Thioanisole-Trifluoroacetic acid

Y Kiso, K Ukawa, T Akita. Efficient removal of /V-bcnzyloxycarbonyl group by a push-pull mechanism using thioanisole-trifluoroacetic acid, exemplified by a synthesis of Met-enkephalin. Chem Commun 101, 1980. 

Methylbenzyhydramine (MBHA) resin (1.18 g, 0.85 meq amino groups/g resin) was weighed into the reaction vessel and washed with two portions of chloroform (26 ml each). The resin was prewashed with 22% thioanisole (5 ml)/66% trifluoroacetic acid (TFA) in 14 ml dichloromethane (DCM) for 5 minutes, and then deprotected for 30 minutes with the same thioanisole/TFA mixture. The resin was washed with three portions of chloroform (20 ml each), two portions of 2-propanol (26 ml each) and two portions of DCM (26 ml each). The resin was neutralized with two portions of 12% diisopropylethylamine (DIPEA) (26 ml each), and then washed with four portions of DCM (26 ml each), followed by two portions of 1 1 DCM dimethylformamide (DMF) (26 ml each). A solution of a Boc-protected amino acid (2.5 mole equivalents) and 1-hydroxybenzotriazole (HOBt) (2.5 mole equivalents) was introduced as a solution in 10 ml DMF, and DCC was added (256 mg in 6 DMF). Coupling was allowed to proceed for three hours,... 

A mixture consisting of the Step 10 product (50 mg), 0.1 ml of thioanisole, and 1 ml trifluoroacetic acid was stirred in an ice bath for 15 minutes, then concentrated. The residue was stirred with diisopropyl ether and 35 mg product isolated, mp = 209°C. M + H 274... 

Yoshiaki K, Masatoshi I, Kouki K, Tadashi A, Hideki M. Synthesis of a newly isolated opioid tridecapeptide, rimorphin, from pituitary using a trifluoroacetic acid-thioanisole deprotection system. Chem. Pharm. Bull. 1983 31 1818-1820. 

The peptides and peptide mixtures were cleaved from the resins and the side chains were deprotected with trifluoroacetic acid phenol ethanedithiol thioanisole water (96 2 1 2 1, v/w/v/v/v) (1 ml) within 3 h. The products were filtered from the resins, which were washed once with acetic acid (0.3 ml), and were precipitated at — 20 °C by the addition of cold n-heptane diethylether (1 1, v/v) (5 ml). The precipitates were washed twice by sonication with n-heptane diethylether (1 1, v/v) and were lyophilized from acetic acid water tert.-butyl alcohol (1 10 50, v/v/v), yielding individual peptides, the completely randomized peptide amide libraries Xn and 220 undecapeptide amide sublibraries O/X 0-NH2. The biotinylated peptide sequence (see below) was obtained by elongating the ApoB 100 peptide 2877-2894 with two spacer amino acids (Ahx), followed by biotin using the coupling method described above. 

Trifluoroacetic acid slowly cleaves Cbz groups allowing the selective removal of Boc groups. However, Kiso and co-workers noted a marked acceleration in the presence of thioanisole, and the method is illustrated in Scheme 8.53 by the simultaneous cleavage of a diphenylmethyl ester and a Cbz group in the last step of a synthesis of Acivicin. ... 

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... 

Figure 21 RPC of synthetic peptides on C8 and cyano (CN) columns. Column Zorbax SB-Ce (150 x 4.6 mm ID. S-fim particle size, 94-A pore size) and Zorbax SB-300 CN (150 x 4.6 mm ID, 6jim, 300 A) (Hewlett-Packard, Little Falls Site, DE). Mobile phase linear AB gradient, where eluent A is 0.05% aqueous trifluoroacetic acid (TFA), pH 2.0, and eluent B Is 0.05% TFA in acetonitrile gradient rate, 1% acetonitrile/min flow rate, 1 mL/min temperature, 26 C. (Left) 35B denotes 35-residue peptide (sequence shown in Table 1) T denotes thioanisole DTT denotes dithiothreitol. (Right) P22 denotes hydrophobic 22-residue peptide (sequence shown in Table 1). I denotes impurity sample was dissolved in 70% eluent A/30% eluent B.

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