[spankytank]

I'm about to start working on compound 1, and the target compound 2 differs only in the inversion of a methyl group. The synthesis route I'm currently working on consists of first using a enzyme for hydroxylating 1, followed by a acid catalyzed dehydration of the alcohol and then a enantioselective reductase to yield the product 2. This however seems like a pretty complicated and laborsome process just for inverting a single methyl group, so I'm wondering if there are some other reactions/mechanisms that could make my life a bit easier? Appreciate all response!

[Babcock_Hall]

What have you come up with, so far?

[rolnor]

If you make a enolate (wich is non-chiral) with a strong base lika lithiumdiisopropylamine (-78°C) and then add a chiral acid, could this result in the wanted enantiomere? The problem is to find chiral acid that works, not easy. It should probably be a bulky acid to get the wanted result. Or the charge on the enolate will be mainly on the ester-oxygen and then the protonation with acid can not give anything but racemic ester?

[clarkstill]

Or you could add a chiral auxiliary (Evans, Crimmins, Oppoltzer, etc) to the parent acid (R)-3-(benzoylthio)-2-methyl propanoic acid, or the racemic acid, form the enolate and do a kinetic protonation (low temperature, e.g. 2,6-dimethylphenol).

OR just take the achiral 3-benzoylthiopropanoic acid, and do the same as above but with a source of CH3+ rather than H+.

Although just looking at it now, it might be tricky to hydrolyze off the auxiliary in the presence of the thioester. I'd probably opt for the Crimmins auxiliary since you can directly re-form the ester with MeOH.

[kriggy]

I think you have multiple options:

a)As was described by rolnor: form enolate and protonate with chiral acid, I recently saw it described in the literature but I dont recall where. It might have been this review but Im not sure
Chem. Rev.2006,106,2711− 2733

b) make racemic product and separate the enantiomers by crystalization

c) make non-methylated product and do enantioselective methylation using some chiral catalyst or auxiliary (evans is pretty good for that and can be removed at mild conditions

[spankytank]

Appreciate the inputs, I'll look into it!

[rolnor]

I think it will be problem, the sulphur can eliminate via a E1cB if you make the enolate I am afraid.

[clarkstill]

Fair point. Maybe a Noyori type asymmetric reduction?

[rolnor]

This reduction is for ketones?

[clarkstill]

Fair point - I guess it's more Knowles than Noyori, but the same idea (i.e. Rh/Ru, BINAP ligands).

Regardless it's probably a crap idea, the substrate substitution pattern isn't really right so who knows how well it would fare, plus S might poison the catalyst. :S

[rolnor]

Is it possible ta add the thiobenzoic acid to the corresponding acrylate ester enantioselective like a Michael addition? This will be reversible, but with a week base its possible?
http://organicreactions.org/index.php?title=Catalytic_enantioselective_Michael_reaction