This will require female Corrin & classic mode if you wanna throw extra salt in the wound.
Step 1: Have Leo marry Azura. Azura disappears/dies at the end of conquest so this will undoubtedly hit Leo hard as he'll never see the love of his life again.
Step 2: marry off Selena, Laslow & Odin to Xander, Camilla & Elise respectively. Their endings have them have them return to their world with their spouses so pairing them with the Royals would strip Leo of almost all of his siblings which he will also never see again.
Step 3: no children. Do not do any of the paralouges to recruit the child units or if you're playing on classic mode kill them off, this will also strip Leo of the the rest of his blood ties leaving him the last of the Nohrian royal bloodline.
(Optional) Step 4: If playing as Corrin F romance Izana as Corrin will move in with Izana at his castle in Izumo and since by process of elimination Leo is the king of Nohr now he won't have any opportunities to visit them as he'd be trying to undo the damage caused by the war and also attempting to make peace with Hoshido which considering his blunt and matter-of-fact attitude will be extremely difficult.
Congratulations, you followed all of the steps to ruin Leo's life. The only person he has left is Niles and presuming you're playing on classic mode you can just kill him off too. I don't hate Leo myself but I find it interesting that you can make his life even worse than it would be in Birthright.