Pyrrole-assisted and easy oxidation of cyclic α-amino acid- derived diketopiperazines under mild conditions

Article abstract of DOI:10.1002/adsc.201100112

A new procedure for the aerobic oxidation of α-amino acids acylated by pyrrole-carboxylic acid with triplet dioxygen is introduced. The reaction is general for a variety of pyrrole-amino acid derivatives and represents a very practical and controllable method for the selective preparation of α-hydroperoxy- or α-hydroxy-α-amino acid diketopiperazines with molecular dioxygen. Furthermore, the non-catalyzed direct oxidation of amino acid derivatives at the α-position with molecular dioxygen represents a fundamental question. Copyright

Full text of DOI:10.1002/adsc.201100112

FULL PAPERS
DOI: 10.1002/adsc.201100112
Pyrrole-Assisted and Easy Oxidation of Cyclic a-Amino Acid-
Derived Diketopiperazines under Mild Conditions
Hua Tian,a Ludmila Ermolenko,a Marion Gabant,a Carine Vergne,a
Cꢀline Moriou,a Pascal Retailleau,a and Ali Al-Mourabita,*
a
ICSN-UPR 2301, Centre de Recherche de Gif-sur-Yvette, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax : (+33)-1-6907-7247; phone: (+33)-1-6982-4585; e-mail: ali.almourabit@icsn.cnrs-gif.fr
Received: February 17, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100112.
Abstract: A new procedure for the aerobic oxidation with molecular dioxygen. Furthermore, the non-cata-
of a-amino acids acylated by pyrrole-carboxylic acid lyzed direct oxidation of amino acid derivatives at
with triplet dioxygen is introduced. The reaction is the a-position with molecular dioxygen represents a
general for a variety of pyrrole-amino acid deriva- fundamental question.
tives and represents a very practical and controllable
method for the selective preparation of a-hydroper- Keywords: amino acids; diketopiperazines; dioxy-
oxy- or a-hydroxy-a-amino acid diketopiperazines gen; peroxidation; pyrroles
Introduction
Previously, during our investigation of biomimetic
syntheses of marine metabolites, we reported the un-
The oxygenization reaction directly involving triplet expected oxidation of the pseudo-peptide pyrrole-pro-
O2 represents a fundamental question in organic and line as a key step in the formation of the natural
biological chemistry.[1] There are limited reports on product dispacamide skeleton.[12] We then decided to
reactions involving triplet dioxygen without activa- study the mechanism of the oxidation step of this re-
tion.[2] Triplet dioxygen is inert to most ground-state action. We have used a-amino acid derivatives to test
organic molecules. The usually observed peroxidation their reactivity towards molecular dioxygen without
requires the presence of photo-excitable sensitizers or any activation. The mechanism of this interesting re-
metal catalysis. The production of toxic reactive di- action with various amino acids and the conditions
oxygen species (ROS) as well as dioxygen-mediated controlling its progression will be described.
oxidation is well known in many metabolic process-
es.[3] In Nature, dioxygen is largely used by activating
enzymes involved in metabolically important oxida- Results and Discussion
tive transformations as a primary oxidant.[4] From a
synthetic point of view, dioxygen-consuming reactions Preliminary trials conducted with the phenylalanine
proceed more readily with electron-rich aromatic derivative 1a (Scheme 1) in the presence of tetrame-
structures, such as flavins,[5] pterins,[6] and quinones.[7] thylguanidine as a base showed the formation of sev-
Reactions incorporating O2 to form hydroperoxide in- eral compounds. The rearrangement compound 4a, as
termediates in the dark and without any photo-activa- well as pyrrole-carboxamide (2) and acid (3) were iso-
tion are rare. Herein, we would like to report a new lated from the reaction mixture. Since we had occa-
and easy aerobic oxidation of a-amino acids acylated sionally isolated the minor compounds 5a and 7a in
by pyrrole-2-carboxylic acid. The a-hydroxy[8] and our earlier preliminary trials,[13] the identification of
a,b-dehydro[9] amino acid derivatives as a higher oxi- the isomers 4a and 7a by their NMR spectra was not
dized level of amino acids have been widely discov- obvious. The structure of 4a was determined by X-ray
ered in fungal metabolites.[10] Easton very recently re- diffraction analysis (Scheme 1). While the simple hy-
ported the peculiar resistance of free amino acids and drolysis can explain the formation of 3, the mecha-
peptides to a-hydrogen atom transfer.[11]
nism leading to the unexpected amide 2 and the pyr-
rolopyrazinedione 4a was not intuitive. Thus, the in-
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vestigation of the mechanism of the reaction became
essential.
Since we had assumed the key role of the diketopi-
perazine intermediate 5a,[12] we decided to prepare a
series of amino acid derivatives for reactivity and
mechanistic studies. Oxidation of cyclic dipeptides in
the presence of light and initiators was reported by
Schmidt in 1976.[14] Pyrrolopyrazines of type 5a are
deemed to be susceptible to hydrolysis.[15] The initial
phenylalanine-derived substrate 5a was synthesized in
98% yield from the pseudo-peptide 1a in the presence
of sodium hydride followed by treatment with acetate
buffer at pH 3.8.[16] We next investigated its oxidation
in various conditions. Preliminary trials revealed that
the reaction was strongly related to the solvent and
the presence or absence of a base. While in the ab-
sence of a base in THF solution, 5a was relatively
stable, a slow conversion into oxidized compounds
was observed in acetonitrile. About one-half of the
starting material was consumed after two days. Re-
markably, compound 5a was totally consumed in only
2 h in DMF. Hydroperoxide 6a and the corresponding
reduced derivative 7a were isolated in 86% and 9%
yields, respectively (Scheme 2). The structures of 6a
and 7a were elucidated on the basis of their spectro-
scopic characteristics and unambiguously confirmed
by X-ray diffraction analysis.
Importantly, the use of air dioxygen instead of pure
O2 slightly affects the rate and the yield of the oxida-
tion.
Scheme 1. Oxidative transformation of 1a in the presence of
O2 and tetramethylguanidine. X-ray analysis of 4a.
Scheme 2. DKP oxidation with molecular dioxygen in neutral conditions and ORTEP diagrams of 6a and 7a.
