yield, respect-
ively. Although the thermal reaction using Et3N in MeOH produced a higher yield than
did using Et3N in n-BuOH, the boiling point of MeOH (64.7 ꢀC) is too low to bring
about a rise in the pressure in a MW reactor vessel. Thus, MeOH is barely suitable for

4
S. HAN AND Y.-D. GONG
Table 1. The optimization of 1,3-disubstituted-2,5-DKPs cyclization.
Entry
Reaction type
Thermal heating
Thermal heating
Base
NaH
Et3N
Et3N
K2CO3
Et3N
Solvent
MeOH
MeOH
n-BuOH
D.W.
D.W.
n-BuOH
n-BuOH
Temp (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
65
65
120
180
180
180
180
24
24
16
0.5
0.5
0.5
0.5
40
75
71
21
66
81a
67
Thermal heating
Microwave irradiation
Microwave irradiation
Microwave irradiation
Microwave irradiation
Et3N
DIPEA
aOptimized condition.
Table 2. Results of the synthesis of 1,3-disubstituted-2,5-DKPs.
Yield Enanꢀomer
Yield Enanꢀomer
Entry No R1
R2-NH2
Entry No R1
R2-NH2
(%)
Raꢀo (%) a
(%)
Raꢀo (%) a
1
2
3
4
5
6
7
8
9
3a Me
3b Me
3c Me
3d Me
3e Me
74
79 : 21
10
11
12
13
14
15
16
17
18
3j
3k Bn
3l Bn
iPr
74
98 : 2
73 : 27
53 : 47
74 : 26
79 : 21
80 : 20
64 : 36
77 : 23
85 : 15
87
71
90
59
72
84
70
88
87 : 13
76 : 24
88 : 12
69 : 31
94 : 6.
74 : 26
94 : 6
87
71
90
59
72
84
70
88
3m Bn
3n Bn
3o Bn
3p Bn
3q Bn
3r Bn
3f
iPr
3g iPr
3h iPr
3i
iPr
98 : 2
aEnantiomers were separated by chiral HPLC. (Supplementary Information) (S)-enantiomers are major isomers.
MW. Therefore, we used n-BuOH, which is a polar protic solvent with a high boiling
point (117.7 ꢀC). We also tried using DIPEA in n-BuOH (Table 2, entry 7), but it could
not give a better yield than Et3N did.

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Table 3. Results of the synthesis of chiral pure N-PMB-1,3-diubstituted-2,5-DKPs.a
Yield
(%)
Yield
(%)
R2-NH2
Entry
10
No
6j
R1
iPr
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
R2-NH2
Entry
No
6a
6b
6c
6d
6e
6f
R1
Me
Me
Me
Me
Me
iPr
1
2
3
4
5
6
7
8
9
90
88
96
93
65
81
80
82
84
78
89
89
92
83
94
61
77
80
11
6k
6l
12
13
6m
6n
6o
6p
6q
6r
14
15
6g
6h
6i
iPr
16
iPr
17
iPr
18
aThe optically pure products were obtained and checked by chiral HPLC (Supporting Information).
We monitored and compared both reaction times and direct conversion of the com-
ponents between conventional thermal heating (Table 1, entry 3) and heating by MW
radiation (Table 1, entry 6) via HPLC per time (Supporting Information, Fig. S1).
As a result, the cyclization with thermal heating using Et3N in n-BuOH gave a mod-
erate yield but took a long time (16 h), whereas MW irradiation with the same reagent
gave a better yield under similar reaction conditions in only 30 min.
MW irradiation reduced reaction time rapidly and gave higher yields with better pur-
ity than did thermal heating. We thus obtained diverse 1,3-disubstituted 2,5-DKP deriv-
atives by a rapid and efficient method (Table 2). However, unfortunately, enantiomeric
mixtures were obtained. Generally, the base-catalyzed cyclizations have a tendency to
cause racemizations of chiral materials. Especially, for phenylalanine and its derivatives
(Table 2, entries 11–18), a racemate can easily be formed.[23] Chiral purities of com-
pounds are significant, but most purifications of an enantiomeric mixture are difficult,
and chiral column chromatography is expensive. Therefore, to obtain a pure enantio-
meric product, a modified synthetic method is necessary. To improve enantioselectivity
of cyclization, we tried a modified synthetic approach. We envisaged that N-PMB group

6
S. HAN AND Y.-D. GONG
Figure 2. Comparison of the chiral HPLC analysis data of product 3k. (a) 3k derived from synthetic
Scheme 1 (Table 3, entry 11), (b) 3k obtained from PMB deprotection of 6k.
Scheme 2. Synthetic approach of chiral pure N-PMB-1,3-disubstituted-2,5-DKP 6. Reaction condition:
(a) Et3N, NaBH4, MeOH, r.t., 2 h. see Ref. [24]; (b) Et3N, CH2Cl2, r.t., 1 h. see Ref. [25]; (c) Et3N, n-BuOH,
180 ꢀC, 30 min, microwave irradiation.
leads to a thermodynamic preference for the enantiomer observed as both N-R groups
will generally sit in a pseudo equatorial position, so that even if deprotonation occurs it
does not epimerize (Fig. 2).
The modified method is shown in Scheme 2. The synthetic Scheme 2 was accomplished
by starting from a reaction with L-amino methyl ester 5 and p-methoxybenzaldehyde. We
synthesized N-PMB-a-chloroacetyl amino methyl esters 5 as precursors of 1,3-disubstituted
2,5-DKPs 6 in good yields.
In contrast to cyclization by the previous method, this step achieved a better yield with
less side product. The desired products 6 were obtained readily without column purifica-
tion. Furthermore, it was confirmed by chiral HPLC (Supporting Information) that the
afforded N-PMB-protected 1,3-disubstituted-2,5-DKP derivative 6 was enantiomerically
pure. This sequence improved the chiral purity of products better than did Scheme 1.
We carried out deprotection of (S)-1,3-dibenzyl-4-(4-methoxybenzyl)piperazine-2,5-
dione 6k using CAN (cerium (IV) ammonium nitrate). And the products were sepa-
rated by chiral HPLC to check enantiomeric purity.
As mentioned, (a) 1,3-dibenzylpiperazine-2,5-dione 3k derived from synthetic
Scheme 1 consisted of 73% of (S)-isomer and 27% of (R)-isomer. However, by using
CAN in ACN at 60 ꢀC, MW irradiation afforded the desired product (b) (S)-1,3-diben-
zylpiperazine-2,5-dione 3k with a pure isomer. To sum up, PMB protection of chiral
amino acid materials and deprotection with CAN make it possible to control the stereo-
chemistry of this protocol.

