(1) If you're dead-set on F and don't hold a high-tier elite status, you'll almost certainly need to buy it confirmed. There won't be no-status upgrades available. If you *do* buy it confirmed, as pinworm suggests you need to make sure that F is really offered on all segments. No legacy carrier flies nonstop STL-TPA that I'm aware of. That means you'll be on four very short segments. The smallest RJ's don't have an F cabin at all.

(2) My personal opinion is that this route isn't remotely worth spending money, miles, or limited upgrades on for F. Even if you fly four mainline jets, you're going to get 1 drink per flight, 2 max, and not really any kind of "first class" ambiance. You'll get a bag of pretzels per flight, most likely.

(3) If you hold no status on any carrier, I'd fly the Southwest nonstop STL-TPA. If you want, price the coach nonstop, price the F ticket (it'll end up being about $275 vs. the aforementioned $631 for the September example), buy the coach nonstop and think of something MUCH more interesting then a few pretzels and four beers to spend $700 on. When in doubt, nonstops beat connections. When you hold no elite status on any airline, Southwest's system is far better than a legacy. (If you do hold a status, I'd still buy a coach ticket on your preferred airline - even if your upgrade odds are low.)

(4) printingray is absolutely correct: TPA is a nice easy-to-use airport. I used to fly there often. I was always willing to pay a premium to use it vs. MCO, although the prices were usually about the same. Since a lot of travel portals have "surrounding airports" options, make sure you're selecting TPA and not an MCO itin that happens to be $20 cheaper. (Assuming you actually want to be in Tampa.)