A traceless solid-phase approach to functionalized tetramic acids and 2-amino-4-pyrrolinones

Article abstract of DOI:10.1055/s-2005-918941

A novel traceless route for the synthesis of optically active functionalized tetramic acids and 2-amino-4-pyrrolinones on solid support is described. p-Nitrophenyl carbonate linker on Wang resin is used to anchor L-α-Amino acids by their N-terminus thus leaving the carboxylic function free for further elaboration. High yields and ee, in combination with the versatility implied by the wide range of commercially available building blocks, are the major advantages of the proposed methodology. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918941

LETTER
2763
A Traceless Solid-Phase Approach to Functionalized Tetramic Acids and
2-Amino-4-pyrrolinones
A
T
raceless Solid-
y
P
hase
A
ppro
r
achtoF
i
unction
a
alized
T
etr
k
amic
A
cids os C. Prousis, Anastasia Detsi, Olga Igglessi-Markopoulou*
National Technical University of Athens, School of Chemical Engineering, Laboratory of Organic Chemistry, Zografou Campus,
Athens 157 73, Greece
E-mail: ojmark@orfeas.chemeng.ntua.gr
Received 10 June 2005
membered nitrogen heterocycles, namely 3-substituted-
2,4-pyrrolinediones (tetramic acids) and 3-substituted-2-
amino-4-pyrrolinones. Tetramic acids comprise a well-
known family of naturally occurring nitrogen hetero-
Abstract: A novel traceless route for the synthesis of optically
active functionalized tetramic acids and 2-amino-4-pyrrolinones on
solid support is described. p-Nitrophenyl carbonate linker on Wang
resin is used to anchor L-a-Amino acids by their N-terminus thus
leaving the carboxylic function free for further elaboration. High cycles, bearing a wide variety of substituents on the het-
yields and ee, in combination with the versatility implied by the
erocyclic ring and possessing various pharmacological
wide range of commercially available building blocks, are the major
and biological properties such as anticancer, antiviral and
advantages of the proposed methodology.
antibacterial activity.3 As a result, the development of
Key words: tetramic acids, 2-amino-4-pyrrolinones, carbamate
resin, solid-phase synthesis
synthetic routes towards tetramic acids has been a chal-
lenging field for many research groups over the years.
Solid-phase methodologies for the synthesis of optically
active tetramic acids have been recently reported and in-
Heterocyclic compounds, both naturally occurring and
synthetically produced, exhibit various pharmacological
and biological properties and are, therefore, interesting
synthetic targets in the search of therapeutic agents.
Especially small heterocyclic molecules are considered
‘privileged’ structures for the synthesis and development
of new drugs.
volve N-acylation of amino acids linked via an ester bond
to the resin and cyclic cleavage in basic conditions
(Dieckmann cyclization)4a–4c, cyclative Claisen-type con-
densation of N-acylated a-amino acids loaded on Wang
resin4d or condensation of N-acylated amino acids with
polymer-supported cyclic malonic ester followed by mild
cyclative cleavage.5 In addition, the pyrrolinone scaffold
is the key building block for the development of antican-
cer, antithrombotic and antimicrobial agents, and has been
used for the synthesis of nonpeptidyl peptidomimetics.6
Solid-phase organic synthesis is an attractive, constantly
growing field of organic chemistry, since it provides rapid
access to combinatorial libraries of compounds required
for biological screening. The major advantages of this
technique include simple separation and purification pro-
cesses, which can be easily automated, and the use of high
concentration of reagents. Moreover, transferring tradi-
tional solution chemistry to the solid phase or exploring
new synthetic routes on solid support offers the opportu-
nity for the development of novel methodologies, which
may have otherwise been difficult or even impossible.1
In earlier work, we have demonstrated that N-urethane-
