Photons set to Proximity, Wild Weasel standing by.
I would think that a pre-Federation start would probably not be in the best interest of the game. Maybe immediate Pre-Fed, but the C3C mod started in 2063, it was very boring sitting around waiting to be able to build my first Starship. True that Civ starts the same way, you plant your first city, and then wait until that city becomes productive before you can do anything else. Also, I didn't care that the time went by so fast, it's a problem in Civ too, but I think that the Star Trek mod exaggerated the problem. You just finish building that first NX Class, and now it says, Build a Constitution Class.
I would say, run the game from 2150 to 2400, using Month long turns. This would be the "Epic" setting, giving us an even 3000 turns to play (very epic). Normal setting would be the same timeframe but using 2 Month turns. While the quick setting would use 4 month turns. This would allow ships to be useful longer.
Setting the game in the Starfleet Battles has advantages, it is still Star Trek, but you don't have to scratch your head saying, now what can I use for the Romulan Early Destroyer, SFB has already given you one. (Three in the Romulan's case)
We can break the scenario into the following eras. (Pre-TOS, TOS, TMP)SFB, (Post-TMP, Pre-TNG) Lost Era, TNG. For those people that don't like TOS, they can start in TMP or post-TMP. For those people who don't like TNG, they just set the game to end sooner.
Races: I would take the Borg out, balancing them would be a major pain. Vulcans just aren't big enough if we start where I propose, they dismantle most of their fleet in 2154. Ferengi I think should be in there, as long as they aren't as overpowered as they were in BOTF. The Dominion, no, more below. Bajorans, no, Xindi, no, Andorians, no, same as the Vulcans. With Starfleet Battles races, I would probably leave out the Andromedans, they were like the Borg of SFB.
Map: If we make a "standard" map for all the games, I would say that each race starts the game with three or four planets already colonized. (There was nothing I hated more in BOTF than to find that I started three sectors from another major power and had no room to expand, or the C3C game, when the ANDORIANS took my first extra-solar colony one turn before I could plant a settlement.) I really wish they had used a hex grid so we could put the ENTIRE galaxy in this game. As it stands though, with just the Alpha and Beta Quadrants, we could even leave the Dominion out of the game, make them a non-playable race that spawns a few ships near the Bajoran Wormhole every so often after the Wormhole is discovered. Same as the Borg, occasionally one of their ships will show up and ravage the country side, won't go away until you destroy them. Have the top row of tiles represent the Delta and Gamma Quadrants and make it so that no one can claim culturally those tiles.
Resources: I want to get away from the various grades of Dilithium that was in the C3C game. I would say early resources would be Antimatter, Lithium and Dilithium. Early Starships could use either, ships constructed with Dilithium would be faster. Mid range Starships use only Dilithium, and by the Late eras, Dilithium is not needed at all (some Tech would take that requirement away) Antimatter is needed for all FTL ships, until the Romulans develop Artificial singularities, which should be somewhere in the middle range.
Tech Tree: Some obvious techs: Duotronic circuits, Terraforming (required for any colonies on non-class M planets), Warp Drive upgrades, Weapon upgrades, FTL Communications, Metaphasic Sheilding, Borg Contact (more below)
Wonders: Genesis Device, Dyson Spheres, Respective Acadamies, Utopia Planetia.
Miscellanious: A Dominion Alliance event would be useful, some race, after the Bajoran Wormhole is found, that is losing (badly) could build a wonder called the Dominion Alliance, and they suddenly get a fleet of Dominion ships to help them out and the ability to build Dominion Ships, which would be cheaper to construct. Borg Contact on the tech tree, would be like Liberalism, you automatically get to discover a new technology for free(and probably some other big bonus considering what it's unleashing), but now the Borg(Barbarian units) can show up in any Delta Quadrant tile and start on a rampage.
Lastly: I have no Idea how the Combat system is coded, if its something that can be modded or not. But the one on one combat system in CIV doesn't work well in a Star Trek model, If there was some way to work it out so that a stack attack works that would be wonderful.