Efficient synthesis of 2,5-diketopiperazines by Staudinger-mediated cyclization

Article abstract of DOI:10.1055/s-0031-1290446

Solution- and solid-phase Staudinger-mediated cyclizations were assessed to efficiently prepare hetero-2,5-diketopiperazines from their protected azido dipeptide thioesters under microwave irradiation. Short reaction time, good yields and ease of purification are the main assets of this methodology. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290446

LETTER
▌2337
letter
Efficient Synthesis of 2,5-Diketopiperazines by Staudinger-Mediated Cycliza-
tion
Staudinger-Mediated Cyclization to 2,5-Diketopiperazines
Lucas K. Beagle,a Finn K. Hansen,a,b Jean-Christophe M. Monbaliu,a,c Michael P. DesRosiers,a Angela M. Phillips,a
Christian V. Stevens,c Alan R. Katritzky*a,d
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax +1(352)3929199; E-mail: Katritzky@chem.ufl.edu
b
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
c
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium
d
Chemistry Department, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Received: 30.04.2012; Accepted after Revision: 25.06.2012
The head-to-tail condensation is the most straightforward
Abstract: Solution- and solid-phase Staudinger-mediated cycliza-
methodology for preparing cyclic peptides and has been
tions were assessed to efficiently prepare hetero-2,5-diketopipera-
widely described in previous literature. However, the
zines from their protected azido dipeptide thioesters under
head-to-tail condensation of small peptidic sequences is
generally recognized as a difficult reaction. The cyclic di-
mer was often reported rather than the desired cyclic
monomer. These undesired formations of the cyclic dimer
can be reduced by carrying out the reaction in highly di-
lute conditions.19 Beyond their highly constrained cyclic
structure, the primary hurdle is then to bring the N- and C-
termini of the peptide in a close spatial proximity by in-
ducing a turn in the peptidic sequence. This folding was
usually induced by including specific residues in the pep-
tide sequence such as, proline,20 pseudoproline ana-
logues,21 other cyclic unnatural amino acids or other non-
proteogenic residues.22–24 Recently, Tai et al. reported the
macrocyclization of linear tetrapeptides by using poly-
mer-imprinted cavities as templates.25
microwave irradiation. Short reaction time, good yields and ease of
purification are the main assets of this methodology.
Key words: azides, cyclization, cyclic peptides, Staudinger, meth-
odology
Peptide and peptide-like structures have drawn a great
deal of attention from the scientific community especially
in the area of medicinal chemistry.1,2 While small linear
peptides have shown great promise as targets for bioactiv-
ity, they intrinsically suffer from disadvantages due to
their in vivo instability.
Contrastingly, their cyclic analogues are usually associat-
ed with lower vulnerabilities to enzymatic degradation
and a tunable lipophilicity due to their conformation and
structure.3 Small cyclic peptides recently displayed an ex-
pansive range of interesting biological activities including
efficient interaction with opioid receptors,4–6 potency in a
variety of cytotoxic mechanisms in living systems,7–11 and
valuable neuroprotective properties.12 In addition to these
activities, much investigation has been given to the unique
antibacterial, antifungal, antimalarial, and antiviral prop-
erties that have been associated with selected examples.13–18
Generally, head-to-tail condensation of di- and tripeptides
required harsh and prolonged reaction conditions, even
though some recent improvements with microwave-
assisted peptidic cyclization have been reported.26,27 No-
table epimerization, side reactions and low yields were of-
ten reported.28–34 Tetra- and pentapeptides do cyclize
under sequence-specific conditions (see above) and clas-
sical peptide coupling conditions.21 Hexapeptides were
usually reported to cyclize without any particular prob-
lem.
Although a wide range of cyclic oligopeptides are avail-
able from natural sources, intensive research programs
have been devoted to obtain them from synthetic sources.
Common methods have mainly involved three pathways:
(a) head-to-tail condensation between the N- and C-termi-
ni of the corresponding linear peptides, (b) dimerization
from two symmetrical peptide subunits, and (c) methods
other than peptidic coupling.1,2 Many of these syntheses
start from the appropriately protected amino acid or pep-
tidic subunits and these methods are often described in ei-
ther solution or solid phases.19 Of the synthetic methods
reported in the literature, the head-to-tail condensation is
of the greatest interest to us.
