Solid-phase synthesis of optically active substituted 2-aminofuranones using an activated carbonate linker

Article abstract of DOI:10.3390/molecules14103914

An efficient three-step solid-phase synthesis of diverse 3,5-disubstituted-2-aminofuranones has been developed. α-Hydroxy acids loaded on a nitrophenyl carbonate derivative of Wang resin are used as acylating agents for the C-acylation of active methylene

Full text of DOI:10.3390/molecules14103914

Molecules 2009, 14, 3914-3921; doi:10.3390/molecules14103914
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Solid-Phase Synthesis of Optically Active Substituted
2-Aminofuranones Using an Activated Carbonate Linker
Dimitris Matiadis, Kyriakos C. Prousis and Olga Igglessi-Markopoulou *
Laboratory of Organic Chemistry, School of Chemical Engineering, National Technical University of
Athens, Zografou Campus, Athens 15773, Greece
* Author to whom correspondence should be addressed; E-Mail: ojmark@orfeas.chemeng.ntua.gr;
Tel.: +30 210 772 3 079; Fax: +30 210 772 3 072.
Received: 8 September 2009; in revised form: 29 September 2009 / Accepted: 30 September 2009 /
Published: 30 September 2009
Abstract: An efficient three-step solid-phase synthesis of diverse 3,5-disubstituted-2-
aminofuranones has been developed. α-Hydroxy acids loaded on a nitrophenyl carbonate
derivative of Wang resin are used as acylating agents for the C-acylation of active
methylene compounds and the resulting intermediates provided, through a cyclative
cleavage reaction, the desired product.
Keywords: 2-aminofuranones; solid-phase synthesis; heterocycles; lactones; acylations
Introduction
Multistep organic syntheses can be substantially facilitated by conducting reactions on substrates
that are covalently attached to insoluble supports. The principles of “solid-phase synthesis” were
introduced in 1963 by Merrifield [1]. Since then, the concept of solid phase synthesis has been applied
extensively in numerous areas [2-5] such as peptides and oligonucleotides, and there has been
significant progress in small molecules, especially heterocycles, due to several advantages over
solution-phase methodologies.
A crucial point in the design of compound libraries and, in particular, for cyclative cleavage
strategies [6,7], is the careful choice of the appropriate linker unit. The linkers connect the solid
support to the third element which is usually the starting material and can be classified as traditional or
classical if the site of attachment of the resin remains following cleavage, and traceless if they allow

Molecules 2009, 14
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the release of the desired molecules without any linker-derived functional groups remaining in the
products and diversity linkers [8,9].
Four main factors contribute to the popularity of this technique: (i) the simplified reaction
procedures − reactions can be accomplished in only three steps: addition of reagents, filtering and
finally washing the resin; (ii) purification and isolation steps are eliminated as the only purification
needed is the washing of the resin; (iii) the capability of using high concentrations of reagents, as well
as (iv), automation of synthesis, which is a basic requirement for multiple parallel syntheses.
Among organic small molecules, heterocyclic compounds have received particular attention in
combinatorial chemistry because they are important structural components of bioactive molecules. The
synthetic methods for the various substituted (functionalized) aminofuranones are very limited in the
chemical literature. Recently, substituted 4-amino-2-furanones have been prepared due to their
potential use for the treatment and/ or prophylaxis of diseases, particularly of retroviral disorders in
humans or animals by Bayer Healthcare AG [10]. Moreover, this class of heterocycles were provided
from (S)-ketone cyanohydrins, their ureido derivatives as antitumor agents and their 5-hydroxy
derivatives as antibiotics [11-17]. Stereoselective synthesis of 3-amino-2-furanones by intramolecular
cycloaddition of α-allyloxycarbonylnitrons has been published [18]. Several 2-amino-4-furanone
herbicides have been introduced as they exhibit activity against a wide range of weeds and show
selectivity to several crops [19,20]. However, as far as we know, the solid phase synthesis of 2-amino-
4-furanones has not yet been established. Our group has reported in a previous work the synthesis of
many 2-aminofuranone derivatives in solution phase [21].
Figure 1. General structure of 2-aminofuranones.
Our group has paid particular attention to the synthesis of tetramic [22], tetronic [23] and
thiotetronic acids [24], as well as other heterocycles which contain two points of diversity in solution
and, recently, in solid phase synthesis via cyclization reactions of functionalized butenoates derived
from active esters of α-amino acids and α-hydroxy acids [25]. As part of our research programme we
required a concise three step solid-phase method to construct 3,5-disubstituted-2-aminofuranones. A
diverse set of α-hydroxy acid building blocks were all used successfully: aryl, methyl, disubstituted, or
unsubstituted, enabling us to obtain a library of 3, 5-disubstituted 2-aminofuranones. The proposed
methodology was achieved as shown in Scheme 1.

