Synthesis of functionalized, unsymmetrical 1,3,4,6-tetrasubstituted 2,5-diketopiperazines

Article abstract of DOI:10.1021/jo0619635

A general and efficient method for the synthesis of unsymmetrical 1,3,4,6-tetrasubstituted 2,5-diketopiperazines (DKPs) is described. Cyclization of N-amide alkylated dipeptide methyl esters, followed by alkylation, furnished the corresponding tetrasubsti

Full text of DOI:10.1021/jo0619635

Synthesis of Functionalized, Unsymmetrical 1,3,4,6-Tetrasubstituted
2,5-Diketopiperazines
Marcus Tullberg, Morten Grøtli, and Kristina Luthman*
Department of Chemistry, Medicinal Chemistry, Go¨teborg UniVersity, SE-412 96 Go¨teborg, Sweden
luthman@chem.gu.se
ReceiVed September 22, 2006
A general and efficient method for the synthesis of unsymmetrical 1,3,4,6-tetrasubstituted 2,5-diketo-
piperazines (DKPs) is described. Cyclization of N-amide alkylated dipeptide methyl esters, followed by
alkylation, furnished the corresponding tetrasubstituted DKPs in good overall yields. The influence of
steric hindrance in the alkylation reactions appeared to be of lesser importance as long as reactive alkylating
agents were used. Furthermore, we have demonstrated the use of tetrasubstituted DKPs as a scaffold for
further chemical manipulations to produce novel DKPs with desired properties.
Introduction
unsymmetrical tetrasubstituted derivatives contain substituents
with functional groups which can be further modified.7 Some
of the 1,3,4,6-tetrasubstituted DKPs found in nature have
chemically very complex substituents but are still symmetrically
substituted.8 The direct cyclization of a linear substituted
dipeptide9 or the four-component Ugi reaction7,10 are the most
common synthetic procedures for this type of compound.
The 2,5-diketopiperazine (DKP) motif is common in many
natural products and in pharmacologically active compounds
exhibiting a wide range of biological activities, e.g., antibiotic,1
antifungal,2 and anticancer3 effects. 2,5-Diketopiperazines are
also considered to be privileged structures for drug develop-
ment.4 3,6-Disubstituted 2,5-diketopiperazines are rigid struc-
tures with the side chains in the 3- and 6-positions arranged in
a well-defined spatial manner. Additional specific substitutions
on the lactam nitrogen atoms of the DKPs would make the ring
system a potentially useful scaffold.
The present study concerns the synthesis of tetrasubstituted
DKPs. By introduction of the appropriate substituents in defined
positions, the DKPs can be used as scaffolds for further
functionalization in a regioselective manner. As an illustration,
this strategy will be used for the preparation of potential-turn
mimetics of biologically active peptides.
There are many reports in the literature on 1,3,4,6-tetrasub-
stituted 2,5-diketopiperazines.5 However, most of these deriva-
tives are symmetric; i.e., two of the substituents on opposite
sides of the ring are identical,6 and only a few of the
In the first instance, a general and robust method for the
synthesis of a series of tetrasubstituted DKPs is needed. The
objective is to define the optimal reaction protocol for the
introduction of different substituents and to investigate the
possibility of further modification of these substituents regi-
oselectively.
* To whom correspondence should be addressed. Tel.: +46-31-772 2894.
Fax: +46-31-772 3840.
(1) Rameshkumar, N.; Ashokkumar, M.; Subramanian, E. H.; Ilavarasan,
R.; Sridhar, S. K. Eur. J. Med. Chem. 2003, 38, 1001-1004.
(2) McCleland, K.; Milne, P. J.; Lucieto, F. R.; Frost, C.; Brauns, S. C.;
van de Venter, M.; Du, Plessis, J.; Dyason, K. J. Pharm. Pharmacol. 2004,
56, 1143-1153.
(6) Shemyakin, M. M.; Antonov, V. K.; Shkrob, A. M.; Shchelokov, V.
I.; Agadzhanyan, Z. E. Tetrahedron 1965, 21, 3537-3572.
(7) Borthwick, A. D.; Davies, D. E.; Exall, A. M.; Livermore, D. G.;
Sollis, S. L.; Nerozzi, F.; Allen, M. J.; Perren, M.; Shabbir, S. S.; Woollard,
P. M.; Wyatt, P. G. J. Med. Chem. 2005, 48, 6956-6969.
(8) Marco, J. A.; Sanz, J. F.; Yuste, A.; Jakupovic, J. Tetrahedron Lett.
