I agree with your second paragraph that any concept of uploading is inherently squishy as we don't even understand the problem domain well enough to show how to do such a project.

As far as colony ships go, I think it would be hard to feed people for a couple of centuries, keep the systems running, and keep the passengers from going insane. It would have to be very big for even a few people in my mind for the agricultural requirements.

Colony ships would be massively difficult. Maybe even impossibly difficult? but the impossibility would be in the details and the effort. We'd be designing a very complex, very touchy system full of parts that could break. But... I'm just saying, there's nothing in our current understanding of science that makes it impossible, like faster than light travel, and the goal is clear; we'd know it when we finished it, unlike uploading humans.