A novel rearrangement of cyclic glutamine derivatives: Ring contraction in 3,6-diamino-2,3,4,5-tetrahydropyridin-2-ones to yield 5-iminoproline amides

Article abstract of DOI:10.1002/ejoc.201100404

A new rearrangement of the cyclic L-glutamine derivative(S)-6- carbamoylamino-3-(methylamino)-2,3,4,5-tetrahydropyridin-2-one (2) and its descarbamoyl analogue 10-H was found to yield enantiomerically pure 5-carbamoylimino-1-methyl-L-proline amide (12-CON

Full text of DOI:10.1002/ejoc.201100404

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100404
A Novel Rearrangement of Cyclic Glutamine Derivatives: Ring Contraction in
3,6-Diamino-2,3,4,5-tetrahydropyridin-2-ones to Yield 5-Iminoproline Amides
Vladimir N. Belov,*[a][‡] Viktor V. Sokolov,[a][‡‡] Boris D. Zlatopolskiy,[b] and
Armin de Meijere*[a]
Dedicated to Professor Oleg Nefedov on the occasion of his 80th birthday
Keywords: Rearrangement / Amino acids / Nitrogen heterocycles / Cyclization
A new rearrangement of the cyclic
L
-glutamine derivative
benzyloxycarbonyl-N-methyl)amino]-2,3,4,5-tetrahydropyr-
idin-2-one (8) led directly to 5-iminoproline amide 12-H (via
10-H and the bicyclic orthoamidine 11-H) in 66% overall
(S)-6-carbamoylamino-3-(methylamino)-2,3,4,5-tetrahydro-
pyridin-2-one (2) and its descarbamoyl analogue 10-H was
found to yield enantiomerically pure 5-carbamoylimino-1-
yield from 3. Carbamoylation of
8 with ZNCO (Z =
methyl-
L
-proline amide (12-CONH2) and its descarbamoyl
PhCH2OCO) followed by hydrolytic removal of both Z
groups gave 5-(carbamoylimino)proline amide 12-CONH2
(via 2 and orthoamidine 11-CONH2) in 70% overall yield
from 3.
analogue 12-H, respectively. Cyclic amidines 2 and 10-H
were generated from the amide N2-ZGlnOEt 3 in seven and
six steps, respectively. Deprotection of (S)-6-amino-3-[(N-
than that of the N,NЈ-diacylated guanidine group in com-
pound 1. However, a very similar type of functionality had
previously been described,[2f,3] and acylated amidines were
not reported to be highly susceptible to hydrolysis. Replace-
ment of N-1 in heterocycle 1 with a carbon atom would be
advantageous, as it would convert the 2,3-diaminopropionic
acid fragment in 2 into a configurationally more stable glut-
amine residue.
Introduction
The total synthesis of the new naturally occurring antibi-
otic TAN-1057A/B[1] and various structural analogues have
been the subject of numerous investigations.[2] In the course
of
a number of structure–activity relationship stud-
ies,[2d,2j–2m] several analogues of the TAN-1057A/B hetero-
cycle 1 have also been prepared. For example, replacement
of N-3 in tetrahydropyrimidinone fragment 1 with a carbon
atom has recently been reported (Figure 1).[2f] Another
interesting option was conceived to be substitution of the
other nitrogen atom (N-1) in fragment 1 with a CH2 group.
This replacement would convert the acylated guanidine
moiety in 1 into an acylated amidine moiety. The required
tetrahydropyridinone derivative 2 was anticipated to be sus-
ceptible to hydrolysis, as it contains an amidine fragment
bearing an N-acyl and an NЈ-carbamoyl group, and its cen-
tral carbon atom would be much more electron deficient
Figure 1. N1-Deaza analogue 2 of heterocycle 1, the key fragment
of the biologically most potent A-diastereomer of the natural anti-
biotic TAN-1057.
