My guess is that 2 cylinders won't be enough to maintain speed on the highway out of boost, depending on your gearing. You're probably better off regearing it and leaving all 4 cylinders enabled.
What RPM are you running at 50mph? My Insight's 1.0L 3 cylinder is practically WoT at 75mph at just about 3000rpm, but I have electric assist to make such a small motor drivable and give passing power. Granted, I practically never drive faster than 55 and it has plenty of guts at lower speeds, but your car weights almost exactly twice as much and has significantly worse aerodynamics. If you're frequently downshifting, you're going to ruin you economy as you'll be in a poor-BSFC range.
Honda's solution was, instead of reducing displacement, to run the motor lean keep the throttle plate open and reduce pumping losses, while keeping power on tap that doesn't require revving the snot out of it. I get the best economy at about 1750rpm with an air:fuel ratio of ~22-25:1.
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