protected a-amino acids are valuable precursors for the
synthesis of optically active tetramic acids and N-ure-
thane-protected functionalized butenoates, since urethane
(carbamate)-type protecting groups (e.g. benzyloxy-
carbonyl-, tert-butoxycarbonyl-) are stable to the reaction
conditions and prevent racemization.7 In this context, we
set out to transfer our methodology to the solid phase
using a carbamate linker to attach a-amino acids via their
N-terminus to the resin. This type of linker, a benzyloxy-
carbonyl protecting group equivalent, would offer us the
opportunity to efficiently bind a-amino acids to the solid
support via the amine function and, at the same time, leave
the carboxylic function free for the chemical modifica-
tions required.8
Our research group has a longstanding interest in the syn-
thesis of heterocyclic compounds in solution. Therefore
we set out to adapt some of our protocols to the solid
phase aiming at the development of more rapid and ad-
vantageous construction of libraries of small heterocyclic
compounds. As a result, we have recently reported the sol-
id-phase synthesis of optically active substituted 2-amino-
4-pyrrolinones via spontaneous postcleavage cyclization,
using activated esters of a-amino acids attached to 2-chlo-
rotrityl resins as acylating agents.2
The p-nitrophenyl carbonate Wang resin 1 (Scheme 1)
was the resin of choice as it can react with a-amino acids
and is compatible and stable with the conditions of our
synthetic protocol, yet labile under cleavage conditions
that do not cause decomposition of the desired compounds
generated. Reaction of 1 with preactivated a-amino acids
furnished the corresponding carbamate-protected resin-
bound amino acids 3.9 In a typical experiment,10 L-a-ami-
no acids 2 or N-methyl-glycine (sarcosine) were stirred in
a solution of BSA in DMF, at 55 °C for 1 hour, DMAP
In this paper we document the development of a novel
solid-phase traceless synthesis of functionalized five-
SYNLETT 2005, No. 18, pp 2763–2766
0
3
.1
1
.2
0
0
5
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-918941; Art ID: G16105ST
© Georg Thieme Verlag Stuttgart · New York

2764
K. C. Prousis et al.
LETTER
Table 1 Compounds 5 Used in Resin-Bound C-Acylation
was added and the mixture was subsequently added to p-
nitrophenyl carbonate resin 1, pre-swollen in DMF. After
stirring for 24 hours, the carbamate resin 3 was filtered
and washed sequentially with DMF, MeOH and CH2Cl2.
Efficient binding of the a-amino acids on the resin was
confirmed by IR monitoring, which showed the character-
istic carbonyl signal of the urethane carbonyl group at
1718 cm–1 and lacked the bands at 1525 and 1347 cm–1,
attributed to the nitro group.11,12
Compound R1
R2
H
X
Y
5a
5b
5c
5d
5e
5f
CH2C6H5
COOCH3
COOCH3
COOCH3
COOCH3
COOC2H5
COOC2H5
COOC2H5
COOC2H5
CN
COOCH3
COOCH3
COOCH3
COOCH3
COOC2H5
CN
CH(CH3)2
CH2CH(CH3)2
H
H
H
CH3
CH3
H
H
NO2
O
R1
CH2C6H5
CH(CH3)2
CH2CH(CH3)2
CH2C6H5
CH(CH3)2
CH2CH(CH3)2
OH
O
O
+
HN
R2
5g
5h
5i
H
CN
O
O
1
2
H
CN
H
CN
O
R1
5j
H
CN
CN
OH
O
N
R2
O
5k
H
CN
CN
O
3
Treatment of carbamate resins 5 with 50% TFA in CH2Cl2
at room temperature for one hour resulted in the cleavage
of the C-acylation precursors from the resin followed by
spontaneous cyclization to the corresponding five-mem-
bered nitrogen heterocycles 6a–e and 7a–f (Scheme 3 and
Scheme 4). After filtering and repetitively washing the
resin with CH2Cl2, alternating with MeOH, the desired
compounds were isolated in high yields (55–85%) and
purities, without any further purification step (Table 2).15
Structure elucidation of all the synthesized compounds
was accomplished by means of 1H NMR spectroscopy and
elemental analyses.16 The physical and spectroscopic data
of all known compounds were in full accordance with
those reported previously.17
Scheme 1 Attachment of a-amino acids to p-nitrophenol carbonate
resin. Reagents and conditions: 4 equiv of 2, 10 equiv of BSA, 2 equiv
of DMAP, DMF, 24 h, r.t.