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Pyrrole-Assisted and Easy Oxidation of Cyclic a-Amino Acid-Derived Diketopiperazines
À
À
À
It is clear that the reaction dramatically depends on and
N-2 C-3 C-4 N-5
(6b/6a,
19.18/7.48)
the solvent and the pH of the reaction mixture. Our (Scheme 2)[17] indicated that diketopiperazine ring
first concern was to selectively prepare hydroperoxide adopted the twist form in 6b while it was nearly flat
derivatives of type 6a in good yield. The general pro- in 6a. Henceforth, one may assume that substrates 5a
cedure was successfully applied to various amino and 5 possibly have similar conformations, respective-
acids. The cyclic compounds 5b–g were prepared from ly. This tension difference is believed to account for
1b–g by the route used for the synthesis of 5a. Treat- the observed reaction rate difference.
ment of the proline derivative 5b with O2 in the same
conditions gave quantitatively hydroperoxide 6b in rolic cyclic amino acid derivatives in the same condi-
30 min (entry 3). The structure of 6b was also con- tions. Cyclo(Pro,Pro) (11) was prepared from the
We next wanted to test the oxidation of a non-pyr-
AHCTUNGTRENNUNG
firmed by X-ray analyses. The slight reactivity differ- commercial HCl salt of l-proline in the presence of
ence between 5a and 5b could be explained by confor- NaHCO3 in 50% yield.[18] As expected, we found that
mational consideration as shown by X-ray analyses of cyclo
ACHTUNGTRENUN(NG Pro,Pro) (11) when in contact with triplet
the corresponding products 6a and 6b. The dihedral oxygen in DMF did not give rise to the corresponding
À
À
À
angles of C-6 N-5 C-4 C-3 (6b/6a, À21.28/À9.78), peroxide 12 (Table 1). The peroxidation of such deriv-
Table 1. The oxidation of diketopiperazines with O2 in DMF.[a]
Diketopiperazine
R1
R2
Reducant
–
ACHTUNGTNER(NUNG n-Bu)2S
–
Products [%][b]
1
2
3
4
5
6
7
8
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
5f
5f
5g
5g
CH2Ph
CH2Ph
H
H
6a (86), 7a (9)
7a (95), 4a (trace)
6b (100)
7b (93)
6c (93), 7c (5)
7c (96)
-CH2CH2CH2-
-CH2CH2CH2-
A
2-methylpropyl
2-methylpropyl
4-methoxybenzyl
4-methoxybenzyl
indol-3-ylmethyl
indol-3-ylmethyl
CH2CH2SCH3
CH2CH2SCH3
CH2CH2SCH3
CH2Ph
H
H
H
H
H
H
H
H
H
Me
Me
–
–
ACHTUNGTNER(NUNG n-Bu)2S
–
ACHTUNGTNER(NUNG n-Bu)2S
–
PPh3
–
PPh3
(n-Bu)2S
–
6d (88), 7d (10)
7d (94)
9
7e (33), 8[e] (5)
7e (93)
10
11
12
13
14
15
16
7f (6), 7h[c] (88)[d]
7f (50)
7f (75), 7h (15)
6g (53), 7g (31), 4g (4)
7g (75), 4g (20)
No reaction
Bn
–
ACHTUNGTNER(NUNG n-Bu)2S
–
11=cyclo
G
[a]
[b]
[c]
[d]
[e]
The reaction was performed at room temperature in 0.04M DMF solution.
isolated yield.
R1 for 7h=CH2CH2SOCH3.
1
dr=3.5:1, determined by H NMR.
8=
.
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atives is only possible in the presence of light and an tube when triphenylphosphine was added to the reac-
initiator.[14] The contrast is disconcerting since the pyr- tion with 5e. A similar result was observed for the
rolic cyclic amino acid derivative reacts rapidly with methionine derivative 5f. The oxidation of 5f in the
3O2. The result is unchanged when the reaction was presence of four equivalents of dibutyl sulfide could
carried out in the dark.
decrease the amount of sulfide oxide 7h from 88% to
The oxidation of pyrrolic derivatives was further 15% (entries 11 and 13) while the yield of 7f was in-
extended to cyclic pseudo-peptides derived from leu- creased to 75%. Interestingly, the intramolecular sul-
cine and O-methyltyrosine in excellent yields fide oxidation into 7h could be minimized by the ad-
(Table 1, entries 5 and 7). Treatment of indole and dition of 4 equivalents of dibutyl sulfide.
sulfur-containing amino acid derivatives 5e and 5f
It is worthy of note that the N-methylated deriva-
(Table 1, entries 9 and 11) under similar conditions tive 5g needed two days for full conversion. In the
gave only moderate to low yields. The propensity of presence of dibutyl sulfide, 20% of 7g was rearranged
these amino acid chains to over-oxidation is not com- into 4g through ring opening followed by amide ex-
patible with the hydroperoxide, which is the product change and hemiacetalization (Scheme 3).
of the reaction. The strong oxidizing properties of the
The same mechanism is probably contributing to
hydroperoxide, especially when adjacent to a carbonyl the formation of 4a obtained from 1a in the presence
group,[19] explain the formation of the corresponding of tetramethylguanidine (Scheme 1). The formation
hydroxy derivatives. In the case of the indole 5e of the amide 2 becomes conceivable from 1a through
(entry 9), we have identified the hydroxy derivative the diketopiperazine intermediate and the rearrange-
7e and the over-oxidation compound 8. The latter ment process presented in Scheme 3.
compound is the result of an epoxidation of 7e fol-
The above work provides an example of an inter-
lowed by its intramolecular cyclization. We therefore esting oxidation without any metal or light catalysis.
decided to add a reducing agent to the reaction mix- Neither weak acid such as AcOH nor radical scaveng-
ture, which could immediately convert the formed hy- er such as 2,6-di-tert-butyl-4-methylphenol could in-
droperoxide compound into its non-reactive hydroxy hibit the oxidation. In contrast, a strong acid such as
derivative. Several experiments with NEt3 and tert-bu- TFA and a radical scavenger such as tert-butylmercap-
tylmercaptan[20] showed occasionally either over-oxi- tan completely inhibit the peroxidation. Based on the
dation compounds or complete inhibition of the O2 above observations, a possible mechanism was pro-
oxidation reaction. After extensive experimentation, posed. The first step would be the enolization of dike-
we found that dibutyl sulfide or triphenylphosphine[21] topiperazines of type 5 into A (Scheme 4). The 8p-
can efficiently prevent over-oxidation through perox- electron anti-aromatic conjugation system in A is
ide reduction without hampering the desired reaction. probably generated from the electron-deficient dike-
The reaction conditions in the presence or absence of topiperazine cycle. Then, a single-electron transfer
a reducant were tested for the entire selected series (SET) process can occur between the enolate anion A
of amino acid derivatives (Table 1). Thus, treatment and the O2 triplet affording the anion radical superox-
of 5a in the presence of dibutyl sulfide during 3 h ide and the radical (B) which reacts with molecular
gave 7a in 95% yield (entry 2). The presence of the dioxygen to give the radical hydroperoxide C (path
reducing agent proved essential to avoid non-desired a). Another possible pathway is the reaction of B
over-oxidation compounds and to obtain the hydroxy- with the residual anion radical superoxide affording
lated product in good yield. The procedure was found the anion D (path b). Final hydroperoxide product 6
to be general for the selective preparation of com- could be either formed from C in a chain reaction
pounds of type 6 or 7 (Table 1).
with 5 generating a new radical B or from D by a
The result of the reaction depends upon the pres- simple protonation.
ence or absence of the reducant. In the particular
This oxidation reaction by triplet dioxygen can be
case of tryptophan derivative 5e, the reaction in the an interesting method to generate a,b-dehydro amino
presence of the reducant PPh3 gave 7e in 93% acid derivatives as a useful synthetic block.[23] Dehy-
(entry 10). 31P NMR analysis[22] revealed that triphe- drated compounds 9a and 9b were prepared from the
nylphosphine oxide was co-generated in the NMR alcohols 7a and 7b by simple treatment with a catalyt-
Scheme 3. Mechanism of the rearrangement of 7g into 4g.
