Benzyloxycarbonyl group acid sensitivity

The conversion of 3 to 8 is summarized in Scheme 2. The trityl group (too large and too acid sensitive for the ensuing steps) was removed from N, and both N s were protected by Cbz (benzyloxycarbonyl) groups. Protection of the tertiary OH specifically as the robust TBS (f-butyldimethylsilyl) group was found to be necessary for the sequence involving the electrophilic aromatic substitution step, 5 to 6, and the Stille coupling steps (6 + 7 —> 8). 

Dimethoxy-aa-dimethyl-benzyloxycarbonyl constitutes an improvement over the 3,5-dimethoxybenzyloxycarbonyl group (see Scheme 16). The photochemical removal is easier (faster by a factor of 6), proceeding in high yield and, in numerous experiments, in quantitative yields. The group is, however, sensitive to mild acid, a disadvantage on many occasions. On the other hand, it can be photolyzed under conditions that do not affect a benzyloxycarbonyl group. 

Soon it became obvious that acid sensitivity of the benzyloxycarbonyl group can be increased by appropriate modifications of the benzyl group. Electron-releasing substituents give rise to more stable cations, hence the p-methoxybenzyloxycarbonyl group... 

To avoid decomposition of the sensitive 2-hydroxy azide side chain with Lewis acid, the azide functional group was reduced to amine. These conditions also deprotected the carboxy terminus. After TBS deprotection in acidic conditions, the 2-amino alcohol was treated with excess BBtj for deprotection of Cbz (benzyloxycarbonyl) and OMe groups. Synthesis of biphenomycin B 53 was completed in 14 steps affording 15% overall isolated yield. 

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