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Synthesis 2004(1): 80-86  
DOI: 10.1055/s-2003-42492
PAPER
© Georg Thieme Verlag Stuttgart · New York

Fluorous Coupling Reagents: Application of 2-Chloro-4,6-bis[(heptadecafluorononyl)oxy]-1,3,5-triazine in Peptide Synthesis

Marcin W. Markowicz, Roman Dembinski*
Department of Chemistry, Oakland University, 2200 N. Squirrel Rd., Rochester, Michigan 48309-4477, USA
e-Mail: dembinsk@oakland.edu;
Further Information

Publication History

Received 22 August 2003
Publication Date:
19 November 2003 (online)

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Abstract

Benzyloxycarbonyl N-protected and C-terminus methyl ester protected amino acids react in THF in the presence of 4-methylmorpholine and fluorous condensation reagent, 2-chloro-4,6-bis[(heptadecafluorononyl)oxy]-1,3,5-triazine, to form di- and tri­peptides that are isolated without the use of fluorous solvent in very good yields (98-91%).

Key Words

chlorotriazine - 1,3,5-triazine - fluorous - peptides - amides

40

The term ‘hydroxytriazine’ is used for the triazine by-product. However, energetically favored hydroxyimino-amide equilibrium is attributed to excellent leaving group properties.

48

A flask was charged with 1 (0.506 g, 0.500 mmol), 2c (0.111 g, 0.497 mmol), 3c·HCl (0.070 g, 0.50 mmol), and THF (10 mL). The mixture was cooled to 0 °C and a solution of NMM in THF (10% v/v, 1.15 mL, 1.05 mmol) was added dropwise. The mixture was stirred for 2 h at 0 °C. The ice bath was removed and the mixture was allowed to reach r.t. while stirring for 14 h. Work-up similar to General Procedure gave 4c as a white solid (0.086 g, 56%).

51

4-{4,6-Bis[(heptadecafluorononyl)oxy]-1,3,5-triazin-2-yl}-4-methylmorpholinium chloride (5) was isolated by filtration and characterized by 1H NMR spectroscopy. 1H NMR (acetone-d 6): δ = 5.20 (t, J = 13.8 Hz, 4 H, CF2CH2O), 3.91 (t, J = 4.8 Hz, 4 H, NCH2CH 2O), 3.76 (t, J = 4.8 Hz, 4 H, NCH 2CH2O), 2.12 (s, 3 H, CH3).

53

Peak assigned to traces of 2,4,6,-tris[(heptadecafluorononyl)oxy]-1,3,5-triazine.

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‘L’ and ‘R’ denote ‘left’ and ‘right’ amino acid fragments for the Cbz-Aaa- and Aaa-OMe fragments, where assignments were possible.

56

‘*’ denotes the chemical shift for the minor isomer.

58

Ipso signal was not observed.