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Pyrrole-Assisted and Easy Oxidation of Cyclic a-Amino Acid-Derived Diketopiperazines
Scheme 4. The proposed mechanism for the O2 oxidation.
Chromatographic purifications were performed by the flash
technique using silica gel P60 (230–400 mesh). THF was dis-
tilled from sodium/benzophenone and freshly used. Spectro-
scopic data and HR-MS analyses are reported for all new
compounds. NMR spectra were recorded on Brucker
Avance 300 MHz and 500 MHz spectrometers for 1H and
13C NMR and 2D NMR experiments. Chemical shifts (ex-
pressed in ppm) of 1H and 13C NMR spectra were refer-
enced to the solvent peaks dH =2.05 and dC =29.9, 206.7 for
acetone-d6, dH =2.50 and dC =39.5 for DMSO-d6, dH =7.26
and dC =77.2 for CDCl3, dH =3.58, 1.73 and dC =64.7, 25.2
for THF, dH =8.04, 2.93, 2.72 and dC =162.4, 34.9, 29.8 for
DMF-d7. 31P NMR spectrum was recorded with 120-sec
pulse (>5T1) cycle and 12 accumulations before Fourier
transformation, while the relaxation time (T1) of triphenyl-
phosphine and its oxide were 1.9 and 13.8 sec at 308C, re-
spectively, as indicated in J. Magnetic Resonance, 1979, 33,
127–134. HR-MS were obtained with using an electrospray
source (Lockspray) coupled with a time of flight analyser
(LCT, Micromass). Samples were prepared in acetonitrile
and injected in the MS system using a Waters 2795 system.
IR spectra were acquired (neat) using a Perkin–Elmer Spec-
trometer BX FT-IR system.
Scheme 5. Example of dehydration of alcohols of type 7 into
alkenes of type 9.
ic amount of HCl in acetonitrile in quantitative yield
(Scheme 5).
In conclusion, we have demonstrated that the aero-
bic peroxidation at the a-position of a-amino acids
acylated by pyrrolecarboxylic acid proceeds easily
with triplet dioxygen in DMF under neutral condi-
tions in good yields. This oxidation in the presence of
a reducing reagent such as dibutyl sulfide or triphe-
nylphosphine afforded the corresponding a-hydroxide
derivatives in excellent yields. This reaction is general
for a variety of pyrrole-amino acid derivatives and
represents a very practical method for the selective
preparation of a-hydroperoxy- or a-hydroxy-a-amino
acid derivatives with molecular dioxygen. The study
of this oxidation could clarify the mechanism of simi-
lar bioorganic reactions involving ground state O2
such as the oxidation of the chemiluminescent lucifer-
ins,[24] flavins[19] or uric acid.[25] Furthermore, the easily
available peroxides could be highly interesting for se-
General Procedure for the Synthesis of Pyrrole-
amino Acid Methyl Esters 1
To
a mixture of 2-(trichloroacetyl)pyrrole (10.0 mmol,
1 equiv.) and the HCl salt of an amino acid methyl ester
(15.0 mmol, 1.5 equiv.) in dry acetonitrile (150 mL) was
added Et3N (20 mmol, 2 equiv.). The reaction mixture was
stirred at room temperature during 48 h, then filtered and
lective oxidative reactions such as with flavins.[19] Fur- concentrated. The residue was dissolved in EtOAc and
washed successively with 1N HCl, H2O and brine, dried,
concentrated and purified by flash chromatography using
heptane/EtOAc.
ther studies on the oxidation mechanism and its appli-
cation in synthesis are ongoing.
Pyrrole-Phe-OMe ester (1a): Prepared from phenylala-
nine methyl ester using the general procedure described
above as a white solid; yield: 82% yield. IR (neat): nmax
=
Experimental Section
1735, 1633 cmÀ1 1H NMR (300 MHz, CDCl3): d=9.77 (s,
;
1H), 7.31–7.20 (m, 3H), 7.16–7.12 (m, 2H), 6.93 (m, 1H),
6.54 (m, 1H), 6.35 (d, J=7.8 Hz, 1H), 6.17 (m, 1H), 5.05
(td, J=7.8 and 5.7 Hz, 1H), 3.73 (s, 3H), 3.21 (d, J=5.7 Hz,
2H); 13C NMR (75 MHz, CDCl3): d=172.3, 160.8, 136.0,
General Remarks
Commercially available reagents and solvents were pur-
chased from Aldrich and used without further purification.
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129.4, 128.7, 127.2, 125.3, 122.3, 110.0, 109.9, 53.2, 52.4, 38.3;
MS (ESI+): m/z=273.0 [M+H]+.
Pyrrole-Pro-OMe ester (1b): Prepared from proline
methyl ester by the procedure described above; yield: 95%
(see ref.[12]).
General Procedure for the Synthesis of
Diketopiperazine Pyrrole-AA 5
Methyl ester (pyrrole-AA) 1 (10 mmol, 1 equiv.) was dis-
solved in degassed anhydrous THF (200 mL) and was
cooled to 08C. Sodium hydride (335 mg, 14 mmol,
1.4 equiv.) was added and the mixture was stirred at 08C for
five minutes and then at room temperature for the time in-
dicated in each case. After the completion of the reaction,
the mixture was poured into acetate buffer pH 3.8 (300 mL)
and quickly extracted with AcOEt. The organic layer was
dried on MgSO4, the solvent was evaporated and the residue
was then dried under vacuum during 12 h to give the corre-
sponding diketopiperazine 5. The compound was stored and
used without further purification.
Pyrrole-Leu-OMe ester (1c): Prepared from leucine
methyl ester using the general procedure described above as
a pale yellow solid; yield: 87%. IR (neat): nmax =1731,
1631 cmÀ1 1H NMR (300 MHz, CDCl3): d=9.93 (s, 1H),
;
6.90 (m, 1H), 6.67 (m, 1H), 6.43 (d, J=8.4 Hz, 1H), 6.21
(m, 1H), 4.83 (m, 1H), 3.76 (s, 3H), 1.81–1.76 (m, 3H), 1.00
(dd, J=5.0 Hz and 6H); 13C NMR (75 MHz, CDCl3): d=
173.9, 161.0, 125.3, 122.1, 109.7, 109.7, 52.3, 50.5, 41.8, 24.9,
22.8, 21.9; MS (ESI+): m/z=239.0 [M+H]+.