1991, 32, 5193-5194.
(3) Kanoh, K.; Kohno, S.; Asari, T.; Harada, T.; Katada, J.; Muramatsu,
M.; Kawashima, H.; Sekiya, H.; Uno, I. Bioorg. Med. Chem. Lett. 1997, 7,
2847-2852.
(4) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Mol. DiVersity 2002,
5, 289-304.
(5) For a representative reference, see: Veerman, J. J. N.; Bon, R. S.;
Hue, B. T. B.; Girones, D.; Rutjes, F. P. J. T.; van Maarseveen, J. H.;
Hiemstra, H. J. Org. Chem. 2003, 68, 4486-4494.
(9) Nitecki, D. E.; Halpern, B.; Westley, J. W. J. Org. Chem. 1968, 33,
864-866.
10.1021/jo0619635 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/07/2006
J. Org. Chem. 2007, 72, 195-199
195

Tullberg et al.
SCHEME 1 a
TABLE 1. Isolated Yields for the Reductive Amination of 11 to
Form 15-17a,b
compound
R1
yield (%)
15
16
17
benzyl
88
70
60
trans-3-phenyl-2-propenyl
3-cyclohexenylmethyl
a Reaction conditions: R1-CHO, acetic acid, NaBH(OAc)3, 1,2-dichlo-
b
roethane. For the synthesis of 11, see ref 11.
and amino acid methyl esters as shown in Scheme 1. The yields
were generally good (74-89%). Reductive amination can also
be performed with the use of the appropriate aldehydes, but
this reaction gave more complex mixtures with subsequent
purification problems.
Synthesis of Amide Alkylated Dipeptides 7-10. The
peptide coupling reactions gave generally good yields of
N-alkylated dipeptides (52-88%); however, the synthesis of 8
(Boc-Phe-N-benzyl-NleOMe) proved to be difficult. Despite the
use of a range of different coupling reagents such as PyAOP,
PyBOP, PyBroP, HOAt, TBTU, HATU, and EDC,13 only low
yields of product were obtained despite successful reports in
the literature.5 A slightly higher yield (54%) was obtained when
using 2.0 equiv of N-benzylated NleOMe (3) with EDC/HOAt
as coupling reagents.5 Fortunately, unreacted 3 could be
recovered after flash chromatography.
Synthesis of N-Terminally Alkylated Dipeptides 15-17.
The reductive amination of 11 (Phe-NleOMe·HCl) gave moder-
ate to good yields (60-88%) of the N-terminally alkylated
dipeptides 15-17 (Table 1). Care was taken to ensure full
conversion to the imines by the addition of 1.0 equiv of acetic
acid. Once the imine was formed, the reduction proceeded
smoothly with the use of sodium triacetoxyborohydride as the
reducing agent. Compound 11 was synthesized as previously
described.11
a Reagents and conditions: (a) EDC/NMM, CH2Cl2; (b) HCl(g)/CH3OH;
(c) H2O, 200 °C, 10 min, microwave (MW) heating; (d) Et3N, H2O, 140
°C, 10 min, MW heating; (e) BEMP, R4-Br, CH2Cl2 for 24 h at rt or DMF
for 30 min at 60 °C with the use of MW heating. In case of low yield
Bu4NI was added, and the reaction was heated for 3 h at 60 °C with the
use of MW heating.
Results and Discussion
Cyclization of N-Amide Alkylated Dipeptides to Trisub-
stituted DKPs 18-21. Two different methods for cyclization
to trisubstituted DKPs were tested: either direct cyclization of
the Boc-protected dipeptide methyl esters at 200 °C14 or
General. The synthetic procedure to obtain tetrasubstituted
DKPs involved the cyclization of N-terminally or N-amide
alkylated dipeptides (Scheme 1). The fourth substituent was
introduced via N-alkylation in the final step in the synthesis.
We have previously shown that the solution-phase synthesis of
2,5-diketopiperazines using microwave-assisted heating pro-
ceeded in high yields independent of the amino acid sequence.11
In the current work, three amino acids (Phe, Nle, and Ser) were
used to study the influence of steric hindrance in the cyclization
of the alkylated dipeptides and in the alkylation of the
trisubstituted 2,5-DKPs. In addition, one compound (28),
containing four substituents which could be further chemically
modified, was synthesized in order to study the regioselective
manipulation of such tetrasubstituted DKPs.