[a] Institut für Organische und Biomolekulare Chemie der
Georg-August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: +49-551-393231
E-mail: ameijer1@gwdg.de
[b] Klinik für Nuklearmedizin, Aachen University, RWTH,
Pauwelsstr. 30, 52074 Aachen, Germany
[‡] Current address: Facility für Synthetische Chemie,
Max-Planck-Institut für Biophysikalische Chemie,
Am Fassberg 11, 37077 Göttingen, Germany
Fax: +49-551 2012505
Results and Discussion
The best starting material for compound 2 was envisaged
to be l-glutamine. A literature search indicated that l-glut-
amine should easily be transformable into tetrahydropyrid-
inone derivative 2 with the same configuration at the
E-mail: vbelov@gwdg.de
[‡‡]Permanent address: Department of Chemistry,
Saint Petersburg State University,
Universitetskii pr. 26, 198054 Saint Petersburg, Russia
Eur. J. Org. Chem. 2011, 4093–4097
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. N. Belov, V. V. Sokolov, B. D. Zlatopolskiy, A. de Meijere
SHORT COMMUNICATION
stereogenic center as in the biologically most potent A-dia- rated amidine group in compound 8 was achieved under
stereomer of TAN-1057. Indeed, cyclic amidines with one anhydrous conditions with the very reactive benzyloxy-
acylated nitrogen incorporated into a five- or six-membered carbonyl isocyanate[10] (Z-isocyanate, Scheme 2). Subse-
ring are easily available from ethyl 3-cyanopropionate or 4- quent hydrogenolytic removal of both Z groups in resulting
cyanobutyrate, respectively, by a three-step procedure start- 9 was expected to afford required 2 with a secondary amino
ing with the transformation of the nitrile into an imino es- group in the 3-position. Indeed, the isolated product had
ter[4] followed by aminolysis and spontaneous cyclization of the required molecular mass as proved by electron impact
the resulting amidine to yield 2-amino-1-pyrrolin-5-one or ionization (EI) mass spectrometry and showed seven signals
6-amino-2,3,4,5-tetrahydropyridin-2-one.[5] Tetrahydropyr- in the 13C NMR spectrum. Thus, the target seemed to be
idinone derivative 2 should thus be accessible by performing achieved in seven steps with a high overall yield (66%).
1
an analogous transformation with Z-protected ethyl 2- However, in the H NMR spectrum (in [D6]DMSO), the
amino-4-cyanobutyrate (5, Z = PhCH2OCO). To obtain es- signals of all NH protons are singlets with chemical shifts
ter 5, N2-Z-l-glutamine[6] was first converted into N2- Ͼ6 ppm, so that none of them could be attributed to the
ZGlnOEt[7] (3, Scheme 1), and then the amide moiety in aliphatic amino group. Moreover, no fragmentation with an
amido ester 3 was dehydrated under very mild conditions, elimination of the methylamino residue was registered in
that is, by treatment with trifluoroacetic anhydride/pyridine the EI mass spectrum, although such an elimination under
in dichloromethane.[8] The newly installed nitrile function electron impact ionization is well documented for tetra-
in 4 played an important role in the subsequent transforma- hydropyrimidinone derivative 1 and its analogues.[1,2] Yet,
tions for two reasons: Compound 4 could be selectively the alternative structure 12-CONH2 fits all the observed
methylated at N-2 without competitive Nω-methylation.[9] spectroscopic data. For example, in the 2D NOESY spec-
After that, the nitrile group in resulting 5 cleanly underwent trum, the cross-peaks indicate that four amide protons form
the Pinner transformation, that is, conversion into imino two pairs. The signal of a CH proton has cross-peaks with
ester 6 by treatment with hydrogen chloride in ether in the the signals of two amide protons belonging to one pair. As
presence of ethanol (Scheme 1). To keep the Z protecting expected, the rearranged compound 12-CONH2 could not
group intact, this reaction was carried out at –5 to –10 °C. be acetylated with AcOH in the presence of N-[3-(dimeth-
When run at the temperature of an ice bath,[4] benzyl chlo- ylamino)propyl]-NЈ-ethylcarbodiimide
and
4-(dimeth-
ride, formed by cleavage of the Z protective group, could be ylamino)pyridine (10%) (EDC/DMAP) at room tempera-
extracted with diethyl ether from salt 7 to the extent of ca. ture in dimethylformamide.[11]
10 mol-%.
