A Traceless Solid-Phase Approach to Functionalized Tetramic Acids and 2-Amino-4-pyrrolinones

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-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.

tetramic acids - 2-amino-4-pyrrolinones - carbamate resin - solid-phase synthesis

References

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General Procedure for the Preparation of Polymer-Bound Carbamate Amino Acids 3.
l-α-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.

<A NAME="RG16105ST-11">11</A> Salvino JM. Gerard B. Ye HF. Sauvagnat B. Dolle RE. J. Comb. Chem.  2003,  5:  260 

<A NAME="RG16105ST-12">12</A>

Representative IR analysis of neat resin 3 (R = CH₂C₆H₅), obtained on a Bruker EQUINOX 55 using the DuraSamplIR II equipment.

<A NAME="RG16105ST-13">13</A>

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.

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Representative IR analysis of neat resin 5a obtained on a Bruker EQUINOX 55 using the DuraSamplIR II equipment.

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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.

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5-Benzyl-3-methoxycarbonyl Tetramic Acid (6a). Mp 141-143 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.64 (dd, J = 13.8, 7.2 Hz, 1 H, PhCH ₂), 3.03 (dd, J = 13.5, 3.3 Hz, 1 H, PhCH ₂), 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.
5-Isopropyl-3-methoxycarbonyl Tetramic Acid (6b).
Mp 59-62 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.64 [d, J = 6.3 Hz, 3 H, (CH ₃)₂CH], 0.90 [d, J = 6.9 Hz, 3 H, (CH ₃)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-d ₆): δ = 0.86 [s, 6 H, (CH ₃)₂CHCH₂], 1.05-1.15 [m, 1 H, (CH₃)₂CHCH ₂], 1.40-1.50 [m, 1 H, (CH₃)₂CHCH ₂], 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-d ₆): δ = 2.76 (dd, J = 13.8, 7.2 Hz, 1 H, PhCH ₂), 3.05 (dd, J = 14.0, 4.2 Hz, 1 H, PhCH ₂), 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-d ₆): δ = 0.75 [d, J = 6.7 Hz, 3 H, (CH ₃)₂CH], 0.98 [d, J = 7.3 Hz, 3 H, (CH ₃)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.
2-Amino-3-cyano-5-isobutyl-4-pyrrolinone (7f).
¹H NMR (300 MHz, DMSO-d ₆): δ = 0.88 [d, J = 6.3 Hz, 6 H, (CH ₃)₂CHCH₂], 1.19-1.29 [m, 1 H, (CH₃)₂CHCH ₂], 1.39-1.50 [m, 1 H, (CH₃)₂CHCH ₂], 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.

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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.