One-pot synthesis of symmetrical and unsymmetrical diketopiperazines from unprotected amino acids

Article abstract of DOI:10.1055/s-2007-984875

An efficient synthesis of symmetrical and unsymmetrical proline-type diketopiperazines using a phosphite-promoted coupling was used to generate diketopiperazines with overall good yields from unprotected amino acids. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984875

LETTER
2127
One-Pot Synthesis of Symmetrical and Unsymmetrical Diketopiperazines
from Unprotected Amino Acids
S
ynthesis of Symm
n
etrical and
U
n
nsymmetric
e
al Diketopiperazi
F
nes riedrich,a Manuel Jainta,a Martin Nieger,b Stefan Bräse*a
a
Institute of Organic Chemistry, University of Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: braese@ioc.uka.de
b
Laboratory of Inorganic Chemistry, University of Helsinki, 00014 Helsinki, Finland
Received 25 April 2007
Retrosynthetically, these molecules can be reduced to
diketopiperazines and then thiolated as originally devised
by Schmidt and co-workers.10 In this regard, an efficient
synthesis of symmetrical diketopiperazines was needed.
Although various methods are applicable, we focused on
a one-step synthesis from the corresponding free amino
acid. Yamamoto et al. reported a straightforward route to
the molecules by condensation of amino acids in the pres-
ence of a bulky boronic acid.11
Abstract: An efficient synthesis of symmetrical and unsymmetri-
cal proline-type diketopiperazines using a phosphite-promoted
coupling was used to generate diketopiperazines with overall good
yields from unprotected amino acids.
Key words: amino acids, diketopiperazines, thiolation, hetero-
cycles
Amino acids can be found in a great variety and play an
important role in nature. One interesting structural motif
is the class of the epithiodiketopiperazines, diketopipera-
zines with a disulfide bridge (Figure 1). In some cases,
like silvatin,1 gliotoxin,2 gliovictin, sporidesmin,3 and sca-
brosinester (3),4–6 total syntheses or studies have already
been reported, but the majority of this group is still un-
explored.4,7 Within this group the rostratins 1, four new
marine mycotoxins, have been recently reported by
Fenical et al.8
Although this transformation is suitable for many sub-
strates, we were faced with some problems using more
functionalized substrates.
Ugi et al. described the syntheses of symmetrical
diketopiperazines from amino acids in the presence of a
stoichiometric amount of dichloromethoxyphosphine
(Scheme 1).12 In this manuscript, we extend this method
to more functionalized proline derivatives.
O
O
R3PCl2
R2
R1
O
O
R1
R2
H
3° amine
OH
N
NH
O
+
H
COOH
N
OH
O
N
N
S
toluene, ∆
N
S
H
H
H
COOH
S
H
N
OCH3
H3CO
N
S
OH
O
H
O
O
OH
(rac)-4
5
6
O
R1 = H, R2 = H, CH3, C3H7
R1–R2 = (CH2)3, CH2SCH2
R3 = OMe, N(i-Pr)2, Cl
rostratin C (1)
aranotin (2)
R1
O
R1
R2
O
Scheme 1 Synthesis of diketopiperazines as reported by Ugi12
3a CH3
3b CH3
3c C3H7
3d CH3
3e C3H7
CH3
H
O
O
S
C3H7
C3H7
C5H11
C5H11
N
N
S
O
O
H
After some optimization of reaction time and workup, we
dimerized a number of proline derivatives to obtain the
symmetrical diketopiperazines 8a–d (Scheme 2). This
method is also applicable for hexahydroindolecarboxylic
acid (9), which gave the dimer 10 in 94% yield. This
molecule already contains the complete framework of the
rostratins B–D (Figure 1).
O
O
R2
scabrosinester (3)
Figure 1 Some naturally occurring symmetrical epithiodiketo-
piperazines
In order to further investigate the chemistry of these natu-
ral products, we started a program to synthesize symmet-
rical epithiodiketopiperazines. These compounds do not
only represent the core of many natural products but have
recently attracted attention in conformational studies.9
Under these conditions, dimerization of the unsaturated
analogues indoline-2-carboxylic acid (11) and indole-2-
carboxylic acid (13), afforded the corresponding pentacy-
clic diketopiperazines in 83% and 57% yield, respectively
(Scheme 3).
In all cases, complete retention of the stereochemistry was
observed by NMR spectroscopy and it could be unequiv-
ocally proven by X-ray crystallography of cyclo-Pro-Pro
(8a, Figure 2).13
SYNLETT 2007, No. 13, pp 2127–2129
Advanced online publication: 27.06.2007
DOI: 10.1055/s-2007-984875; Art ID: G13507ST
© Georg Thieme Verlag Stuttgart · New York
1
3
.0
8
.2
0
0
7