Scheme 2. Ring contraction in (S)-6-amino-3-(methylamino)-
Scheme 1. Synthesis of Z-protected (S)-6-amino-3-(methylamino)-
2,3,4,5-tetrahydropyridin-2-one (8) as a potential key intermediate
2,3,4,5-tetrahydropyridin-2-ones 2 and 10-H. Reagents and condi-
tions: (a) ZNCO, DMF, 0 °C to r.t.; (b) H2 (1 atm), Pd/C (10% Pd,
oxidized form), DMF; (c) ZOC6F5, iPr2NEt, DMF, 55 °C, 12 h.
en route to the tetrahydropyridinone derivative
2 (Z =
C6H5CH2OCO). Reagents and conditions: (a) (CF3CO)2O, pyr-
idine, CH2Cl2, 0 °C to r.t.; (b) MeI, Ag2O, DMF, 0 °C to r.t.;
(c) gaseous HCl, EtOH, ether, –10 to –5 °C; (d) 10% NH3 in EtOH;
(e) 20% aq. NaOH.
The formation of compound 12-CONH2 can be rational-
ized by assuming that the initially formed 3-methylami-
Upon treatment with a slight excess amount of dry am- notetrahydropyridinone derivative 2 undergoes intramolec-
monia in anhydrous ethanol at room temperature, imino ular nucleophilic addition onto the endocyclic imino group
ester 6 was smoothly transformed into amidine 7. Then eth- to form the rather strained 1-amino-2,7-diazabicyclo[2.2.1]-
anol was evaporated, and aqueous NaOH was added to the heptan-3-one derivative 11-CONH2. The bicyclic intermedi-
oily residue with cooling. The solution was adjusted to ate 11-CONH2 with its orthoamidine moiety cycloreverts
pH 12–13. The thick precipitate that was immediately with the acylamino group acting as the better nucleofuge
formed turned out to be the desired compound 8. Carbam- and forms the stable 5-carbamoylimino-1-methylproline
oylation of the exocyclic nitrogen atom of the ring-incorpo- amide (12-CONH2) with a new amidine fragment incorpo-
4094
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Eur. J. Org. Chem. 2011, 4093–4097

A Novel Rearrangement of Cyclic Glutamine Derivatives
(300.5 MHz for 1H) spectrometers. All NMR spectra are referenced
to tetramethylsilane as an internal standard (δ = 0 ppm) using the
signals of the residual protons of CHCl3 (δ = 7.26 ppm) in CDCl3
or [D5]DMSO (δ =2.50 ppm) in [D6]DMSO. Multiplicities of sig-
nals are described as follows: s = singlet, br. s = broad singlet, d =
doublet, m = multiplet, mc = centrosymmetrical multiplet. EI-MS
were recorded with a Finnigan MAT 95 at 70 eV and ESI-MS were
recorded with a Finnigan LCQ. Elemental analyses were performed
in the Mikroanalytisches Laboratorium des Instituts für Or-
ganische und Biomolekulare Chemie. Reactions were carried out
rated into a five-membered ring. This new amidine frag-
ment is deprived of the activating acyl group in precursor
2.
Interestingly, when compound 8 was directly subjected to
hydrogenolysis without carbamoylation, the same type of
rearrangement also took place (8 Ǟ 10-H Ǟ 11-H Ǟ 12-
H in Scheme 2). In this case, along with the spectroscopic
evidence, chemical proof of the new rearrangement was
provided by conversion of amidine 12-H into the corre-
sponding N-benzyloxycarbonyl derivative 12-Z by using O- under an atmosphere of argon with magnetic stirring in Schlenk
flasks equipped with septa or reflux condensers with bubble
counters using a standard manifold with vacuum and argon lines.
The purity of the products was checked by TLC on Merck ready-
to-use plates with silica gel 60 (F254). Column chromatography was
performed with Merck silica gel, grade 60, 0.06–0.20 mm.
benzyloxycarbonylpentafluorophenol (ZOC6F5), and it was
shown that compounds 12-Z and 8 are not identical.