Pyrrole-Tyr-(OMe)-OMe ester (1d): Prepared from para-
methoxytyrosine methyl ester using the general procedure
described above as a pale yellow solid; yield: 74%. IR
Pyrrole-Phe diketopiperazine (5a): Prepared from the cor-
responding methyl ester 1a by the general procedure as a
white solid; yield: 98%. IR: nmax =1722, 1671, 1626,
(neat): nmax =1735, 1664, 1598, 1449 cmÀ1
;
1H NMR
1
1421 cmÀ1; H NMR (300 MHz, CDCl3): d=7.42 (dd, J=1.5,
(300 MHz, CDCl3): d=9.94 (brs, 1H), 6.97 (d, J=8.3 Hz,
1H), 6.85–6.81 (m, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.50–6.46
(m, 1H), 6.36 (d, J=7.8 Hz, 1H), 6.16–6.09 (m, 1H), 4.98–
4.88 (m, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 3.07 (d, J=5.8 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=172.2, 160.6, 158.7,
130.3, 127.7, 125.3, 122.1, 114.0, 109.8, 55.2, 53.1, 52.3, 37.3;
MS (ESI+): m/z=239.0 [M+H]+.
3.4 Hz, 1H), 7.22–7.10 (m, 5H), 6.93 (dd, J=1.5, 3.4 Hz,
1H), 6.39 (t, J=3.4 Hz, 1H), 4.59 (ddd, J=2.1, 4.1, 7.8 Hz,
1H), 3.39 (dd, J=4.1, 13.7 Hz, 1H), 3.09 (dd, J=7.8,
13.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=164.0, 157.2,
134.3, 129.4, 128.9, 127.7, 125.1, 119.5, 118.5, 115.5, 58.6,
41.0; MS (ESI+): m/z=241.1 [M+H]+; HR-MS (ESI): m/z=
241.0967, calcd. for C14H13N2O2 [M+H]+: 241.0977.
Pyrrole-Pro diketopiperazine (5b): Prepared from the cor-
responding methyl ester 1b by the general procedure for 2 h
30 min as a white solid; yield: 93%. IR (neat): nmax =1727,
1641, 1435,1409 cm1; 1H NMR (300 MHz, CDCl3): d=7.44
(dd, J=1.5, 3.2 Hz, 1H), 7.06 (dd, J=1.5, 3.4 Hz, 1H), 6.47
(dd, J=3.2, 3.4 Hz, 1H), 4.48 (dd, J=6.4, 10.8 Hz, 1H), 3.83
(m, 1H), 3.63 (m, 1H), 2.56 (m, 1H), 2.21–1.95 (m, 3H);
13C NMR (75 MHz, CDCl3): d=164.5, 155.2, 127.3, 118.8,
117.8, 115.5, 61.4, 44.7, 29.0, 22.2; MS (ESI+): m/z=191.1
[M+H]+, 213.1 [M+Na]+; HR-MS (ESI): m/z=213.0642,
calcd. for C10H10N2O2Na [M+Na]+: 213.0640.
Pyrrole-Try-OMe ester (1e): Prepared from tryptophane
methyl ester using the general procedure described above as
a pale yellow solid; yield: 63%. IR (neat): nmax =1732, 1634,
1557, 1513 cmÀ1 1H NMR (300 MHz, CDCl3): d=10.03 (s,
;
1H), 8.29 (s, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.36 (d, J=
8.1 Hz, 1H), 7.35 (m, 2H), 6.98 (d, J=2.3 Hz, 1H), 6.88 (m,
1H), 6.47–6.38 (m, 2H), 6.18 (m, 1H), 6.21 (m, 1H), 5.11
(td, J=8.1 and 5.3 Hz, 1H), 3.70 (s, 3H), 3.41 (d, J=5.3 Hz,
2H); 13C NMR (75 MHz, CDCl3): d=172.6, 161.2, 136.5,
125.3, 122.9, 122.3, 120.1, 120.0, 118.5, 112.6, 110.3, 110.0,
53.5, 52.6, 27.9; MS (ESI+): m/z=312.0 [M+H]+.
Pyrrole-Met-OMe ester (1f): Prepared from methionine
methyl ester using the general procedure described above as
a white solid; yield: 70%. IR (neat): nmax =3271, 1734, 1632,
Pyrrole-Leu diketopiperazine (5c): Prepared from the cor-
responding methyl ester 1c by the general procedure for
1
1558, 1521 cmÀ1; H NMR (300 MHz, CDCl3): d=9.84 (br s,
40 min as a white powder; yield: 85%. IR (neat): nmax
=
1H), 6.94 (m, 1H), 6,78 (d, J=7.8 Hz, 1H), 6.67 (m, 1H),
6.22 (m, 1H), 4.89 (td, J=7.8 and 5.1 Hz, 1H), 3.76 (s, 3H),
2.25 (m, 2H), 2.06 (s, 3H), 2.00 (m, 2H); 13C NMR
(75 MHz, CDCl3): d=172.8, 161.1, 125.1, 122.4, 110.1, 109.8,
52.6, 51.5, 31.7, 30.1, 15.4; MS (ESI+): m/z=239.0 [M+H]+.
Pyrrole-(N-Me-Phe)-OMe ester (1g): Prepared from pyr-
role 2-carboxylic acid and N-methylphenylalanine methyl
ester using the procedure described above for 3 h as a white
solid; yield: 72%. IR (neat): nmax =3260, 2949, 1735, 1587,
1720, 1644, 1430, 1327 cmÀ1 1H NMR (300 MHz, DMSO-
;
d6): d=8.40 (brs, 1H), 7.57 (dd, J=1.6, 3.1 Hz, 1H), 6.95
(dd, J=1.6, 3.4 Hz, 1H), 6.58 (dd, J=3.1, 3.4 Hz, 1H), 4.51
(dt, J=2.4, 6.0 Hz, 1H), 1.88–1.79 (m, 1H), 1.77–1.71 (m,
2H), 0.88 (d, J=6.0 Hz, 1H), 0.79 (d, J=6.0 Hz, 1H);
13C NMR (300 MHz, DMSO-d6): d=165.7, 155.8, 126.0,
118.9 (CH), 116.6 (CH), 115.0 (CH), 55.2 (CH), 43.1 (CH2),
23.6 (CH), 22.4 (CH3), 22.2 (CH3); MS (ESIÀ): m/z=205.0
[MÀH]À; HR-MS (ESI): m/z=205.0976, calcd. for
C11H13N2O2 [MÀH]À: 205.0977.
1
1402, 1112, 738, 698 cmÀ1; H NMR (300 MHz, CDCl3): d=
9.99 (br s, 1H), 7.31–7.16 (m, 5H), 6.94 (m, 1H), 6.51 (m,
1H), 6.23 (dd, J=3.8, 2.7 Hz, 1H), 5.24 (br s, 1H), 3.75 (s,
3H), 3.44 (dd, J=14.3, 5.2 Hz, 1H), 3.18 (dd, J=14.3,
10.2 Hz, 1H), 3.16 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
171.4, 162.7, 137.2, 128.8, 128.5, 126.7, 124.4, 121.6, 113.2,
113.0, 109.7, 60.7, 52.3, 35.0; MS (HR-MS-ESI): m/z=
309.1216, calcd. for C16H18N2O3 [M+Na+]: 309.1215.
