2014 E250 Bluetec 4-matic (sport package, not luxury package) owner here, 19K miles currently. To directly answer your question, the E350 is unlikely to be as reliable as an Acura, but having said that Acura has recently been shown to be not so reliable.
The thing about Mercedes products (I've owned many many of them) is that they are mostly designed to be maintained. They design most of the mechanical parts to be serviced rather than just replaced, and (especially with diesel models) the engineering of them are top notch. The W212 (internal designation) is a very robust vehicle overall. M-B designed them much in the vein of the earlier cars, even mimicking the interior design of the famous W124 (1986-1995) in some respects.
I know Consumer Reports may cause some eye-rolls around enthusiast corners, but the E250 Bluetec was the second highest rated vehicle they have evaluated OF ALL TIME, only exceeded by the Tesla Model S. Buy their auto issue from this year and check it out for yourself: Look carefully at the reliability matrix towards the back. You'll see the 2014-2015 models are almost all red (good) with no major system issues listed. The editors actually did a video discussion review of the car, worth the watch... more than half of the video is just on the E250. https://www.youtube.com/watch?v=AQcvUmZ8x3k
Personally, I chose to go with MB-Tex over leather, skipped the fancy radar cruise control, and skipped many of the crazy electronics. I do have NAV, which I think is essential, and a panoramic sunroof. As is noted in another review, my car also had an issue early on with the heater box under the dash. There was a TSB on them, it's not a complex fix. As others have suggested, buy one with a service history, certified if possible, and if not at least buy one that is under factory warranty so that you can buy an extended warranty. My credit union will get my sale on a warranty, mostly because they incentivise them... I am able to buy a bumper-to-bumper extended warranty to 10years/140K miles for $2900.
Now, having said all of that... drive one. If you don't love it, esp compared to an Acura, I'll be shocked. They are so solid and reassuring on the road it's crazy. And the ride, even with the sport models, is second to none.