If you described the problem as high chts and low EGTs and inability to run LOP that is a classic symptom of timing being off spec.

Moisture exists in fuel whether it falls out to be sumped or not. Your tanks could have also had condensation on the top of fuel tanks that was released to the bottom and stayed mixed, as you taxied and took off. You fueled from a UST and that fuel was probably approximately 50f. Matching temp of fuel in tank, warm hangar I assume. Condensation can occur. Then you took off and climbed to altitude. The temps in the FL's are so cold the water could be "squeezed" out as ice particles. Perhaps clogging the system somewhere, as very small ice crystals can.

Do you use anything to suspend water in your fuel? Is it recommended by your POH or engine manufacturer?

Hope you find out quickly what the problem is and it is a simple fix.

I had this happen once in a former engine during cruise. My plane is a single and after more then an hour of flight it sputtered. I went full rich, switched tanks, and turned on the low boost. It cleared up while I was switching tanks but I was still a bit shaken and taking a hard look at landing options. With the engine running smoothly I turned the low boost off and re-leaned. After a few minutes and with an airport in sight, I decided to "test" my offending tank. I switched tanks uneventfully and flew two more hours to complete the flight.

It never happened again. That engine has been replaced and the new engine has about 800 hours on it. The tanks, valves, strainer and lines are the same. Of course the new engine has a new fuel pump, spider, throttle, etc.

I never found out what caused the disconcerting issue and the next few flights were not as relaxing as usual. Now that more then 1000 hours have passed I don't think about it any more. I figure it was, as some have described here, water in the fuel that came out during that flight but never showed up in the sump.

Ok, I think Alex has the right guess. I "think" you did not spend enough time in mayday mode to really tell what happened. Don't take it personally, I'm just guessing from stuff you described. Let's us know what it is.

Haven't found the problem yet but the mechanics at Marco seem to be competent and knowledgeable.
Mark Day at Blue Ash Aircraft in Cincy (plug: if you need a mechanic in sw Ohio pm me for Mark's info, he's one of the rare ones) has spent a lot of time on it and found the data showed #2 dying first, followed by 4 & 6, so they're concentrating on that side. Upper deck rail, gaskets, injectors, o-rings, etc all look good. They replaced the fuel spider and will do flow and compression checks tomorrow.

Regarding RAM, this is the first I've dealt with them. After less than a minute on the first call I was talking with Merle who asked all the right questions. He was stumped and said I'll get back with you. Called back a few hours later to say we're sending you a new spider at our cost, can't imagine that's the problem but don't know what else it could be. Merle called again today to ask if it fixed the problem. I'm impressed so far.

Watched a NetJets Phenom 300 depart for Michigan today and contemplated how easy that would be...soon decided I'd rather be at the airport with my boys than laying in the sun...piston advantages

Here's what came out of the fuel lines going to each injector

These are from one of the fuel filters on the right side

There were also 1/4" long aluminum drill shavings in the filter that I didn't get a picture of.
The fuel in the cups from the first flow check sparkled...like brass flakes, wasn't magnetic.
Strange.

The right aux tank was replaced in October. This trip was the 2nd time I've used that tank since replacement. Both times the tank was filled and emptied completely.
When I set that filter on the wing a small pile of metal fell out of the inside, about 50% of which was magnetic. The other 50% was aluminum and brass (colored). Can't comprehend how replacing a bladder would put all of that inside the bladder.

Jack-- WOW... So are you confident you found the problem?
I guess on the bright side it could of been worse..
Glad you are making progress with issue..

intently watching this thread. sounds like a more severe case of what happened to me in December in the 340 (RAM VI conversion, 800TT).

I lost only cylinder #6, right side; briefly. EGT fell off, then TIT decreased. Low-Thrust detector was blipping intermittently, but not frankly blaring. mags normal, etc.

the engine workup was normal, and RAM thought it was definitely a fuel issue. My conclusion was a tiny piece of crap temporarily clogging the injector.

you've got to wonder what's in a 35 yr old fuel tank...

They don't see how any fuel was getting through the injectors on the left side. Those lines had a lot of junk in them, worse than the right side for some reason.
Yes, they're confident that was the problem.
I just can't come up with a good explanation for the source of the random debris, or the timing of it coming through the system.

If your filter system is like mine, a clogged filter will by pass.

If your technique for priming is to push the throttles and mixtures forward and then switch in the boost pumps, it is likely you are inadvertently causing a pressure surge that opens the by pass, and allow the junk to get past the filter.

Better is to switch the pump(s) on before pushing the throttle and mixture up.

Jack are you referring to the right nacelle or locker tank. The 421C does not have aux tanks. The locker tanks use an electric fuel pump and should have an in line filter to the main tank.

Right nacelle.