2128
A. Friedrich et al.
LETTER
O
The reaction was also carried out generating the coupling
reagent dichloromethoxyphosphine in situ. For that pur-
pose we quenched one equivalent of trichlorophosphine
with one equivalent of anhydrous methanol at –10 °C.14
Dilution with toluene, then addition of an amino acid and
a base, gave the diketopiperazines with no significant dif-
ferences in yields.
H
N
H
N
MeOPCl2, Et3N
HOOC
N
H
R
R
toluene, reflux, 2 h
R
O
7
8
7a
7b
7c
7d
R = H
66% 8a
R = OTBDMS
R = Ot-Bu,
R = OBn
51%
52%
96%
8b
8c
8d
Extending this method, we also generated unsymmetrical
diketopiperazines in a one-pot reaction. To obtain the
cross-coupled substrates, treatment of the first amino acid
7a with the coupling reagent at elevated temperature was
necessary. After subsequent addition of the second amino
acid (13, 15, 17) and heating to reflux, we observed the
formation of the unsymmetrical diketopiperazines (16,
18, 19) in good yields (Scheme 4).
H
H
H
MeOPCl2,
Et3N
H
O
COOH
H
H
N
toluene,
reflux, 4 h
94%
N
N
H
H
O
H
9
10
R
Scheme 2 Synthesis of substituted cyclo-Pro-Pro derivatives
H
MeOPCl2, Et3N
N
HO2C
+
toluene, reflux, 3 h
H2N
CO2H
15 R = H
7a
17 R = OBn
H
H
O
N
O
NH
OR
16 R = H 52%
18 R = OBn 32%
H
MeOPCl2, Et3N
N
HO2C
+
CO2H
toluene, reflux, 3 h
54%
N
H
7a
13
Figure 2 X-ray crystal structure of 8a
H
O
N
N
MeOPCl2, Et3N
CO2H
O
toluene, reflux, 5 h
N
H
19
83%
11
Scheme 4 Preparation of unsymmetrical diketopiperazines
H
O
N
N
To reach for the above-mentioned higher functionalized
epithiodiketopiperazines, we tested some thiolation meth-
ods starting with our previous synthesized diketopipera-
zines (Scheme 5). The method using sodium amide and
elemental sulfur in liquid ammonia, developed by
Schmidt and co-workers.10 was found to be the most
effective way to introduce the sulfur functionality. Our
unsubstituted model system cyclo-Pro-Pro (8a) could be
O
H
12
MeOPCl2, Et3N
CO2H
toluene, reflux, 3 h
57%
N
H
13
O
N
N
O
O
H
N
1) NaNH2, S8, NH3
O
N
N
H
S
S
14
N
2) KI3, CHCl3
50%
Scheme 3 Preparation of unsaturated diketopiperazines
O
O
8a
20
Scheme 5 Synthesis of epithiodiketopiperazines
Synlett 2007, No. 13, 2127–2129 © Thieme Stuttgart · New York