(12) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862. (b) Salvatore, R.
N.; Nagle, A. S.; Jung, K. W. J. Org. Chem. 2002, 67, 674-683. (c) Paradisi,
F.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 2001, 12, 3319-3324.
(13) PyAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate); PyBOP ((benzotriazol-1-yloxy)tripyrrolidino-phos-
phonium hexafluorophosphate); PyBroP (bromotripyrrolidino-phosphonium
hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole); TBTU (O-
(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate); HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophos-
phate); EDC (N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide); BEMP
(2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphos-
phorine).
(14) (a) Lopez-Cobenas, A.; Cledera, P.; Sanchez, J. D.; Lopez-Alvarado,
P.; Ramos, M. T.; Avendano, C.; Menendez, J. C. Synthesis 2005, 3412-
3422. (b) Lopez-Cobenas, A.; Cledera, P.; Sanchez, J. D.; Perez-Contreras,
R.; Lopez-Alvarado, P.; Ramos, M. T.; Avendano, C.; Menendez, J. C.
Synlett 2005, 1158-1160. (c) Carlsson, A.-C.; Jam, F.; Tullberg, M.; Pilotti,
Å.; Ioannidis, P.; Luthman, K.; Grøtli, M. Tetrahedron Lett. 2006, 47, 5199-
5201.
Synthesis of N-Alkylated Amino Acids 1-5.12 The N-
alkylated amino acids were synthesized using alkyl bromides
(10) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama,
T. J. Am. Chem. Soc. 2002, 124, 6552-6554.
(11) Tullberg, M.; Grøtli, M.; Luthman, K. Tetrahedron 2006, 62, 7484-
7491.
196 J. Org. Chem., Vol. 72, No. 1, 2007

1,3,4,6-Tetrasubstituted 2,5-Diketopiperazines
TABLE 2. Isolated Yields of DKPs Using Two Different
Cyclization Methodsa
TABLE 3. Isolated Yields Obtained in the N-alkylation Reactions
of DKPs 18, 19, and 21
yield
compound
R1
R2
R3
R4
(%)
22
23
24
25
26
27
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
methyl
methyl
methyl
methyl
benzyl
methyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
propargyl
allyl
n-pentyl
benzyl
benzyl
2-phthalimido-
ethyl
77a
72a
81b
74c
83c
52b
DKP starting material
R1
R2
R3
yield (%)
18
19
20
21
18
19
20
7
8
9
10
12
13
14
benzyl
benzyl
benzyl
methyl
benzyl
propargyl n-butyl
n-butyl
n-butyl
70
40
62
78
73
40
72
p-Br-Bn propargyl CH2OBn
28
p-Br-Bn propargyl CH2OBn allyl
94c
benzyl
benzyl
benzyl
methyl
benzyl
propargyl n-butyl
n-butyl
n-butyl
a The reaction was run at rt for 24 h in CH2Cl2. b MW heating at 60 °C
for 3 h in DMF in the presence of Bu4NI. c MW heating at 60 °C for 30
min in DMF.
a Reaction conditions: 50 mg of each starting material in water (4 mL)
was used for the cyclization reactions. When the use of the hydrochloride
salt of the dipeptide methyl ester took place, triethylamine (2.0 equiv) was
added to the reaction. (i) The reaction was run at 200 °C for 10 min with
the use of MW heating. (ii) The reaction was run at 140 °C for 10 min
(MW heating) in the presence of 2.0 equiv of triethylamine.
smoothly as shown in Table 3. The alkylation of 18 with
propargyl or allyl bromide proceeded at room temperature,
giving 22 and 23 in good yields (77 and 72%, respectively).
Attempts to alkylate 18 using n-pentyl or benzyl bromides to
obtain 24 and 25 using PS-BEMP at room temperature failed,
and no products could be isolated. However, with microwave
heating at 60 °C in DMF for 3 h the compounds were isolated
in 31 and 74% yields, respectively.16 Compound 25 could also
be formed in similar yield when heated for only 30 min at 60
°C. In reactions requiring microwave heating, BEMP was used
instead of PS-BEMP since the polymer-based base had a
tendency to stick to the glass walls of the reaction vessel.
Compound 19 was benzylated with benzyl bromide and BEMP
with the use of microwave heating for 30 min at 60 °C, affording
26 in 83% yield.