Molecules 2009, 14
Scheme 1. Synthetic protocol methodology for 3, 5-disubstituted-2-aminofuranones via
3916
cyclative cleavage.
OH
NO2
O
O
i
2
+
HO
+
OH
O
O
R3 R2
NO2
O
3
R2 = H, Me, Ph
R3 = H, Me
Cl
O
(4 members)
R3
R2
O
R3
O
R2
R1
ii
O
iii
O
OH
R1
O
O
O
CN
OH
CN
(4x2=8 members)
R1 = COOEt, CN
(2 members)
4
5
O
R1
iv
R3
R2
NH2
O
(4x2=8 members)
1
Reagents and conditions: (i) NMM, dry CH2Cl2, 0 ºC → r.t., (ii) 4-DMAP, DMF, r.t., (iii)
HOBt, DCC, NaH, 0 ºC → r.t., (iv) TFA/DCM (1/1), r.t.
Results and Discussion
Commercially available 4-nitrophenyl carbonate on Wang resin was chosen as polymer support. We
also tried the synthesis of the polymer support from Wang resin because of the ease of preparation and
the high cost of the commercial resin. The treatment of Wang resin 2 with p-nitrophenyl chloroformate
and N-methylmorpholine according to a literature method [26] gave the desired polymer support.
However, the overall yield and the purity of the final products were significantly decreased by a factor
of over 15% using the synthesized resin.

Molecules 2009, 14
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Table 1. Yields of 4-aminofuranones 1a-h.
Product
1a
R1
CO2Et
CN
R2
H
R3
H
%yield
40
1b
H
H
52
1c
1d
1e
1f
1g
1h
CO2Et
CN
CO2Et
CN
CO2Et
CN
Me
Me
Ph
Ph
Me
Me
H
H
H
H
Me
Me
37
52
58
43
53
54
The key step of our methodology involves the attachment of the appropriate α-hydroxy acid on the
activated carbonate Wang resin 3. The α-hydroxy acids were immobilized by attachment of their
hydroxy function to the resin. Nucleophilic attack of this building block at the activated carbonyl
group, the p-nitrophenyl group is a good leaving group, leaded to the formation of a new carbonate
bond between the resin and the α-hydroxy acid. A fourfold excess of the latter was applied to ensure
exhaustive loading of the resin. The progress of the reaction was monitored by FT-IR spectroscopy
which showed the disappearance of the NO2 bands at 1,525 and 1,347 cm-1 after 48 hours and a shift of
the carbonate carbonyl group from 1,768 to 1,747 cm-1.
A C-acylation reaction of an active methylene compound with the polymer supported α-hydroxy
acid 4 gave the C-acylated derivative 5. This reaction was also monitored successfully by FT-IR which
showed the expected appearance of the bands at 2,180 cm-1 which come from the cyano group.
Acid treatment of the latter with 50% trifluoroacetic acid in CH2Cl2 resulted in cyclative cleavage
of the intermediate product giving the desired compounds in satisfactory yields. The cyclization
reaction was expected [27] to yield both 2-imino-4-furanones or 2-imino-4-furanols (imidotetronic
acids) and 2-amino-4-furanones. However, NMR data showed clearly only the tautomeric
aminofuranone derivative. No 1H- or 13C-NMR signal coming from imino group appeared, as expected
from an imidotetronic acid. It is worth pointing out that our synthesis proceeds without significant
racemization. When started from optically pure α-hydroxy acids, the corresponding aminofuranones
are formed with retention of the configuration at C-5. The optical purity of the compound 1f was
confirmed by chiral HPLC and the enantiomeric ratio was found 87:13 (see Experimental Section).
The structure of compounds 1a-h was confirmed by analytical and spectrometric data. The NMR
and HRMS data are the expected for the new compounds and in full accordance with those previously
reported for the known compounds [21]. No reaction byproducts were identified as NMR data analysis
and TLC showed that the two impurities were unreacted α-hydroxy acids and trace resin impurities.
Conclusions
We have demonstrated an efficient traceless solid phase approach to optically active 2-
aminofuranones starting from the α-hydroxy acid chiral pool. The three step synthesis of the products
(loading, acylation, cleavage) was carried out under mild conditions thereby reducing unwanted side
effects e.g. racemization or byproduct formation. Further investigation to apply the carbonate linker to
other oxygen heterocycles is now in progress.