Traceless Staudinger ligation is a powerful tool, but some-
time cumbersome, for creating amide bonds34 and has
shown to be effective in both solution and solid phase for
the creation of medium and large peptide sequences.35–37
We were not able to find literature precedents for the use
of the straightforward Staudinger cyclization for the syn-
thesis of small cyclic peptides such as hetero-2,5-diketo-
piperazines.
As part of our on-going research program dedicated to
simple and efficient methods for the preparation of small
cyclic peptides utilizing innovative methodologies, we
now demonstrate a novel, mild and atom-economic tan-
dem deprotection–cyclization strategy for the preparation
of cyclic dipeptides utilizing and assessing a solid- and
SYNLETT 2012, 23, 2337–2340
Advanced online publication: 10.09.2012
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1
4
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4
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DOI: 10.1055/s-0031-1290446; Art ID: ST-2012-S0377-L
© Georg Thieme Verlag Stuttgart · New York

2338
L. K. Beagle et al.
LETTER
solution-phase Staudinger-mediated cyclization, that al-
lows rapid, convenient, and cost-effective cyclization.
Table 1 Optimization of the Preparation of Cyclo(glycyl-L-leucyl)
2a by Staudinger Cyclization
O
The starting material was prepared according to altera-
tions optimized from reported procedures.38 Azido glycyl-
L-leucyl thiophenol ester 1a was obtained in 65% overall
yield in three steps starting from chloroacetyl chloride and
L-leucine (for full experimental details see Supplementary
Information). A first screening of the reaction window
was undertaken in order to identify suitable reaction con-
ditions for the proposed Staudinger-mediated cyclization
in solution phase. The azido-protected dipeptide thioester
1a was reacted under microwave irradiation in the pres-
ence of a phosphine to give cyclic peptide 2a. Upon suc-
cessful reaction, our investigations into optimal reaction
conditions involved differing solvents, addition or exclu-
sion of water from the reactions, different phosphines, and
subjection to microwave irradiation (Table 1). It was
found that reaction in CH2Cl2 under microwave irradia-
tion with five equivalents of water gave the highest yields
and lowest reaction times (entry 3). Triphenyl phosphine
was also studied to effect the cyclization (entry 7), how-
ever, higher yields and the easy removal of the corre-
sponding oxide emphasized tributylphosphine as an
effective promoter for the desired cyclization. Due to its
O
H
N
Ph
PX3 (1.5 equiv)
conditions
NH
N3
S
HN
O
O
2a
1a
Entry
Reaction conditions
Yield (%)
1
2
3
4
5
6
7
Bu3P, anhyd CH2Cl2, r.t., 12 h
55
66
78
70
65
63
58
Bu3P, anhyd CH2Cl2,a MW,b 30 min
Bu3P, CH2Cl2, H2O (5 equiv), MW,b 5 min
Bu3P, THF, H2O (5 equiv), MW,b 5 min
Bu3P, MeCN, H2O (5 equiv), MW,b 5 min
Bu3P, toluene, H2O (5 equiv), MW,b 5 min
Ph3P, CH2Cl2, H2O (5 equiv), MW,b 5 min
a Reaction was quenched with H2O.
b Reaction was carried out at 50 °C, 50 W.
low solubility in dichloromethane, cyclo(glycyl-L-leucyl) tails).39 N-Boc-protected amino acyl benzotriazoles were
2a was simply filtered from the reaction mixture and coupled with 3-thiopropanoic acid, followed by classical
washed with dichloromethane. The title compound was DCC coupling with the AM resin. Further Boc deprotec-
obtained in 78% yield, without any further purification, tion and coupling with azido glycyl benzotriazole afford-
offering an extremely convenient procedure for the prep- ed the solid-phase supported starting materials with high
aration of 2,5-diketopiperazines. Analysis of the mother yields (87–94%). The supported sequences were then sub-
liquor revealed a minimal loss of cyclic dipeptide. The op- jected to our optimized procedure using 1.5 equivalents of
timized conditions were utilized on a slightly different se- tributylphosphine and five equivalents of water in dichlo-
quence bearing a methyl ester as leaving group. After five romethane at 50 °C under microwave irradiation (50 W).
