Well for something not done before, why not something along the lines of the carving up of Africa by the major European powers in the 19th century? This might give people a chance to play as natives or any one of Britain, France, Germany, Italy, Ottomans etc. What you all think of that?

Or perhaps the Chinese colonies around the same period, Boxer rebellion et al?

Perhaps even Aztec/Inca TW would work, Cortez/Pizarro and associated cronies. They could happen like a scripted event like the Mongol invasion in MTW.

If it wasn't for AOE3, an American colonies TW might work