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Synlett 2003(6): 0817-0820
DOI: 10.1055/s-2003-38757
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solid-phase Synthesis of 2,3,5-Triketopiperadine

Shingo Makino*, Eiji Nakanishi, Takashi Tsuji
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc. 1-1. Suzuki-cho. Kawasaki-ku. Kawasaki-shi. 210-8681, Japan
Fax: +81(44)2105876; e-Mail: shingo_makino@ajinomoto.com;
Further Information

Publication History

Received 26 November 2002
Publication Date:
17 April 2003 (online)

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Abstract

The synthesis of 2,3,5-triketopiperadines on solid-support has been achieved for the first time. Cyclization of 4 using oxalyl diimidazole proceeded excellently with N-methyl amino acids except for Sarcosine (Sar). On the other hand, this cyclization did not proceed well when amino acids without N-methyl substitution were used. This can be explained by the lower energy difference between the trans and cis configurations of oxalyl amide 5 by the introduction of N-methyl substitution, because cis conformation is necessary for the cyclization to proceed. This cyclization also worked well with amino acids with a six-membered ring such as tetrahydroisoquinoline-3-carboxylic acid (Tic) and piperidine-2-carboxylic acid (Pic), which are N-alkylated amino acids. Although the purity of the target compounds was found to be low in the case of Sar and amino acids with a five-membered ring such as proline (Pro) and thiazolidine-4-carboxylic acid (Thz) under the same cyclization conditions, we were able to successfully optimize the reaction conditions to give the target compounds with good purity. Furthermore, it was demonstrated that 2,3,5-triketopiperadines with three points diversity could be prepared on solid-support with high purity, showing the generality of this method.

Key words

combinatorial chemistry - solid-phase synthesis - heterocyclic - cyclization - 2,3,5-triketopiperadines - oxalyl diimidazole

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4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin (100-200 mesh, loading 0.53 µmol/g) was purchased from Novabiochem (http://www.nova.ch).

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Representative Procedure for the synthesis of 7o: 4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin (NOVAbiochem, 100-200mesh, loading 0.53 mmol/g, 60 mg) was put into a 2.5 mL syringe [12] fitted with a poly-ethylene filter. 1-Aminomethylnaphthalene-NaCNBH3-NMP-AcOH (150 µL/32 mg/1.0 mL/10 µL) was added to the syringe, and the syringe was shaken for 16 h at 25 °C, then for 8 h at 60 °C. The resin was washed with MeOH (2 mL ¥ 3), DMF (2 mL ¥ 3) and CH2Cl2 (2 mL ¥ 3), and dried under vacuum for 3 h. After 4-nitrophenylacetic acid (73 mg) was pre-activated with N, N′-diisopropyl-carbodiimide (DIC)-1-hydroxy-7-azabenzotriazole (HOAt)-NMP (29 µL/55 mg/1.2 mL) at 25 °C for 1 h, this solution was added to the syringe and the syringe was shaken at 25 °C for 16 h. The resin was washed with DMF (2 mL ¥ 3) and CH2Cl2 (2 mL ¥ 3), and dried under vacuum for 3 h. The resin was treated with SnCl2⟨2H2O-NMP-EtOH (1.0 g/2.0 mL/0.1 mL) at 25 °C for 38 h, and washed with DMF (2 mL ¥ 3), CH2Cl2 (2 mL ¥ 3), and dried under vacuum for 3 h. Fmoc-Tic-OH-DIC-HOAt-NMP (192 mg/37 µL/65 mg/1 mL) was added to the syringe, and the syringe was shaken for 16 h at 25 °C. The resin was washed with DMF (2 mL ¥ 3) and CH2Cl2 (2 mL ¥ 3), treated with 20% piperidine-NMP for 30 min, washed with DMF (2 mL ¥ 3) and CH2Cl2 (2 mL ¥ 3), and dried under vaccum for 3 h. After the resin was swelled with NMP for 10 min, oxalyl diimidazole-NMP (0.2 g/2 mL) was added to the syringe. [Procedure A: The syringe was shaken at at 25 °C for 16 h.] [Procedure B: After shaking the syringe for 20 min, the resin was washed with dry NMP (2 mL ¥ 3), then the syringe was added NMP (2 mL) and shaken at 25 °C for 16 h.] [Procedure C: Instead of NMP in Procedure B, imidazole-NMP (0.2 g/2 mL) was added to the syringe, and the syringe was shaken at 25 °C for 16 h.] The resin was washed with DMF (2 mL ¥ 3) and CH2Cl2 (2 mL ¥ 3), and dried under vacuum for 3 h. Finally, the resin was treated with 95% trifluoroacetic acid (TFA)-H2O for 1 h and the solution was concentrated. [13] The residue was dissolved with 50% CH3CN-H2O and lyophilized to give the crude product 7o. (Yield 92% in case of Procedure A) 1H NMR (Varian VXR-300S, 300 MHz, DMSO-d 6) δ 3.29 (dd, J = 15.9 Hz, 4.2 Hz, 1 H), 3.47 (dd, J = 15.9 Hz, 11.7 Hz, 1 H), 3.57 (s, 2H ), 4.43 (d, J = 17.7 Hz, 1 H), 4.76 (d, J = 5.7 Hz, 2 H), 4.82 (dd, J = 11.7 Hz, 4.2 Hz, 1 H), 5.30 (d, J = 17.7 Hz, 1 H), 7.18-7.34 (m, 6 H), 7.39-7.48 (m, 4 H), 7.50-7.58 (m, 2 H), 7.86 (dd, J = 7.5 Hz, 1.8 Hz, 1 H), 7.93-7.97 (m, 1 H), 8.03-8.06 (m, 1 H), 8.68 (t, J = 5.4 Hz, 1 H). 13C NMR (Varian VXR-300S, 300 MHz, DMSO-d 6) δ 169.58, 168.31, 156.43, 152.17, 136.91, 134.36, 133.20, 132.44, 132.04, 130.88, 130.80, 129.54, 129.54, 128.44, 128.39, 127.91, 127.55, 126.69, 126.61, 126.29, 126.13, 125.73, 125.59, 125.29, 123.44, 56.41, 44.10, 41.77, 40.36, 32.10. ESIMS m/z 504, 1007 [MH] +.

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Disposable polypropylene/polyethylene syringes are available from Aldrich (Milwaukee, WI).

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Genevac HT-8 available from Genevac Limited (Farthing Road, Lpswich, IP1 5AP, UK).