The yield of 24 was only 31% even with the use of
microwave-assisted heating for 3 h. Steric hindrance cannot
explain the low yield, as the benzyl group in 26 can be expected
to be as sterically demanding as the pentyl group in 24. Instead,
the low yield of 24 is probably due to the lower reactivity of
pentyl bromide in comparison with that of allyl, propargyl, and
benzyl bromide. However, when pentyl bromide was exchanged
for the corresponding iodide with the use of 1.0 equiv of
tetrabutylammonium iodide, the yield increased from 31 to
81%.17 The low-yielding alkylation of 18 with N-(2-bromoet-
hyl)phthalimide is probably due to a combination of steric
hindrance and low reactivity of the alkylating agent. Even with
the use of 1.0 equiv of tetrabutylammonium iodide, the yield
of 27 was only 52%.
cyclization of the hydrochloride salts of the Boc-deprotected
dipeptide methyl esters at 140 °C in the presence of 2.0 equiv
of triethylamine (Table 2). Both methods used microwave-
assisted heating with water as solvent. No significant difference
in yields between the two methods was found. The small
difference in yield obtained in the synthesis 20 from 9 or 14
(Table 2) could be explained by the fact that 20 prepared from
9 required column chromatography in order to separate unre-
acted dipeptide from the target DKP, whereas 14 could easily
be separated from 20 by filtration. Probably due to steric
interactions in the cyclization, compound 19 was formed in low
yields (40%) with both cyclization procedures. Compounds 18
and 20, however, were formed in moderate to good yields (62-
73%). Compound 10 was cyclized with the Boc-group still
attached, thus minimizing the number of reaction steps. How-
ever, in the cyclization of 10, which is a solid, care had to be
taken not to heat the reaction mixture too fast, in order to avoid
decomposition of the dipeptide. Therefore, the reaction vessel
was heated to 200 °C during a period of 3 min.
Cyclization of the Terminally N-Substituted Compounds
15-17. Attempts to cyclize the N-alkylated dipeptides 15-17
(Table 3) were performed using water as solvent and microwave-
assisted heating ranging from 140 °C for 10 min to 200 °C for
10 h. Unfortunately none of the desired products could be
isolated from the reactions; only unreacted starting material
could be detected in 1H-NMR spectra. The starting material was
found to be heat-stable, as no trace of decomposition could be
Apparently, efficient alkylation of the DKPs is restricted to
reactive alkyl bromides. Then, the reaction time could be
reduced from 3 h to 30 min with the use of microwave-assisted
heating, affording higher yields of product due to easier workup
as a result of less-complex reaction mixtures.
1
detected in H-NMR spectra. Apparently, the nucleophilicity
and steric hindrance of the N-terminal nitrogen are important
for efficient cyclization, and unless small N-alkyl groups are to
be introduced, it is preferred to do the cyclization on the
N-alkylated amides instead.
A. Further Modifications of Substituents in DKP 28. The
different substituents introduced in the tetrasubstituted DKP 28
Alkylation on the Lactam Nitrogen of the DKPs. The most
common method for the alkylation of lactam nitrogens of DKPs
is based on the use of sodium hydride base.15 However, in our
hands the use of sodium hydride proved unsuccessful, whereas
when the use of the stronger, polymer-supported base BEMP13
(PS-BEMP) was employed, the alkylation reactions proceeded
(15) (a) Ohta, A.; Okuwaki, Y.; Komaru, T.; Hisatome, M.; Yoshida,
Y.; Aizawa, J.; Nakano, Y.; Shibata, H.; Miyazaki, T.; Watanabe, T.
Heterocycles 1987, 26, 2691-2701. (b) Yoshimura, J.; Yamaura, M.;
Suzuki, T.; Hashimoto, H. Chem. Lett. 1983, 1001-1002.
(16) Fara, M. A.; Diaz-Mochon, J. J.; Bradley, M. Tetrahedron Lett. 2006,
47, 1011-1014.
(17) Finkelstein, H. Ber. Dtsch. Chem Ges. 1910, 43, 1528-1532.
J. Org. Chem, Vol. 72, No. 1, 2007 197

Tullberg et al.
