The Use of Tin(IV) Chloride for Mild and Selective Boc Deprotection on TFA Cleavable Rink-Amide MBHA Resin

Abstract

An efficient, straightforward and inexpensive method for selective Boc deprotection on Rink-amide MBHA resin using tin(IV) chloride in dichloromethane is presented. Preliminary results suggest that the low degree of cleavage from the resin accompanying the Boc deprotection may depend on steric hindrance associated with the resin. This method can be useful as a selective deprotection step in solid-phase syntheses of cyclic peptides and small molecules in which only a few Boc deprotection steps are required.

Key words

Boc - deprotection - orthogonal protecting groups - SPPS - SPOS - Rink-amide MBHA resin

References and Notes

• 1 Zhang AJ. Russell DH. Zhu JP. Burgess K. Tetrahedron Lett.  1998,  39:  7439 
• 2 Trivedi HS. Anson M. Steel PG. Worley J. Synlett  2001,  1932 
• 3 Lejeune V. Martinez J. Cavelier F. Tetrahedron Lett.  2003,  44:  4757 
• 4 Boeglin D. Bonnet D. Hibert M. J. Comb. Chem.  2007,  9:  487 
• 5 Frank R. Schutkowski M. Chem. Commun.  1996,  2509 
• 6 Miel H. Rault S. Tetrahedron Lett.  1997,  38:  7865 
• 9 Gude M. Ryf J. White PD. Lett. Pept. Sci.  2002,  9:  203 
• 11 Kaiser E. Colescott RL. Bossinger CD. Cook PI. Anal. Biochem.  1970,  34:  595 
• 12 Christensen T. Acta Chem. Scand., Ser. B  1979,  33:  763 

7

Only the first experiment, to confirm the feasibility of applying SnCl₄ for Boc deprotection on Rink-amide MBHA resin, was performed with a freshly opened bottle of SnCl₄. All other experiments were conducted without prior purification of the reagent.

8

Novabiochem^®: Novabiochem Catalog 2006/2007, 3.4.

10

In this experiment, since there was no Boc group present, only cleavage from the resin may occur. Considering at least one equivalent of SnCl₄ is required for complete Boc deprotection, the amount of SnCl₄ reacting with the peptide-resin amide bond is considerably higher and we would expect a greater loss of substrate through cleavage.

13

General procedure for SnCl₄-mediated Boc deprotection on Rink-amide MBHA resin: The resin was pre-washed with anhyd CH₂Cl₂ (2 × 2 min). The resin was subsequently treated with SnCl₄ (2 equiv, 0.02 M in anhyd CH₂Cl₂,
2 × 5 min). Upon addition of the deprotection solution, gas evolution was observed due to rapid CO₂ release and the resin became a bright red color. The resin was then washed with DMF (1 × 3 min), 20% MeOH in DMF (1 × 3 min), 10% DIEA in DMF (1 × 3 min) and DMF (2 × 2 min). The initial wash with DMF instantly restored the resin to its original color.