[alphahydroxy]

I regularly Boc/Methyl protect serine using the folowing conditions:


Acetyl chloride (~3eqv) added dropwise to serine in methanol, then reflux. Vac down to a white fluffy solid.

Suspend in dry THF, Add Boc₂O in THF dropwise over 1 hour, then reflux. Vac down to give around 95% over the two steps


dunno if this will work as well for the more hindered proline, but doesn't seem too far off...

[Wisemanleo]

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

Well, while I was looking for the Cs2CO3/ MeI/ DMF literature, I came across an efficient & mild prep for esterification that used KOH, DMSO, and Me-I. But I didn't find the yield to be too great, even though the literature reported upwards of 95%. However, the paper was meant for aliphatic and aromatic carboxylic acids. So I finally found another prep that used exactly my substrate for methylation, and used similar conditions to the KOH/DMSO/MeI, however the reaction time was 10 hours as opposed to 2 hours that I had done.

[kiwi]

ah those sound like pretty good conditions too, presuming you don't see racemisation with your substrate. this week i tried a Cs2CO3-mediated reaction (a phenol etherification - same principle) but with catalytic Cs2CO3 (1:9 Cs2CO3/K2CO3) - it flew along just like a stoichometric Cs2CO3 example. so there is another option that cuts back on Cs use

[adain]

sounds so delicious! Thanks

[fanxy]

Maybe you can try adding some lewis acid such as AlCl3 to NaBH4.
Ive got a great yield in this type reactions .

[Dan]

The alpha N may activate the ester enough to reduce it with NaBH₄, that's certainly not unusual with alpha hydroxy esters, and I've had a TfOH salt of a proline related ester that did go with 5 eq of NaBH₄ in EtOH. Altenatively, I found a good prep a while back for reducing unactivated esters with NaBH4 using refluxing t-BuOH or THF with slow addition of methanol:

Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull. Chem. Soc. Jpn. 1984, 57,
1948–1953.