Molecules 2009, 14
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Experimental
General
All reagents were purchased from Aldrich, Fluka and Acros and used without further purification.
Dry dichloromethane was predried with CaCl2 and distilled from P2O5 and dry THF was distilled from
Na/Ph2CO. Flash column chromatography was carried out on silica gel Macherey-Nagel
0.063-0.2 mm/70-230 mesh. Melting points were determined on a Gallenkamp MFB-595 melting point
apparatus and are uncorrected. IR spectra were recorded on a Jasco 4200 FTIR spectrometer. HRMS
were carried out in the Liverpool University Mass spectra core facility on a VG 7070E instrument and
were obtained by chemical ionization (CI) with ammonia. NMR spectra were recorded on a Varian
Gemini-2000 300 MHz spectrometer operating at 300 MHz (1H) and 75 MHz (13C). Chemical shifts δ
are reported in ppm relative to DMSO-d6 (1H: δ = 2.50, 13C: δ = 39.52) and CD3OD (13C: δ = 49.00). J
values are given in Hz. HPLC separations were performed using a DAICEL CHIRALPAK AS (4.6 x
250 mm) column incorporated in an HPLC system consisting of a Varian 2510 HPLC pump, Varian
2510 variable λ detector and a SRI Model 203 Peaksimple chromatography data system using n-
hexane/ethanol as eluent. Optical rotations were measured on a Perkin Elmer 241 polarimeter.
General procedure for the synthesis of 3,5-disubstituted-2-aminofuranones
4-Nitrophenyl carbonate on Wang resin (0.75 g, 0.90 mmol, 1.2 mmol/g) 3 was suspended and
swelled for 10 min in dry DMF (10 mL). The resin was treated with the appropriate α-hydroxy acid
(3.60 mmol) and 4-DMAP (5.40 mmol). The mixture was gently stirred under Argon at r.t. for 48 h.
The resin filtered and washed with 3 x 10mL each of DMF, methanol and CH2Cl2 and then dried in
vacuo to provide the immobilized α-hydroxyacids 4.
The loaded resin was swelled for 10 minutes in anhydrous THF (10mL) and subsequently treated
with HOBt (3.60 mmol) at 0 °C for 45 min, followed by dropwise addition of a solution of DCC (3.36
mmol in 3-4 mL THF) at 0 °C. The mixture was gently agitated at r.t. for 1.5 h. To the mixture was
added a solution of the active methylene compound in NaH/THF. The latter, is prepared by adding
dropwise the active methylene to a suspension of sodium hydride in anhydrous THF at 0 °C and left
stirring at rt for 1h. The resulting mixture stirred at room temperature for 24 hours. The resin was
filtered and washed with 3 × 10 mL each of methanol and CH2Cl2 and then dried on an oil pump to
afford the immobilized C-acylation products 5. An 18 mL mixture of TFA/DCM (50:50) was added to
resin 5 and stirred at room temperature for 1h. The red coloured resin was filtered and washed with
3 × 10 mL each of MeOH and CH2Cl2 and then, the combined filtrates were evaporated to dryness
under reduced pressure. The crude products were then purified by column chromatography on silica
gel (CH2Cl2/ MeOH 97:3).
2-Amino-3-ethoxycarbonyl-4-furanone (1a) [21]: White solid, mp: 246-248 ºC (lit. mp: 245-246 ºC),
Rf = 0.35 (DCM: MeOH = 92 :8), 1H-NMR (DMSO-d6): δ 1.20 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 4.13
(q, J = 7.2 Hz, 2H, CO2CH2CH3), 4.51 (s, 2H, CH2), 8.12/9.13 (2s, 2H, NH2); 13C-NMR (DMSO-d6): δ
13.84 (CO2CH2CH3), 58.18 (CO2CH2CH3), 73.70 (C-5), 85.66 (C-3), 163.61 (CO2CH2CH3), 179.99
(C-2), 190.13 (C-4).

