This is a scenario where Spider-Man was introduced back in Phase One alongside a handful of other heroes (Fantastic Four, X-Men, Ant-Man and the Wasp) and so has had a trilogy of movies by the time Infinity War and Endgame occur. 

The first movie has Vulture as the main antagonist (salvager who lost his job due to the Baxter Building and Stark Industries leading the rapidly changing world and putting him out of work, leading to him adapting as a weapons manufacturer) with Shocker and Tinkerer as secondary villains. 

The second movie has Mysterio as the main antagonist pretending to be a hero, with Scorpion as a secondary villain simultaneously hunting Spider-Man and representing the contrast between Spider-Man and Mysterio in terms of public image compared to who they are in reality (he was created to hunt down Spider-Man but aids Mysterio, the real villain)

The third movie has Kraven as the main antagonist with Chameleon as the secondary one. Kraven comes to New York shortly after the events of Civil War (in which Peter declared neutrality) to hunt not only Spider-Man, but other street-level heroes such as the Defenders, Punisher and Cloak and Dagger. Chameleon is simultaneously aiding his brother and pursuing his own agenda. 

Thoughts on this roster of villains for an alternate MCU Spider-Man trilogy?