SCHEME 2. Synthesis of Functionalized, Unsymmetrically
1,3,4,6-Tetrasubstituted 2,5-Diketopiperazinesa
the use of an alkyl halide in the presence of a sterically hindered
strong organic base (BEMP) furnished the corresponding
tetrasubstituted DKPs in good overall yields. The influence of
the steric hindrance in the alkylation reactions appeared to be
of lesser importance as long as reactive alkyl bromides were
used. However, cyclization of N-alkylated dipeptide methyl
esters, using microwave-assisted heating in water failed, thus
indicating the importance of the nucleophilic strength of the
N-terminal nitrogen for efficient cyclization.
Furthermore, we have demonstrated that a 1,3,4,6-tetrasub-
stituted 2,5-diketopiperazine is a useful scaffold. High regiose-
lectivity in functionalization reactions could be obtained by using
orthogonal chemical reactions on a tetrasubstituted DKP. This
strategy will allow the synthesis of novel DKPs with desired
properties and is currently being explored in our laboratory for
the development of â-turn mimetics.
Experimental Section
Compounds 2 and 11 were synthesized as described in ref 11.
Representative Example of Cyclization of Amide Alkylated
Dipeptides to Trisubstituted 2,5-DKPs: c(L-Phenylalanyl-N-
propargyl-L-norleucinyl) (20). A solution of 9 (50 mg, 0.14 mmol)
in water (4 mL) was heated at 200 °C for 10 min in a microwave
cavity. The crude product was purified by flash chromatography
using EtOAc/hexane (3:2) as eluent to give pure 20 as white crystals
(26 mg; 62%). Mp: 117-119 °C. [R]D: -122.6° (c 1, CH2Cl2).
1H NMR (CDCl3): δ 7.34-7.24 (m, 5H), 6.44 (s, 1H), 4.73 (dd,
J ) 17.6, 2.6 Hz, 1H), 4.30-4.24 (m, 1H), 4.22 (dd, J ) 6.6, 3.3
Hz, 1H), 3.80 (dd, J ) 17.6, 2.6 Hz, 1H), 3.33 (dd, J ) 13.7, 3.8
Hz, 1H), 2.98 (dd, J ) 13.9, 8.8 Hz, 1H), 2.29 (t, J ) 2.6 Hz, 1H),
1.85-1.76 (m, 1H), 1.52-1.43 (m, 1H), 1.32-1.07 (m, 4H), 0.87
(t, J ) 7.1 Hz, 3H). 13C NMR (CDCl3): δ 167.3, 165.0, 135.6,
129.9, 129.1, 127.6, 76.9, 73.6, 58.9, 56.8, 41.4, 33.7, 31.2, 26.6,
22.4, 14.0. Anal. Calcd for C18H22N2O2: C, 72.46; H, 7.43; N, 9.39.
Found C, 72.3; H, 7.6; N, 9.6.
a Reagents and conditions: (a) N-Azide-L-phenylalaninol, CuIISO4,
sodium ascorbate/CH2Cl2:H2O (1:1), rt, 20 h; (b1) BH3‚THF/THF, -40
°C, 4 h; (b2) H2O2/NaOH, 0 °C, 2 h; (c) PdII(OAc)2, tri(o-tolyl)phosphine,
Et3N, methyl acrylate/DMF, 150 °C, 30 min, MW heating.
could be functionalized in different ways (Scheme 2). This
provides opportunities for using 28 as a scaffold for the synthesis
of series of novel DKPs.
Representative Example of N-Alkylations of Trisubstituted
DKPs Using BEMP as Base: c(N-pentyl-L-phenylalanyl-N-
methyl-L-norleucinyl) (24). Compound 18 (50 mg, 0.18 mmol)
was dissolved in DMF (4 mL) and BEMP (0.10 mL, 0.36 mmol),
1-bromopentane (33 µL, 0.27 mmol) and tetrabutylammonium
iodide (99.7 mg, 0.27 mmol) were added, and the mixture was
heated at 60 °C for 3 h. The reaction mixture was concentrated in
vacuo, and the crude product was purified by flash chromatography
using EtOAc/hexane (3:2) as eluent to give pure 24 as a colorless
oil (48 mg, 81%). [R]D: -42° (c 0.3, CH2Cl2). 1H NMR (CDCl3):
δ 7.41-7.08 (m, 5H), 4.26-4.16 (m, 1H), 3.87-3.83 (m, 1H),
3.77-3.73 (m, 1H), 3.58-3.53 (m, 1H), 2.99-2.89 (m, 1H), 2.88
(s, 3H), 2.87-2.70 (m, 1H), 1.97-1.87 (m, 1H), 1.86-1.75 (m,
1H), 1.60-1.45 (m, 2H), 1.39-1.05 (m, 8H), 0.91-0.75 (m, 6H).
