Author Topic: 4-Me 4-hydroxy trans crotonic acid, OTC?  (Read 1120 times)

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4-Me 4-hydroxy trans crotonic acid, OTC?
« on: October 10, 2004, 05:16:00 PM »
4-alkyl 4-hydroxy trans-crotonic acids & their salts are potent GHB receptor ligands. How about an OTC synthesis from levulinic acid?

The problem is slightly tricky, because just heating levulinic acid will produce a lactone with the wrong stereochemistry, even if hydrolyzed.


Good, Bad ("CC(O)/C=C/C(=O)O.CC(O)/C=C\C(=O)O")

So here is my idea:


ketalize ("CC(=O)CCC(=O)O.C(OCC)(OCC)OCC>>CC(OCC)(OCC)CCC(=O)OCC")

1. convert levulinic acid into its ketal with acid/triethyl or trimethyl orthoformate. Yield 90%


pyrolize ("CC(OCC)(OCC)CCC(=O)OCC>>CC(OCC)/C=C/C(=O)OCC.OCC")

2. Pyrolyze the ketal in the presence of acidic catalyst to produce an enol ether, which will isomerize (I think) at the temperature employed (~250 C)to conjugate with the carbonyl group. Yield probably about 90% (so says organicum)


hydrolyze ("CC(OCC)/C=C/C(=O)OCC>>CC(O)/C=C/C(=O)O")

3. Hydrolyze the ether and ester under acidic conditions to yield the desired compound. Consume and enjoy. Yield ??

At worst, I suppose this method would produce a racemic mixture, but in actuality, the steric hinderance would probably make the trans-isomer the predominant one. Hopefully.

Ketalization of levulinic acid:
JACS 1955, 4069
Leibig's Annalen 1983, 913
Carbohydrate Research #319,63

I will link the last article shortly.

Would this work?