A sample of compound 12-CONH2 was analyzed on a
chiral HPLC column with the teicoplanin-modified station-
ary phase (Chirobiotic T) in polar solvent mode optimized
for the separation of amino acids (see the Experimental Sec-
tion for details). This column under the given conditions
reliably separates enantiomers of all natural amino acids
Ethyl (S)-2-[(N-Benzyloxycarbonyl-N-methyl)amino]-4-cyanobutan-
oate (5): Compound 5 was synthesized from ethyl (S)-2-(benzyloxy-
carbonylamino)-4-cyanobutanoate (4)[7] according to the pre-
viously published general method.[9] To a mixture of compound 4
(21.4 g, 73.8 mmol) and Ag2O (65 g, 0.28 mol) in anhydrous DMF
(200 mL) was added MeI (35 mL, 80 g, 0.56 mol) dropwise at +5
to 10 °C (external cooling with water was applied). The reaction
mixture was stirred overnight at room temperature and then filtered
through Celite. The filter cake was washed with CH2Cl2 (1 L). The
and many of their derivatives. Only one peak with tR
=
8.1 min (area 92%) and an impurity with tR = 2.8 min
(peak area 8%) was observed. These results suggest that
most likely the recrystallized sample of compound 12-
CONH2 is a single enantiomer [because under the given
separation conditions, the differences in retention times of combined organic solutions were washed with sat. aq. Na2S2O3
(3ϫ200 mL) and then with water (8ϫ300 mL). After drying of the
organic solutions over MgSO4, the solvent was evaporated under
reduced pressure, and the residual oil was kept in vacuo (0.1 Torr)
until its weight became constant (21.5 g; corresponds to 96% yield).
1H NMR (250 MHz, CDCl3): δ = 1.17–1.28 (m, 3 H, CH3), 2.07–
2.20 (m, 1 H, 3-H), 2.31–2.46 (m, 3 H, 3-H, 4-H), 2.92 (s, 3 H,
MeN), 4.07–4.24 (m, 2 H, CH2O), 4.53–4.67 (m, 1 H, 2-H), 5.17
(s, 2 H, CH2O), 7.26–7.36 (m, 5 H) ppm. 13C NMR (62.9 MHz,
CDCl3, signals of the major amide rotamer are marked*): δ = 14.1
(C-4), 14.4 (CH3), 24.9* (C-3), 32.2*/32.6 (MeN), 58.4/58.8*
the (R)- and (S)-amino acids, e.g., l- and d-pyroglutamic
acids, are expected to be 1–3 min].
The scope and limitations of this new rearrangement
were briefly investigated. When tetrahydropyridinone deriv-
atives of type 9 did not contain a 3-(N-methylamino) group
but a 3-amino group, the rearrangement was also observed,
but in this case the transformation was not so clean and
high yielding. When Nα-methylasparagine derivatives were
used, the corresponding azetidine derivatives could not be
isolated, but rather complex mixtures of oligomers and (CH2O), 61.7 (CHN), 67.7*/67.8 (CH2O), 118.8 (CN), 127.7, 128.1,
128.5 (CH), 136.2 (C), 156.8 (CONH), 169.8 (COO) ppm.
polymers were obtained.
(S)-6-Amino-3-[(N-benzyloxycarbonyl-N-methyl)amino]-2,3,4,5-tetra-
hydropyridin-2-one (8): To a solution of compound 5 (19 g,
62 mmol) in anhydrous ether (150 mL) was added anhydrous EtOH
(5 mL), and the solution was saturated with dry HCl while stirring
at –10 °C (cooling with an ice/NaCl mixture). The reaction mixture
was kept at –5 to –10 °C overnight. Volatile materials were evapo-
rated in vacuo at 0 °C and then at room temperature. The glassy
residue was washed with anhydrous ether (2ϫ50 mL; with decan-
tation) and kept under reduced pressure (0.5 Torr) for 3 h. The resi-
due (compound 6) was dissolved in anhydrous EtOH (70 mL), and
a 10% solution of NH3 in EtOH was added, until the pH value of
a sample of the reaction mixture diluted with water became 8–9.