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7
Conclusions
We developed the rapid microwave-assisted synthetic method to obtain chirally
pure 1,3-disubstituted 2,5-DKPs via a base-catalyzed cyclization reaction. Usually
base-catalyzed cyclization tends to cause racemization. Because the same holds true for
Scheme 1, we reduced reaction time and increased yield effectively via MW irradiation
but the enantiopurity of the cyclized product was poor. The cyclized enantiomeric mix-
tures were separated by chiral HPLC, and the ratios of isomers were analyzed quantita-
tively. The above provision of 1,3-disubstituted 2,5-DKPs was refined via N-protection
of amino ester. This approach provides enantiopure 1,3-disubstituted 2,5-DKP. As a
final outcome, we established a rapid enantiospecific synthetic sequence and analyzed
the enantiomers of 1,3-disubstituted 2,5-DKPs by chiral HPLC precisely.
General
All chemicals were reagent grade and used as purchased. Reactions were monitored by
TLC analysis using Merck silica gel 60 F-254 thin layer plates for solution-phase synthe-
sis. Microwave reactions were conducted by microwave synthesizer (Biotage Initiatorþ).
Flash column chromatography was carried out on Merck silica gel 60 (230–400 mesh).
Optical rotation value was checked by polarimeter (Rudolph Autopol V). An ATR-IR
spectrometer (Smiths detection) and automatic melting-point apparatus (Stuart SMP40)
1
were used. H NMR and 13C NMR spectra were recorded in d (ppm) units relative to
deuterated solvent (CDCl3, DMSO-d6) as an internal reference using a 500-MHz NMR
instrument (Bruker). Liquid chromatography tandem mass spectrometry (Agilent 6460
Triple Quad LC/MS) analysis was performed using an electrospray ionization (ESI)
mass spectrometer with a photodiode-array detector (PDA). High-resolution mass spec-
trometry spectra were obtained using a TOF LC/MS system (Agilent 6550 iFunnel Q-
TOF LC/MS). Reaction monitoring and analysis of enantiomers were carried out with
High Performance Liquid chromatography (Agilent 1260 infinity series HPLC). Agilent
ZORBAX Eclipse Plus C18 4.6 ꢁ 250 mm LC column and Daicel Chiralpak IA 4.6 x
250 mm (CSP A), Agilent Chiradex 4.0 ꢁ 250 mm (CSP B) LC column cartridge
were used.
Experimental
Representative procedure for the preparation of compounds 3
In a 10-mL sealed microwave reactor vessel, a mixture of N-a-chloroacetyl amino
methyl ester 2 (3.0 mmol, 1.0 eq.), primary amine (3.6 mmol, 1.2 eq.), Et3N (1.254 mL,
9.0 mmol, 3.0 eq.) in n-BuOH (1.5 mL) was stirred with irradiation at 180 ꢀC for
30 min. After cooling to r.t., the resulting mixture was evaporated under reduced pres-
sure. The residue was dissolved in CH2Cl2. The organic phase was washed with H2O
and a saturated aqueous solution of citric acid and NaHCO3. The organic layer was
separated, dried with anhydrous Na2SO4, and evaporated. The obtained crude oil was
purified by column chromatography (eluent: CH2Cl2/MeOH) on silica gel and tritu-
rated with diethyl ether to afford the desired product 3. All synthesized compounds

8
S. HAN AND Y.-D. GONG
were characterized by NMR and MS spectra which can be found in Supporting
Information.
Representative procedure for the preparation of compounds 6
In a 10-mL sealed microwave reactor vessel, a suspension of N-PMB-a-chloroacetyl
amino methyl ester 5 (1.5 mmol, 1.0 eq.), primary amine (1.8 mmol, 1.2 eq.), Et3N
(4.5 mmol, 3.0 eq.) in n-BuOH (0.75 mL) was stirred with irradiation at 180 ꢀC for
30 min. After cooling to r.t., the reaction mixture was evaporated. The crude mixture
was washed with H2O and neutralized with a saturated aqueous solution of citric acid
and NaHCO3. The precipitate was formed, then filtered and dried under high vacuum.
The crude product was triturated with diethyl ether, n-Hexane, and a small portion of
MeOH to yield the desired product 6. All synthesized compounds were characterized by
NMR and MS spectra which can be found in Supporting Information.
Funding
All authors were supported by the Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the Ministry of Education [No.
2016R1D1A1B04932654], and the Ministry of Trade, Industry & Energy, and the Korean
Institute for Advancement of Technology through the industrial infrastructure program for fun-
damental technologies [No. 2014M3A9A9073847] in Korea.
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