[Wisemanleo]

I've been searching the literature for a way to methylate the carboxy group of t-boc-L-proline and then follow it by reduction to t-boc-L-prolinol, but much of the literature uses obscure catalysts or a rather expensive methodology.

May I have some tips and suggestions as to how I may go about this?

Thanks

[Wisemanleo]

Alright, my brand new copy of Vogel came in today. According to Vogel, I can methylate carboxylic acids to make methyl esters by reaction of an aromatic carboxyl acid with diazomethane, or by reaction with a boron trifluoride-methanol reagent.

Can this method be applied to L-Proline, or must the carboxylic acid group be aromatic?

[Wisemanleo]

Can someone tell me if I'm going against forum rules with this thread?

[Sam (NG)]

I don't see why you would be against forum rules, t-boc to protect the amino group i'm assuming.  Why do you want to methylate the carboxyl group before producing the prolinol?  Surely you can just use LAH like this: LAH reduction of Valine (mentions reduction of proline) ?

[kiwi]

theres plenty of ways to go about this. you could methylate like you suggest (i recommend the Cs2CO3 method: neutralise the acid with aq Cs2CO3, vac or freezedry down. take up the Cs salt in DMF, add MeI, voila.)
but why methylate at all? surely you can just reduce the carboxylic acid straight down to the alcohol, with something like borane-THF. if thats too exotic, i think you can generate it in situ from cheap-as-chips NaBH4.

[Wisemanleo]

Thanks Sam and kiwi for the reply 

I have actually tried several times reducing it first with LiAlH4, and it only works to a certain extent. I seem to get quite a bit of impurities, and in one case I observed an aromatic spot on my TLC plates, when there is nothing aromatic about L-Proline to begin with. The method I followed for reduction is very similar to http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0530.

Hence, I am choosing to methylate first to avoid any side reactions that might have happened with the reduction route. So thanks for the Cs₂CO₃ method, I'm going to check it out!

Edit: NaBH4?! That's not reactive enough to react with carboxylic acids. I've seen some papers use it, but they involved coupling the reagent to a metal or high concentrations of H₂SO₄.

[kiwi]

nah not NaBH4, you use NaBH4 + lewis/protic acid to generate diborane, B2H6, which forms borane-THF, BH3.THF when you bubble it into THF. LAH is quite unreactive towards carboxylic acids, but much more reactive toward esters. borane-THF has the opposite chemoselectivity, very easily reduces free acids, but barely touches esters. for more info, see pg 1544-6 of March.

[alphahydroxy]

You can use NaBH₄ + I₂ to generate BH₃ in situ too.

I don't know about proline, but I've used thionyl chloride or acetyl chloride in methanol to form the methyl esters of amino acids before.

[Wisemanleo]

I'm actually trying to avoid NaBH4-halide reagents, but thanks~

Thionyl/acetyl chloride in methanol? Hmm...how? Does it work in a similar fashion as using methyl iodide?

[sjb]

Thionyl/acetyl chloride in methanol? Hmm...how? Does it work in a similar fashion as using methyl iodide?

Acetyl chloride I'm less sure about, but thionyl would probably work to convert the acid to the acid chloride, then the excess of methanol would esterify that readily. I think the carboxyl would be more reactive than the hydroxyl so there would be less chance of MeOH -> MeCl despite the large excess of it.

S

[alphahydroxy]

I'm actually trying to avoid NaBH4-halide reagents, but thanks~

Thionyl/acetyl chloride in methanol? Hmm...how? Does it work in a similar fashion as using methyl iodide?

The thinoyl / acetyl chloride generates HCl in situ. The rest is just standard acid promoted trans-esterification

some refs for esterification of proline with thionyl chloride/methanol:


Journal of Organic Chemistry, 68(12), 5006-5008; 2003               

Tetrahedron Letters, 47(18), 3005-3008; 2006                                       

Bioorganic & Medicinal Chemistry Letters, 15(6), 1629-1632; 2005


These seem to be essentially quantitative yield. Refs for the use of acetyl chloride are a little thin on the ground, but they are there. Bear in mind that the product of the reaction is the hydrochloride salt of the ester, and this needs to be freed in the course of any further reactions

[Wisemanleo]

Back again~

I was able to methylate my boc-protected proline, however in only 60% yield. The literature I followed reported over 90% in yield. I attribute this to be caused by my extraction method.

The extraction involved using ice cold water. Amino acids are generally difficult to remove in this type of extraction because of hydrogen bonding. I know that ether is definitely not a polar enough solvent to pull the bocprolinemethylester out of the aqueous layer. I tried ethyl acetate, and it worked somewhat better, but not good enough. Has anyone here performed amino acid extractions?

[kiwi]

i've made some horribly polar things in my time, and ethyl acetate works well as an extraction solvent. you'll be amazed at what goes into dichloromethane as well. some people use mixtures for extractions - off the top of my head i think 2:1 chloroform/ethyl acetate is popular. but are you sure your in situ HCl isn't blasting off your Boc group? stranger things have happened

[Wisemanleo]

2:1 chloroform/ethyl acetate sounds good, I will try that out.

And no, I'm not using HCl in any of my reactions yet. I will use it later to deprotect. I have yet to do my reduction as I was still trying to solve my extraction problems. But it seems that I might end up having to buy some LiCl to do the reduction with NaBH4, as it seems that LAH just isn't popular in the literature when it comes to reducing amino acids.

[kiwi]

but how are you esterifing your amino acids? if you are using AcCl/SOCl2/TMSCl etc in methanol you have HCl around. if you are using Cs2CO3/ MeI/ DMF then extraction is probably the issue; you can wash DMF out better with dilute LiCl (5%) than water if this is the case