The reaction mixture was kept at room temperature for 22 h, the
ethanol was evaporated in vacuo, and the residue (compound 7)
was dissolved in cold water (50 mL). The solution was made basic
(pH 12–13) with 20% aq. NaOH added with stirring at 0 °C. A
colorless voluminous precipitate was formed almost immediately.
It was removed by filtration, washed with cold water, and dried to
give 15.0 g (87%) of the title compound with m.p. 206–208 °C. An
analytical sample (1.9 g) was recrystallized from EtOH (150 mL)
and dried in vacuo; m.p. 212 °C. [α]2D0 = –39 (c = 0.52, DMF). Rf
= 0.27 (CH2Cl2/MeOH, 10:1). 1H NMR (250 MHz, [D6]DMSO,
signals of the major amide rotamer are marked*): δ = 1.85 (mc, 1
H, 4-H), 2.03 (mc, 1 H, 4-H), 2.60 (mc, 1 H, 5-H), 2.68 (mc, 1 H,
5-H), 2.70/2.72* (2 s, Σ 3 H, NMe), 4.48 (mc, 1 H, 3-H), 5.04 (A
Conclusion
Thus, a novel high-yielding (66–70%) route to 5-imino-
1-methylproline amides 12-CONH2 and 12-H in seven and
six steps, respectively, from enantiomerically pure N2-benz-
yloxycarbonyl-l-glutamine ethyl ester (3) is reported. Com-
pounds 12-CONH2 and 12-H may have interesting bio-
logical activities, as 12-H is the amide of (S)-5-imino-1-
methylproline, which was isolated from a highly bioactive
extract of the Caribbean sponge Cliona tenuis.[12] The latter
as well as its methyl ester have previously been prepared in
five- and six-step syntheses in 42% overall yield.[12] Two 2-
iminopyrrolidinecarboxylic acid derivatives have exhibited
antibacterial activities,[13] and a series of substituted 2-imi-
nopyrrolidines have been shown to be potent and selective
inhibitors of human inducible nitric oxide synthase.[14]
Experimental Section
General: NMR spectra were recorded with Bruker AM 250
1
(250 MHz for H and 62.9 MHz for 13C) and Varian Mercury-300
Eur. J. Org. Chem. 2011, 4093–4097
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V. N. Belov, V. V. Sokolov, B. D. Zlatopolskiy, A. de Meijere
SHORT COMMUNICATION
part of AB system, JAB = 12.7 Hz, CHHO), 5.08 (B part of AB
57 (20), 42 (17). MS (CI, NH3): m/z (%) = 142 (100) [M + H]+,
system, JAB = 12.7 Hz, CHHO), 5.09 (s, Σ 2 H, CH2O), 7.32–7.38 283 (19) [2M + H]+.
(m, 5 H), 8.11 (br. s, 2 H, NH2) ppm. 13C NMR (62.9 MHz, [D6]-
5-Benzyloxycarbonylimino-1-methyl-L-proline Amide (12-Z): A mix-
DMSO, signals of the major amide rotamer are marked*): δ = 23.3/
23.90* (CH2), 27.3 (CH2), 31.1/31.7* (Me), 57.1 (CH), 66.4
(CH2O), 127.4, 127.7, 127.8, 128.0, 128.5, 128.6 (CH), 137.2 (C),
156.2 (OCON), 174.2 (C-2/6), 177.6 (C-6/2) ppm. MS (EI, 70 eV):
m/z (%) = 275 (24) [M]+·, 231 (4), 184 (5), 156 (9), 140 (12), 112
(18), 91 (100), 83 (20), 65 (8). C14H17N3O3 (275.3): calcd. C 61.08,
H 6.22, N 15.26; found C 60.81, H 6.34, N 15.41.
