An efficient green synthesis of proline-based cyclic dipeptides under water-mediated catalyst-free conditions

Article abstract of DOI:10.1016/j.tetlet.2009.12.134

l-Proline-based cyclic dipeptides were synthesized from N-Boc-protected dipeptide methyl esters under catalyst-free condition using water as a solvent. One-pot deprotection and cyclization have been used as the key steps, providing an efficient and environmentally friendly approach. Clean reaction conditions, easy isolation, and good yields of cyclic dipeptides are the salient features of the proposed methodology.

Full text of DOI:10.1016/j.tetlet.2009.12.134

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Tetrahedron Letters 51 (2010) 1303–1305
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient green synthesis of proline-based cyclic dipeptides under
water-mediated catalyst-free conditions
Habeebullah Thajudeen a, Kyungseok Park b, Surk-Sik Moon a, In Seok Hong a,
*
a Department of Chemistry, Kongju National University, 182 Shinkwan-dong, Gongju, Chungnam 314-701, Republic of Korea
b Division of Agricultural Microbiology, National Academy of Agricultural Science, Suwon 441-707, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
L-Proline-based cyclic dipeptides were synthesized from N-Boc-protected dipeptide methyl esters under
Received 5 November 2009
Revised 21 December 2009
Accepted 25 December 2009
Available online 7 January 2010
catalyst-free condition using water as a solvent. One-pot deprotection and cyclization have been used
as the key steps, providing an efficient and environmentally friendly approach. Clean reaction conditions,
easy isolation, and good yields of cyclic dipeptides are the salient features of the proposed methodology.
Ó 2010 Elsevier Ltd. All rights reserved.
In nature, amino acids can be found in a great variety. Their
imperative role in life is indisputable. In particular, conformation-
ally restricted amino acids have been the focus of significant inter-
est due to their importance in drug designing. Among the amino
acids, proline has attracted considerable attention in recent years
due to its characteristic secondary amino group, which induces
amide bonds to adopt a cis conformation favoring intramolecular
cyclization of N-free proline-containing dipeptide methyl ester
into bicyclic diketopiperazine structures. Indeed, many diketopi-
perazines (DKPs) with important biological implications contain
the proline moiety.1,2
Recent reports describing research in the area of 2,5-diketopi-
perazines (DKPs) show that this class of compounds is useful in
medicinal chemistry, combinatorial chemistry, and targeted organ-
ic synthesis.3,4 A variety of DKPs have been found to possess inter-
esting biological properties such as antitumor5, antimicrobial6, and
antiviral activities.7 Studies on their synthesis and modes of action
have been reported.8–13 Proline-based DKPs have been shown to
inhibit several enzymes, as well as to recognize, modulate, and
control the activity of many receptors.14–17
be achieved through two steps, (1) deprotection of the N-Boc group
with acid or base20–22, followed by (2) intramolecular cyclization
under thermal conditions.8 On the other hand, it is worth noting
that N-Boc deprotection can also be achieved by utilizing water
without requiring any acid/base catalyst. Wang et al. recently em-
ployed this strategy to produce several N-Boc amino-protected
derivatives.23 Several groups11,24,25 have reported an efficient
method for the synthesis of DKPs from N-Boc-protected dipeptide
ester using microwave conditions. Menendez and co-workers
reported solvent-free conditions for cyclization of N-Boc-protected
amino esters, and in few cases they employed 10% silica gel to
enhance the conversion.25 Tullberg et al.11 performed a compara-
tive study between microwave and conventional heating with var-
ious solvents at different reaction conditions for the cyclization of
dipeptide methyl esters and found water to be an excellent solvent
for the preparation of DKPs.
A variety of approaches have been developed to enable efficient
head-to-tail water-mediated cyclization for the synthesis of 2,5-
diketopiperazines in two steps. However, to the best of our knowl-
edge, the green synthesis of L-proline-based cyclic dipeptides from
With growing interest in developing environmentally friendly
reaction and atom-economic processes, the application of green
solvents is considered a preferable route in organic chemistry.
Compared to conventional solvents, water is preferred for organic
reactions because it displays unparalleled and unique physical
properties. Moreover, it is nontoxic, cheap, hazardless in handling,
and environmentally benign.18,19
N-Boc-protected dipeptide methyl ester in one-pot under simple
and inexpensive conditions has not yet been reported. Herein, we
report on a mild, catalyst-free, green procedure for one-pot synthe-
sis of
L-proline-based cyclic dipeptides from N-Boc-protected
dipeptide ester using water as a solvent.
The synthesis of N-Boc-protected linear dipeptides (3a–k) is
outlined in Table 1. The dipeptides were synthesized by the
coupling of various N-Boc-protected amino acids26 (1a–k) with
2,5-Diketopiperazines-based amino acids are head-to-tail cyclic
dipeptides synthesized by the coupling of an N-Boc-protected
L-proline methyl ester hydrochloride (2) in DMF solution using
a
-amino acid with an
a
-amino acid ester, followed by N-Boc
N,N-diisopropylethylamine (DIPEA) and 2-(1H-benzotriazol-1-yl)-
1,1,3,3,-tetramethyluronium hexa-fluorophosphate (HBTU) as a
coupling reagent at room temperature (Table 1, entry 1–11). In
most cases, isolated yields ranged from good to excellent except
deprotection and intramolecular cyclization. This can generally
* Corresponding author.
E-mail address: ishong@kongju.ac.kr (I.S. Hong).
for L-serine and L-aspargine (Table 1, entries 9 and 10).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.134