Pyrrole-TyrACTHNUGTRNEUNG(OMe) diketopiperazine (5d): Prepared from
the corresponding methyl ester 1d by the general procedure
for 30 min as a pale yellow solid; yield: 93%. IR (neat)
nmax =1718, 1654, 1508, 1419 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d=7.41 (dd, J=1.2, 3.4 Hz, 1H), 7.20 (br. s, 1H),
7.03 (d, J=8.5 Hz, 2H), 6.91 (dd, J=1.2, 3.4 Hz, 1H), 6.69
(d, J=8.5 Hz, 2H), 6.38 (t, J=3.4 Hz, 1H), 4.55 (ddd, J=
2.1, 4.0, 7.3 Hz, 1H), 3.65 (s, 3H), 3.29 (dd, J=4.0, 13.7 Hz,
1H), 3.07 (dd, J=7.3, 13.7 Hz, 1H); 13C NMR (CDCl3): d=
164.1, 159.0, 157.3, 130.5, 126.1, 125.1, 119.4, 118.3, 115.4,
114.2, 58.7, 55.2, 40.2; MS (ESI+): m/z=293.1 [M+Na]+;
1530
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1525 – 1533

Pyrrole-Assisted and Easy Oxidation of Cyclic a-Amino Acid-Derived Diketopiperazines
HR-MS (ESI): m/z=293.0899, calcd. for C15H14N2O3Na
[M+Na]+: 293.0902.
115.8, 94.5, 41.5; HR-MS (ESI): m/z=271.0709,: calcd. for
C14H11N2O4 [MÀH]À: 271.0719. The single crystal was cul-
tured by solvent diffusion of THF and heptane mixed solu-
tion.
Pyrrole-Try diketopiperazine (5e): Prepared from the cor-
responding methyl ester 1e by the general procedure for 2 h
and purified by flush chromatography (CH2Cl2/EtOAc: 1/1)
as an orange froth; yield: 83%. IR (neat): nmax =1727,
Pyrrole-Pro-OOH (6b): Prepared from 5b by the general
procedure for 0.5 h as a white solid; yield: quantitative. IR
1
1663 cmÀ1; H NMR (300 MHz, CDCl3): d=8.43 (br. s, 1H),
(neat): nmax =3114, 1738, 1629, 1428, 1335 cmÀ1 1H NMR
;
7.51 (d, J=7.9 Hz, 1H), 7.37 (dd, J=1.5, 3.2 Hz, 1H), 7.20
(d, J=7.9 Hz, 1H), 7.07 (ddd, J=1.1, 7.0, 7.9 Hz, 1H), 7.00
(ddd, J=1.1, 7.0, 7.9 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.90
(dd, J=1.5, 3.4 Hz, 1H), 6.64 (br. s, 1H), 6.32 (dd, J=3.2,
3.4 Hz, 1H), 4.54 (ddd, J=1.9, 3.7, 8.3 Hz, 1H), 3.52 (dd,
J=3.7, 14.4 Hz, 1H), 3.19 (dd, J=8.3, 14.4 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=164.4, 157.1, 136.3, 126.7,
125.2, 124.0, 122.4, 119.8, 119.6, 118.4, 118.4, 115.3, 111.4,
108.4, 57.7, 31.3; MS (ESI+): m/z=302.1 [M+Na]+; HR-MS
(ESI): m/z=302.0903, calcd. for C16H13N3O2Na [M+Na]+:
302.0905.
(500 MHz, DMF-d7): d=12.6 (s, 1H); 7.61 (dd, J=3.2,
1.6 Hz, 1H), 6.99 (dd, J=3.4, 1.6 Hz, 1H), 6.58 (t, J=
3.3 Hz, 1H), 3.9 (td, J=11.1, 8.0 Hz, 1H), 3.63 (ddd, J=
11.3, 8.7, 5.1 Hz, 1H), 2.53 (td, J=13.8, 10.0 Hz, 1H), 2.53
(td, J=13.8, 10.0 Hz, 1H), 2.10–2.03 (m, 2H); 13C NMR
(DMF-d7, 75 MHz): d=162.2, 155.6, 127.8, 119.3, 117.0,
115.1, 97.3, 44.3, 32.7, 19.8; HR-MS (ESI): m/z=223.0714,
calcd. for C10H11N2O4 [M+H]+: 223.0719. The single crystal
was cultured by solvent diffusion of THF and heptane
mixed solution.
Pyrrole-Leu-OOH (6c): Prepared from 5c by the general
procedure for 10 h as a pale yellow oil; yield: 93%. The hy-
droperoxide was purified by column flash chromatography
with heptane/EtOAc: 6/4. IR (neat): nmax =3164, 2948, 1720,
Pyrrole-Met diketopiperazine (5f): Prepared from the cor-
responding methyl ester 1f by the general procedure for 2 h
30 min as a white solid; yield: 95%. IR (neat): nmax =1719,
1
1
1644, 1426 cmÀ1; H NMR (300 MHz, CDCl3): d)=8.26 (br.
1649, 1433 cmÀ1; H NMR (300 MHz, DMF-d7): d=12.71 (s,
s, 1H), 7.53 (dd, J=1.5, 3.2 Hz, 1H), 7.11 (dd, J=1.5,
3.4 Hz, 1H), 6.52 (dd, J=3.2, 3.4 Hz, 1H), 4.63 (td, J=1.5,
5.5 Hz, 1H), 2.70 (m, 2H), 2.40–2.31 (m, 2H), 2.08 (s, 3H);
13C NMR (75 MHz, CDCl3): d=164.5, 157.9, 125.1, 119.7,
118.5, 115.3, 56.0, 33.1, 29.2, 15.1; MS (ESI+): m/z=225.1
[M+H]+; HR-MS (ESI): m/z=247.0519, calcd. for
C10H12N2O2SNa [M+Na]+: 247.0517.
1H), 8.90 (br s, 1H), 7.70 (dd, J=3.2, 1.5 Hz, 1H), 7.07 (dd,
J=3.5,1.6 Hz, 1H), 6.63 (t, J=3.3 Hz, 1H), 2.12 (dd, J=
15.0, 9.9 Hz, 1H), 1.85 (m, 2H), 0.94 (d, J=6.5 Hz, 1H),
0.76 (d, J=6.48 Hz, 1H); 13C NMR (75 MHz, DMF-d7): d=
162.9, 157.0, 126.2, 119.8, 117.7, 115.4, 93.2, 41.8, 24.4, 23.0,
22.0;
C11H14N2O4Na [M+Na]+: 261.0851.