13C NMR (CDCl3): δ 165.8, 165.2, 136.1, 129.7, 128.8, 126.9,
62.1, 60.6, 47.2, 37.8, 32.5, 32.4, 32.0, 31.5, 22.1, 21.3, 14.0, 13.9.
Anal. Calcd for C21H32N2O2: C, 73.22; H, 9.36; N, 8.13. Found
C, 73.4; H, 9.6; N, 7.9.
A1. 1,2,3-Triazole Formation from the Propargyl Group.
It was possible to convert the propargyl group in 28 into a 1,4-
substituted triazole derivative (29) in high yield (95%) using
an azide obtained from phenylalaninol.18 It is expected that the
use of different azides would provide easy access to a wide
range of new chemical entities.
A2. Hydroboration of the Allyl Group. The allyl group was
oxidized to the primary alcohol (30) by hydroboration of 29
using borane in THF. The subsequent removal of the borane
was achieved with the use of hydrogen peroxide in the presence
of sodium hydroxide. The reaction was first run at room
temperature, resulting in a complex reaction mixture according
to TLC. When cooling of the solution of 29 in THF to -40 °C
was done before addition of the borane and cooling to 0 °C
was done before the oxidation step, the reaction proceeded
smoothly, providing 30 in good yield (81%).
Synthesis and Further Modifications of Substituents in DKP
28. c(N-Allyl-4-bromo-L-phenylalanyl-N-propargyl-O-benzyl-L-
serinyl) (28). Compound 21 (0.10 g, 0.23 mmol) was dissolved in
DMF (4 mL) and BEMP (0.31 mL, 0.45 mmol), and allyl bromide
(30 µL, 0.35 mmol) was added. The mixture was heated in the
microwave at 60 °C for 30 min. The reaction mixture was
concentrated in vacuo, and the crude product was purified by flash
chromatography using EtOAc/hexane (3:2) as the eluent to give
pure 28 as white crystals (0.10 g, 94%). Mp: 103-105 °C. [R]D:
A3. Heck Reaction on the Aryl Bromide. The final
modification involved a Pd-mediated coupling of methyl acrylate
with the bromide-substituted benzyl group. The reaction was
run using standard Heck conditions (palladium diacetate (10%),
tri(o-tolyl)phosphine (20%), triethylamine (2.0 equiv)), and the
product (31) was obtained in good yield (83%).
Conclusion
1
-87.3° (c 2, CH2Cl2). H NMR (CDCl3): δ 7.38-7.25 (m, 7H),
A general and efficient method for the synthesis of unsym-
metrical DKPs has been developed. Cyclization of N-amide
alkylated dipeptide methyl esters, followed by alkylation with
(18) Fan, Q.-H.; Ni, N.-T.; Li, Q.; Zhang, L.-H.; Ye, X.-S. Org. Lett.
2006, 8, 1007-1009.
198 J. Org. Chem., Vol. 72, No. 1, 2007

1,3,4,6-Tetrasubstituted 2,5-Diketopiperazines
6.90 (d, J ) 8.4 Hz, 2H), 5.62 (dddd, J ) 17.4, 9.9, 4.7, 0.8 Hz,
1H), 5.18 (dd, J ) 10.1, 0.9 Hz, 1H), 5.01 (dd, J ) 17.0, 1.7 Hz,
1H), 4.63-4.59 (m, 1H), 4.63 (dd, J ) 17.6, 2.6 Hz, 1H), 4.47 (d,
J ) 12.1 Hz, 1H), 4.38 (d, J ) 12.1 Hz, 1H), 4.38-4.36 (m, 1H),
4.20 (t, J ) 5.9 Hz, 1H), 3.88 (dd, J ) 17.6, 2.6 Hz, 1H), 3.69 (dd,
J ) 9.9, 2.6 Hz, 1H), 3.12 (dd, J ) 9.9, 2.6 Hz, 1H), 3.13-3.10
(m, 2H), 3.01 (dd, J ) 15.2, 7.9 Hz, 1H), 2.26 (t, J ) 2.6 Hz, 1H).
