Aqueous phosphoric acid as a mild reagent for deprotection of tert-butyl carbamates, esters and ethers

ORGN 470

Bryan Li, bryan.li@pfizer.com, Martin A. Berliner, Richard A. Buzon, Charles K-F Chiu, Steve Colgan, steve.colgan@pfizer.com, Takushi Kaneko, takushi_kaneko@groton.pfizer.com, Nandell Keene, William S. Kissel, Tung V. Le, Kyle R. Leeman, kyle_r_leeman@groton.pfizer.com, Lisa Newell, John Weaver, Michael Witt, and Zhijun Zhang. Pfizer Global Research and Development, Groton, CT 06340
Aqueous phosphoric acid (85 wt%) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, tert-butyl esters and tert-butyl ethers. The reaction conditions are mild and offer good selectivity in the presence of other acid sensitive groups, including CBZ carbamates, azetidine, benzyl and methyl esters, TBDMS and methyl phenyl ethers. The mildness of the reaction is further demonstrated in the synthesis of clarithromycin derivative 4, in which a tert-butyl ester is removed in the presence of cyclic carbamate, lactone, ketal, acetate ester and epimerizable methyl ketone functionalities. The reaction preserves stereochemical integrity of substrates. The reactions are high yielding, and the workup is convenient.