[MissPhosgene]

Hello,

   My boss has asked me to develop a synthetic route to a target which is essentially completely unprecedented and then make it. Since I am an undergrad, I assumed he meant search the literature and use what you have found. The molecule contains, among other things, an extremely rare trans-aminocyclobutanol with a tertiary center at the alcohol. I have a few ways to make it with complete control of stereochemistry (at least on paper), but nothing which is "lit". Is it a terrible idea for me to present those methods to him? I don't have any grad students or post-docs I can ask for help before going to him, so I am a little nervous.

I am having some trouble with my eyes turning red after I have been in lab for a while. I think it is due to working with acid chlorides because it happens when I use them and persists for a few weeks after I am done.  I handle them in the hood, fan going, sash low, syringes, and closed flasks. I wear gloves and change them frequently. Obviously I always have goggles on. I have to go back a few steps this week to make more of an intermediate I need and that requires that I use acid chlorides. Could I be right in thinking I have a reaction to acid chlorides? If so, is there any way I can prevent it? I typically spend 25-30 hours a week at my hood and the red-eyes have started to scare me a bit. I let my boss know and I now have closed goggles. However, I haven't worked with acid chlorides in a few weeks and think that may be the reason my eyes stopped turning red as opposed to the goggles preventing it. I've done my best to minimize exposure to them, but maybe there is something else I can do?

By red I mean completely blood-shot. It's a slightly delayed response in that it takes a few hours after I leave lab for them to reach their maximum redness.

Jacqueline

[Doc Oc]

As to your first question, that is an incredibly difficult synthesis.  What else is bonded to the carbinol carbon? (BTW, I'm assuming you meant quaternary carbon instead of tertiary).

As for the acid chlorides, a lot of those are pretty nasty and could definitely be affecting your eyes (but I've never heard of the specific problem you're having).  Are you making sure to quench your needles and flasks?

[MissPhosgene]

Thanks for the reply!

The carbon atom is tertiary. I didn't word my description properly, so I attached a partial structure. The molecule is made of fused rings only. It would be super to make it using ground-state reactions because there aren't too many good ones for cyclobutanes and especially ones with the substitution pattern like the one I will do my best to make.

 Knowing more reactions would help a lot. I took a grad synthesis class last semester and aced it, but it wasn't enough. I cant wait to go to graduate school and learn synthesis and physical organic all the time. 

It seems that most of the really good synthetic strategies come from people who can see many reactions backwards and forwards at the same time. I hope I can do that one day... it's hit or miss right now. Sometimes I can make up syntheses in less than a minute, sometimes it takes months. It seems the way to do it is by knowing how things work mechanistically and by reading papers to learn strategy.

I quench my syringes and flasks in the hood with water immediately after I am done using them. Tomorrow I'll find out if acyl chlorides are the culprit.

Best

[Doc Oc]

I don't envy you, that molecule doesn't look easy to make.  It might make it easier for you to look for methods that aren't stereoselective first.  Then once you have a good framework of literature to work from there, move on to asymmetric methods (FWIW, this is how most total synthesis works, the racemic synthesis gets published first followed by a string of asymmetric syntheses).  As you noted, cyclobutanes aren't easy molecules to make.  I think I've seen some organometallic routes towards substitituted cyclobutanes, but then I was also thinking that building off of the furan ring would be easier.  However, none of the methods I've seen made spiro-linked bicyclic systems, that's a whole 'nother nightmare (although I have seen separate methodology papers on making spiro-linked compounds).  I'll dig around and see if I can find those papers again and then post the references here.  As to your original question, I can't imagine your PI being frustrated with you for showing initiative in designing the synthesis.  This would be a tough molecule for a seasoned organic chemist to make, it's unrealistic to expect an undergrad to crack the synthesis on their own.

That's how I quench acyl chlorides as well and I haven't had any problems.  Maybe you could try and use an aqueous basic solution to quench the acid that's generated from it.  And let them sit in the hood for a little bit so they're not at their nastiest when you pour them into the waste container/throw out the needles.