ture of 12-H (0.21 g, 1.5 mmol), ZOPfp (0.52 g, 1.6 mmol), iPr2NEt
(0.19 g, 0.25 mL, 1.5 mmol), and N,N-dimethylacetamide (2.0 mL)
was heated at 55 °C for 12 h. The solvent was evaporated in vacuo,
the residue was taken up in ether and transferred onto a filter,
washed with a small amount of cold water, then again with ether,
and dried in vacuo; m.p. 149–151 °C. Yield: 0.27 g (66%). Rf = 0.50
(CH2Cl2/MeOH, 10:1). 1H NMR (250 MHz, [D6]DMSO): δ = 1.83
(mc, 1 H, 3-H), 2.21 (mc, 1 H, 3-H), 2.81 (s, NMe), 2.85 (m, 4-H,
Σ 5 H), 4.18 (dd, J = 9, 4 Hz, 1 H, 2-H), 5.01 (s, 2 H, OCH2), 7.31
(br. s, 1 H, CONH2), 7.38 (s, 5 H, C6H5), 7.67 (s, 1 H, CONH2)
ppm. 13C NMR (62.9 MHz, [D6]DMSO): δ = 24.8 (CH2), 30.2
(CH2), 30.8 (CH3), 64.0 (CH), 66.0 (CH2O), 127.8 (CH), 128.0 (2
CH), 128.5 (2 CH), 137.6 (C), 162.5 (C), 172.4 (C), 174.1 (C) ppm.
MS (EI, 70 eV): m/z (%) = 275 (16) [M]+·, 231 (28) [M –
H2NCO]+·, 168 (22) [M – C7H7O]+·, 97 (21), 91 (100). HRMS (EI):
calcd. for C14H17N3O3 [M]+· 275.1270; found 275.1269.
5-Carbamoylimino-1-methyl-L-proline Amide (12-CONH2): To a
suspension of 8 (1.6 g, 5.8 mmol) in anhydrous DMF (30 mL) was
added ZNCO (1.06 g, 6.00 mmol) dropwise at room temperature.
The course of the reaction was monitored by TLC on SiO2
(CH2Cl2/MeOH, 10:1). Compound 9 has a higher Rf value than
compound 8. If the spot of the starting material was still detected
at 254 nm, a few more drops of ZNCO were added. When the reac-
tion was complete, 10% Pd/C (200 mg, oxidized form, VWR) was
added, and the suspension was vigorously stirred for 2.5 h under
an atmosphere of hydrogen. TLC indicated that compound 9 had
been consumed, and a single new UV-active spot of a more polar
compound with Rf = 0.19 was observed (CH2Cl2/MeOH, 4:1). The
reaction mixture was filtered through Celite; the filter cake was
washed with anhydrous DMF (10 mL). The solvent was evaporated
in vacuo, and the residue was taken up in cold anhydrous ethanol.
A solid colorless substance was filtered off, washed with a small
amount each of cold ethanol and ether, then dried. Yield: 0.86 g
(80%), m.p. 159–160 °C. [α]2D0 = +25 (c = 0.51, MeOH). RP-HPLC
[Gemini column, 5 μ C18, 110 Å, 4.6ϫ250 mm with precolumn
(“Phenomenex”); gradient: 0–4% MeOH (0–6 min), 4–90% MeOH
(6–20 min), 90% MeOH (23–26 min); flow rate: 1 mL/min; detec-
Acknowledgments
This work was financially supported by Bayer AG. The authors are
grateful to Reinhard Machinek, Holm Frauendorf, and their co-
workers for recording NMR and mass spectra. We thank Mrs. E.
Pfeil for measuring the optical rotation values and Rene Kandler
for helping with HPLC analyses.
[1] a) N. Katayama, S. Fukusumi, Y. Funabashi, T. Iwahi, H. Ono,
J. Antibiot. 1993, 46, 606–613; b) Y. Funabashi, S. Tsubotani,
K. Koyama, N. Katayama, S. Harada, Tetrahedron 1993, 49,
13–28.
tion at 220 nm, inj. vol.: 5 μL, probe conc.: 3 mg/mL, H2O]: tR
=
4.5 min (peak area 95%). Chiral HPLC [Chirobiotic T column, 5 μ,
4.6ϫ250 mm (“ISCO”); eluent: 10% aq. EtOH; flow rate: 1.7 mL/
min; detection at 220 nm, inj. vol.: 10 μL, probe conc.: 1 mg/mL,
H2O]: tR = 8.1 min (peak area 92%; one additional peak with tR
[2] For the total syntheses of TAN-1057A/B, see: a) V. V. Sokolov,
S. I. Kozhushkov, S. Nikolskaya, V. N. Belov, M. Es-Sayed, A.
de Meijere, Eur. J. Org. Chem. 1998, 777–783; b) C. Yuan,
R. M. Williams, J. Am. Chem. Soc. 1997, 119, 11777–11784; c)
for a total synthesis of TAN-1057A, see: V. N. Belov, M.
