Applications of the N-tert-Butylsulfonyl (Bus) Protecting Group in Amino Acid and Peptide Chemistry

Abstract

The utility of the tert-butylsulfonyl group (Bus) for the temporary protection of amino acids and peptides is reported. Compatibility and orthogonality in the presence of other N- and O-protecting groups were studied.

tert-butylsulfonyl group - amino-group protection - amino acids - orthogonal N-protection

References and Notes

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<A NAME="RS08309ST-1B">1b</A> Ribiere P. Declerck V. Martinez J. Lamaty F. Chem. Rev.  2006,  106:  2249 

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<A NAME="RS08309ST-9">9</A>

General Procedure for the Formation of tert -Butyl-sulfonamides
A solution of l-phenylanine ethyl ester hydrochloride (1a, 58 mg, 0.25 mmol) in CH₂Cl₂ (3 mL) was cooled to 0 ˚C
and treated with Et₃N (0.35 mL, 2.5 mmol), followed by dropwise addition of tert-butylsulfinyl chloride (62 µL, 0.5 mmol) in CH₂Cl₂ (1 mL). The reaction mixture was stirred at 0 ˚C until TLC showed consumption of the starting material (1 h). Upon completion, sat. aq NaHCO₃ (5 mL) were added, and the layers separated (note: acidic washes should be avoided as tert-butylsulfinamides 2a are known to be unstable at low pH). The organic layer was then dried over Na₂SO₄ and concentrated under reduced pressure. Flash column chromatography (EtOAc-hexane, 3:2) afforded pure sulfinamide 2a which was directly taken up in CH₂Cl₂ (5 mL), and treated with MCPBA (58 mg, 0.34 mmol) at 0 ˚C. After the oxidation was complete by TLC (at r.t. for 1 h), the mixture was diluted with a mixture of sat. aq NaHCO₃ (5 mL) and sat. aq Na₂SO₃ (5 mL). The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The organic extracts were combined, dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (EtOAc-hexane, 1:1) to afford tert-butylsulfonyl-l-phenylalanine ethyl ester (3a, 66 mg, 84% over 2 steps) as a colorless solid.

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General Procedure for the Cleavage of tert -Butylsulfonamides
To a solution of anisole (0.22 mL, 2.0 mmol) and tert-butylsulfonyl-l-alanine methyl ester (3d, 45 mg, 0.2 mmol) in CH₂Cl₂ (3 mL) was slowly added TfOH (0.2 N in CH₂Cl₂, 3 mL) at 0 ˚C. The solution was stirred at 0 ˚C for 2 h, then warmed to 4 ˚C for 10 h (TLC monitoring, EtOAc-hexane, 2:3), then H₂O (6 mL) was added. The aqueous layer was neutralized with DOWEX Monosphere 550A (OH^- form) anion-exchange resin at 0 ˚C until pH 8.5, then MeOH (6 mL) was added, and the resin was filtered. The filtrate was combined and acidified with aq 1 M HCl (3 mL). The aqueous layer was frozen and lyophilized to afford l-alanine methyl ester hydrochloride salt(1d) (24 mg, 85%), as a colorless oil.

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Enantiomeric and diastereomeric purities were determined by HPLC and ^¹H/^¹9F NMR spectra of Mosher amides. For example: Mosher amides: phenylalanine (de >99.9%) and alanine (de >99.9%) Column: AD-RH 150 × 4.6 mm; dipeptides: 21 (de >99.9%), 22 (de >99.9%), 29 (de >99.9%), and 30 (de = 99.86%), column: AS-RH 150 × 4.6 mm; 23 (de = 95.66%) and 31 (de = 96.24%), column: OJ-R 150 × 4.6 mm; 23 (de = 95.50%) and 31 (de = 92.22%), column: C-18 250 × 4.6 mm.