Edit: Did a cursory search and came across this paper for spiro-linked THF/cyclobutanes.
Org. Lett.  2007, 9, 541.

[azmanam]

Also a good place to start looking for inspiration is the 'publications page' on your boss's website.  Typically, projects are offshoots of previous methodology papers from the research group.  Perhaps your research group has done work on cyclobutanes before?  or perhaps your group has made spirocyclic molecules before?  If you're working in the lab, you can always ask senior group members if previous work from your research group would be applicable to the present problem.

[MissPhosgene]

J-Bone: Thanks so much for the paper! I have been searching Scifinder for a while regarding the spiro-cyclobutane. Found lots of stuff especially aldol, but not the paper you listed.
I tried quenching my glassware and syringes the way you suggested. It helped but didn't fix the problem. Methyl oxalyl chloride is volatile so I may be getting exposed to it when I open the bottle. Can that happen even with the hood fan on and the sash closed so that there is room enough for my arms?

Azmanam: It's pretty much just me in lab. I go to a really small school without a graduate program (Near Cornell, which is great because they have made their graduate classes available with no fee).  I appreciate your suggestions! The groupings are totally new to me... probably not for my boss, but part of my task is to do this without asking for his help.

When I come up with something worth posting do you guys want to see it and point out problems and what's good? I'll do it after my boss takes a look. I'm pretty sure he will allow me to put it up..

It would be cool to see how you would make it, but not until I have decided on a route.

Jacqueline

[Doc Oc]

As incredibly useful as SciFinder is, there are days when it is my worst enemy.  A lot of times it helps to strip down the structure to only the bare minimum parts you need (ie; take the amine and any stereochemistry off of the rings and just search for spiro-THF/cyclobutane).  This is something that I spent a lot of time figuring out while studying for my qualifying exam (seriously, a LOT).

I'd definitely be interested in any ideas you have and would be willing to help you however I can.

[macman104]

If you plan on handling the methyl oxalyl chloride frequently, it may be worth seeing if you have a schlenk tube that you could store a large portion in.  That way, future handling won't require you to be exposed to the fumes, and you can refill the schlenk tube less frequently.

[MissPhosgene]

The Schlenk tube is a good idea. 

I gave all of you mole snacks. Thanks for the help.

[movies]

It is a very challenging problem your supervisor has suggested to you!  I would be very interested to hear what you have come up with, since it sounds like you have made some progress on deconvoluting the problem.

I have worked with a lot of acid chlorides lately and I would recommend quenching with aqueous NH₄OH rather than just water.  The added nucleophilicity of ammonia takes care of the acid chlorides almost instantly.  The trick also works for things like tosyl chloride, which is notoriously water stable (and flash column stable too).

[Doc Oc]

Hey MP, I don't know if you're still working on this synthesis but I saw a seminar today that had some chemistry in it that you might find useful.  Basically you can use 2,4-pentanedione to make a substituted pyridine.  After digging around the references and SciFinder I found this paper that describes how a fused pyridine/thiophene can be constructed using the right substrates.  If you use an amide instead of the thioamide that should give you the pyridine/furan ring with some functional handles that you can continue to use for construction (and avoid the whole nasty business of working around the reactivity of a substituted pyridine; they're a pain in the ass).

J. Med. Chem.  2006, 49, 2898 (it's in the middle of Scheme 3)

[MissPhosgene]

Hello J-Bone,

   Thanks for the paper! Until I am finished making what I am currently doing, I will not start on the spiro-cyclobutane compound, so working on it's synthetic design is continuous. Your consideration is very much appreciated .

I never thought making a 2,3-disubstituted (aryl/alkyl) maleimide could be as difficult as it's turning out.  The best I have gotten yet is heating until the SM disappears by thermal decomposition (had to heat it until it decomposed a way to vent disguised as a test to see if the desired reaction goes thermally) or some hydrolysis products. Reaction I am trying to optimize works for all other model systems (that I tried) except the one I want.

Best.