[syndakitz]

I'm working with my grad student on a long synthesis problem...helping him make the synthesis of our final product faster/easier lab work and better yields. The reaction I'm looking at at the moment is the protection of L-valine methyl ester HCl with boc anhydride so we can do a grignard reaction on the methyl ester. I've asked several professors and found contradicting papers on whether this reaction needs to be under anhydrous conditions or not.
Our present synthesis is as follows:

Solid sodium hydrogencarbonate (14.4 g, 170 mmol) was
added in one portion to a stirred solution of l-valine methyl ester hydro-
chloride (9.5 g, 56.7 mmol) in dry tetrahydrofuran/methanol (4:1)
(150 mL) at 0 8C, immediately followed by addition of solid Boc2O
(18.5 g, 84.9 mmol). The reaction was allowed to warm to room tempera-
ture, stirred for 20 h and then quenched with water (100 mL). The organ-
ic product was extracted with diethyl ether (2 ” 300 mL), washed with sa-
turated sodium hydrogencarbonate (2 ” 100 mL), brine (2 ” 100 mL),
dried over magnesium sulphate and concentrated in vacuo. Purification
of the crude product by flash column chromatography (silica gel; hexane/
ethyl acetate 9:1 ! 6:1) afforded 8 as a colourless oil

this is a proposed alternative to the reaction above:

http://dx.doi.org/10.1016/j.tetlet.2007.09.126

There are several other papers I found using water as a solvent, or not caring that the materials in the reaction were not water free. So, what I'm hoping is that someone can help me with is explain why or why not the boc2o hydrolysis is a competing reaction with the protection step and if so how much it will effect the yields, and what best step to go about the synthesis - base catalyzed or acid catalyzed

(mod edit to shorter link, sjb)

[Scintillation]

Hi Syndakitz,

I've done that kind of protection once. The substrate was a liquid, so I just added Boc2O to it without any solvent.

Boc2O melts at 23'C (Aldrich), so I'd try heating it a little bit (maybe 30'C) and add your amino acid neat.

Try it tomorrow!

MB

[Doc Oc]

Although it helps if your solvents are relatively dry, this protection can tolerate some adventitious moisture, it will just require a larger excess of Boc etherate.

For what it's worth, I've done Boc protections of various amines in both DCM and THF without problems.  The solvents were relatively dry, but like I said, just add a little more Boc2O if they're not.

Don't EVER trust a reference from Tet Lett unless it has detailed supplementary information included (which the article you linked does not).  It's a well-known dumping ground for bad papers in the organic chemistry circle.

[OC pro]

Just take dichloromethane or tetrahydrofuran right out of the can. Add Boc2O and triethylamine and stir for 2-3h. Acidic work-up (washing of the organic layer with 1N HCl) will give you material with >95% purity.
By the way: amino acids are generally boc-protected in aqueous media (we do it a lot). Boc2O is not that much moisture sensitive. It reacts much faster with amine functions.

[discodermolide]

as a side note the Grignard may be easier if you use the Weinreb amide

[syndakitz]

Any idea what the difference in yields between aqueous media and anhydrous conditions are or does it really not make that big of a difference?

[poorstudent83]

Hi there,

I've prepared the Boc protected version of L-proline methyl ester in quantitative yields. The synthesis was done in air and did not require anhydrous conditions.

Mail me if you'd like the procedure!

[labrat12]

Would it be possible to send me this procedure? Thanks.

Hi there,

I've prepared the Boc protected version of L-proline methyl ester in quantitative yields. The synthesis was done in air and did not require anhydrous conditions.

Mail me if you'd like the procedure!

[zsinger]

I would have said the same as Discoderm………look that up…..you might find it easier.
                 -Z