Anchoring a-amino acids by their amine functionality to
p-nitrophenol carbonate resin enabled the activation of the
free carboxylic function as a benzotriazolyl ester, which
in turn reacted with sodium dimethyl malonate, ethyl cy-
anoacetate or malononitrile (active methylene compounds
4) in THF at room temperature to provide the correspond-
ing resin-bound C-acylation compounds 5 after 24 hours
(Scheme 2, Table 1).13 After the C-acylation reaction, the
resin beads give a red color when treated with iron(III)
chloride solution, characteristic of the presence of an enol
system, providing therefore a strong indication of product
formation. Further proof of the completion of the C-acyl-
ation reaction was again given by IR analysis, since the
spectra showed a shift of the signal of the urethane carbo-
nyl group to 1684 cm–1 and a characteristic peak at 1646
cm–1 for the C=O stretching of the enolized b-keto ester
functionality.14
In addition, the enantiomeric excess (ee) of the 5-alkyl
tetramic acids and 2-amino-4-pyrrolinones synthesized
has been determined by HPLC analysis, using a chiral sta-
tionary phase (Table 2 and Table 3). The results indicate
that our solid-phase methodology leads to compounds in
which the stereochemical integrity of the chiral center is
retained to a great extent.
O
R1
O
R1 COOR3
COOR3
X
Y
OH
O
N
R2
O
N
R2
H2C
+
O
OH
O
O
5a–e
3
4
TFA/CH2Cl2 1:1,
r.t., 1 h
O
R1
X
HO
R1
COOR3
O
O
N
R2 OH
Y
N
O
R2
5
6a–e
Scheme 2 C-Acylation of active methylene compounds. Reagents
and conditions: NaH (60% in oil; 5 equiv), 4 (5 equiv), HOBt (4
equiv), DCC (4 equiv), THF, 24 h, r.t.
Scheme 3 Synthesis of tetramic acids.
Synlett 2005, No. 18, 2763–2766 © Thieme Stuttgart · New York

LETTER
A Traceless Solid-Phase Approach to Functionalized Tetramic Acids
2765
Table 2 Yields and ee of Tetramic Acids 6a–e
case of the acid induced release of C-acylation com-
pounds 5f–k from the resin, the cyclization follows a dif-
ferent route: the nucleophilic attack is preferred to the
carbon of the protonated cyano group than to the less elec-
trophilic carbon of the methoxycarbonyl group, producing
the 2-amino-4-pyrrolinones 7a–f.
Compd R1
R2
H
R3
Yield (%)a ee (%)b
6a
6b
6c
6d
6e
CH2C6H5
CH3
CH3
CH3
CH3
80
75
78
82
82
84
80
–
CH(CH3)2
H
CH2CH(CH3)2
H
In conclusion, we have developed a solid-phase traceless
synthesis of optically active functionalized tetramic acids
and 2-amino-4-pyrrolinones using a carbamate linker to
bind L-a-amino acids and sarcosine to Wang resin. The C-
acylation precursors are tethered on the solid support by
acylating various active methylene compounds (dimethyl
malonate, cyanoacetic esters and malononitrile) with the
benzotriazolyl esters of the resin-bound amino acids. The
acidic cleavage protocol leads to the tandem cyclization of
the released C-acylation compounds to the desired tetram-
ic acids and 2-amino-pyrrolinones by forming a new C–N
bond integral to the heterocyclic system. Moreover, the
described protocol is applicable to the synthesis of N-
methyl tetramic acids, which constitute an integral part of
many natural products.3b,c The wide variety of commer-
cially available a-amino acids and active methylene
compounds is a major advantage of the described method-
ology, since these are the required building blocks that
will enable access to diverse tetramic acids and 2-amino
pyrrolinones. Application of this methodology to the
synthesis of tetramic acids bearing functionalized sub-
stituents on position 5 of the heterocyclic ring as well as
to the synthesis of N-alkylated optically active tetramic
acids is currently under investigation.
