Solid Phase Synthesis of Substituted 2-Amino-4-Pyrrolinones via Spontaneous Postcleavage Cyclization

Anastasia Detsi; Pavlos Emirtzoglou; Kyriakos Prousis; Apostolos N. Nikolopoulos; Vasso Skouridou; Olga Igglessi-Markopoulou

doi:10.1055/s-2003-45002

LETTER

Solid Phase Synthesis of Substituted 2-Amino-4-Pyrrolinones via Spontaneous Postcleavage Cyclization

Anastasia Detsi*^a, Pavlos Emirtzoglou^a, Kyriakos Prousis^a, Apostolos N. Nikolopoulos^a, Vasso Skouridou^b, Olga Igglessi-Markopoulou*^a
^a Laboratory of Organic Chemistry, School of Chemical Engineering, National Technical University of Athens, Zografou Campus, Athens 157 73, Greece
Fax: +3(210)7723072; e-Mail: ojmark@orfeas.chemeng.ntua.gr;
^b Biotechnology Laboratory, School of Chemical Engineering, National Technical University of Athens, Zografou Campus, Athens 157 73, Greece

Abstract

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Abstract

The solid phase synthesis of 2-amino-4-pyrrolinones is described. α-Amino acid benzotriazolyl esters attached to 2-chlorotrityl resin are used as acylating agents for the C-acylation of cyanoacetates and the polymer-bound C-acylation products are cleaved from the resin using very mild acidic conditions and spontaneously cyclized to the desired heterocyclic compounds. Reaction monitoring was effected by FT-IR on the resin beads.

Key words

2-amino-4-pyrrolinones - solid phase synthesis - polymer-bound benzotriazolyl esters of α-amino acids

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References

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(2-Chlorotrityl resin)-l-Phe-OBt (1, 1.13 mmol/g), (2-chlorotrityl resin)-l-Val-OBt (2, 0.88 mmol/g), (2-chlorotrityl resin)-l-Leu-OBt (3, 1.0 mmol/g) were purchased from NovaBiochem.

General Procedure for the Preparation of the Resin-Bound C-Acylation Products 4-7: Methyl or ethyl cyanoacetate (2.5 mmol) was added dropwise to a suspension of sodium hydride (2.5 mmol, 0.1 g of 60% NaH dispersion in oil) in anhyd THF (5 mL) and the thick slurry thus formed was stirred at r.t. for 1 h. The slurry was added to the appropriate resin (0.5 mmol), swelled in anhyd THF (5 mL), and the mixture was gently stirred under Ar overnight, at r.t. The resin was filtered and washed thouroughly alternating with THF (10 mL), MeOH (10 mL) and CH₂Cl₂ (10 mL; this cycle was repeated 3 times) and then dried in vacuo to provide the resin-bound C-acylation products 4-7. All compounds gave red colour when treated with iron(III) chloride solution.

FT-IR (KBr) spectroscopic data for the resin-bound C-acylation compounds 4-7:
Compound 4: 2191 s (CN), 1772 w (C=O ester keto-form), 1698 s (C=O ester enol-form) cm^-1.
Compound 5: 2188 s (CN), 1755 w (C=O ester keto-form), 1686 s (C=O ester enol-form) cm^-1.
Compound 6: 2188 s (CN), 1734 m (C=O ester keto-form), 1675 s (C=O ester enol-form) cm^-1.
Compound 7: 2189 s (CN), 1737 w (C=O ester keto-form), 1678 s (C=O ester enol-form) cm^-1.

General Procedure for the Cleavage, Cyclization and Isolation of Substituted 2-Amino-4-pyrrolinones 8-11: Cleavage followed by spontaneous cyclization was accomplished by suspending 0.5 mmol of the resin-bound C-acylation compounds 4-7 in 1% TFA in CH₂Cl₂ (8 mL) and gently stirring under Ar, at r.t. overnight. The resin was filtered and washed thoroughly alternating with CH₂Cl₂ (10 mL) and MeOH (10 mL; this cycle was repeated 3 times) and the filtrate was evaporated in vacuo. The pure 2-amino-4-pyrrolinones 8-11 were obtained after flash column chromatography using 9:1 CH₂Cl₂-MeOH.

Spectroscopic and physical data for compound 9:
2-Amino-3-ethoxycarbonyl-5-benzyl-4-pyrrolinone(9): 65% yield, mp 202-204 °C (lit. [10] 203-206 °C). ¹H NMR (300 MHz, CDCl₃/CD₃OD): δ = 1.26 (t, 3 H, J = 7.0 Hz), 2.50 and 2.54 (dd, 1 H, J = 14 Hz, J = 9.9 Hz), 3.16 and 3.21 (dd, 1 H, J = 14.0 Hz, J = 3.0 Hz), 3.83 (d, 1 H, J = 7.8 Hz), 4.16 (q, 2 H, J = 7.0 Hz), 7.14-7.24 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃/CD₃OD): δ = 14.20, 38.12, 59.28, 63.68, 87.48, 126.67, 128.52, 129.01, 137.49, 165.86, 169.52, 192.44. FT-IR (CH₂Cl₂): 3008 and 2928 w, br (NH and NH₂), 1651 m (C=O ketone and C=O ester) cm^-1.

The enantiomeric ratios were determined by HPLC analysis using a CHIRALPAK AS column (4.6 × 250 mm), [210 nm, 0.5 mL/min, hexane-EtOH (80:20)].