Brands, S. Raddatz, J. Krüger, S. Nikolskaya, V. V. Sokolov, A.
de Meijere, Tetrahedron 2004, 60, 7579–7589; for a review on
the medicinal chemistry of natural antibacterials, see: d) F.
von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Häbich,
Angew. Chem. 2006, 118, 5194–5254, Angew. Chem. Int. Ed.
2006, 45, 5072–5129; for a review on natural guanidine deriva-
tives, see: e) R. G. S. Berlinck, Nat. Prod. Rep. 1999, 16, 339–
365; for TAN-1057A/B analogues, see: f) L. Zhang, C. U. Kim,
L. Xu, Tetrahedron Lett. 2007, 48, 3273–3275; g) L. Xu, L.
Zhang, C. M. Bryant, C. U. Kim, Tetrahedron Lett. 2003, 44,
2601–2604; h) L. Zhang, L. Xu, C. U. Kim, Tetrahedron Lett.
2003, 44, 5871–5873; i) P. Lin, A. Ganesan, Synthesis 2000,
14, 2127–2130; j) M. Brands, R. Endermann, R. Gahlmann, J.
Krüger, S. Raddatz, Bioorg. Med. Chem. Lett. 2003, 13, 241–
245; k) M. Brands, Y. C. Grande, R. Endermann, R.
Gahlmann, J. Krüger, S. Raddatz, Bioorg. Med. Chem. Lett.
2003, 13, 2641–2645; l) M. Brands, R. Endermann, R.
Gahlmann, J. Krüger, S. Raddatz, J. Stoltefuß, V. N. Belov, S.
Nizamov, V. V. Sokolov, A. de Meijere, J. Med. Chem. 2002, 45,
4246–4253; m) R. M. Williams, C. Yuan, V. J. Lee, S. Cham-
berland, J. Antibiot. 1998, 51, 189–201; n) M. Kordes, M.
Brands, M. Es-Sayed, A. de Meijere, Eur. J. Org. Chem. 2005,
3008–3016; o) N. Aguilar, J. Krüger, Molecules 2002, 7, 469–
474.
1
= 2.8 min). H NMR (250 MHz, [D6]DMSO): δ = 1.82 (mc, 1 H,
3-H), 2.14 (mc, 1 H, 3-H), 2.66–2.81 (m, 4-H), 2.73 (s, NMe, Σ 5
H), 3.98 (dd, J = 8.8, 3.9 Hz, 1 H, 2-H), 5.98 (br. s, 1 H, NCONH2),
6.20 (br. s, 1 H, NCONH2), 7.21 (s, 1 H, CONH2), 7.64 (s, 1 H,
CONH2) ppm. 13C NMR (62.9 MHz, [D6]DMSO): δ = 25.1 (CH2),
29.1 (CH2), 30.4 (CH3), 63.2 (CH), 165.0 (C), 169.7 (C), 173.2 (C)
ppm. MS (EI, 70 eV): m/z (%): 184 (12) [M]+·, 140 (70) [M –
H2NCO]+·, 123 (8) [M – H2NCO – NH3]+·, 97 (100) [M – H2NCO –
HNCO]+·, 82 (6), 57 (18), 42 (17). C7H12N4O2 (184.2): calcd. C
45.64, H 6.57, N 30.42; found C 45.39, H 6.66, N 30.22.