H
H
CH3
CH3
CH2CH3 74
–
a Overall yield, calculated on the basis of the starting p-nitrophenyl
carbonate resin.
b Enantiomeric excess was determined by HPLC analysis, using a
CHIRALPAK AS column (4.6 × 250 mm; 254 nm, 0.6 mL/min,
hexane–EtOH 60:40).
O
R1
X
O
N
CN
H
OH
O
5f–k
TFA/CH2Cl2 1:1,
r.t., 1 h
O
X
R1
NH2
N
H
7a–f
Scheme 4 Synthesis of 2-amino-3-substituted-4-pyrrolinones.
Table 3 Yields and ee of 2-Amino-4-pyrrolinones 7a–f
Acknowledgment
Compound R1
X
Yield (%)a ee (%)b
K.C.P. is grateful to the A.G. Leventis Foundation for financial
support.
7a
7b
7c
7d
7e
7f
CH2C6H5
COOC2H5
COOC2H5
COOC2H5
CN
84
77
74
58
53
52
80c
88c
78d
82e
96e
80e
CH(CH3)2
References
CH2CH(CH3)2
CH2C6H5
(1) (a) Krchñák, V.; Holladay, M. W. Chem. Rev. 2002, 102,
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(4) (a) Weber, L.; Iaiza, P.; Biringer, G.; Barbier, P. Synlett
1998, 1156. (b) Romoff, T. T.; Ma, L.; Wang, Y.; Campbell,
D. A. Synlett 1998, 1341. (c) Matthews, J.; Rivero, R. A. J.
Org. Chem. 1998, 63, 4808. (d) Kulkarni, B. A.; Ganesan,
A. Tetrahedron Lett. 1998, 39, 4369.
CH2CH(CH3)2
CN
a Overall yield, calculated on the basis of the starting p-nitrophenyl
carbonate resin.
b Enantiomeric excess was determined by HPLC analysis, using a
CHIRALPAK AS column (4.6 × 250 mm).
c 210 nm, 0.6 mL/min, hexane–EtOH 80:20.
d 210 nm, 0.8 mL/min, hexane–EtOH 80:20.
e 254 nm, 0.6 mL/min, hexane–EtOH 80:20.
The cleaved C-acylation compounds derived from acyl-
ation of dimethyl malonate (resins 5a–e), spontaneously
cyclize in the acidic medium, to the corresponding 2,4-
pyrrolidine-diones (tetramic acids) 6a–e by the nucleo-
philic attack of the nitrogen electron pair to the carbonyl
carbon of the methoxycarbonyl group. However, in the
(5) Liu, Z.; Ruan, X.; Huang, X. Bioorg. Med. Chem. Lett. 2003,
13, 2505.
Synlett 2005, No. 18, 2763–2766 © Thieme Stuttgart · New York

2766
K. C. Prousis et al.
LETTER
(6) (a) Missbach, M. PCT Int Appl. WO9610028, 1996.
(b) Saudi, M. N. S.; El Semary, M. M. A.; El Sawaf, G.
Pharmazie 2002, 57, 519. (c) Miller, P. C.; Owen, T. J.;
Molyneaux, J. M.; Curtis, J. M.; Jones, C. R. J. Comb. Chem.
1999, 1, 223. (d) Smith, A. B. III.; Nittoli, T.; Sprengeler, P.
A.; Duan, J. J.-W.; Liu, R.-Q.; Hirschmann, R. F. Org. Lett.
2000, 2, 3809.
(7) (a) Detsi, A.; Markopoulos, J.; Igglessi-Markopoulou, O.
Chem. Commun. 1996, 1323. (b) Detsi, A.; Gavrielatos, E.;
Adam, M. A.; Igglessi-Markopoulou, O.; Markopoulos, J.;
Theologitis, M.; Reis, H.; Papadopoulos, M. Eur. J. Org.
