Facile synthesis of aliphatic isothiocyanates and thioureas on solid phase using peptide coupling reagents

Tetrahedron Letters

Volumn 45, Issue 2, 2004, Pages 269-272

  Boas, Ulrik ^a   Gertz, Heidi ^a   Christensen, Jørn B ^b   Heegaard, Peter M H ^a  

^a TECHNICAL UNIVERSITY OF DENMARK   (Denmark)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

Combinatorial chemistry; Isothiocyanates; Peptide coupling reagents; Solid phase synthesis; Thioureas

Indexed keywords

ALIPHATIC COMPOUND; AMINO ACID; CARBON DISULFIDE; ISOTHIOCYANIC ACID DERIVATIVE; REAGENT; THIOUREA DERIVATIVE;

ARTICLE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; SOLID; STANDARD; SYNTHESIS;

EID: 0346995410     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2003.10.182     Document Type: Article

References (28)

1. For a general review on isothiocyanates and thioureas, see: Patai S. The Chemistry of Cyanates and their Thioderivatives. 1977;Wiley, Chichester. Applications of isothiocyanates as useful intermediates in bioconjugate chemistry, see for example, Fernández J.M.G., Mellet C.O., Blanco J.L.J., Mota J.F., Gadelle A., Coste-Sarguet A., Defaye J. Carbohydr. Res. 268:1995;57-71.
2. For a general review on isothiocyanates and thioureas, see: Patai S. The Chemistry of Cyanates and their Thioderivatives. 1977;Wiley, Chichester. Applications of isothiocyanates as useful intermediates in bioconjugate chemistry, see for example, Fernández J.M.G., Mellet C.O., Blanco J.L.J., Mota J.F., Gadelle A., Coste-Sarguet A., Defaye J. Carbohydr. Res. 268:1995;57-71.
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13. See, for example, Makino S., Suzuki N., Nakanishi E., Tsuji T. Tetrahedron Lett. 41:2000;8333-8337 Li M., Wilson L.J., Portlock D.E. Tetrahedron Lett. 42:2001;2273-2275 Kesarwani A.P., Srivastava G.K., Rastogi S.K., Kundu B. Tetrahedron Lett. 43:2002;5579-5581.
14. See, for example, Makino S., Suzuki N., Nakanishi E., Tsuji T. Tetrahedron Lett. 41:2000;8333-8337 Li M., Wilson L.J., Portlock D.E. Tetrahedron Lett. 42:2001;2273-2275 Kesarwani A.P., Srivastava G.K., Rastogi S.K., Kundu B. Tetrahedron Lett. 43:2002;5579-5581.
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21. SPS of thioureas, general procedure: Deprotected amino acid derivatised 2-chlorotrityl resin (0.10 g, 0.19 mmol, theoretical loading: 1.9 mmol/g) was suspended in DMF (0.50 mL). Carbon disulfide (1.00 mL) was added followed by HBTU (0.29 g, 0.76 mmol) or PyBOP (0.40 g, 0.76 mmol) and DIPEA (0.39 mL, 2.28 mmol). The suspension was shaken for 30 min at rt. The solvent was removed by suction, and the resin was washed with DCM (10 times), DMF (5 times), and air was flushed through for 10 min to remove residual carbon disulfide. The derivatised resin was swelled in DMF (1.5 mL) and amine (5 equiv, 0.95 mmol) was added. If the amine was a hydrochloride, DIPEA (0.33 mL, 1.9 mmol) was added and the mixture was shaken for 2 h at rt. The solvent was removed by suction and the resin was washed with DMF (5 times) and DCM (5 times). The thiourea compound was released from the resin using 20% HFIP (2.5 mL) for 30 min, the product was collected by suction and the cleavage mixture was removed in vacuo.
22. abstract
23. The yields are based on the amount of amino acid coupled to the resin. The actual loading of amino acid was determined by Fmoc quantification: 5 mg resin (ca. 10 μmol theoretical loading) was swelled in 20% piperidine/DMF (25 mL), the mixture was shaken for 30 min and the absorption (290 nm) was measured. A 20% piperidine/DMF solution was used as reference.
24. IR-spectral data can be found in the supporting information.
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26. +).
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28. A way to circumvent the formation of thiohydantoins could be to introduce 2-hydroxy-4-methoxybenzyl (Hmb) protection of the last backbone amide at the N-terminal. The Hmb group has found wide use for preventing peptide aggregation during Fmoc solid-phase peptide synthesis, see for example, Johnson T., Quibell M. Tetrahedron Lett. 35:1994;463-466.