minutes under microwave irradiation at 50 W and 50 °C, After five minutes, a simple filtration followed by a treat-
the yield of cyclo(glycyl-L-leucyl) 2a dropped to 60%. ment of the filter cake with hot methanol to separate the
This experimental result was supported by computations resin from the expected diketopiperazines, and then final-
undertaken at the B3LYP/6-31G* level of theory which ly recrystallization of the mother liquor resulted in pure
demonstrated a lower activation barrier in case of thiophe- 2a–c in good yields (72–81%, entries 4–6, Table 2).
nol as leaving group (21.6 kcalmol–1 vs. 30.0 kcalmol–1 Again, the [α]D values were consistent with the values re-
for the ester)
ported in the literature.40–42 The yields for the solid phase
were similar or higher yielding than their solution-phase
counterparts. The physicochemical properties of cyc-
lo(glycyl-L-leucyl) 2a, cyclo(glycyl-L-phenylalanyl) 2b
and cyclo(glycyl-L-alanyl) 2c were consistent with the
previously reported data. Remarkably, the linker-amino-
methyl resin was recovered and reused for further cycliza-
tions without significant decrease in yield (entry 7, Table
2).
Upon optimization of our methodology on the model se-
quence 1a, we subjected the azido thioesters 1b,c to the
same conditions affording the corresponding cyclic di-
peptides 2b,c in good yield (74–78%, entries 2 and 3, Ta-
ble 2). Their [α]D values were consistent with the values
reported in the literature. The major advantage in the for-
mation of cyclic dipeptides in our methodology, is the
ease of purification, which allows for a simple filtration
followed by drying under reduced pressure of the purified Azido tripeptide thioesters and their AM resin-linker sup-
product, as well as the very short reaction times under mi- ported analogues were prepared according to similar strat-
crowave irradiation.
egies (See Supplementary Information for experimental
details). Interestingly, when our methodology was applied
to the formation of cyclic tripeptides, only the resulting
2,5-diketopiperazines were isolated in 70–74% yield,
whether the solution- or the solid-phase approaches were
utilized (Table 3). The formation of which is due to the
cleavage of the amide bond over the desired, activated
thioester bond. Even though the undesired formation of
2,5-diketopiperazines upon cyclization of higher peptides
In order to fully assess the versatility of this Staudinger-
mediated cyclization method, a similar but solid-phase ap-
proach was considered. A modified aminomethyl (AM)
resin with high loading capacity (1.66 mmol·g–1) bearing
a 3-thiopropionic acid linker was prepared according to a
modified literature precedent by Kent and co-workers
(See Supplementary Information for full experimental de-
Synlett 2012, 23, 2337–2340
© Georg Thieme Verlag Stuttgart · New York

LETTER
Staudinger-Mediated Cyclization to 2,5-Diketopiperazines
2339
(Figure 1). We found that the formation of the diketopi-
perazine was more exothermic by 13.3 kcalmol–1 than the
formation of the cyclic tripeptide (ΔH° = –18.9 kcalmol–1).
The formation of the diketopiperazine appeared thus to be
under thermodynamic control.
Table 2 Solution- and Solid-Phase Synthesis of 2,5-Diketopipera-
zines[43]
O
method A (solution phase)
O
R1
NH
PBu3 (1.5 equiv)
N3
S
HN
N
Ph
H2O (5 equiv)
CH2Cl2
MW, 50 °C, 50 W
5 min
H
R1
O
1a–c
O
2a–c
method B (solid phase)
R1
O
PBu3 (1.5 equiv)
O
NH
H
N3
S
N
H2O (5 equiv)
CH2Cl2
MW, 50 °C, 50 W
5 min
N
HN
H
R1
O
O
1d–f
O
2a–c
Entry
R1
Yield (%)
Figure 1 Competitive cyclization through TS6 (left) and TS9 (right)
1
2
3
4
5
6
7
i-Bu (2a)
Bn (2b)
Me (2c)
i-Bu (2a)
Bn (2b)
Me (2c)
Bn (2b)
78a
74a
78a
79b
72b
81b
82c
In conclusion, 2,5-diketopiperazines were successfully
synthesized from their corresponding azido dipeptide
thioesters in good to excellent yields, using a straightfor-
ward Staudinger-mediated cyclization-type procedure.