13C NMR (CDCl3): δ 165.5, 164.2, 137.1, 135.9, 132.0, 131.9,
131.5, 131.2, 128.7, 128.2, 128.1, 121.3, 119.6, 77.5, 73.5, 73.3,
69.9, 60.3, 60.2, 47.3, 39.3, 34.2. Anal. Calcd for C25H25BrN2O3:
C, 62.38; H, 5.23; N, 5.82. Found C, 62.2; H, 5.4; N, 5.9.
(3S,6S)-1-Allyl-3-(benzyloxymethyl)-6-(4-bromobenzyl)-4-[((1-
(1S)-1-hydroxy-3-phenyl-prop-2-yl)-1H-1,2,3-triazol-4-yl)meth-
yl]piperazine-2,5-dione (29). Compound 28 (0.35 g, 0.73 mmol)
and (S)-2-azido-3-phenyl-propan-1-ol18 (0.13 g, 0.73 mmol) were
dissolved in CH2Cl2 (1 mL) and a premixed solution of sodium
ascorbate (73 µL, 73 µmol) (1.0 M in H2O), copper(II) sulfate
pentahydrate (0.73 mL, 7.3 µmol) (10 mM in H2O) was added,
and the mixture was stirred vigorously for 20 h at rt. The reaction
mixture was concentrated in vacuo and purified by flash chroma-
tography using CH2Cl2/CH3OH (8:1) as eluent to give pure 29 as
a white fluffy powder (0.46 g, 95%). [R]D: -109° (c 1, CH2Cl2).
1H NMR (CDCl3): δ 7.42 (s, 1H), 7.32 (d, J ) 8.4 Hz, 2H), 7.26
(d, J ) 7.0 Hz, 2H), 7.25-7.17 (m, 2H), 7.16 (d, J ) 7.0 Hz, 2H),
7.13 (d, J ) 7.0 Hz, 2H), 6.98 (d, J ) 7.0 Hz, 2H), 6.82 (d, J )
8.4 Hz, 2H), 5.54 (dddd, J ) 17.4, 9.9, 4.7, 0.8 Hz, 1H), 5.10 (d,
J ) 10.3 Hz, 1H), 4.92 (d, J ) 17.2 Hz, 1H), 4.84 (d, J ) 15.0
Hz, 1H), 4.69-4.59 (m, 1H), 4.46 (dd, J ) 15.2, 4.6 Hz, 1H),
4.32 (q, J ) 21.6, 11.3 Hz, 2H), 4.26 (d, J ) 15.0 Hz, 1H), 4.11-
4.07 (m, 2H), 4.00 (t, J ) 5.5 Hz, 1H), 3.95-3.87 (m, 1H), 3.76
(dd, J ) 9.9, 2.6 Hz, 1H), 3.34 (dd, J ) 9.9, 2.6 Hz, 1H), 3.21-
3.03 (m, 4H), 3.00 (dd, J ) 15.9, 7.0 Hz, 1H). 13C NMR (CDCl3):
δ 166.0, 164.5, 141.7, 137.1, 136.6, 136.2, 131.7, 131.4, 131.3,
129.0, 128.8, 128.6, 128.3, 128.2, 124.3, 121.1, 119.3, 73.5, 69.6,
65.2, 63.5, 61.0, 60.6, 47.4, 39.8, 39.7, 37.8. Anal. Calcd for C34H36-
BrN5O4: C, 62.01; H, 5.51; N, 10.63. Found C, 62.1; H, 5.6; N,
10.7.
dried (Na2SO4), and concentrated in vacuo. The crude product was
purified by flash chromatography using CH2Cl2/CH3OH (8:1) as
the eluent to give pure 30 as a colorless oil (82 mg, 81%). [R]D:
-54.8° (c 2, CH2Cl2). 1H NMR (CDCl3): δ 7.37-6.90 (m, 15H),
4.79 (d, J ) 14.6 Hz, 1H), 4.65 (s, 1H), 4.55 (t, J ) 11.0 Hz, 1H),
4.23 (q, J ) 20.5, 12.1 Hz, 2H), 4.13 (d, J ) 14.6 Hz, 1H), 4.02-
3.92 (m, 4H), 3.63 (t, J ) 5.9 Hz, 1H), 3.58-3.50 (m, 1H), 3.22-
3.06 (m, 4H), 3.00-2.88 (m, 2H), 2.33-2.27 (m, 1H), 2.19 (dd, J
) 12.1, 3.6 Hz, 1H), 1.75-1.55 (m, 2H), 1.13 (dd, J ) 23.1, 6.2
Hz, 1H). 13C NMR (CDCl3): δ 169.3, 169.0, 147.2, 146.1, 142.8,
136.7, 132.2, 131.1, 129.1, 128.8, 128.7, 128.5, 127.8, 127.2, 124.5,
120.3, 73.3, 70.0, 67.2, 63.7, 61.6, 55.0, 52.3, 47.7, 41.55, 37.8,
35.4, 28.8. Anal. Calcd for C34H38BrN5O5: C, 60.36; H, 5.66; N,
10.35. Found C, 60.3; H, 5.6; N, 10.3.
(3S,6S)-3-(Benzyloxymethyl)-4-[((1-(1S)-1-hydroxy-3-phenyl-
prop-2-yl)-1H-1,2,3-triazol-4-yl)methyl]-1-(3-hydroxypropyl)-6-
(4-(2-methoxycarbonyletenyl)benzyl)piperazine-2,5-dione (31).
Compound 30 (48 mg, 71 µmol), palladium(II) acetate (1.6 mg,
7.1 µmol), tri(o-tolyl)phosphine (4.0 mg, 14 µmol), triethylamine
(20 µL, 1.4 mmol), and methyl acrylate (13 µL, 1.4 mmol) were
dissolved in DMF (3 mL) and heated in a microwave at 150 °C
for 30 min. The reaction mixture was filtered through Celite with
EtOAc and concentrated in vacuo. The crude product was purified
by flash chromatography using CH2Cl2/CH3OH (8:1) as the eluent
to give pure 31 as a colorless oil (40 mg, 83%). [R]D: -65.6° (c
1, CH2Cl2). 1H NMR (CDCl3): δ 7.62 (d, J ) 16.1 Hz, 1H), 7.40-
6.90 (m, 15H), 6.35 (d, J ) 16.1 Hz, 1H), 4.81 (d, J ) 15.0 Hz,
1H), 4.68-4.62 (m, 1H), 4.54 (t, J ) 11.0 Hz, 1H), 4.23 (d, J )
6.6 Hz, 2H), 4.13 (d, J ) 15.0 Hz, 1H), 4.02-3.93 (m, 4H), 3.78
(s, 3H), 3.63 (t, J ) 5.9 Hz, 1H), 3.58-3.50 (m, 1H), 3.22-3.06
(m, 4H), 3.00-2.88 (m, 2H), 2.33-2.27 (m, 1H), 2.22-2.15 (m,
1H), 1.74-1.56 (m, 2H), 1.12 (dd, J ) 23.1, 6.2 Hz, 1H). 13C NMR
(CDCl3): δ 169.5, 169.4, 167.6, 144.7, 141.1, 138.3, 138.0, 136.7,
136.6, 132.1, 131.1, 129.0, 128.9, 128.8, 128.5, 127.8, 127.6, 127.1,
123.8, 117.3, 73.5, 73.3, 69.9, 63.7, 61.6, 54.9, 51.8, 48.3, 41.5,
37.8, 35.4, 31.5. Anal. Calcd for C38H43N5O7: C, 66.94; H, 6.36;
N, 10.27. Found C, 66.8; H, 6.35; N, 10.4.
(3S,6S)-3-(Benzyloxymethyl)-6-(4-bromobenzyl)-4-[((1-(1S)-
1-hydroxy-3-phenyl-prop-2-yl)-1H-1,2,3-triazol-4-yl)methyl]-1-
(3-hydroxypropyl)piperazine-2,5-dione (30). Compound 29 (0.10
g, 0.15 mmol) was dissolved in THF (2 mL) and cooled to -40
°C followed by addition of BH3·THF complex (0.38 mL, 0.38
mmol) (1 M in THF). After 2 h the reaction was allowed to reach
rt over a period of 3 h. After 12 h the reaction mixture was cooled
to 0 °C whereupon NaOH (2 mL, 6 mmol) (3 M aq) and H2O2 (2
mL, 18 mmol) (30% w/w in H2O) were added. The reaction was
stirred for 2 h whereupon the mixture was extracted with EtOAc,
Acknowledgment. Financial support was obtained from the
Knut and Alice Wallenberg Foundation and the Swedish
Research Council.
Supporting Information Available: Compound characterization
data for compounds 1, 3-10, 12-19, 21-23, and 25-27; NMR
spectra of compounds 28-31. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0619635
J. Org. Chem, Vol. 72, No. 1, 2007 199