As portugal, you will likely have the lion's share of the Americas (and then, everywhere else), due to the bonuses you get exploring and colonising things. This means you can pick and choose to a large extent, taking the native americans, colonising the carribean and northern brazil, without question.
Once you have colonies, you are essentially invincible until your enemies can find them, regardless if they are kamchatka or the azores, so once you're into the new world, everything is fine, so long as you have rough naval superiority. The only tough part is surviving the early years - until trade 7 (Quest for the New World should be in your first slot, really). For this, you want to ally with Castille and break your alliance with England, as they will be dragged into fighting France very very fast. Castille will drag you into small wars with North Africa early on, which you can join and then do very little in, and eventually white peace out. Use it to get war taxes.
Just remember that there's no point in leaving the Americans alive, you'd be much better off coring them early.