The starting materials were synthesized using readily
available α-amino acids and established methodologies.
In particular, our procedure allows short reaction times
and ease of purification. The modified aminomethyl resin
can be recovered and reused, which makes our solid-
phase approach remarkably cost-efficient compared to
known SPPS procedures. This work will serve as a basis
for the synthesis of solid- and solution-phase supported
synthesis of small cyclic peptides utilizing Staudinger cy-
clization protocols.
a Method A (solution phase).
b Method B (solid phase).
c Linker-aminomethyl resin was recovered and reused (see Support-
ing Information).
is a known phenomenon,37 the competitive cleavage of an
amide bond versus the more labile thioester bond is un-
precedented and requires further investigation. Specific
sequence design is in progress and should allow for an ef-
ficent synthesis of cyclic tripeptides utilizing our method-
ology.
Acknowledgment
This work was supported by the Belgian American Educational
Foundation, Inc. (B.A.E.F., fellowship to J.C.M.M.), by the Re-
search Foundation-Flanders (FWO-Vlaanderen, Belgium to
J.C.M.M.), by the Kenan Foundation (University of Florida) and the
King Abdulaziz University (Saudi Arabia).
Table 3 Attempted Solid-Phase Synthesis of Cyclic Tripeptides
O
O
R1
Supporting Information for this article is available online at
PBu3 (1.5 equiv)
H
NH
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
N
S
N3
N
R2
H2O (5 equiv)
CH2Cl2
MW, 50 °C, 50 W
5 min
HN
H
O
O
O
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2337–2340

2340
L. K. Beagle et al.
LETTER
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added and stirring was continued for 5 min at r.t. H2O (0.1
mL, 5 mmol) was added and stirring was continued again for
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General Procedure for the Solid-Phase Synthesis of
2,5-Diketopiperazines from Supported Azido Peptide
Thioesters 1d–f: To a stirred suspension of 1d–f (1 mmol)
in anhyd CH2Cl2 (4 mL), tributylphosphine (0.37 mL, 1.5
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(S)-3-Isobutylpiperazine-2,5-dione (2a): Yield: 78% (0.13
g); white microcrystals; mp 248.0–250.0 °C. 1H NMR (300
MHz, DMSO-d6): δ = 8.26 (br s, 1 H), 7.99 (br s, 1 H), 3.79–
3.89 (m, 1 H), 3.56–3.70 (m, 2 H), 1.69–1.84 (m, 1 H), 1.49–
1.56 (m, 2 H), 0.89 (d, J = 6.7 Hz, 3 H), 0.87 (d, J = 6.6 Hz,
3 H). 13C NMR (75 MHz, CDCl3): δ = 168.8, 166.3, 52.9,
44.2, 42.1, 23.6, 22.9, 21.8. Anal. Calcd for C8H14N2O2: C,
56.45; H, 8.29; N, 16.46. Found: C, 56.63; H, 8.41; N, 16.28.
(S)-3-Benzylpiperazine-2,5-dione (2b): Yield: 74% (0.15
g); white microcrystals; mp 251.0–252.0 °C. 1H NMR (300
MHz, DMSO-d6): δ = 8.11–8.18 (m, 1 H), 7.84–7.90 (m, 1
H), 7.21–7.32 (m, 3 H), 7.10–7.18 (m, 2 H), 4.02–4.09 (m, 1
H), 3.26–3.42 (m, 2 H), 3.08 (dd, J = 13.5, 4.4 Hz, 1 H), 2.87
(dd, J = 13.5, 4.9 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ =
167.4, 166.0, 136.1, 130.2, 128.3, 127.0, 55.7, 43.8. Anal.
Calcd for C11H12N2O2: C, 64.49; H, 5.92; N, 13.72. Found:
C, 64.43; H, 6.06; N, 13.65.
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129.0795; found: 130.1637.
Synlett 2012, 23, 2337–2340
© Georg Thieme Verlag Stuttgart · New York