[Sam1b]

Hi, I hope you are all well.

I'm a biochem student on a project, where I have been tasked to synthesise one of the compounds my enzyme might produce. I have to reduce one of the carboxylic acid groups of both tt-muconic acid to feasibly synthesise 6-Hydroxy-trans,trans-2,4-hexadienoic acid, CAS: 88973-47-1. I am having trouble differentiating between these groups for chemoselectivity.

I've tried to come up with a synthesis, I was thinking of starting with the methyl ester of muconic acid, reducing the carboxylic acid using borane-THF, then cleaving the methyl ester protecting group with an acid/base. Other ideas I was thinking about were starting from tt-muconic acid, potentially making the acid anhydride or using 1 equivalent of DIBAL for example, but would this not produce mixture of products.

Please correct any misconceptions I might have and I would appreciate your insight and advice. Thank you.

[wildfyr]

Make the ethyl or propyl ester, but do it so that you end up with with some diester, some monoester, some dicarboxylic acid remaining. I.e strong acid catalyst, fisher esterification, 1 eq of alcohol.

Disperse products into DCM/water. the Muconic acid should go into the water layer with neutral water in a couple washes (Its like 1g/L soluble in water, good enough, and the esters will be totally insoluble). Then do a bicarb wash of DCM layer, this will get the monoester into the water layer. If its an awful dispersion you can try methyl ester instead of ethyl. Take this water layer, then add fresh DCM, add HCl to neutralize bicarb to pH 6-7, and you will have the monoester in DCM. This can be reduced with LAH to yield the desired product.

This all off the top of my head, no guarantees!

[rolnor]

Hi, I hope you are all well.

I'm a biochem student on a project, where I have been tasked to synthesise one of the compounds my enzyme might produce. I have to reduce one of the carboxylic acid groups of both tt-muconic acid to feasibly synthesise 6-Hydroxy-trans,trans-2,4-hexadienoic acid, CAS: 88973-47-1. I am having trouble differentiating between these groups for chemoselectivity.

I've tried to come up with a synthesis, I was thinking of starting with the methyl ester of muconic acid, reducing the carboxylic acid using borane-THF, then cleaving the methyl ester protecting group with an acid/base. Other ideas I was thinking about were starting from tt-muconic acid, potentially making the acid anhydride or using 1 equivalent of DIBAL for example, but would this not produce mixture of products.

Please correct any misconceptions I might have and I would appreciate your insight and advice. Thank you.

The anhydride is a good idea, borane could react with the double bonds I think. DIBAL or NaBH4 could work

[Babcock_Hall]

https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/60c743b5842e655f66db2313/original/muconic-acid-esters-as-bio-based-acrylate-mimics.pdf
The tertiary-butyl ester of muconic acid is another possible starting point.  We have reduced a free carboxylic acid to an aldehyde in two steps in the presence of a tertiary-butyl ester with Dibal-H a few times (I realize that you need the alcohol).  I also found a paper on di-esters of muconic acid that might be of marginal interest (see link above).

[Sam1b]

Thank you all for your help !

Make the ethyl or propyl ester, but do it so that you end up with with some diester, some monoester, some dicarboxylic acid remaining. I.e strong acid catalyst, fisher esterification, 1 eq of alcohol.

Disperse products into DCM/water. the Muconic acid should go into the water layer with neutral water in a couple washes (Its like 1g/L soluble in water, good enough, and the esters will be totally insoluble). Then do a bicarb wash of DCM layer, this will get the monoester into the water layer. If its an awful dispersion you can try methyl ester instead of ethyl. Take this water layer, then add fresh DCM, add HCl to neutralize bicarb to pH 6-7, and you will have the monoester in DCM. This can be reduced with LAH to yield the desired product.

This all off the top of my head, no guarantees!

https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/60c743b5842e655f66db2313/original/muconic-acid-esters-as-bio-based-acrylate-mimics.pdf
The tertiary-butyl ester of muconic acid is another possible starting point.  We have reduced a free carboxylic acid to an aldehyde in two steps in the presence of a tertiary-butyl ester with Dibal-H a few times (I realize that you need the alcohol).  I also found a paper on di-esters of muconic acid that might be of marginal interest (see link above).

Would LAH reduce both of the groups? Or potentially could I use Dibal-H as Babcock_Hall suggested, would the propyl ester work or should I esterify to the T-butyl as I believe Fischer esterification wouldn't work for T-butyl esters?