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H. Thajudeen et al. / Tetrahedron Letters 51 (2010) 1303–1305
Table 1
Table 3
Synthesis of linear dipeptides containing a proline
Synthesis of cyclic dipeptides containing a proline
Entry
R (1a–k)
Boc-(L-amino acid)
Yielda (%)
Entry
R (3a–k)
Productsa
Yieldb (%)
1
2
3
4
5
6
7
8
9
HO–C6H4–CH2–
C6H5–CH2–
CH3–
(CH3)2CH–
(CH3)2CHCH2–
CH3CH2CH(CH3)–
H–
–CH2CH2CH2–
HO–CH2–
H2N–COCH2–
CH3CH(OH)–
Tyr
Phe
Ala
Val
Leu
Ile
Gly
Pro
Ser
Asn
Thr
95
92
85
86
90
93
82
88
47
45
94
1
2
3
4
5
6
7
8
9
HO–C6H4–CH2–
C6H5–CH2–
CH3–
(CH3)2CH–
(CH3)2CHCH2–
CH3CH2CH(CH3)–
H–
–CH2CH2CH2–
HO–CH2–
H2N–COCH2–
CH3CH(OH)–
Tyr-Pro
Phe-Pro
Ala-Pro
Val-Pro
Leu-Pro
Ile-Pro
Gly-Pro
Pro-Pro
Ser-Pro
Asn-Pro
Thr-Pro
84
88c
76
86
73
70
90
92
91
92
75
10
11
10
11
a
Isolated yield after column chromatography.
a
b
c
All
Isolated yield after column chromatography.
In this case, 1,4-dioxane (20%, v/v) was added.
L-cyclic dipeptides.
We explored the cyclization of N-Boc-protected Tyr-Pro methyl
ester as a model substrate in water under autoclave conditions.
Wang et al.23 reported that the addition of a lesser amount of water
in the deprotection step resulted in incompletion of the reaction
whereas the use of excess water (>1 mL/mmol) did not signifi-
cantly influence the reaction rate and product yield. The experi-
ments were carried out with various time intervals (1–6 h), using
distilled, deionized water (20 mL/mmol) at 130 °C. On the basis
of these observations, we set the optimum reaction time as 4 h
in order to obtain satisfactory results (Table 2).
Using these optimized reaction conditions, the efficiency of this
aqueous approach was studied for the syntheses of a wide variety
of amino acid (AA)-Pro cyclic dipeptides, and the results are sum-
marized in Table 3.
N-Boc deprotection and cyclization of 3a–k were achieved in a
single step during the synthesis of cyclic dipeptides (4a–k) by the
use of water.27 As can be seen from the results in Table 3, the iso-
lated yields of 4a–k were in a range of 70–92%. A comparative
observation can be made with Cledera et al., who employed a tem-
perature of 200 °C in an argon atmosphere for the synthesis of 2,5-
DKP derivatives,28 whereas our approach involved a temperature
of only 130 °C and delivered good yields. Above all, our technique
did not require an inert atmosphere, in contrast with conventional
to increase the yield to an acceptable level. The presence of a bulky,
hydrophobic phenyl group presumably reduced the solubility of
the reactants, and consequently the reaction rate under the normal
reaction conditions was minimal. Hence, an enhanced yield of 88%
for this reaction was realized simply by the addition of 1,4-dioxane
(20%, v/v) to the reaction mixture. In this cyclization method, there
was no significant epimerization at the Pro stereocenter, which
was confirmed by crude NMR experiment.
This method was extended to more amino acids for broad syn-
thetic application. The cyclization of N-Boc-protected
L-Ala-L-Ala
methyl ester, Gly-Gly methyl ester, and Gly- -Trp methyl ester
L
was carried out in water under the same condition. The crude reac-
tion mixture showed almost one spot in TLC. The calculated yields
of each cyclization reactions from the crude NMR analysis were
97%, 95%, and 98% respectively. Therefore, this technique can be
useful for the synthesis of other 2,5-diketopiperazine.
