HBr in trifluoroacetic acid

Protect glycine as its Boc derivative and anchor this to the solid support. Remove the protecting group and treat with Boc-protected phenylalanine and DCCI. Remove the Boc group with HCl then treat with HBr in trifluoroacetic acid to cleave Phe-Gly from the solid support. 

The dipeptide is released from the polymer and the BOC-protecting group by adding hydrogen bromide (HBr) in trifluoroacetic acid. 

Remove the Boc group with HCl and then treat with HBr in trifluoroacetic acid to cleave Phe-Gly from the solid support. 

After removal of the S-Trityl groups by silver nitrate (Zervas, 1962), the free thiol groups were oxidized by diiodoethane (Weygand, 1962). Bty releasing the peptides obtained from the polymer by treatment with HBr in trifluoroacetic acid followed by purification on Dowex 50, E. Bondi of our department obtained an 80% overall yield of H2N Cys-Cys-AlaOH. 

In the final step of the process, the completed peptide chain must be removed from the support this generally involves HBr in trifluoroacetic acid or anhydrous HF. Although the synthesis can be done manually, automation is now readily available, and synthesis takes from 20 to 60 min per amino acid. In favorable cases, peptides up to 70 units long can be made in this way (but the difficulty of the syntheses also depends on the exact composition of the desired peptide)—beyond that, segments must be made individually and then coupled together. 

Then another N-protected amino acid is coupled to the free amino group of the polymer-bound substrate using the dicyclohexylcarbodiimide activation or the active ester method. The N-deblocking and coupling steps are repeated until the desired sequence is formed. Finally the resin-peptide bond is split by a suitable acid cleavage reaction with HBr—AcOH, trifluoroacetic acid or HF. This results in a simultaneous N-deblocking and deprotection of most of the side-chain functionalities. 

The classical reagent, HBr in acetic acid, can be replaced by HBr in triflu-oroacetic acid, HBr in liquid SO2 or by liquid SO2 itself. Of course the benzyloxycarbonyl group is rapidly cleaved by liquid HF or by a solution of trifluo-romethanesulfonic acid in trifluoroacetic acid. It should be mentioned that it is removed by the much less aggressive trifluoroacetic acid as well. At elevated temperatures the reaction proceeds fairly rapidly, at room temperature it requires several days for completion. Addition of thioanisole (Yajima et al 1978) greatly accelerates the process... 

When iV-Boc-alanine (160) reacts with this polymer, 161 is formed (an alanine-loaded polymer). The remainder of the synthesis is essentially a DCC-coupling procedure. When 161 is treated with HCl, the Boc group is removed, and treatment with DCC and IV-Boc-valine leads to 162. This sequence of reactions is repeated, using other protected amino acids, until the desired peptide is prepared. In the example at hand, the final product is gly-pro-ser-ala-ala-his-val-leu-val-ala-P, 163 (P represents the polymer bead). When 163 is treated with HBr and trifluoroacetic acid, the peptide gly-pro-ser-ala-ala-val-leu-val-ala (164) is released from the bead and isolated. The polymer is left behind with bromomethyl fragments (Br-CH2-P), which can be recycled. 

An alternative view of these addition reactions is that the rate-determining step is halide-assisted proton transfer, followed by capture of the carbocation, with or without rearrangement Bromide ion accelerates addition of HBr to 1-, 2-, and 4-octene in 20% trifluoroacetic acid in CH2CI2. In the same system, 3,3-dimethyl-1-butene shows substantial rearrangement Even 1- and 2-octene show some evidence of rearrangement, as detected by hydride shifts. These results can all be accoimted for by a halide-assisted protonation. The key intermediate in this mechanism is an ion sandwich. An estimation of the fate of the 2-octyl cation under these conditions has been made ... 

A number of 5-sulfenylthiocarbonates have been prepared to protect thiols. A benzyl derivative, R =CH2Ph, is stable to trifluoroacetic acid (25°, 1 h), but not to HBr/AcOH, and provides satisfactory protection during peptide syntheses a t-butyl derivative, R = t-Bu, is too labile in base to provide protection. A methyl derivative, R =CH3, has been used to protect a cysteine fragment that is subsequently converted to a cystine. ... 

This reaction has been studied in mote detail, and a study of the cyclization of thiobenzamide using DMSO as oxidant led to the following conclusions. There must be an oxygen donor oxidant present and it is essential to use a solvent of high polarity such as dimethyl formanide (DMF). An acid catalyst is essential and the counterion is also important HCl and HBr are good catalysts but sulfuric acid, methanesulfonic acid, and trifluoroacetic acid do not give... 

To be a useful protecting group, the Boc group must be removed under reaction conditions that do not affect other functional groups in the molecule. It can be removed with an acid such as trifluoroacetic acid, HCl, or HBr. 

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