LETTER
Synthesis of Symmetrical and Unsymmetrical Diketopiperazines
2129
easily thiolated to yield the expected product 20 in 50%
References and Notes
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Med. Chem. 2004, 12, 5991.
In summary, an efficient method to generate highly func-
tionalized symmetrical and unsymmetrical diketopipera-
zines in a one-pot reaction has been developed. The
scalability, easy workup and good yields are the advantag-
es of this method. Furthermore it was shown that the reac-
tion is free of racemization or inversion and leads reliably
and successfully to the expected diketopiperazines. Over-
all, this one-flask cyclization quickly assembles diketo-
piperazines, which are common structural features in
natural products.
(6) Ernst-Russell, M. A.; Chai, C. L. L.; Hurne, A. M. Aust. J.
Chem. 1999, 52, 279.
(7) (a) Fang, M.; Fang, H.; Huang, Y.; Zhao, Y. Tetrahedron
Lett. 2005, 46, 2147. (b) Williams, D. E.; Bombuwala, K.;
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General Method for the Dimerization of a-Amino Acids
The amino acid (4.2 mmol) was dissolved in 30 mL anhyd toluene
and Et3N (16.6 mmol) and methyldichlorophosphite (4.2 mmol)
was added via canula under argon. The solution was heated under
reflux for 3–6 h. Afterwards, the hot solution was filtered off and the
precipitate was washed with hot toluene. The filtrate was evaporat-
ed and the resulting crude product was purified by flash column
chromatography.
(S,S)-(6a,7,13a,14)-Tetrahydropyrazino [1,2-a:4,5-a¢]diindol-6-
13-dione (12)
Rf = 0.38 (hexanes–EtOAc, 3:1); [a]D20 –2.21 (c 1.00, CHCl3); mp
263–268 °C. IR (neat): 3344, 3069, 3050, 2898, 2863, 1793, 1681,
1603, 1483, 1462, 1446, 1410, 1343, 1315, 1245, 1213, 1182, 1156,
1131, 1086, 1018, 996, 928, 867, 849, 776, 756, 713, 647, 563, 528
cm–1. 1H NMR (400 MHz, CDCl3): d = 3.46 (dd, J = 9.6, 16.8 Hz, 2
H, 7,14-H), 3.82 (dd, J = 9.6, 16.8 Hz, 2 H, 7,14-H), 4.99 (dd,
J = 9.6, 16.8 Hz, 2 H, 6a,13a-H), 7.13 (dt, J = 1.0, 8.0 Hz, 2 H, 1,8-
H), 7.29 (t, J = 8.0 Hz, 4 H, 3,4,10,11-H), 8.13 (d, J = 8.0 Hz, 2 H,
2,9-H). 13C NMR (100 MHz, CDCl3): d = 30.0 (s, 2 C, C-7,14), 61.6
(t, 2 C, C-6a,13a), 115.7 (t, 2 C, C-4,11), 125.0 (t, 4 C, C-2,3,9,10),
127.9 (t, 2 C, C-1,8), 129.7 (t, 2 C, C-7a,14a), 140.5 (q, 2 C, C-
4a,11a), 164.2 (q, 2 C, CO). MS (EI, 70 eV): m/z = 290 [M+].
HRMS: m/z calcd for C18H14N2O2 [M+]: 290.1055; found:
290.1049. Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65.
Found: C, 74.45; H, 5.08; N, 9.65.
(12) Ugi, K.; Scheeser, R. G. DE 4330191, 1996.
(13) CCDC-650358 contains the crystallographic data for 8a.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.uk/data_request/cif.
(14) (a) Lloyd, J. R.; Lowther, N.; Hall, D. J. Chem. Soc., Perkin
Trans. 2 1985, 245. (b) Turhanen, P. A.; Niemi, R.;
Peräkylä, M.; Järvinen, T.; Vepsäläinen, J. J. Org. Biomol.
Chem. 2003, 1, 3223.
Acknowledgment
Financial support from the Landesgraduiertenförderung Baden-
Württemberg (fellowship for A. Friedrich) is gratefully acknowled-
ged. We thank Alfred Wagner for dedicated experimental help.
Synlett 2007, No. 13, 2127–2129 © Thieme Stuttgart · New York

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