In conclusion, we have described an efficient and green protocol
for one-pot deprotection and cyclization of L-proline-based cyclic
dipeptides. The notable features of the proposed technique include
the use of water as a solvent medium and a feasible reaction tem-
perature. Furthermore, the transformation proceeded well during
the course of the reaction without requiring an inert atmosphere.
Furthermore, the procedure offers several advantages including
the absence of any catalyst, improved yields, and simple yet clean
reaction conditions, making it a useful and attractive strategy in
cyclic dipeptide chemistry.
heating.25,28 The isolated yield for the simple analog cyclo-
Pro was 90% (Table 3, entry 7) whereas the isolated yields of cyclo-
-Leu- -Pro and cyclo- -Ile- -Pro (Table 3, entry 5 and 6) were
moderate. The lower isolated yields for cyclo- -Leu- -Pro and cy-
clo- -Ile- -Pro (70% and 73%) compared to cyclo-Gly- -Pro (90%)
were presumably due to the influence of the hindered bulky units
present in the former (Leu, Ile). The isolated yield of cyclo- -Phe-
L-Gly-L-
L
L
L
L
L
L
L
L
L
L
L-
Acknowledgment
Pro (Table 3, entry 2) was considerably lower under the normal
reaction conditions and hence slight modification was necessary
This study was carried out with the support of the Cooperative
Research Program for Agricultural Science & Technology Develop-
ment (Project No. 200901OFT102966214), RDA, Republic of Korea.
Table 2
Effect of reaction time on water-mediated cyclization of L-Tyr-L-Pro linear dipeptide
References and notes
Entry
Time (h)
Yielda (%)
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1305
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L
-proline methyl ester hydrochloride
(0.5 g, 3.0 mmol) in DMF. The reaction mixture was stirred at room
temperature overnight. The DMF was removed in vacuo and the residue was
diluted in EtOAc, washed with NaHCO3, brine, dried over anhydrous Na2SO4,
and filtered. The solvent was evaporated in vacuo. The resulting crude product
was purified by column chromatography using silica gel (ethyl acetate/hexane,
1:1) affording the corresponding linear dipeptide.
27. Representative experimental procedure for cyclization:
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Aalten, D. M. F. J. Med. Chem. 2004, 47, 5713.
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autoclave with a pressure regulating system. The autoclave was sealed and the
mixture was heated to 130 °C for 4 h. The reaction was then stopped by cooling
and depressurizing the autoclave. Water was evaporated in vacuo, the
remaining residue was purified by column chromatography using silica gel
(MeOH/MC, 0.5:9.5).
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26. Representative experimental procedure for peptide coupling:
(CDCl3, 400 MHz) d 7.05 (2H, d), 6.77 (2H, d), 5.72 (1H, s), 4.21 (1H, dd), 4.08
(1H, t), 3.66–3.59 (1H, m), 3.56- 3.51 (1H, m), 3.44–3.39 (1H, m), 2.75 (1H, dd),
2.29 (1H, m), 2.02–1.96 (1H, m), 1.94–1.83 (2H, m); 13C NMR (CDCl3, 100 MHz)
d 169.8, 165.3, 155.6, 130.5 (2C), 127.4, 116.3 (2C), 59.3, 56.4, 45.6, 36.1, 28.5,
22.7; ESI-MS (m/z): calcd for C14H16N2O3 (M+H)+: 261.1161, found: 261.1226;
[a
]
D = À71.3 (c 0.5, MeOH) [lit.29
[a]D = À72 (c 0.5, MeOH)].
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DIEA (0.78 g, 6.0 mmol), N-Boc-L-tyrosine (0.85 g, 3.0 mmol), and HBTU (1.37 g,