Pyrrole-Tyr(OMe)-OOH (6d): Prepared from 5d by the
HR-MS
(ESI):
m/z=261.0853,
calcd.
for
Pyrrole-(N-Me-Phe) diketopiperazine (5g): Prepared
from the corresponding methyl ester 1g by the general pro-
ACHTUNGTRENNUNG
general procedure for 6 h as a yellow oil; yield: 88%. The
hydroperoxide was purified by column flash chromatogra-
phy with heptane/EtOAc: 4/6. IR (neat): nmax =3190, 1741,
cedure for 1 h as a white solid; yield: 90%. IR (neat): nmax
=
1717, 1656, 1650, 1373, 1326, 758, 750 cmÀ1 1H NMR
;
1
(300 MHz, CDCl3): d=7.27 (dd, J=3.5,1.5 Hz, 1H), 7.15–
7.08 (m, 3H), 6.98–6.90 (m, 2H), 6.72 (dd, J=3.5,1.5 Hz,
1H), 6.27 (t, J=3.5 Hz, 1H), 4.52 (t, J=4.4 Hz, 1H), 3.33
(d, J=4.1 Hz, 1H), 3.32 (d, J=4.1 Hz, 1H), 3.17 (s, 3H);
13C NMR (75 MHz, CDCl3): d=164.2, 156.2, 133.2, 128.9,
128.5, 127.6, 125.5, 117.9, 117.6, 115.4, 65.2, 38.7, 32.2; HR-
MS (ESI): m/z=255.1131, calcd. for C15H15N2O2 [M+H]+:
255.1134.
1650, 1513, 1467, 1644, 1582, 1454 cmÀ1; H NMR (THF-d8,
300 MHz): d=11.69 (s, 1H), 8.03 (br s, 1H), 7.42 (dd, J=
3.3, 1.5 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.82 (dd, J=3.3,
1.5 Hz, 1H), 6.72 (d, J=8.8 Hz, 2H), 6.35 (t, J=3.3 Hz,
1H), 3.66 (s, 3H), 3.43 (d, J=13.4 Hz, 1H), 2.93 (d, J=
13.4 Hz, 1H); 13C NMR (THF-d8, 75 MHz): d=162.7, 160.1,
157.6, 132.4, 127.1, 125.5, 119.9, 118.0, 115.4, 114.5, 94.8,
55.2, 40.4; HR-MS (ESI): m/z=303.2889, calcd. for
C15H15N2O5 [M+H+]: 303.2895.
Pyrrole-PheACHTUNTRGNEUNG(NMe)-OOH (6g): Prepared from 5g by the
General Procedure for the Oxidation of
Diketopiperazines Pyrrole-AA 5 into Hydroperoxides
6
general procedure for 48 h; yield: 53%. Purification was
made by column flash chromatography with heptane/
EtOAc: 6/4. IR (neat): nmax =3103, 1716, 1650, 1415, 1326,
1261, 750, 614 cmÀ1 1H NMR (300 MHz, acetone-d6): d=
;
Diketopiperazine 5 (1 mmol) was dissolved in dry DMF
(25 mL) and then dioxygen was bubbled into the stirred so-
lution for the time indicated in each case at room tempera-
ture. Upon completion of the reaction, the solvent was
evaporated and the hydroperoxide 6 was purified as indicat-
ed for each compound.
11.91 (br s, 1H), 7.44 (dd, J=3.3, 1.5 Hz, 1H), 7.20–7.12 (m,
3H), 7.10–7.04 (m, 2H), 6.75 (dd, J=3.5, 1.5 Hz, 1H), 6.41
(dd, J=3.5, 3.3 Hz, 1H), 3.42 (d, J=13.5 Hz, 1H), 3.36 (d,
J=13.5 Hz, 1H), 3.26 (s, 3H); 13C NMR (75 MHz, acetone-
d6): d=161.8, 155.8, 132.1, 129.6, 128.5, 127.6, 125.4, 118.5,
117.5, 115.5, 97.8, 38.9, 26.38; HR-MS (ESI): m/z=287.1027,
calcd. for C15H15N2O4 [M+H]+: 287.1032.
Pyrrole-Phe-OOH (6a): Prepared from 5a by the general
procedure for 2 h as a white solid; yield: 86%. The hydro-
peroxide was purified by column flash chromatography with
heptane/EtOAc: 1/1. IR (neat): nmax =3143, 1745, 1668,
General Procedure for the Oxidation of
Diketopiperazine Pyrrole-AA 5 into Alcohol 7 in the
Presence of Reductant
1496, 1455, 1639, 1582,1466 cmÀ1
;
1H NMR (500 MHz,
DMF-d7): d=12.94 (br s, 1H), 9.08 (br s, 1H), 7.63 (dd, J=
3.3,1.4 Hz, 1H), 7.39–7.22 (m, 5H), 6.92 ( dd, J=3.0, 1.4 Hz,
1H), 6.54 (t, J=3.3, 3.0 Hz, 1H), 3.56 (d, J=13.0 Hz, 1H),
3.56 (d, J=13.0 Hz, 1H); 13C NMR (75 MHz, dioxane-d8):
d=162.4, 157.3, 133.4, 131.2, 129.1, 128.2, 126.4, 120.2, 118.7,
Diketopiperazine pyrrole-AA 5 (1.0 mmol) was added to a
solution of the corresponding reductant (4.0 mmol of Bu2S
or 3.0 mmol of Ph3P) in dry DMF (24 mL) and stirred for
Adv. Synth. Catal. 2011, 353, 1525 – 1533
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1531

Hua Tian et al.
FULL PAPERS
the time indicated in each case in the presence of an O2
flow. Upon completion of the reaction, the solvent was
evaporated and the alcohol 7 was purified.
Pyrrole-Phe-OH (7a): Prepared from 5a in the presence
of Bu2S for 3 h; yield: 95%. Purification was made by
column flash chromatography in heptane/EtOAc: 6/4 and
furnished alcohols 7a and 4a (trace).
J=13.3 Hz, 1H), 3.00 (d, J=13.3 Hz, 1H); 13C NMR
(75 MHz, THF-d8): d=165.8, 159.9, 156.4, 132.3, 127.2,
126.8, 119.7, 117.6, 115. 5, 114.3, 85.2, 55.2, 45.5; HR-MS
(ESI): m/z=287.2909, calcd. for C15H15N2O4 [M+H+]:
287.2901.
Pyrrole-Try-OH (7e): Prepared from 5e in the presence of
Ph3P for 3 h as a yellow solid; yield: 93%. The alcohol was
purified by silica column chromatography with heptane/
EtOAc: 6/4. IR (neat): nmax =3314, 3220, 3140, 1732, 1660,
7a: IR (neat): nmax =3217, 3117, 1728, 1668, 1496, 1455,
1
1646, 1580, 1464 cmÀ1; H NMR (300 MHz, dioxane-d8): d=
1
7.57 (br s, 1H), 7.46 (dd, J=3.2, 1.5 Hz, 1H), 7.21–7.15 (m,
5H), 6.83 (dd, J=3.4, 1.5 Hz, 1H), 6.83 (dd, J=3.4, 3.2 Hz,
1H), 5.73 (br s, 1H), 3.4 (d, J=13.3 Hz, 1H), 3.08 (d, J=
13.2 Hz, 1H); 13C NMR (75 MHz, dioxane-d8): d=166.0,
156.2, 134.3, 131.1, 128.8, 127.9, 126.7, 119.9, 118.2, 115.9,
85.5, 47.1; HR-MS (ESI): m/z=255.0759, calcd. for
C14H11N2O3 [MÀH]À: 255.0770. The single crystal was cul-
tured by solvent diffusion of THF and toluene mixed solu-
tion.
