Aside from the fact that almost every single leader in both of my files took more than one attempt, a few stick out as being particularly difficult.
In my first playthrough...
I remember having to try a few approaches with Shade, but I breezed through him once I made a few swaps in my lineup.
I got hung up on Noel due to his Cinccino, not sure how I got past it, but I managed it without burning the field.
Radomus was a lot of fun, but I know I failed a lot. I think eventulaly the exp from getting 4 or 5 of his team down pushed me over the hump and I could deal or take the little bit of damage to tip the balance in my favor.
Pretty much every leader post agate gave me trouble. I don't remember how for Samson, but I remember Charlotte kicking my ass a lot, stealth rock and somehow getting her to switch out her volcarona helped, and prankster light clay meowstic to set both screens and then die helped, but I don't remember any further details. M3G4 T3RR4 stonewalled me until I remembered that it was a fight about gen 1 bullshit, and raised the Abra I had lying around to alakazam, burned through several episodes of Archer grinding on Indra until I twerked him up to a good level, then getting a few dozen Speed and SpAtk EVs for good measure. Then he basically RAWR'd all over Terra's first few 'mons, then I figured out how far Alakazam would get on its own, and set up the rest of my team accordingly so that RAWRCHOMP would go down like a RAWRCHUMP. Ciel however, was a looong grind as I leveled my sneasel (sadly not from the mystery egg) and swinub (sadly not bred for icicle crash) up so that I could ice shard through half her bullshit. I still had to get lucky with sturdy donphan and bounce against togekiss or risk getting shrekt by it.
In my second playthrough, I feel like I've done worse so far, as Florina, Kiki, Serra, and Noel -- the worst of them all since his porygon-Z also got in on the action -- were basically walls I had to climb via defeat-grinding and luck with statuses and ancient power. I'm at Radomus now, but I have a good-ish feeling even if he lays down trick room on my speedy team.