5-Imino-1-methyl-L-proline Amide (12-H): To a suspension of 8
(0.80 g, 2.9 mmol) in anhydrous DMF (15 mL) was added 10% Pd/
C (100 mg, oxidized form, VWR). The mixture was vigorously
stirred for several hours under an atmosphere of hydrogen. The
starting material gradually dissolved in the course of the deprotec-
tion procedure. The reaction mixture was filtered through Celite;
the filter cake was washed with anhydrous DMF (10 mL). The sol-
vent was evaporated in vacuo, and the residue was taken up in
methanol. The title compound was precipitated as a colorless solid
by addition of anhydrous ether. A very hygroscopic substance was
filtered off, washed with diethyl ether, and dried in vacuo. Yield:
0.35 g (85%). 1H NMR (250 MHz, [D6]DMSO): δ = 1.77 (mc, 1 H,
3-H), 2.15 (mc, 1 H, 3-H), 2.36–2.51 (m, 2 H, 4-H), 2.69 (s, NMe,
3 H), 3.97 (dd, J = 8.8, 3.9 Hz, 1 H, 2-H), ca. 5.8 (br. s, 1 H,
C=NH), 7.4 (s, 1 H, CONH2), 8.0 (s, 1 H, CONH2) ppm. MS (EI,
70 eV): m/z (%) = 141 (8) [M]+·, 97 (100) [M – H2NCO]+·, 82 (7),
[3] Acyclic amidines with N-[alkyl(aryl)amino]sulfonyl- and NЈ-
alkoxycarbonyl substituents have been described: G. Ham-
precht, R.-D. Acker, E. Hädicke, Liebigs Ann. Chem. 1985,
2363–2370.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4093–4097

A Novel Rearrangement of Cyclic Glutamine Derivatives
[4] H. Ueno, A. Maruyama, M. Miyake, E. Nakao, K. Nakao, K.
R. A. Lerner, K. D. Janda, Proc. Natl. Acad. Sci. USA 1997,
94, 11777–11782).
L. Castellanos, C. Duque, S. Zea, A. Espada, J. Rodrigues, C.
Jiménez, Org. Lett. 2006, 8, 4967–4970. In this report, (S)-5-
imino-1-methylproline and the corresponding methyl ester were
prepared in five and six steps, respectively, in 42% overall yield.
Umezu, I. Nitta, J. Med. Chem. 1991, 34, 2468–2473.
ˇ
[5] Cf.: M. Protiva, V. Rerˇicha, J. O. Jilek, Chem. Listy 1954, 48,
[12]
[13]
1210–1211.
[6] C. Ressler, H. Ratzkin, J. Org. Chem. 1961, 26, 3356–3360.
[7] T. Itoh, Bull. Chem. Soc. Jpn. 1963, 36, 25–29.
[8] E. W. Della, H. Gangodawila, Aust. J. Chem. 1989, 42, 1485–
1492.
[9] Methyl iodide in the presence of Ag2O in DMF has been
shown to provide full conversion of N-Z and N-Boc amino
acids into the corresponding N-methyl derivatives without ap-
preciable racemization: R. K. Olsen, J. Org. Chem. 1970, 35,
1912–1915.
[10] L. Grehn, M. L. S. Almeida, U. Ragnarsson, Synthesis 1988,
992–994. Acetylation of compound 8 gave a product that was
unstable in the presence of water. Carbamoylation in the pres-
ence of water was found to be ineffective.
[11] These are standard conditions for the peptide coupling reaction
(e.g., C. Gao, C.-H. Lin, C.-H. L. Lo, S. Mao, P. Wirsching,
R. E. Mitchell, K. L. Teh, Org. Biomol. Chem. 2005, 3, 3540–
3543.
[14] a) T. J. Hagen, A. A. Bergmanis, S. W. Kramer, K. F. Fok, A. E.
Schmelzer, B. S. Pitzele, L. Swenton, G. M. Jerome, C. M.
Kornmeier, W. M. Moore, L. F. Branson, J. R. Connor, P. T.
Manning, M. G. Currie, E. A. Hallinan, J. Med. Chem. 1998,
41, 3675–3683; b) S. Tsymbalov, T. J. Hagen, W. M. Moore,
G. M. Jerome, J. R. Connor, P. T. Manning, B. S. Pitzele, E. A.
Hallinan, Bioorg. Med. Chem. Lett. 2002, 12, 3337–3339.
Received: March 23, 2011
Published Online: June 8, 2011
Eur. J. Org. Chem. 2011, 4093–4097
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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