1580, 1467 cmÀ1; H NMR (300 MHz, acetone-d6): d=10.10
(br s, 1H), 7.80 (br s, 1H), 7.72 (dd, J=7.5, 2.0 Hz, 1H),
7.37 (dd, J=3.2, 1.6, Hz, 1H), 7.3 (d, J=7.8 Hz, 1H), 7.3 (d,
J=7.8 Hz, 1H), 7.08–6.96 (m, 2H), 6.75 (dd, J=3.4, 1.6 Hz,
1H), 6.36 (dd, J=3.4, 3.1 Hz, 1H), 6.32 (br s, 1H), 3.8 (d,
J=14.2 Hz, 1H), 3.44 (d, J=14.2 Hz, 1H); 13C NMR
(75 MHz, acetone-d6): d=166.4, 156.6, 137.2, 126.9, 128.7,
125.9, 122.2, 120.1, 119.8, 117.8, 115.8, 112.0, 108.0, 86.1,
36.3; HR-MS (ESI): m/z=294.0876, calcd. for C16H12N3O3
[MÀHÀ]: 294.0879.
4a: IR (neat): nmax =3358, 3179, 3062, 1657, 1493, 1454,
1693, 1681, 1545,1440 cmÀ1
;
1H NMR (300 MHz, CDCl3):
Pyrrole-Met-OH (7f): Prepared from 5f in the presence
of Bu2S for 2 h as a yellow solid; yieled: 75%. The alcohol
was purified by silica column chromatography in EtOAc.
15% of 7h was isolated as a yellow solid in addition.
7f: IR (neat): nmax =3244, 3100, 1735, 1632, 1580,
d=8.24 (br s, 1H), 7.19–7.04 (m, 4H), 6.94 (dd, J=3.9,
1.4 Hz, 1H), 6.66 (m, 2H), 6.38 (dd, J=3.9, 2.8 Hz, 1H),
4.75 (s, 1H), 3.32 (d, J=13.3 Hz, 1H), 3.24 (d, J=13.3 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=171.6, 155.5, 131.4,
129.4, 128.5, 128.2, 124.8, 120.9, 116.6, 112.8, 85.8, 50.4; HR-
MS (ESI): m/z=279.0742, calcd. for C14H12N2O3Na [M+
Na]+: 279.0746. The single crystal was cultured by solvent
diffusion of acetone and heptane mixed solution.
1
1469 cmÀ1; H NMR (300 MHz, THF-d8): d=8.06 (br s, 1H),
7.5 (dd, J=3.1, 1.9 Hz, 1H), 6.96 (dd, J=3.3, 1.9 Hz, 1H),
6.48 (dd, J=3.3, 3.1 Hz, 1H), 6.31 (br s, 1H), 2.58–2.43 (m,
3H), 2.13–2.07 (m, 1H), 2.04 (s, 3H); 13C NMR (75 MHz,
THF-d8): d=165.1, 127.0, 120.2, 117.9, 115.5, 84.3, 39.1, 28.7,
15.1; HR-MS (ESI): m/z=239.0500, calcd. for C10H11N2O3S
[MÀH]À: 239.0490.
Pyrrole-Pro-OH (7b): Prepared from 5b in the presence
of Bu2S for 3 h and purified by recrystallization from
CH2Cl2 and heptane. The mother liquid was concentrated
and purified by silica column chromatography in heptane/
EtOAc: 1/1; total yield: 93%. IR (neat): nmax =3214, 3124,
7h: dr.=3.5; IR (neat): nmax =3217, 3114, 1737, 1660,
1
1579,1462 cmÀ1; H NMR (300 MHz, DMF-d7): d=9.08 (br
1
1740, 1616, 1428, 1326, 1133, 1025, 956, 742 cmÀ1; H NMR
s, 0.72H), 9.02 (br s, 0.21H), 7.83 (dd, J=3.2, 1.5 Hz, 1H),
7.76 (br s, 1H), 7.21 (dd, J=3.4, 1.5 Hz, 1H), 6.82 (dt, J=
(300 MHz, DMSO-d6): d=7.57 (dd, J=3.4, 1.5 Hz, 1H),
7.23 (s, 1H), 6.95 (dd, J=3.3, 1.5 Hz, 1H), 6.54 (dd, J=3.4,
3.3 Hz, 1H), 3.65–3.48 (m, 2H), 2.27–2.16 (m, 2H), 2.16–
1.91 (m, 2H); 13C NMR (75 MHz, DMSO-d6): d=163.9,
154.6, 127.0, 119.7, 116.8, 115.1, 88.1, 44.2, 34.9, 19.5; HR-
MS (ESI): m/z=205.0611, calcd. for C10H9N2O3 [MÀH]À:
205.0613. The single crystal was cultured by solvent diffusion
of THF and heptane mixed solution.
3.5, 1.5 Hz, 1H), 3.25–3.15 (m, 1H), 3.1–2.98), 2.87–2.75ACHTUNGTRENNUNG(m,
1H), 2.82 (s, 3H), 2.73–2.58 (m, 1H); 13C NMR (75 MHz,
DMF-d7): d=164.8, 156.8, 126.6, 120.3, 117.6, 115.6, 83.8,
48.5 (minor), 48.1 (major), 38.4 (minor), 38.1 (major), 31.7
(minor), 31.3 (major); HR-MS (ESI): m/z=255.0443, calcd.
for C10H11N2O4S [MÀH]À: 255.0440.
Pyrrole-PheACHTUNTRGNEUNG(NMe)-OH (7g): Prepared from 5g in the
Pyrrole-Leu-OH (7c): Prepared from 5c in the presence
of Bu2S for 20 h as a pale yellow solid; yield: 96%. The alco-
hol was purified by recrystallization from CH2Cl2 and hep-
presence of Bu2S for 48 h as a white solid; yield: 75%. 7g
and 4g were purified by column chromatography in hep-
tane/EtOAc: 6/4.
tane. IR (neat): nmax =3235, 1962, 1727, 1642, 1417 cmÀ1
;
7g: IR: nmax =3125, 1737, 1614, 1444, 1369, 1337, 771,
1H NMR (300 MHz, DMSO-d6): d=7.88 (br s, 1H), 7.56
(dd, J=3.3,1.5 Hz, 1H), 6.99 (dd, J=3.5, 1.5 Hz, 1H), 6.57
(t, J=3.3 Hz, 1H), 6.16 (br s, 1H), 2.28 (dd, J=14.0, 7.5 Hz,
1H), 1.95 (dd, J=14.0, 5.6 Hz, 1H), 1.77 (sept dd, J=7.5,
6.7, 5.6 Hz, 1H), 0.96 (d, J=6.7 Hz, 1H), 0.8 (d, J=6.7 Hz,
1H); 13C NMR (75 MHz, DMSO-d6): d=165.7, 157.0, 126.8,
120.6, 118.3, 116.1, 85.1, 47.6, 25.1, 24.1, 23.2; HR-MS (ESI):
m/z=223.2481, calcd. for C11H15N2O3 [M+H]+: 223.2479.
