The easiest POD is to prevent the Constitution, and just have a TL where the Articles of Confederation get amended. In OTL, Jefferson agreed to the Louisiana Purchase even though he knew that his own reading of the constitution didn't give him that authority (he just figured the benefit was so very great, all other considerations kind of had to yield). If the USA remains a far more decentralised, confederal union, there will not be any way to get that sort of thing done, and the purchase just never happens. Americans moving in will still "pull a Texas" in various places, but that will initially yield independent settler republics, which may or may not see fit to join this confederal USA (which will probably not have a strong army, so can't offer any real protection anyway). Expansion will be a slow, more piecemeal process, which will allow Britain to move in on all of Oregon. Meanwhile, this confederal USA may not be able (or willing) to win a war against Mexico. If Anglo settlers in California still manage to tear themselves away from Mexico, they may very well end up becoming an independent republic. (Possibly under British protection, which Britain would offer because that would mean independent California is viable, and it therefore doesn't join the USA.)
Thecherry on top, by the way, would be if this confederal USA is more markedly Jeffersonian in its early years, and as such sympathises with france against Britain. An alt-War of 1812 sees Britain landing troops in New Orleans, and turning the city and environs into a British protectorate. With Britain controlling the mouth of the Mississippi, a lot of American motivation for wanting to settle the Louisiana Country (which is part of that river's watershed) would be gone. And also, Jeffersonianism would be discredited, so the USA may as a result ave a belated "Constitutional Convention" after this war, resulting in a much tighter federation, which turns to Hamiltonian policies. Such a USA would then be more interested in promoting its own industry and manufacturing, and would tend towards urbanism. The typically Jeffersonian desire for agrarian land out west would be much diminished.
So, the tl;dr for the above -- more Jeffersoniasm/decentralism first, followed by more Hamiltonianism/centralism.