Chem. 2001, 4337. (c) Detsi, A.; Afantitis, A.; Athanasellis,
G.; Markopoulos, J.; Igglessi-Markopoulou, O.; Skylaris, C.
K. Eur. J. Org. Chem. 2003, 4593.
(15) General Procedure for Cleavage–Cyclization.
Resin-bound C-acylation compounds 5 were swollen in 4
mL CH2Cl2 for 10 min and then 4 mL TFA were added.
After stirring for 1 h, the resin was filtered off, washed
alternating with 10 mL CH2Cl2, MeOH three times and the
solvents were evaporated in vacuo. The residues were
dissolved in a small amount of MeOH and Et2O was added
to afford the desired products as solids.
(16) 5-Benzyl-3-methoxycarbonyl Tetramic Acid (6a).
Mp 141–143 °C. 1H NMR (300 MHz, DMSO-d6): d = 2.64
(dd, J = 13.8, 7.2 Hz, 1 H, PhCH2), 3.03 (dd, J = 13.5, 3.3
Hz, 1 H, PhCH2), 3.55 (s, 3 H, COOCH3), 4.03 (dd, J = 6.9,
3.9 Hz, 1 H, CH-NH), 7.15–7.27 (m, 5 H, arom.) ppm. Anal.
Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67. Found: C,
62.99; H, 5.51; N, 5.33.
(8) (a) Yang, L. Tetrahedron Lett. 2000, 41, 6981.
(b) Gouilleux, L.; Fehrentz, J.-A.; Winternitz, F.; Martinez,
J. Tetrahedron Lett. 1996, 37, 7031.
(9) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron
Lett. 1996, 37, 937.
5-Isopropyl-3-methoxycarbonyl Tetramic Acid (6b).
Mp 59–62 °C. 1H NMR (300 MHz, DMSO-d6): d = 0.64 [d,
J = 6.3 Hz, 3 H, (CH3)2CH], 0.90 [d, J = 6.9 Hz, 3 H,
(CH3)2CH], 1.90–2.01 [m, 1 H, (CH3)2CH], 3.19 (s, 1 H,
CH–NH), 3.49 (s, 3 H, COOCH3), 6.41 (s, 1 H, NH) ppm.
Anal. Calcd for C9H13NO4: C, 54.27; H, 6.53; N, 7.04.
Found: C, 54.48; H, 6.51; N, 7.33.
5-Isobutyl-3-methoxycarbonyl Tetramic Acid (6c).
Mp 98–101 °C. 1H NMR (300 MHz, DMSO-d6): d = 0.86 [s,
6 H, (CH3)2CHCH2], 1.05–1.15 [m, 1 H, (CH3)2CHCH2],
1.40–1.50 [m, 1 H, (CH3)2CHCH2], 1.71–1.80 [m, 1 H,
(CH3)2CHCH2], 3.29 (dd, J = 9.0, 3.3 Hz, 1 H, CH-NH),
3.49 (s, 3 H, COOCH3) 6.57 (br s, 1 H, NH) ppm. Anal.
Calcd for C10H15NO4: C, 56.34; H, 7.04; N, 6.57. Found: C,
56.49; H, 6.87; N, 6.81.
2-Amino-5-benzyl-3-cyano-4-pyrrolinone (7d).
Mp 200 °C (dec.). 1H NMR (300 MHz, DMSO-d6): d = 2.76
(dd, J = 13.8, 7.2 Hz, 1 H, PhCH2), 3.05 (dd, J = 14.0, 4.2
Hz, 1 H, PhCH2), 4.03 (dd, J = 8.3, 2.7 Hz, 1 H, CH–NH),
7.20–7.35 (m, 5 H, arom.), 7.61 (br s, 2 H, NH2), 7.70 (s, 1
H, NH) ppm. Anal. Calcd for C13H11N3O: C, 67.59; H, 5.20;
N, 19.70. Found: C, 67.85; H, 5.32; N, 19.59.
2-Amino-3-cyano-5-isopropyl-4-pyrrolinone (7e).
