The B-29 was always a bit underpowered. The early R-2800 developed 1,500 HP in 1939 and 1,850 some 12 or so months later. But 1941 it was making 2,000 HP at max approved boost and rpm.
The FIRST R-3350 made 2,250 HP in 1937 and languished a bit while the R-2600 was developed. It first flew in 1941 at that same HP, but was stretched to 2,800 and ginally 3,500 HP after the war. During the war it always made more HP than the R-2800.
What could have happened if they had concentrated in the R-3350 when it first came out? We already know ... it COULD have been developed as many as 5 years sooner to the same levels it was ...because it actually happened, only 5 years later.
So, say the B-29 would cruise at 60 % power, albeit not especially fast at that power, then 60% of 2,200 HP is 1,320 HP each. The R-2800 in 1941 was making 1,200 HP. If you fly THAT at 60% power you get 1,200 HP, or an aggregate of 480 HP less with the R-2800 in cruise (assuming 60% power). It's 800 HP less at max power, not inconsequential. Actually it's 10% more power than the R-2800 made and max boost.
The B-29 could make 357 mph on four 2,200 HP R-3350's and they regularly attacked Japan at 325 mph+, making them very hard to catch and shoot down for the Japanese at the time. Had they used the 2,000 HP R-2800, the top speed would likely be in the 346 mph range with a commensure drop in over-the target-speed to around 314+ mph, maybe less. That's maybe catchable even for a Zero at 20,000 feet and would render the plane a bit more vulnerable. I can't say how much MORE vulnerable, but a bit more.
Once the R-3350 developed to 2,800 HP, the R-2800 was left far in the dust as a bomber engine. Yes, I KNOW it made a lot of power in experimental models but, for WWII is was basically a 2,000 to 2,200 HP engine at war emergency power. The R-2800 wasn't going to swing the same prop at the same speed as the R-3350, so the predicted data above are probably optimistic. Basically, I don't believe a plane known for being a bit underpowered could afford to lose 480 HP at cruise and 800 HP at top speed and still have the very effective bomb load the B-29 had.
Could it have flown with R-2800's? Sure.
Would it have been as effective as what was done? That's a what-if that nobody can answer ... they never DID it, so any opinion is as good as another.
I would not have gone that route and they historically didn't, either. But I suppose it MIGHT have resulted in more B-29's to the point that maybe they could have been deployed to Europe as well as the Pacific, I don;t know. Had THAT eventuality happened, it could have made a huge difference ... but is, again, a what-if that can be argued either way.
They MAY have even considered that option and discarded it, so the opportunity was recognized and not implemented, I don't know. I DO know the B-29 was very effective and hard hitting, with the heaviest normal bomb load of the war by a bomber in large scale production.
Don't even tell me about Grand Slams ... they were never a "normal" bomb load and the Lancasters that carried them were structurally in dangerous waters. It was done out of necessity, not with any regularity. They dropped a total of 42 Grand Slams in the entire war, less than .03% of Lancaster sorties.