Molecules 2009, 14
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2-Amino-3-cyano-4-furanone (1b) [21]: White solid, mp: 259-260 ºC (lit. mp: 260-261 ºC), Rf = 0.31
1
(DCM: MeOH = 95 :5), H-NMR (DMSO-d6): δ 4.71 (s, 2H, CH2), 9.24 (s, 2H, NH2); 13C-NMR
(DMSO-d6): δ 67.51 (C-5), 77.90 (C-3), 113.78 (CN), 179.89 (C-2), 193.08 (C-4).
(S)-2-Amino-3-ethoxycarbonyl-5-methyl-4-furanone (1c): White solid, mp: 220-221 ºC, αD = -66.0
(c = 0.01 MeOH), Rf = 0.29 (DCM: MeOH = 95 :5), 1H-NMR (DMSO-d6): δ 1.20 (t, J = 6.9 Hz, 3H,
CH2CH3), 1.29 (d, J = 6.9 Hz, 3H, CHCH3), 4.12 (q, J = 6.9 Hz, 2H, CH2CH3), 4.63 (q, J = 6.9 Hz,
1H, CHCH3), 8.13/9.09 (2H, s/s, NH2); 13C-NMR (CD3OD): δ 14.83 (CO2CH2CH3), 16.95 (CH3),
60.66 (CO2CH2CH3), 83.99 (C-5), 86.69 (C-3), 165.61 (CO2CH2CH3), 180.95 (C-2), 195.46 (C-4);
HRMS: m/z [M +H]+ calcd. for C8H12NO4 186.02663 found 186.02679.
(S)-2-Amino-3-cyano-5-methyl-4-furanone (1d): White solid, mp: 240-241 ºC, αD = -95.3 (c = 0.01
1
MeOH), Rf = 0.34 (DCM: MeOH = 95 :5), H-NMR (DMSO-d6): δ 1.32 (d, J = 6.9 Hz, 3H, CH3),
13
4.82 (q, J = 6.9 Hz, 1H, CH), 9.18 (2H, br, NH2); C-NMR (CD3OD): δ 16.76 (CH3), 68.51 (C-5),
84.92 (C-3), 113.55 (CN), 179.91 (C-2), 196.80 (C-4); HRMS: m/z [M +NH4]+ calcd. for C6H10N3O2
156.07730 found 156.07689.
(S)-2-Amino-3-ethoxycarbonyl-5-phenyl-4-furanone (1e) [21]: White solid, mp: 211-212 ºC (lit. mp:
1
211-212 ºC), αD = +16.8 (c=0.02 MeOH), Rf = 0.32 (DCM: MeOH = 97 :3), H-NMR (DMSO-d6):
1.20 (t, J = 6.9 Hz, 3H, CO2CH2CH3), 4,14 (q, J = 6.9 Hz, 2H, CO2CH2CH3), 5.62 (s, 1H, CH), 7.26-
13
7.41 (M, 5H, Ph), 8.34/9.34 (2s, 2H, NH2); C-NMR (DMSO-d6): δ 14.43 (CO2CH2CH3), 58.67
(CO2CH2CH3), 84.06 (C-5), 85.04 (C-3), 126.43 (Ph), 128.80 (Ph), 128.70 (Ph), 134.45 (Ph), 134.80
(Ph), 163.56 (CO2CH2CH3), 179.36 (C-2), 188.55 (C-4).
(S)-2-Amino-3-cyano-5-phenyl-4-furanone (1f) [21]: White solid, mp: 269-270 ºC (lit. mp: 270-271
ºC), αD = -34.0 (c = 0.02 MeOH), Rf = 0.29 (DCM: MeOH = 97 :3), 1H-NMR (DMSO-d6): δ 5.83 (1H,
s, CH), 7.27 -7.43 (5H, m, Ph), 9.43 (2H, br, NH2); 13C-NMR (DMSO-d6): δ 66.19 (C-5), 86.17 (C-3),
113.48 (CN), 126.61 (Ph), 128.76 (Ph), 129.09 (Ph), 133.93 (Ph), 134.45 (Ph), 177.94 (C-2), 190.84
(C-4); HPLC analysis: (n-hexane/ethanol = 1:1; flow rate: 0.80 mL/min; 254 nm) major enantiomer
tR(S) = 6.53 min (87%), minor enantiomer tR (R) = 7.15 min (13%).
2-Amino-5,5-dimethyl-3-ethoxycarbonyl-4-furanone (1g): Pale yellow solid, mp: 202-203 ºC (lit. mp:
1
205-206 ºC), Rf = 0.33 (DCM: MeOH = 97 :3) H-NMR (DMSO-d6): 1.20 (t, J = 6.9 Hz, 3H,
CO2CH2CH3), 1.29 (s, 6H, 2 x CH3), 4.12 (q, J = 6.9 Hz, 2H, CO2CH2CH3), 8.14/9.05 (2s, 2H, NH2);
13C-NMR (DMSO-d6): 14.48 (CO2CH2CH3), 23.11 (CH3), 58.56 (CO2CH2CH3), 82.70 (C-5), 88.12
(C-3), 163.97 (CO2CH2CH3), 177.33 (C-2), 192.77 (C-4); HRMS: m/z [M +H]+ calcd. for C9H14NO4
200.09228 found 200.09224.
2-Amino-3-cyano-5,5-dimethyl-4-furanone (1h): Pale yellow solid, mp: 240-242 ºC (dec.), Rf = 0.24
1
13
(DCM: MeOH = 95 :5), H-NMR (DMSO-d6): 1.33 (s, 6H, 2× CH3), 9.16 (s, 2H, NH2); C-NMR
(DMSO-d6): 22.88 (CH3), 64.64 (C-5), 89.76 (C-3), 113.87 (CN), 176.03 (C-2), 195.05 (C-4); HRMS:
m/z [M +NH4]+ calcd. for C7H12N3O2 170.09295 found 170.09265.

Molecules 2009, 14
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Acknowledgements
The author D.M. gratefully acknowledges National Technical University of Athens for financial
support.
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