613 cmÀ1; H NMR (300 MHz, CDCl3): d=7.19 (dd, J=3.3,
1
1.5 Hz, 1H), 7.08–7.02 (m, 3H), 6.89–6.83 (m, 2H), 6.56 (dd,
J=3.5, 1.5 Hz, 1H), 6.19 (dd, J=3.5, 3.3 Hz, 1H), 5.42 (br s,
1H), 3.27 (s, 2H), 3.06 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=165.5, 155.6, 132.1, 129.1, 128.4, 127.7, 125.0, 118.5, 118.1,
115.8, 88.6, 44.9, 26.9; HR-MS (ESI): m/z=271.1075, calcd.
for C15H15N2O3 [M+H]+: 271.1083.
4g: white solid; IR (neat): nmax =3356, 1708, 1660, 1545,
1
Pyrrole-Tyr
N
1319, 1067, 1088, 699 cmÀ1; H NMR (300 MHz, CDCl3): d=
presence of Bu2S for 15 h as a pale yellow solid; yield: 94%.
The alcohol was purified by recrystallization from CH2Cl2
and heptane. IR (neat): nmax =3220, 3120, 1730, 1664, 1512,
7.2–7.03 (m, 3H), 6.89 (dd, J=3.9, 1.7 Hz, 1H), 6.5 (dd, J=
3.0, 1.7 Hz, 1H), 6.37 (dd, J=4.0, 3.0 Hz, 1H), 4.54, (br s,
1H), 3.29 (d, J=13.2 Hz, 1H), 3.29 (d, J=13.2 Hz, 1H),
2.98 (s, 3H); 13C NMR (75 MHz, CDCl3): d=172.1, 155.9,
131.7, 129.0, 128.4, 128.2, 123.5, 121.2, 115.9, 112.6, 85.6,
51.4, 26.1; HR-MS (ESI): m/z=269.0913, calcd. for
C15H13N2O3 (MÀH)À: 269.0926.
1
1650, 1580,1466 cmÀ1; H NMR (500 MHz, THF-d8): d=7.86
(br s, 1H), 7.39 (dd, J=3.2, 1.4 Hz, 1H), 7.11 (d, J=8.7 Hz,
2H), 6.76 (dd, J=3.2, 1.4 Hz, 1H), 6.69 (d, J=8.7 Hz, 2H),
6.37 (s, 1H), 6.35 (t, J=3.2 Hz, 1H), 3.69 (s, 3H), 3.42 (d,
1532
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1525 – 1533

Pyrrole-Assisted and Easy Oxidation of Cyclic a-Amino Acid-Derived Diketopiperazines
Compound 8: Yellow oil; IR (neat): nmax =3332 (NH
indole), 1737 (C=O amide), 1643 (C=O amide), 1616,
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Kay, J. Hirst, B. F. Luisi, J. Am. Chem. Soc. 2008, 130,
1662–1668.
1
1464 cmÀ1 (C=C); H NMR (300 MHz, acetone-d6): d=7.50
(dd, J=3.1, 1.6 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.08 (t, J=
7.7 Hz, 1H), 7.02 (dd, J=3.5, 1.6 Hz, 1H), 6.71 (t, J=
7.7 Hz, 1H), 6.60 (d, J=7.7 Hz, 1H), 6.52 (dd, J=3.5,
3.1 Hz, 1H), 6.05 (br s, 1H), 5.77 (d, J=2.4 Hz, 1H), 5.17
(br s, 1H), 2.92 (d, J=14.0 Hz, 1H), 2.71 (d, J=14.0 Hz,
1H); 13C NMR (75 MHz, acetone-d6): d=164.2, 157.6, 150.3,
132.4, 130.9, 128.5, 124.6, 121.6, 119.8, 119.2, 116.3, 111.2,
91.3, 87.4, 85.6, 49.8; HR-MS (ESI): m/z=312.3006, calcd.
for C16H14N3O4 [M+H+]: 312.2995.
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General Procedure for Dehydration of Alcohols 7
into 9
Diketopiperazine pyrrole-AA-OH 7 (1 mmol) was dissolved
in CH3CN (15 mL), and then HCl solution in dioxane (4 mL,
0.05 mmol) was added. The mixture was stirred for 10 min
at room temperature, then 10 min at 508. The solvent was
removed to afford the pure light yellow solid; yield: quanti-
tative.
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[13] M. Gabant, PhD Thesis, University Paris XI, Septem-
ber 2008, No. 9100.
9a: IR (neat): nmax =3222 (NH); 1677 (amide); 1613, 1494,
1458 (C=C); 1570 cmÀ1 (pyrrole); 1H NMR (300 MHz,
CDCl3): d=7.99 (br s, 1H), 7.74 (dd, J=1.5, 3.2 Hz, 1H),
7.54–7.46 (m, 5H), 7.35 (s, 1H), 7.23 (dd, J=1.5, 3.6 Hz,
1H), 6.60 (dd, J=3.2, 3.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=154.8, 153.9, 132.6, 129.7, 129.6, 128.8, 126.3,
124.2, 121.5, 120.9, 119.3, 115.5; HR-MS (ESI): m/z=
261.0638, calcd. for C14H10N2O2Na [M+Na]+: 261.0640.
9b: IR (neat): nmax =1726, 1621, 1415, 1321, 736 cmÀ1
;
1H NMR (300 MHz, DMSO-d6): d=7.68 (dd, J=3.2, 1.5 Hz,
1H), 6.99 (dd, J=3.5, 1.5 Hz, 1H), 6.74 (t, J=3.5 Hz, 1H),
6.60 (t, J=3.3 Hz, 1H), 4.03 (t, J=8.9 Hz, 1H), 2.89 (dt, J=
8.9, 3.5 Hz, 1H); 13C NMR (300 MHz, DMSO-d6): d=152.1,
151.7, 133.6, 127.6, 127.0, 119.8, 116.1, 115.4, 44.8, 28.9; HR-
MS (ESI): m/z=211.0482, calcd. for C10H8N2O2Na [M+
Na]+: 211.0483.
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[17] See the Supporting Information.
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We gratefully thank Dr. Charles Giannotti and Prof. Anne
Zaparucha for the fruitful discussions. This work is supported
by CNRS and the ICSN Institute.
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asc.wiley-vch.de
1533