[mopinou]

Hi,

I need some help for the retrosynthetic analysis of the molecule attached down here.
I'm really struggling on this one and any advice would be helpful. The stereochemistry is facultative in this case.

Thank you.

[Babcock_Hall]

What have you thought of, so far?  It is a forum rule that you show your work first, before we can help you.

[mopinou]

Here is what I've done. I hope I'm on the right path.

[rolnor]

I think there could be a way to oxidize the double bond to a hydroxy acid, make a search on scifinder or similar.
offcourse the acetoxy group will limit the conditions, very strong acid could be a problem.

[zarhym]

I guess this should work.

[rolnor]

Nice! You only need the acetyl group?

[mopinou]

Nice ! Now I think I can selectively protect the alcohol fonction near the acid with a TBDPS. The other one will stay untouched because of steric hindrance. Followed by an esterification and a deprotection with TBAF.

[rolnor]

I have worked with epoxides and reacting it with diethyl malonate with base is a slow reaction that needs heating. I think the epoxide in this case can be a bit special because its a tertiary benzylic carbon, very SN1-reactive. It could open to diol during the epoxidation with m-CPBA.

[zarhym]

I am thinking selective acetylation can be achieved due to intramolecular hydrogen bond.
But I am not sure about this.

[zarhym]

I have worked with epoxides and reacting it with diethyl malonate with base is a slow reaction that needs heating. I think the epoxide in this case can be a bit special because its a tertiary benzylic carbon, very SN1-reactive. It could open to diol during the epoxidation with m-CPBA.

I have done a epoxide ring opening reaction with an amine using calcium trifluoroacetate as catalyst following a literature condition.
My understanding of this reaction is via the formation calcium-oxygen complex to active the epoxide ring. It worked great.
It's an open-access literature (http://acta-arhiv.chem-soc.si/61/61-1-67.pdf).

By the way, epoxide ring opening is a well studied reaction. I did find couple of reviews which gave me detailed infomation.


Epoxidation is also a well studied topic. You can also find reviews about this. I agree mCPBA may be too aggressive for this starting material. One milder epoxidation condtion I have done uses tungsten/H2O2 biphase catalytic system. By changing the temperature/concentration, the amount of active tungsten-oxygen complex can be controlled. This methodology is being developed and new papers are available every now and then. You can find this method in this link (https://pubs.acs.org/doi/abs/10.1021/jo990790z). There are much more stories about this methodology if you keep digging.

[rolnor]

I wonder if the cyclic dilactone needs stronger base to be deprotonated, I think you need LDA, K2CO3 is not enough. This epoxide-chemistry looked fine at first glance but there is many problems I can see. The benzylic, tertiary position in the epoxide could react faster with the dilactone then the primary.