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Topic: Cyclization Reaction  (Read 9322 times)

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Offline Nescafe

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Cyclization Reaction
« on: August 07, 2014, 10:08:41 AM »
Hello,

I am trying to cycliz a molecule I have made to form a 7-member ring, on one end I have an amine and the other a carboxylic acid. thus far, I have tried a few coupling reagents with no luck. Any suggestions? the molecule is relatively flexible, prior to this step I did a global deprotection with HCl to remove the boc on the amine and tert-butyl group from the alcohol. I did not purify this step, maybe that is the issue?

Cheers,

Nescafe.

Offline discodermolide

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Re: Cyclization Reaction
« Reply #1 on: August 07, 2014, 01:02:22 PM »
Try heating it to above it's melting point.
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Offline TheUnassuming

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Re: Cyclization Reaction
« Reply #2 on: August 07, 2014, 06:18:06 PM »

Formation of rings in the 7-12 range is notoriously finicky.  Try running again with clean material and starting heating it up until it either works or decomposes.  If it decomposes then you might have to rethink your strategy. 
When in doubt, avoid the Stille coupling.

Offline Nescafe

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Re: Cyclization Reaction
« Reply #3 on: August 07, 2014, 07:26:57 PM »
when you say melt it, you mean without any sort of reagent? or do you mean place the SM (which has the amine and the caroxylic acid) and the reagent (let us say a coupling reagent) and melt them together?

Offline discodermolide

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Re: Cyclization Reaction
« Reply #4 on: August 07, 2014, 08:13:21 PM »
No reagents, just melt the compound.
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Offline Nescafe

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Re: Cyclization Reaction
« Reply #5 on: August 07, 2014, 08:32:14 PM »
Very interesting suggestion, thank you, although, I only have 30mgs and it is an oil.... I am guessing just heat the crap out of it, maybe in a microwave vial?

Offline discodermolide

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Re: Cyclization Reaction
« Reply #6 on: August 08, 2014, 01:00:09 AM »
The object it to get it to cyclise by elimination of water. So uncontrolled heating will just destroy your material. Heat it to around 100°C and check if there is a new product there by TLC.
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Offline clarkstill

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Re: Cyclization Reaction
« Reply #7 on: August 08, 2014, 01:42:02 AM »
Yamaguchi reaction? It's good for forming larger macrocycles, not sure about 7-rings... Also high dilution!

Offline kriggy

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Re: Cyclization Reaction
« Reply #8 on: August 08, 2014, 02:44:03 AM »
I dont know, will it work when makink amide? Why dont you convert the carboxylic acid to more reactive intermediate like acyl chloride? Do I udnerstand corectly that you want to make 7-membered lactam with no other functional groups present in the molecule?

Offline clarkstill

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Re: Cyclization Reaction
« Reply #9 on: August 08, 2014, 03:19:45 AM »
Also, did you remember to add an extra equivalent of base? Since I'm assuming you got the HCl salt from the deprotection...

Offline Nescafe

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Re: Cyclization Reaction
« Reply #10 on: August 08, 2014, 10:10:06 AM »
Yamaguchi reaction? It's good for forming larger macrocycles, not sure about 7-rings... Also high dilution!

I dont think Yamaguchi will work because the amine on one end of the molecule could react with the reagent used which has an acid chloride on it. I have

H2N--------------COOH. Instead of the carboxylic acid reacting with the acid chloride reagent I fear the amine will do so. I think I will try heating it above melting point and see what happens

And Kriggy, yes, that is what I will be trying simultaneously and hope one avenue gives me result!

Offline kevalb56

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Re: Cyclization Reaction
« Reply #11 on: August 08, 2014, 10:28:40 AM »
I think first polymer forms inpalce of cyclisation

Offline kriggy

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Re: Cyclization Reaction
« Reply #12 on: August 08, 2014, 10:49:41 AM »
Depends on condition. HIgh dilution might help. Using template ion migh help too but I think the ring is too small for it. I also hear that things like tosyl on amino group helps with cyclization. But I worked with bigger heterocyclic rings (15 membered N3O2 ring)

Offline clarkstill

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Re: Cyclization Reaction
« Reply #13 on: August 08, 2014, 11:49:59 AM »
Yamaguchi reaction? It's good for forming larger macrocycles, not sure about 7-rings... Also high dilution!

I dont think Yamaguchi will work because the amine on one end of the molecule could react with the reagent used which has an acid chloride on it. I have

H2N--------------COOH. Instead of the carboxylic acid reacting with the acid chloride reagent I fear the amine will do so. I think I will try heating it above melting point and see what happens

And Kriggy, yes, that is what I will be trying simultaneously and hope one avenue gives me result!

Fair point... what have you tried?  I'm guessing standard peptide coupling reagents (DCC, DIC, EDC etc.) didnt work?

Offline Nescafe

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Re: Cyclization Reaction
« Reply #14 on: August 08, 2014, 10:04:47 PM »
I was actually unable to set anything up, I will try some of the suggestions and report back!

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