Mp >250 °C. 1H NMR (300 MHz, DMSO-d6): d = 0.75 [d,
J = 6.7 Hz, 3 H, (CH3)2CH], 0.98 [d, J = 7.3 Hz, 3 H,
(CH3)2CH], 2.01–2.05 [m, 1 H, (CH3)2CH], 3.63 (d, J = 1.8
Hz, 1 H, CH–NH), 7.71 (br s, 2 H, NH2), 7.83 (s, 1 H, NH)
ppm. Anal. Calcd for C8H11N3O: C, 58.17; H, 6.71; N, 25.44.
Found: C, 57.96; H, 6.45; N, 25.26.
(10) General Procedure for the Preparation of Polymer-
Bound Carbamate Amino Acids 3.
L-a-amino acids 2 (2.4 mmol) were dissolved in 5 mL DMF
at 50 °C in the presence of N,O-(bis)trimethylsilylacetamide
(BSA, 1.22 g, 1.48 mL, 6.0 mmol) and then stirred for about
1 h to activate the amino group. The mixture was poured into
the p-nitrophenol carbonate resin 1 (0.5 g, 0.6 mmol, 1.2
mmol/g resin) pre-swollen in 5 mL DMF for 15 min, then
DMAP (0.147 g, 1.2 mmol) was added and the mixture was
stirred for 24 h at r.t. The resulting resin 3 was filtered off
and washed alternating with 10 mL DMF, MeOH, CH2Cl2;
this washing cycle was repeated three times.
(11) Salvino, J. M.; Gerard, B.; Ye, H. F.; Sauvagnat, B.; Dolle,
R. E. J. Comb. Chem. 2003, 5, 260.
(12) Representative IR analysis of neat resin 3 (R = CH2C6H5),
obtained on a Bruker EQUINOX 55 using the DuraSamplIR
II equipment.
(13) General Procedure for the Synthesis of Resin-Bound C-
Acylation Intermediates 5.
Resins 3 were swollen in 5 mL of freshly distilled THF for
15 min, then N-hydroxybenzotriazole (0.324 g, 2.4 mmol)
was added at 0 °C and the reaction mixture was stirred for 30
min at the same temperature. A solution of DCC (0.495 g,
2.4 mmol) in 4 mL THF was added dropwise to the above
mixture at 0 °C, and stirring continued for 1.5 h. Active
methylene compounds 4 (3.0 mmol) were added dropwise to
a suspension of NaH (0.12 g, 3.0 mmol, 60% in oil) in THF
(6 mL) at 0 °C and the mixture was stirred at r.t. for 1 h. The
resulting carbanion slurry was added to the activated resin
and the reaction mixture was stirred for 24 h at r.t The
resulting resin 5 was filtered off and washed alternating with
10 mL THF, MeOH, CH2Cl2; this washing cycle was
repeated three times.
2-Amino-3-cyano-5-isobutyl-4-pyrrolinone (7f).
1H NMR (300 MHz, DMSO-d6): d = 0.88 [d, J = 6.3 Hz, 6
H, (CH3)2CHCH2], 1.19–1.29 [m, 1 H, (CH3)2CHCH2],
1.39–1.50 [m, 1 H, (CH3)2CHCH2], 1.70–1.80 [m, 1 H,
(CH3)2CHCH2], 3.67 (dd, J = 9.0, 3.3 Hz, 1 H, CH–NH),
7.68 (br s, 2 H, NH2), 7.98 (s, 1 H, NH) ppm. Anal. Calcd for
C9H13N3O: C, 60.31; H, 7.31; N, 23.44. Found: C, 60.24; H,
7.34; N, 23.49.
(14) Representative IR analysis of neat resin 5a obtained on a
Bruker EQUINOX 55 using the DuraSamplIR II equipment.
(17) For physical and spectroscopic data of 3-alkoxycarbonyl-1-
methyltetramic acids 6d and 6e see ref. 7c, and for 2-amino-
3-ethoxycarbonyl-pyrrolin-4-ones 7a–c, see ref. 2.
Synlett 2005, No. 18, 2763–2766 © Thieme Stuttgart · New York