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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: kevinmills on October 10, 2012, 06:49:17 AM

Title: a simple method for the methylation of this compound (for a moron)
Post by: kevinmills on October 10, 2012, 06:49:17 AM: I wonder if anyone can help a biochemist with little organic skills to methylate this compound on the primary amine position;
http://www.matreya.com/ProductInfo.aspx?productid=1520
The simpler the better.
Title: Re: a simple method for the methylation of this compound (for a moron)
Post by: mamid on October 10, 2012, 10:13:50 AM: I bet your substrate is quite expensive, therefore you'd want to avoid di- and trimethylation. First thing that comes to mind is formaldehyde (imine formation) followed by reduction (NaBH₄). Check also Larock, Comprehensive Organic Synthesis, or Encyclopedia of Reagents for Organic Synthesis (EROS).
Title: Re: a simple method for the methylation of this compound (for a moron)
Post by: discodermolide on October 10, 2012, 12:00:48 PM: I have no access to the literature but this paper may be worth a look.
http://pubs.acs.org/doi/abs/10.1021/ic00189a010 (http://pubs.acs.org/doi/abs/10.1021/ic00189a010)
Title: Re: a simple method for the methylation of this compound (for a moron)
Post by: Dan on October 11, 2012, 05:40:21 PM: Quote from: mamid on October 10, 2012, 10:13:50 AM
First thing that comes to mind is formaldehyde (imine formation) followed by reduction (NaBH₄).

Problem with this is that I don't think methylene imines are stable enough to be isolated (I could be wrong). You can do reductive amination with formaldehyde and a reducing agent (e.g. H₂/Pd, Zn/AcOH, HCOOH etc.) but primary amines dimethylate.

I don't have time to check right now, but this problem must have been addressed in the literature. Off the top of my head, you could perhaps peracetylate, alkylate the resulting amide, then strip off all the acetates (Zemplen conditions will de-acetylate esters and tertiary amides). Not pretty, but I reckon it's pretty safe.
Title: Re: a simple method for the methylation of this compound (for a moron)
Post by: Dan on October 12, 2012, 06:18:14 AM: Actually this monomethylation of primary amines seems to be a pretty complex problem with no good general solution - especially in your case because you have a lot of other functionality. Practically all solutions I can see involve protecting groups of some kind - forming an amide, sulfonamide or imine followed by methylation with Me-X, then deprotection. If you're going to use a methylating agent Me-X, you will (probably) have to protect all of those alcohols anyway. If I was doing this I think I'd go for the peracetylation-methylation-deacetylation sequence I mentioned before.

One interesting paper I found is this one: Yebeutchou, R.M.; Dalcanale, E. "Highly Selective Monomethylation of Primary Amines Through Host-Guest Product Sequestration" JACS, 2009, 131, 2452 Link (http://pubs.acs.org/doi/pdf/10.1021/ja809614y)

However, I get the feeling that the substrate scope is unlikely to extend to your oligosacchaaride.
Title: Re: a simple method for the methylation of this compound (for a moron)
Post by: Jasim on October 12, 2012, 12:37:40 PM: Convergent synthesis route?

If there is no clear way forward, sometimes one just needs to re-assess how you are getting to that point. Some routes can lead to dead-ends...or at least ends that aren't economically justifiable to continue on that route.

For a target molecule that large, I would think a convergent synthesis approach for the final step would be very suitable. But I don't know what your synth route is. Good luck.